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2024-03-28T18:35:16Z
User contributions
MediaWiki 1.35.14
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=45308
Venous thromboembolism
2020-08-20T22:22:28Z
<p>Benjamintillman: Adding CARAVAGGIO trial</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
*'''2019:''' Key et al. [https://doi.org/10.1200/JCO.19.01461 Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update.] [https://www.ncbi.nlm.nih.gov/pubmed/31381464 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update]<br />
*'''2013:''' Lyman et al. [https://doi.org/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
*'''2007:''' Lyman et al. [https://doi.org/10.1200/JCO.2007.14.1283 American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/17968019 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2019:''' Anderson et al. [https://ashpublications.org/bloodadvances/article/3/23/3898/429211/American-Society-of-Hematology-2019-guidelines-for American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients]<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
=="How I Treat"==<br />
<br />
*'''2020:''' Wang TF, Carrier M. How I treat obese patients with oral anticoagulants. Blood. 2020 Mar 19;135(12):904-911. [https://doi.org/10.1182/blood.2019003528 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31978224 PubMed]<br />
*'''2019:''' Pabinger I, Thaler J. How I treat patients with hereditary antithrombin deficiency. Blood. 2019 Dec 26;134(26):2346-2353. [https://doi.org/10.1182/blood.2019002927 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31697819 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
<br />
*[https://www.myeloma.org/resource-library/imwg-guidelines-prevention-thalidomide-lenalidomide-associated-thrombosis-myeloma IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 10-14 days post-op {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''10- to 14-day course'''<br />
<br />
===Regimen variant #2, 35 days post-op {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Did not meet endpoint of major and clinically relevant nonmajor bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''35-day course'''<br />
<br />
===Regimen variant #3, 180 days {{#subobject:15cd2c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 Carrier et al. 2018 (AVERT)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
| style="background-color:#fc8d59" |Seems to have higher rate of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning within 24 h of initiation of chemotherapy<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#'''AVERT:''' Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. Epub 2018 Dec 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30511879 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Warfarin; low-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment<br />
|-<br />
|[https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2011-03-344333 Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of VTE incidence<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
<br />
#'''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
#'''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://doi.org/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2011-03-344333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Heparin_monotherapy|UFH]]<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course<br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours.<br />
<br />
===Regimen variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 Samama et al. 1999 (MEDENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Placebo<br> 2. [[#Enoxaparin_monotherapy|Enoxaparin]]; 20 mg daily<br />
| style="background-color:#1a9850" |Superior VTE rates<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Warfarin; low-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment<br />
|-<br />
|[https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2011-03-344333 Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of VTE incidence<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of death rate at 30 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
<br />
===References===<br />
<br />
#Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed]<br />
#'''MEDENOX:''' Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; MEDENOX Investigators. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999; 341:793-800. [https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/10477777 PubMed].<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://doi.org/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2011-03-344333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0140-6736(96)91009-0 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Heparin_monotherapy|UFH]]; SC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of necropsy-verified pulmonary embolism of predefined clinical relevance<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of death rate at 30 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic VTE or death due to VTE<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 Khorana et al. 2019 (CASSINI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of objectively confirmed proximal DVT in a lower limb, PE, symptomatic DVT in an upper limb or distal DVT in a lower limb, and death from VTE up to 180 days<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
<br />
#Gärdlund B; Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://doi.org/10.1016/s0140-6736(96)91009-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
#'''CASSINI:''' Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30786186 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic VTE or death due to VTE<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
<br />
===References===<br />
<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Apixaban_monotherapy_2|Apixaban]]; 5 mg twice per day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic recurrent VTE or death from any cause<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE or death from any cause<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Regimen variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Apixaban_monotherapy_2|Apixaban]]; 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic recurrent VTE or death from any cause<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE or death from any cause<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
<br />
#'''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
#'''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Regimen variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
#'''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1915103 Angelli et al. 2020 (CARAVAGGIO)]<br />
|Phase III<br />
|[[Dalteparin (Fragmin)|Dalteparin]]<br />
|Non-inferior recurrent VTE<br />
|Major bleeding similar in both groups<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
#'''CARAVAGGIO''': Angnelli G, Becattini C, Meyer G, Munoz A, Huisman M, Connors J, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro M, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M, Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020 Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29. [https://www.nejm.org/doi/full/10.1056/NEJMoa1915103 link to original article][https://pubmed.ncbi.nlm.nih.gov/32223112/ PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Argatroban (Acova)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban]]; 10 mg/day<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban]]; 20 mg/day<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Bivalirudin (Angiomax)]]<br />
<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1915103 Angelli et al. 2020 (CARAVAGGIO)]<br />
|Phase III<br />
|[[Dalteparin (Fragmin)|Dalteparin]]<br />
|Non-inferior recurrent VTE<br />
|Major bleeding similar in both groups<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
<br />
#'''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://doi.org/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
#'''CARAVAGGIO''': Angnelli G, Becattini C, Meyer G, Munoz A, Huisman M, Connors J, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro M, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M, Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020 Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29. [https://www.nejm.org/doi/full/10.1056/NEJMoa1915103 link to original article][https://pubmed.ncbi.nlm.nih.gov/32223112/ PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Regimen variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|UFH]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
<br />
===References===<br />
<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
UFH: '''<u>U</u>'''n'''<u>F</u>'''ractionated '''<u>H</u>'''eparin<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/293153 Loewe & Hirsch 1947]<br />
| style="background-color:#ffffbe" |Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
''Note: In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200 to 400 mg / 200,000 to 400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism.''<br />
====Anticoagulation====<br />
<br />
*[[Unfractionated heparin (UFH)]] SC 333 units/kg once, then 250 units/kg every 12 hours<br />
<br />
===References===<br />
<br />
#Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban]]; 20 mg/day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Regimen variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban]]; 10 mg/day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Regimen variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://doi.org/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
<br />
*[[Tinzaparin (Innohep)]]<br />
<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
<br />
====Supportive medications====<br />
<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
<br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40614
Heparin-induced thrombocytopenia
2019-10-02T18:01:30Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
==Intravenous Immunoglobulin==<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://annals.org/aim/fullarticle/703546/ Frame et al. 1989]<br />
|First published report<br />
|None<br />
|First report of IVIg use in HIT<br />
|-<br />
|[https://link.springer.com/article/10.1023%2FA%3A1023238915316 Winder et al. 1998]<br />
|Case series<br />
|None<br />
|Three additional cases in the literature<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0012369217307249 Padmanabhan et al. 2017]<br />
|Case series<br />
|None<br />
|Three refractory cases with resolution of thrombocytopenia<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S1473050218302404 Park et al. 2018]<br />
|Case series<br />
|None<br />
|Two additional cases<br />
|}<br />
''Note, there is a growing interest in the use of intravenous immunoglobulin for difficult cases of heparin-induced thrombocytopenia. There are no prospective, randomized studies, but there is a growing body of scientific literature to support the rationale in certain select cases. Thus, IVIg is included on this page for reference.'' <br />
<br />
*Intravenous Immunoglobulin: IVIg 1 g/kg/day x two doses (Winder et al., Padmanabhan et al., and Park et al.); the case reported from 1989 used 0.4 gm/kg/d for three days. <br />
<br />
====References====<br />
<br />
#Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989 Dec 1;111(11):946-7. [https://annals.org/aim/fullarticle/703546/ link to original article][https://www.ncbi.nlm.nih.gov/pubmed/2510573 PubMed]<br />
#Winder A, Shoenfeld Y, Hochman R, Keren G, Levy Y, Eldor A. High-dose intravenous gamma-globulins for heparin-induced thrombocytopenia: a prompt response. J Clin Immunol. 1998 Sep;18(5):330-4. [https://link.springer.com/article/10.1023%2FA%3A1023238915316 link to original article][https://www.ncbi.nlm.nih.gov/pubmed/9793825 PubMed]<br />
#Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. [https://www.sciencedirect.com/science/article/pii/S0012369217307249 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
#Park BD, Kumar M, Nagalla S, De Simone N, Aster RH, Padmanabhan A, Sarode R, Rambally S. Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia. Transfus Apher Sci. 2018 Aug;57(4):561-565. doi: 10.1016/j.transci.2018.06.007. Epub 2018 Jun 26. Review. [https://www.ncbi.nlm.nih.gov/pubmed/30244713 PubMed] [https://www.sciencedirect.com/science/article/pii/S1473050218302404 link to original article]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40613
Heparin-induced thrombocytopenia
2019-10-02T17:52:03Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
==Intravenous Immunoglobulin==<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://annals.org/aim/fullarticle/703546/ Frame et al. 1989]<br />
|First published report<br />
|None<br />
|First report of IVIg use in HIT<br />
|-<br />
|[https://link.springer.com/article/10.1023%2FA%3A1023238915316 Winder et al. 1998]<br />
|Case series<br />
|None<br />
|Three additional cases in the literature<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0012369217307249 Padmanabhan et al. 2017]<br />
|Case Series<br />
|None<br />
|<br />
|}<br />
<br />
*Intravenous Immunoglobulin: IVIg 1 g/kg/day x two doses (Winder et al. and Padmanabhan et al). <br />
<br />
====References====<br />
<br />
#Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989 Dec 1;111(11):946-7. [https://annals.org/aim/fullarticle/703546/ link to original article][https://www.ncbi.nlm.nih.gov/pubmed/2510573 PubMed]<br />
#Winder A, Shoenfeld Y, Hochman R, Keren G, Levy Y, Eldor A. High-dose intravenous gamma-globulins for heparin-induced thrombocytopenia: a prompt response. J Clin Immunol. 1998 Sep;18(5):330-4. [https://link.springer.com/article/10.1023%2FA%3A1023238915316 link to original article][https://www.ncbi.nlm.nih.gov/pubmed/9793825 PubMed]<br />
#Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. [https://www.sciencedirect.com/science/article/pii/S0012369217307249 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40612
Heparin-induced thrombocytopenia
2019-10-02T17:24:34Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
==Intravenous Immunoglobulin==<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0012369217307249 Padmanabhan et al. 2017]<br />
|Case Series<br />
|None<br />
|Resolution of thrombocytopenia in three refractory cases<br />
|}<br />
<br />
*Intravenous Immunoglobulin: IVIg 1 g/kg/day x two doses<br />
<br />
====References====<br />
<br />
#Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. [https://www.sciencedirect.com/science/article/pii/S0012369217307249 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40611
Heparin-induced thrombocytopenia
2019-10-02T14:25:26Z
<p>Benjamintillman: /* References */ IVIG</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
==Intravenous Immunoglobulin==<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0012369217307249 Padmanabhan et al. 2017]<br />
|Case Series<br />
|None<br />
|Resolution of thrombocytopenia<br />
|}<br />
<br />
*Intravenous Immunoglobulin: IVIg 1 g/kg/day x two doses <br />
<br />
====References====<br />
<br />
#Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. [https://www.sciencedirect.com/science/article/pii/S0012369217307249 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40610
Heparin-induced thrombocytopenia
2019-10-02T14:22:26Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
==Intravenous Immunoglobulin==<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0012369217307249 Padmanabhan et al. 2017]<br />
|Case Series<br />
|None<br />
|Resolution of thrombocytopenia<br />
|}<br />
<br />
*Intravenous Immunoglobulin<br />
<br />
====References====<br />
<br />
#Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. [https://www.sciencedirect.com/science/article/pii/S0012369217307249 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40609
Heparin-induced thrombocytopenia
2019-10-02T14:11:21Z
<p>Benjamintillman: /* Other Treatments */ IVIG</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
=Other Treatments=<br />
<br />
== Intravenous Immunoglobulin ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|Padmanabhan et al. 2017<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
<br />
* Intravenous Immunoglobulin<br />
<br />
==== References ====<br />
<br />
# Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17.[https://www.ncbi.nlm.nih.gov/pubmed/28427966 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40608
Heparin-induced thrombocytopenia
2019-10-02T14:05:28Z
<p>Benjamintillman: /* ASH */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
<br /><br />
<br />
= Other Treatments =<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=40607
Heparin-induced thrombocytopenia
2019-10-02T14:04:11Z
<p>Benjamintillman: /* ASH */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=Anticoagulation=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.<br />
<br />
===References===<br />
<br />
#'''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
#'''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
#Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
==Danaparoid monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Fondaparinux monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
<br />
#Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
==Lepirudin monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)]<br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
===References===<br />
<br />
#'''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
==Rivaroxaban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30<br />
<br />
===References===<br />
<br />
#Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
##UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Warm_autoimmune_hemolytic_anemia&diff=40593
Warm autoimmune hemolytic anemia
2019-10-01T20:44:18Z
<p>Benjamintillman: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ British Society for Haematology]==<br />
<br />
*'''2017:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14654/abstract Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia] [https://www.ncbi.nlm.nih.gov/pubmed/28369704 PubMed]<br />
*'''2016:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14478/abstract The diagnosis and management of primary autoimmune haemolytic anaemia] [https://www.ncbi.nlm.nih.gov/pubmed/28005293 PubMed]<br />
<br />
=All lines of therapy=<br />
<br />
==Prednisolone monotherapy {{#subobject:5f27f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 Birgens et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Prednisolone_.26_Rituximab|Prednisolone & Rituximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 1.5 mg/kg/day PO for 2 weeks, then 0.75 mg/kg/day PO for 1 week (week 3), then 0.5 mg/kg/d PO for 1 week (week 4), followed by gradual reduction over the next 4-8 weeks to the lowest dose that was effective in maintaining a normal hemoglobin level.<br />
<br />
*<br />
<br />
===References===<br />
<br />
#Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Rønnov-Jessen D, Vestergaard H, Klausen TW, Schöllkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov;163(3):393-9. Epub 2013 Aug 24. [https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23981017 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:58ugf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 Michel et al. 2016 (RAIHA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Prednisone_.26_Rituximab|Prednisone & Rituximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
<br />
#'''RAIHA:''' Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M, Le Guenno G, Galicier L, Audia S, Royer B, Morin AS, Marie Michot J, Jaccard A, Frenzel L, Khellaf M, Godeau B. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017 Jan;92(1):23-27. Epub 2016 Nov 10. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27696475 PubMed]<br />
<br />
==Prednisolone & Rituximab {{#subobject:598gf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a7c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 Birgens et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisolone_monotherapy|Prednisolone]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 1.5 mg/kg/day PO for 2 weeks, then 0.75 mg/kg/day PO for 1 week (week 3), then 0.5 mg/kg/d PO for 1 week (week 4), followed by gradual reduction over the next 4-8 weeks to the lowest dose that was effective in maintaining a normal hemoglobin level.<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once weekly for 4 weeks<br />
<br />
====Supportive care====<br />
<br />
*Folic acid 5 mg/day PO<br />
<br />
===References===<br />
<br />
#Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Rønnov-Jessen D, Vestergaard H, Klausen TW, Schöllkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov;163(3):393-9. Epub 2013 Aug 24. [https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23981017 PubMed]<br />
<br />
==Prednisone & Rituximab {{#subobject:91ugf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a7c9gc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 Michel et al. 2016 (RAIHA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisone (Sterapred)]]<br />
*[[Rituximab (Rituxan)]]<br />
<br />
===References===<br />
<br />
#'''RAIHA:''' Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M, Le Guenno G, Galicier L, Audia S, Royer B, Morin AS, Marie Michot J, Jaccard A, Frenzel L, Khellaf M, Godeau B. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017 Jan;92(1):23-27. Epub 2016 Nov 10. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27696475 PubMed]<br />
<br />
== Sirolimus monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/1/17 Bride et al. 2016]<br />
| style="background-color:#1a9851" |Phase I/II<br />
|none<br />
| style="background-color:#91cf60" |Durable CR observed in patients with ALPS<br />
|}<br />
Immunosuppressive therapy<br />
<br />
* Sirolimus 2 to 2.5 mg/m<sup>2</sup> per day rounded to the nearest 0.5 (liquid) or 1 mg (tablet), starting on day 1 (maximum initial dose of 4 mg/day)<br />
<br />
References<br />
<br />
# Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;127(1):17-28. doi: 10.1182/blood-2015-07-657981. Epub 2015 Oct 26. [http://www.bloodjournal.org/content/127/1/17 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/?term=26504182 PubMed]<br />
<br />
[[Category:Warm autoimmune hemolytic anemia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Hemolytic process]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Warm_autoimmune_hemolytic_anemia&diff=40592
Warm autoimmune hemolytic anemia
2019-10-01T20:28:39Z
<p>Benjamintillman: /* Regimen #subobject:d3c7eb */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ British Society for Haematology]==<br />
<br />
*'''2017:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14654/abstract Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia] [https://www.ncbi.nlm.nih.gov/pubmed/28369704 PubMed]<br />
*'''2016:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14478/abstract The diagnosis and management of primary autoimmune haemolytic anaemia] [https://www.ncbi.nlm.nih.gov/pubmed/28005293 PubMed]<br />
<br />
=All lines of therapy=<br />
<br />
==Prednisolone monotherapy {{#subobject:5f27f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 Birgens et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Prednisolone_.26_Rituximab|Prednisolone & Rituximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 1.5 mg/kg/day PO for 2 weeks, then 0.75 mg/kg/day PO for 1 week (week 3), then 0.5 mg/kg/d PO for 1 week (week 4), followed by gradual reduction over the next 4-8 weeks to the lowest dose that was effective in maintaining a normal hemoglobin level.<br />
<br />
* <br />
<br />
===References===<br />
<br />
#Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Rønnov-Jessen D, Vestergaard H, Klausen TW, Schöllkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov;163(3):393-9. Epub 2013 Aug 24. [https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23981017 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:58ugf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 Michel et al. 2016 (RAIHA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Prednisone_.26_Rituximab|Prednisone & Rituximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
<br />
#'''RAIHA:''' Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M, Le Guenno G, Galicier L, Audia S, Royer B, Morin AS, Marie Michot J, Jaccard A, Frenzel L, Khellaf M, Godeau B. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017 Jan;92(1):23-27. Epub 2016 Nov 10. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27696475 PubMed]<br />
<br />
==Prednisolone & Rituximab {{#subobject:598gf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a7c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 Birgens et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisolone_monotherapy|Prednisolone]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 1.5 mg/kg/day PO for 2 weeks, then 0.75 mg/kg/day PO for 1 week (week 3), then 0.5 mg/kg/d PO for 1 week (week 4), followed by gradual reduction over the next 4-8 weeks to the lowest dose that was effective in maintaining a normal hemoglobin level.<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once weekly for 4 weeks<br />
<br />
==== Supportive care ====<br />
<br />
* Folic acid 5 mg/day PO<br />
<br />
===References===<br />
<br />
#Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Rønnov-Jessen D, Vestergaard H, Klausen TW, Schöllkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov;163(3):393-9. Epub 2013 Aug 24. [https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12541 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23981017 PubMed]<br />
<br />
==Prednisone & Rituximab {{#subobject:91ugf2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a7c9gc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 Michel et al. 2016 (RAIHA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Prednisone (Sterapred)]]<br />
*[[Rituximab (Rituxan)]]<br />
<br />
===References===<br />
<br />
#'''RAIHA:''' Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M, Le Guenno G, Galicier L, Audia S, Royer B, Morin AS, Marie Michot J, Jaccard A, Frenzel L, Khellaf M, Godeau B. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017 Jan;92(1):23-27. Epub 2016 Nov 10. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.24570 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27696475 PubMed]<br />
<br />
[[Category:Warm autoimmune hemolytic anemia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Hemolytic process]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=39424
Venous thromboembolism
2019-08-06T16:18:09Z
<p>Benjamintillman: /* Older */ 2007 for completion of guidelines from ASCO on this topic</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
*'''2019:''' Key et al. [https://ascopubs.org/doi/abs/10.1200/JCO.19.01461 Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update.] [https://www.ncbi.nlm.nih.gov/pubmed/31381464 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update]<br />
*'''2013:''' Lyman et al. [https://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
*'''2007:''' Lyman et al. [https://ascopubs.org/doi/full/10.1200/JCO.2007.14.1283 American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/17968019 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days post-op {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days post-op {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''35-day course'''<br />
<br />
===Variant #3, 180 days {{#subobject:15cd2c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 Carrier et al. 2018 (AVERT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
| style="background-color:#fc8d59" |Seems to have higher rate of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning within 24 h of initiation of chemotherapy<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#'''AVERT:''' Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. Epub 2018 Dec 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30511879 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
<br />
#'''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
#'''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|UFH<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course<br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours.<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 Samama et al. 1999 (MEDENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Placebo<br> 2. Enoxaparin 20 mg daily<br />
| style="background-color:#1a9850" |Superior VTE rates<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
<br />
===References===<br />
<br />
#Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed]<br />
#'''MEDENOX:''' Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; MEDENOX Investigators. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999; 341:793-800. [https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/10477777 PubMed].<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFH (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 Khorana et al. 2019 (CASSINI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
<br />
#Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
#'''CASSINI:''' Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30786186 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
<br />
===References===<br />
<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
<br />
#'''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
#'''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
#'''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Argatroban (Acova)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Bivalirudin (Angiomax)]]<br />
<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
<br />
#'''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|UFH]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
<br />
===References===<br />
<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/293153 Loewe & Hirsch 1947]<br />
|Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
''Note: In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200 to 400 mg / 200,000 to 400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism.''<br />
====Anticoagulation====<br />
<br />
*[[Unfractionated heparin (UFH)]] SC 333 units/kg once, then 250 units/kg every 12 hours<br />
<br />
===References===<br />
<br />
#Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
<br />
*[[Tinzaparin (Innohep)]]<br />
<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
<br />
====Supportive medications====<br />
<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
<br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=39422
Venous thromboembolism
2019-08-06T16:07:27Z
<p>Benjamintillman: /* ASCO */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
*'''2019:''' Key et al. [https://ascopubs.org/doi/abs/10.1200/JCO.19.01461 Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update.] [https://www.ncbi.nlm.nih.gov/pubmed/31381464 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update]<br />
*'''2013:''' Lyman et al. [https://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days post-op {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days post-op {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''35-day course'''<br />
<br />
===Variant #3, 180 days {{#subobject:15cd2c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 Carrier et al. 2018 (AVERT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
| style="background-color:#fc8d59" |Seems to have higher rate of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning within 24 h of initiation of chemotherapy<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#'''AVERT:''' Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. Epub 2018 Dec 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30511879 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
<br />
#'''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
#'''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|UFH<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course<br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours.<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 Samama et al. 1999 (MEDENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Placebo<br> 2. Enoxaparin 20 mg daily<br />
| style="background-color:#1a9850" |Superior VTE rates<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
<br />
===References===<br />
<br />
#Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed]<br />
#'''MEDENOX:''' Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; MEDENOX Investigators. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999; 341:793-800. [https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/10477777 PubMed].<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFH (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 Khorana et al. 2019 (CASSINI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
<br />
#Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
#'''CASSINI:''' Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30786186 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
<br />
===References===<br />
<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
<br />
#'''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
#'''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
#'''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Argatroban (Acova)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Bivalirudin (Angiomax)]]<br />
<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
<br />
#'''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|UFH]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
<br />
===References===<br />
<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/293153 Loewe & Hirsch 1947]<br />
|Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
''Note: In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200 to 400 mg / 200,000 to 400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism.''<br />
====Anticoagulation====<br />
<br />
*[[Unfractionated heparin (UFH)]] SC 333 units/kg once, then 250 units/kg every 12 hours<br />
<br />
===References===<br />
<br />
#Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
<br />
*[[Tinzaparin (Innohep)]]<br />
<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
<br />
====Supportive medications====<br />
<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
<br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=39420
Venous thromboembolism
2019-08-06T16:00:47Z
<p>Benjamintillman: /* ASCO */ 2019 updated CA-VTE guidelines</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
* '''2019:''' Key et al. [https://www.ncbi.nlm.nih.gov/pubmed/31381464 Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. PubMed] <br />
<br />
=== Older ===<br />
<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update]<br />
*'''2013:''' Lyman et al. [https://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days post-op {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days post-op {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure<br />
<br />
'''35-day course'''<br />
<br />
===Variant #3, 180 days {{#subobject:15cd2c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 Carrier et al. 2018 (AVERT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
| style="background-color:#fc8d59" |Seems to have higher rate of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning within 24 h of initiation of chemotherapy<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#'''AVERT:''' Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. Epub 2018 Dec 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814468 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30511879 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
<br />
#'''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
#'''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|UFH<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course<br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours.<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 Samama et al. 1999 (MEDENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Placebo<br> 2. Enoxaparin 20 mg daily<br />
| style="background-color:#1a9850" |Superior VTE rates<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
<br />
===References===<br />
<br />
#Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed]<br />
#'''MEDENOX:''' Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; MEDENOX Investigators. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999; 341:793-800. [https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/10477777 PubMed].<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
#'''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
#Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
#Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
#'''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFH (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 Khorana et al. 2019 (CASSINI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
<br />
#Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
#'''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
#'''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
#'''CASSINI:''' Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814630 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30786186 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
<br />
===References===<br />
<br />
#'''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
#'''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
#'''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
#'''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
#'''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
#'''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
#'''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Therapeutic anticoagulation x 6-12 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
<br />
#'''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
#'''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
#'''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
#'''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
##'''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Argatroban (Acova)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Bivalirudin (Angiomax)]]<br />
<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
<br />
#'''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|UFH]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
<br />
===References===<br />
<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Fondaparinux (Arixtra)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/293153 Loewe & Hirsch 1947]<br />
|Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
''Note: In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200 to 400 mg / 200,000 to 400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism.''<br />
====Anticoagulation====<br />
<br />
*[[Unfractionated heparin (UFH)]] SC 333 units/kg once, then 250 units/kg every 12 hours<br />
<br />
===References===<br />
<br />
#Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
#'''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
<br />
*[[Lepirudin (Refludan)]]<br />
<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
#'''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
#'''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
<br />
*[[Tinzaparin (Innohep)]]<br />
<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
<br />
====Supportive medications====<br />
<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
<br />
#'''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
#'''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
#'''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
#'''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
#'''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
#'''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
#'''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
##'''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
#'''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
#'''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
<br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=36457
Antiphospholipid antibody syndrome
2019-03-14T21:36:47Z
<p>Benjamintillman: /* Rituximab */ for APS</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
Emerging data suggests the DOACs are inferior to VKAs in patients with APS. The trials are included here for reference, but most do not recommend these agents for APS. Due to the paucity of trials in this particular condition, many seek guidance from the [[venous thromboembolism (VTE)]] literature.<br />
<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x Finazzi et al. 2005 (WAPS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.0 to 4.5)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#1a9850" |Fewer events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
**Note: some trials specify a goal INR 2.5 without a range given<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# '''WAPS:''' Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15869575 PubMed]<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Warfarin and Aspirin ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[http://www.medsci.org/v07p0015.htm Okuma et al. 2009]<br />
|Phase III<br />
|Aspirin monotherapy<br />
|Lower cumulative incidence of ischemic stroke<br />
|}<br />
Note: Small study of 20 patients. All meeting the 2006 Sydney criteria for APS in setting of an ischemic stroke. <br />
<br />
==== Therapy ====<br />
* Warfarin (Coumadin) PO with INR goal 2.0 to 3.0<br />
* Aspirin 100 mg PO<br />
<br />
=== References ===<br />
# Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci 2010; 7(1):15-18. doi:10.7150/ijms.7.15 [http://www.medsci.org/v07p0015.htm link to original article] [https://www.ncbi.nlm.nih.gov/pubmed?term=20046230 PubMed]<br />
<br />
== Rituximab ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed?term=23124321 Erkan et al. 2013 (RITAPS)]<br />
|Phase II<br />
|None<br />
|Some improvement in non-criteria manifestations of APS<br />
|}<br />
Note: This small phase 2 study (19 patients) did not identify any significant change in the antiphospholipid antibody profiles of the enrolled patients, but it did observe some improvements in the non-criteria manifestations of APS. This included thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and cognitive dysfunction. <br />
<br />
==== Therapy ====<br />
* Rituximab 1000mg on D1 and D15 <br />
<br />
=== References ===<br />
# Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013 Feb;65(2):464-71. doi: 10.1002/art.37759. [https://onlinelibrary.wiley.com/doi/full/10.1002/art.37759 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed?term=23124321 PubMed] <br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d73027" |Higher rate of events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.''<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]] PO 20 mg PO once per day<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=36456
Antiphospholipid antibody syndrome
2019-03-14T21:33:57Z
<p>Benjamintillman: /* Warfarin and Aspirin */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
Emerging data suggests the DOACs are inferior to VKAs in patients with APS. The trials are included here for reference, but most do not recommend these agents for APS. Due to the paucity of trials in this particular condition, many seek guidance from the [[venous thromboembolism (VTE)]] literature.<br />
<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x Finazzi et al. 2005 (WAPS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.0 to 4.5)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#1a9850" |Fewer events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
**Note: some trials specify a goal INR 2.5 without a range given<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# '''WAPS:''' Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15869575 PubMed]<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Warfarin and Aspirin ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[http://www.medsci.org/v07p0015.htm Okuma et al. 2009]<br />
|Phase III<br />
|Aspirin monotherapy<br />
|Lower cumulative incidence of ischemic stroke<br />
|}<br />
Note: Small study of 20 patients. All meeting the 2006 Sydney criteria for APS in setting of an ischemic stroke. <br />
<br />
==== Therapy ====<br />
* Warfarin (Coumadin) PO with INR goal 2.0 to 3.0<br />
* Aspirin 100 mg PO<br />
<br />
=== References ===<br />
# Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci 2010; 7(1):15-18. doi:10.7150/ijms.7.15 [http://www.medsci.org/v07p0015.htm link to original article] [https://www.ncbi.nlm.nih.gov/pubmed?term=20046230 PubMed]<br />
<br />
== Rituximab ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed?term=23124321 Erkan et al. 2013 (RITAPS)]<br />
|Phase II<br />
|None<br />
|Some improvement in non-criteria manifestations of APS<br />
|}<br />
Note: This small phase 2 study (19 patients) did not identify any significant change in the antiphospholipid antibody profiles of the enrolled patients, but it did observe some improvements in the non-criteria manifestations of APS. This included thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and cognitive dysfunction. <br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d73027" |Higher rate of events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.''<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]] PO 20 mg PO once per day<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=36455
Antiphospholipid antibody syndrome
2019-03-14T19:47:43Z
<p>Benjamintillman: warfarin and aspirin for APS with ischemic stroke</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
Emerging data suggests the DOACs are inferior to VKAs in patients with APS. The trials are included here for reference, but most do not recommend these agents for APS. Due to the paucity of trials in this particular condition, many seek guidance from the [[venous thromboembolism (VTE)]] literature.<br />
<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x Finazzi et al. 2005 (WAPS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.0 to 4.5)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#1a9850" |Fewer events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
**Note: some trials specify a goal INR 2.5 without a range given<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# '''WAPS:''' Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15869575 PubMed]<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Warfarin and Aspirin ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[http://www.medsci.org/v07p0015.htm Okuma et al. 2009]<br />
|Phase III<br />
|Aspirin monotherapy<br />
|Lower cumulative incidence of ischemic stroke<br />
|}<br />
Note: Small study of 20 patients. All meeting the 2006 Sydney criteria for APS in setting of an ischemic stroke. <br />
<br />
==== Therapy ====<br />
* Warfarin (Coumadin) PO with INR goal 2.0 to 3.0<br />
* Aspirin 100 mg PO<br />
<br />
=== References ===<br />
# Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci 2010; 7(1):15-18. doi:10.7150/ijms.7.15 [http://www.medsci.org/v07p0015.htm link to original article] [https://www.ncbi.nlm.nih.gov/pubmed?term=20046230 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d73027" |Higher rate of events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.''<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]] PO 20 mg PO once per day<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=36454
Antiphospholipid antibody syndrome
2019-03-14T19:36:00Z
<p>Benjamintillman: /* Guidelines */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
Emerging data suggests the DOACs are inferior to VKAs in patients with APS. The trials are included here for reference, but most do not recommend these agents for APS. Due to the paucity of trials in this particular condition, many seek guidance from the [[venous thromboembolism (VTE)]] literature.<br />
<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x Finazzi et al. 2005 (WAPS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.0 to 4.5)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#1a9850" |Fewer events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
**Note: some trials specify a goal INR 2.5 without a range given<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# '''WAPS:''' Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01340.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15869575 PubMed]<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ Cohen et al. 2016 (RAPS)]<br />
| style="background-color:#1a9851" |Phase II/III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d73027" |Higher rate of events<br />
|}<br />
''Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.''<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]] PO 20 mg PO once per day<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''RAPS:''' Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30079-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010562/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27570089 PubMed]<br />
# '''TRAPS:''' Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=36451
Heparin-induced thrombocytopenia
2019-03-12T22:28:51Z
<p>Benjamintillman: Update of Rivaroxaban for HIT - added more recent reference.</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
# Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once, then 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaparinux monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
## UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. [http://www.bloodjournal.org/content/130/9/1104.long?sso-checked=true link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28646118 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=36450
Venous thromboembolism
2019-03-12T22:20:49Z
<p>Benjamintillman: Added MEDENOX</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' Lyman et al. [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Heparin<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course <br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours. <br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 Samama et al. 1999 (MEDENOX)]<br />
|Phase III (C)<br />
|Placebo, Enoxaparin 20mg daily<br />
|Superior VTE rates<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed]<br />
# '''MEDENOX:''' Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; MEDENOX Investigators. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999; 341:793-800. [https://www.nejm.org/doi/full/10.1056/NEJM199909093411103 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/10477777 PubMed].<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Heparin (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
# Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|Heparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/293153 Loewe & Hirsch 1947]<br />
|Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
''Note: In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200 to 400 mg / 200,000 to 400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism.''<br />
====Anticoagulation====<br />
*[[Unfractionated heparin (UFH)]] SC 333 U/kg once, then 250 U/kg every 12 hours<br />
===References===<br />
# Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Bleeding_with_anticoagulation&diff=35640
Bleeding with anticoagulation
2019-02-13T08:13:34Z
<p>Benjamintillman: additional andexanet citation</p>
<hr />
<div>''The purpose of this page will be to focus on toxicity of anticoagulation, i.e., bleeding. It will be further organized over time.''<br />
<br />
=[[Apixaban (Eliquis)]] reversal=<br />
<br />
==[[Factor Xa, recombinant, inactivated-zhzo (Andexxa)]]==<br />
*[[Factor Xa, recombinant, inactivated-zhzo (Andexxa)]] as follows:<br />
**Apixaban dose up to 5 mg: 400 mg IV bolus at a target rate of 30 mg/min then 480 mg IV infusion at a rate of 4 mg/min for 2 hours<br />
**Apixaban dose greater than 5mg or unknown but at least 8 hours since last administration: 400 mg IV bolus at a target rate of 30 mg/min then 480 mg IV infusion at a rate of 4 mg/min for 2 hours<br />
**Apixaban dose greater than 5mg or unknown and less than 8 hours since last administration: 800mg IV bolus at a target rate of 30 mg/min then 960 mg IV infusion at a rate of 8 mg/min for 2 hours<br />
===References===<br />
# '''ANNEXA-A/ANNEXA-R:''' Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. Epub 2015 Nov 11. [https://www.nejm.org/doi/10.1056/NEJMoa1510991 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26559317 PubMed]<br />
# '''ANNEXA-4:''' Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. Epub 2016 Aug 30. [https://www.nejm.org/doi/full/10.1056/NEJMoa1607887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568772/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573206 PubMed]<br />
# '''ANNEXA-4:''' Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bornson MD, Lu G, Conley PB, Verhamme P, Schmidt J; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. Epub 2019 Feb 07. doi: 10.10156/NEJMoa1814051 [https://www.nejm.org/doi/full/10.1056/NEJMoa1814051 link to original article][https://www.ncbi.nlm.nih.gov/pubmed/30730782 PubMed]<br />
<br />
=[[Dabigatran (Pradaxa)]] reversal=<br />
==[[Idarucizumab (Praxbind)]]==<br />
*To be completed<br />
===References===<br />
# '''RE-VERSE AD:''' Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for dabigatran reversal. N Engl J Med. 2015 Aug 6;373(6):511-520. Epub 2015 Jun 22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1502000 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26095746 PubMed]<br />
## '''Update:''' Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. Epub 2017 Jul 11. [https://www.nejm.org/doi/full/10.1056/NEJMoa1707278 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28693366 PubMed]<br />
<br />
=[[Dalteparin (Fragmin)]] reversal=<br />
==[[Protamine sulfate (USP)]]==<br />
*To be completed<br />
<br />
=[[Enoxaparin (Lovenox)]] reversal=<br />
<br />
==[[Protamine sulfate (USP)]]==<br />
*To be completed<br />
<br />
=[[Unfractionated heparin (UFH)]] reversal=<br />
==[[Protamine sulfate (USP)]]==<br />
*To be completed<br />
<br />
=[[Rivaroxaban (Xarelto)]] reversal=<br />
==[[Factor Xa, recombinant, inactivated-zhzo (Andexxa)]]==<br />
*[[Factor Xa, recombinant, inactivated-zhzo (Andexxa)]] as follows:<br />
**Rivaroxaban dose up to 10mg: 400 mg IV bolus at a target rate of 30 mg/min then 480 mg IV infusion at a rate of 4 mg/min for 2 hours<br />
**Rivaroxaban dose greater than 10mg or unknown but at least 8 hours since last administration: 400 mg IV bolus at a target rate of 30 mg/min then 480 mg IV infusion at a rate of 4 mg/min for 2 hours<br />
**Rivaroxaban dose greater than 10mg or unknown and less than 8 hours since last administration: 800mg IV bolus at a target rate of 30 mg/min then 960 mg IV infusion at a rate of 8 mg/min for 2 hours<br />
===References===<br />
# '''ANNEXA-A/ANNEXA-R:''' Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. Epub 2015 Nov 11. [https://www.nejm.org/doi/10.1056/NEJMoa1510991 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26559317 PubMed]<br />
# '''ANNEXA-4:''' Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. Epub 2016 Aug 30. [https://www.nejm.org/doi/full/10.1056/NEJMoa1607887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568772/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573206 PubMed]<br />
# '''ANNEXA-4:''' Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bornson MD, Lu G, Conley PB, Verhamme P, Schmidt J; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. Epub 2019 Feb 07. doi: 10.10156/NEJMoa1814051 [https://www.nejm.org/doi/full/10.1056/NEJMoa1814051 link to original article][https://www.ncbi.nlm.nih.gov/pubmed/30730782 PubMed]<br />
<br />
=[[Warfarin (Coumadin)]] reversal=<br />
==Fresh frozen plasma (FFP)==<br />
==[[Prothrombin Complex Concentrate, Human (Kcentra)]]==<br />
<br />
=Perioperative management=<br />
<br />
=Bleeding risk calculators=<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:General reference pages]]<br />
[[Category:Bleeding disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Acquired_thrombotic_thrombocytopenic_purpura&diff=35602
Acquired thrombotic thrombocytopenic purpura
2019-02-06T21:51:32Z
<p>Benjamintillman: TITAN trial in table</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Initial therapy=<br />
<br />
==Plasma exchange {{#subobject:4b548d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0e1e05|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199108083250604 Rock et al. 1991]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Plasma infusion<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Supportive therapy====<br />
*Total plasma exchange as follows (minimum of 7 treatments in first 9 hospital days):<br />
**Treatments 1 to 3: Exchange of 1.5 times the predicted plasma volume<br />
**Treatments 4 onwards: Exchange of 1.0 times the predicted plasma volume<br />
<br />
====Supportive medications====<br />
*[[Dipyridamole (Persantine)]] 400 mg (route not specified) once per day for at least two weeks<br />
*[[Aspirin]] 325 mg PO once per day for at least two weeks<br />
<br />
===References===<br />
# Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991 Aug 8;325(6):393-7. [https://www.nejm.org/doi/full/10.1056/NEJM199108083250604 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2062330 PubMed]<br />
<br />
==Caplacizumab monotherapy {{#subobject:4c678d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9a4e05|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1505533 Peyvandi et al. 2016 (TITAN)]<br />
|Phase II<br />
|Placebo<br />
|Reduced time to response compared to placebo (p=0.005).<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1806311 Scully et al. 2019 (HERCULES)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Shorter median time to platelet count normalization.<br />
Lower composite outcome events (death, relapse).<br />
|}<br />
====Supportive therapy====<br />
*[[Caplacizumab (Cablivi)]]<br />
* Plasma exchange with discontinuation of plasma exchange five days after normalization of platelet count. <br />
<br />
===References===<br />
# '''TITAN:''' Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D; TITAN Investigators. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11;374(6):511-522. [https://www.nejm.org/doi/full/10.1056/NEJMoa1505533 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26863353 PubMed]<br />
# '''HERCULES:''' Scully M, Cataland SR, Peyvandi F, Coppo P, Knöbl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. Epub 2019 Jan 9. [https://www.nejm.org/doi/10.1056/NEJMoa1806311 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30625070 PubMed]<br />
<br />
=Maintenance/Preemptive treatment=<br />
==Rituximab monotherapy {{#subobject:4cadec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8bca2c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/124/2/204.long Hie et al. 2014]<br />
| style="background-color:#91cf61" |Registry<br />
|-<br />
|}<br />
''Note: this prospective registry trial left precise dosing details to physician discretion.''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] <br />
===References===<br />
# Hie M, Gay J, Galicier L, Provôt F, Presne C, Poullin P, Bonmarchand G, Wynckel A, Benhamou Y, Vanhille P, Servais A, Bordessoule D, Coindre JP, Hamidou M, Vernant JP, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Centre. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014 Jul 10;124(2):204-10. Epub 2014 May 28. [http://www.bloodjournal.org/content/124/2/204.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24869941 PubMed]<br />
## '''Update:''' Jestin M, Benhamou Y, Schelpe AS, Roose E, Provôt F, Galicier L, Hié M, Presne C, Poullin P, Wynckel A, Saheb S, Deligny C, Servais A, Girault S, Delmas Y, Kanouni T, Lautrette A, Chauveau D, Mousson C, Perez P, Halimi JM, Charvet-Rumpler A, Hamidou M, Cathébras P, Vanhoorelbeke K, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Center. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018 Nov 15;132(20):2143-2153. Epub 2018 Sep 10. [http://www.bloodjournal.org/content/132/20/2143.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30201758 PubMed]<br />
<br />
=Relapsed or refractory=<br />
<br />
''These treatments are usually used in addition to therapeutic plasma exchange, not in its place. There are also many treatments reported at the case report or case series level; the reader is guided to the 2015 Blood article, [http://www.bloodjournal.org/content/125/25/3860.long "How I treat refractory thrombotic thrombocytopenic purpura"] for further details.''<br />
<br />
==Methylprednisolone monotherapy {{#subobject:c31d01|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, "High-dose" {{#subobject:0ea120|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 Balduini et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Standard-dose methylprednisolone<br />
| style="background-color:#d9ef8b" |Might have superior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Methylprednisolone (Solumedrol)]] as follows:<br />
**Days 1 to 3: 10 mg/kg/day IV<br />
**Days 4 to 23: 2.5 mg/kg/day IV<br />
<br />
===Variant #2, "Standard-dose" {{#subobject:84ebef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 Balduini et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-dose methylprednisolone<br />
| style="background-color:#fee08b" |Might have inferior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Methylprednisolone (Solumedrol)]] as follows:<br />
**Days 1 to 3: 1 mg/kg/day IV<br />
**Days 4 to 23: 2.5 mg/kg/day IV<br />
<br />
===References===<br />
# Balduini CL, Gugliotta L, Luppi M, Laurenti L, Klersy C, Pieresca C, Quintini G, Iuliano F, Re R, Spedini P, Vianelli N, Zaccaria A, Pogliani EM, Musso R, Bobbio Pallavicini E, Quarta G, Galieni P, Fragasso A, Casella G, Noris P, Ascari E; Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010 Jun;89(6):591-6. Epub 2009 Dec 23. [http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20033409 PubMed]<br />
<br />
==Rituximab monotherapy {{#subobject:4cadec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:8bca2c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.trasci.com/article/S1473-0502(10)00162-X/fulltext de la Rubia et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13408/full Clark et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Full text of de la Rubia et al. 2010 is not available for review.''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week<br />
<br />
====Supportive medications====<br />
*[[Prednisone (Sterapred)]] 50 mg PO once prior to [[Rituximab (Rituxan)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once prior to [[Rituximab (Rituxan)]]<br />
*[[Acetaminophen (Tylenol)]] 325 mg PO once prior to [[Rituximab (Rituxan)]]<br />
<br />
'''4-week course'''<br />
<br />
===Variant #2 {{#subobject:a31c78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/21926591 Froissart et al. 2012]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] (dose not specified) IV<br />
<br />
'''Four doses in 15 days'''<br />
<br />
===References===<br />
# de la Rubia J, Moscardó F, Gómez MJ, Guardia R, Rodríguez P, Sebrango A, Zamora C, Debén G, Goterris R, López R, Peña F, Pujol M, Vidaller A, Del Río-Garma J, Sanz MA; Grupo Español de Aféresis. Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study. Transfus Apher Sci. 2010 Dec;43(3):299-303. Epub 2010 Oct 12. [http://www.trasci.com/article/S1473-0502(10)00162-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20934383 PubMed]<br />
# Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, Schwarzinger M, Galicier L, Vanhille P, Vernant JP, Bordessoule D, Guidet B, Azoulay E, Mariotte E, Rondeau E, Mira JP, Wynckel A, Clabault K, Choukroun G, Presne C, Pourrat J, Hamidou M, Coppo P; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange: experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11. [https://www.ncbi.nlm.nih.gov/pubmed/21926591 PubMed]<br />
# '''Review:''' Lim W, Vesely SK, George JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015 Mar 5;125(10):1526-31. Epub 2015 Jan 8. Review. [http://www.bloodjournal.org/content/125/10/1526.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351502/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25573992 PubMed]<br />
# Clark WF, Rock G, Barth D, Arnold DM, Webert KE, Yenson PR, Kelton JG, Li L, Foley SR; members of the Canadian Apheresis Group. A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab. Br J Haematol. 2015 Jul;170(2):208-17. Epub 2015 Apr 8. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13408/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25855259 PubMed]<br />
<br />
==Vincristine monotherapy {{#subobject:583bc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:8892fc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/10602896 Ferrara et al. 1999]<br />
| style="background-color:#ffffbe" |Pilot, <20 patients<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1, then 1 mg IV once per day on days 4 & 7<br />
<br />
===References===<br />
# Ferrara F, Copia C, Annunziata M, Spasiano A, Di Grazia C, Palmieri S, Prossomariti L, Mele G. Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura. Ann Hematol. 1999 Nov;78(11):521-3. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10602896 PubMed]<br />
<br />
[[Category:Thrombotic thrombocytopenic purpura regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Cytopenias]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Acquired_thrombotic_thrombocytopenic_purpura&diff=35596
Acquired thrombotic thrombocytopenic purpura
2019-02-06T18:57:20Z
<p>Benjamintillman: Added Caplacizumab</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Initial therapy=<br />
<br />
==Plasma exchange {{#subobject:4b548d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0e1e05|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199108083250604 Rock et al. 1991]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Plasma infusion<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Supportive therapy====<br />
*Total plasma exchange as follows (minimum of 7 treatments in first 9 hospital days):<br />
**Treatments 1 to 3: Exchange of 1.5 times the predicted plasma volume<br />
**Treatments 4 onwards: Exchange of 1.0 times the predicted plasma volume<br />
<br />
====Supportive medications====<br />
*[[Dipyridamole (Persantine)]] 400 mg (route not specified) once per day for at least two weeks<br />
*[[Aspirin]] 325 mg PO once per day for at least two weeks<br />
<br />
===References===<br />
# Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991 Aug 8;325(6):393-7. [https://www.nejm.org/doi/full/10.1056/NEJM199108083250604 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2062330 PubMed]<br />
<br />
== Caplacizumab ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1806311 Scully et al. HERCULES 2019]<br />
|Phase III<br />
|placebo<br />
|Shorter median time to platelet count normalization.<br />
Lower composite outcome events (death, relapse).<br />
|}<br />
<br />
==== Supportive therapy ====<br />
* Plasma exchange with discontinuation of plasma exchange five days after normalization of platelet count. <br />
<br />
=== References ===<br />
# Scully M, Cataland SR, Peyvandi F, Coppo P, Knobl P, Kermer Hovinga JA, Metjian A, de la Rubia J, Pavenksi K, Callewart F, Biswas D, De Winter H, et al, for teh HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2019; 380:335-346. [https://www.nejm.org/doi/10.1056/NEJMoa1806311 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30625070 PubMed]<br />
<br />
=Maintenance/Preemptive treatment=<br />
==Rituximab monotherapy {{#subobject:4cadec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8bca2c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/124/2/204.long Hie et al. 2014]<br />
| style="background-color:#91cf61" |Registry<br />
|-<br />
|}<br />
''Note: this prospective registry trial left precise dosing details to physician discretion.''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] <br />
===References===<br />
# Hie M, Gay J, Galicier L, Provôt F, Presne C, Poullin P, Bonmarchand G, Wynckel A, Benhamou Y, Vanhille P, Servais A, Bordessoule D, Coindre JP, Hamidou M, Vernant JP, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Centre. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014 Jul 10;124(2):204-10. Epub 2014 May 28. [http://www.bloodjournal.org/content/124/2/204.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24869941 PubMed]<br />
## '''Update:''' Jestin M, Benhamou Y, Schelpe AS, Roose E, Provôt F, Galicier L, Hié M, Presne C, Poullin P, Wynckel A, Saheb S, Deligny C, Servais A, Girault S, Delmas Y, Kanouni T, Lautrette A, Chauveau D, Mousson C, Perez P, Halimi JM, Charvet-Rumpler A, Hamidou M, Cathébras P, Vanhoorelbeke K, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Center. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018 Nov 15;132(20):2143-2153. Epub 2018 Sep 10. [http://www.bloodjournal.org/content/132/20/2143.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30201758 PubMed]<br />
<br />
=Relapsed or refractory=<br />
<br />
''These treatments are usually used in addition to therapeutic plasma exchange, not in its place. There are also many treatments reported at the case report or case series level; the reader is guided to the 2015 Blood article, [http://www.bloodjournal.org/content/125/25/3860.long "How I treat refractory thrombotic thrombocytopenic purpura"] for further details.''<br />
<br />
==Methylprednisolone monotherapy {{#subobject:c31d01|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, "High-dose" {{#subobject:0ea120|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 Balduini et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Standard-dose methylprednisolone<br />
| style="background-color:#d9ef8b" |Might have superior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Methylprednisolone (Solumedrol)]] as follows:<br />
**Days 1 to 3: 10 mg/kg/day IV<br />
**Days 4 to 23: 2.5 mg/kg/day IV<br />
<br />
===Variant #2, "Standard-dose" {{#subobject:84ebef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 Balduini et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-dose methylprednisolone<br />
| style="background-color:#fee08b" |Might have inferior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Methylprednisolone (Solumedrol)]] as follows:<br />
**Days 1 to 3: 1 mg/kg/day IV<br />
**Days 4 to 23: 2.5 mg/kg/day IV<br />
<br />
===References===<br />
# Balduini CL, Gugliotta L, Luppi M, Laurenti L, Klersy C, Pieresca C, Quintini G, Iuliano F, Re R, Spedini P, Vianelli N, Zaccaria A, Pogliani EM, Musso R, Bobbio Pallavicini E, Quarta G, Galieni P, Fragasso A, Casella G, Noris P, Ascari E; Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010 Jun;89(6):591-6. Epub 2009 Dec 23. [http://link.springer.com/article/10.1007%2Fs00277-009-0877-5 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20033409 PubMed]<br />
<br />
==Rituximab monotherapy {{#subobject:4cadec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:8bca2c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.trasci.com/article/S1473-0502(10)00162-X/fulltext de la Rubia et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13408/full Clark et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Full text of de la Rubia et al. 2010 is not available for review.''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week<br />
<br />
====Supportive medications====<br />
*[[Prednisone (Sterapred)]] 50 mg PO once prior to [[Rituximab (Rituxan)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once prior to [[Rituximab (Rituxan)]]<br />
*[[Acetaminophen (Tylenol)]] 325 mg PO once prior to [[Rituximab (Rituxan)]]<br />
<br />
'''4-week course'''<br />
<br />
===Variant #2 {{#subobject:a31c78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/21926591 Froissart et al. 2012]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] (dose not specified) IV<br />
<br />
'''Four doses in 15 days'''<br />
<br />
===References===<br />
# de la Rubia J, Moscardó F, Gómez MJ, Guardia R, Rodríguez P, Sebrango A, Zamora C, Debén G, Goterris R, López R, Peña F, Pujol M, Vidaller A, Del Río-Garma J, Sanz MA; Grupo Español de Aféresis. Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study. Transfus Apher Sci. 2010 Dec;43(3):299-303. Epub 2010 Oct 12. [http://www.trasci.com/article/S1473-0502(10)00162-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20934383 PubMed]<br />
# Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, Schwarzinger M, Galicier L, Vanhille P, Vernant JP, Bordessoule D, Guidet B, Azoulay E, Mariotte E, Rondeau E, Mira JP, Wynckel A, Clabault K, Choukroun G, Presne C, Pourrat J, Hamidou M, Coppo P; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange: experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11. [https://www.ncbi.nlm.nih.gov/pubmed/21926591 PubMed]<br />
# '''Review:''' Lim W, Vesely SK, George JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015 Mar 5;125(10):1526-31. Epub 2015 Jan 8. Review. [http://www.bloodjournal.org/content/125/10/1526.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351502/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25573992 PubMed]<br />
# Clark WF, Rock G, Barth D, Arnold DM, Webert KE, Yenson PR, Kelton JG, Li L, Foley SR; members of the Canadian Apheresis Group. A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab. Br J Haematol. 2015 Jul;170(2):208-17. Epub 2015 Apr 8. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13408/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25855259 PubMed]<br />
<br />
==Vincristine monotherapy {{#subobject:583bc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:8892fc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/10602896 Ferrara et al. 1999]<br />
| style="background-color:#ffffbe" |Pilot, <20 patients<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1, then 1 mg IV once per day on days 4 & 7<br />
<br />
===References===<br />
# Ferrara F, Copia C, Annunziata M, Spasiano A, Di Grazia C, Palmieri S, Prossomariti L, Mele G. Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura. Ann Hematol. 1999 Nov;78(11):521-3. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10602896 PubMed]<br />
<br />
[[Category:Thrombotic thrombocytopenic purpura regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Cytopenias]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=35594
Heparin-induced thrombocytopenia
2019-02-06T06:42:55Z
<p>Benjamintillman: Tardy-Poncet 2015 study notes</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
<br />
''Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.'' <br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
# Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once, then 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaparinux monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=35593
Heparin-induced thrombocytopenia
2019-02-06T06:37:49Z
<p>Benjamintillman: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract 2015]<br />
|Prospective<br />
|None<br />
|New or extended thrombosis in 25% of patients and major bleeding in 15%.<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
# Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-015-1109-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26556106?dopt=Abstract PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once, then 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaparinux monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=35592
Heparin-induced thrombocytopenia
2019-02-06T06:24:51Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|Tardy-Poncet et al. 2015<br />
|<br />
|<br />
|<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once, then 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaparinux monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=35591
Heparin-induced thrombocytopenia
2019-02-06T06:05:23Z
<p>Benjamintillman: /* Rivaroxaban monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|[[#Fondaparinux_monotherapy|Fondaparinux]]<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] 2400 anti-Xa units IV bolus once, then 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0037-1616046 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaparinux monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|1. [[#Argatroban_monotherapy|Argatroban]]<br> 2. [[#Danaparoid_monotherapy|Danaparoid]]<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one of the HIT patients (8.3%)<br />
|}<br />
''Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.''<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=35590
Venous thromboembolism
2019-02-05T22:46:37Z
<p>Benjamintillman: Added Heparin in Pitkins menstruum from JAMA 1947 for treatment of VTE</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' Lyman et al. [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Heparin<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course <br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours. <br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# Geerts WH, Richard MJ, Code KI, Chen E, Szalai JP, Saibil EA, and Hamilton PH. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996; 335:701-707. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed].<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Heparin (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
# Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|Heparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] SC 100 IU/kg every 12 hours<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|Loewe and Hirsch. [https://jamanetwork.com/journals/jama/article-abstract/293153 JAMA 1947]<br />
|Observational<br />
|None<br />
|2.4% fatality rate due to pulmonary embolism<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
* In Loewe and Hirsch, heparin was administered as a deep subcutaneous injection (200-400mg / 200,000-400,000 IU) in Pitkin menstruum every two to three days for 10 to 14 days for deep vein thrombosis and extended for one to two additional weeks for pulmonary embolism. <br />
<br />
*[[Heparin]] administered subcutaneously, initial dose 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours<br />
===References===<br />
# Loewe, L and Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. [https://jamanetwork.com/journals/jama/article-abstract/293153 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20293012 PubMed]<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism (VTE) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=35233
Venous thromboembolism
2019-01-30T16:12:40Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Johns Hopkins University<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' Lyman et al. [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
''Note: this APEX trial should not be confused with the one in multiple myeloma.''<br />
====Anticoagulation====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg every 12 hours {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996] <br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Heparin<br />
| style="background-color:#1a9850" |Superior DVT rates<br />
| style="background-color:#ffffbf" |No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course <br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours. <br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
''Note: the APEX trial here should not be confused with the one in multiple myeloma.''<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# Geerts WH, Richard MJ, Code KI, Chen E, Szalai JP, Saibil EA, and Hamilton PH. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996; 335:701-707. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed].<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Heparin (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
# Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg twice per day {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg twice per day {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg twice per day<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 5 mg PO twice per day<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
''Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.''<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 10 mg PO twice per day for 7 days, then 5 mg PO twice per day<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO twice per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|Heparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] administered subcutaneously at a dose of 100 IU/kg every 12 hours<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Heparin]] administered subcutaneously, initial dose 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/day {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/day {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/day with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC every 12 hours until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism (VTE) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=34577
Venous thromboembolism
2019-01-23T18:02:23Z
<p>Benjamintillman: Added Geerts et al NEJM 1996 - heparin vs lmwh in trauma patients</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2015:''' Lyman et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' Lyman et al. [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' Lyman et al. [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[https://www.hematology.org/ ASH]==<br />
*'''2018:''' Schünemann et al. [http://www.bloodadvances.org/content/2/22/3198 American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients]<br />
*'''2018:''' Lim et al. [http://www.bloodadvances.org/content/2/22/3226 American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism]<br />
*'''2018:''' Witt et al. [http://www.bloodadvances.org/content/2/22/3257 American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy]<br />
*'''2018:''' Monagle et al. [http://www.bloodadvances.org/content/2/22/3292 American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism]<br />
*'''2018:''' Bates et al. [http://www.bloodadvances.org/content/2/22/3317 American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy]<br />
*'''2018:''' Cuker et al. [http://www.bloodadvances.org/content/2/22/3360 American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Rodgers et al. 2000 (PEP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Enoxaparin_monotherapy|Enoxaparin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Rodgers A, MacMahon S, Collins R, Prentice C; Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg q12h {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 Geerts et al. 1996] <br />
|Phase III<br />
|Heparin<br />
|Superior DVT rates<br />
|No difference in major bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement (ADVANCE-1)<br />
*The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 30 mg SC q12h, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course <br />
*The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours. <br />
<br />
=== References ===<br />
# Geerts WH, Richard MJ, Code KI, Chen E, Szalai JP, Saibil EA, and Hamilton PH. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701-707. [https://www.nejm.org/doi/full/10.1056/NEJM199609053351003 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/8703169 PubMed].<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy|Aspirin]]<br> 2. Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1110899 Goldhaber et al. 2011 (ADOPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''ADOPT:''' Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. [https://www.nejm.org/doi/10.1056/NEJMoa1110899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22077144 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Placebo==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673696910090 Gärdlund et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Heparin (SC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently Hull et al. 2010 (EXCLAIM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d73027" |Inferior composite VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1111288 Kakkar et al. 2011 (LIFENOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No active treatment.''<br />
===References===<br />
# Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. [https://www.sciencedirect.com/science/article/pii/S0140673696910090 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8637340 PubMed]<br />
# '''EXCLAIM:''' Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. [http://annals.org/aim/fullarticle/745859/extended-duration-venous-thromboembolism-prophylaxis-acutely-ill-medical-patients-recently link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20621900 PubMed]<br />
# '''LIFENOX:''' Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. [https://www.nejm.org/doi/10.1056/NEJMoa1111288 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22204723 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1805090 Spyropoulos et al. 2018 (MARINER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for varying durations (see individual studies)<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [https://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [https://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
# '''MARINER:''' Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. [https://www.nejm.org/doi/10.1056/NEJMoa1805090 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30145946 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg BID {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg BID {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Apixaban 2.5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [https://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Apixaban (Eliquis)]] 10 mg PO BID for 7 days, then 5 mg PO BID<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. [[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Anticoagulation====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO BID<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:fc9e30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5a4974|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Heparin_monotherapy|Heparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Enoxaparin (Lovenox)]]<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/203221 Kearon et al. 2006 (FIDO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Dalteparin_monotherapy_2|Dalteparin]]<br> 2. [[#Enoxaparin_monotherapy_3|Enoxaparin]]<br />
| style="background-color:#eeee01" |No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Anticoagulation====<br />
*[[Heparin]] administered subcutaneously, initial dose 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours<br />
===References===<br />
# '''FIDO:''' Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16926353 PubMed]<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Anticoagulation====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/d {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/d {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|2. Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/d with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO BID for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Anticoagulation====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Anticoagulation====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC q12h until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [https://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subgroup analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism (VTE) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Immune_thrombocytopenia&diff=33338
Immune thrombocytopenia
2018-12-12T16:50:57Z
<p>Benjamintillman: Vinblastine loaded platelets</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==ASH==<br />
*'''2011:''' [http://www.bloodjournal.org/content/117/16/4190 The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia]<br />
<br />
=Initial therapy=<br />
<br />
==Dexamethasone monotherapy {{#subobject:7c8c62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:666055|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
<br />
'''One course'''<br />
<br />
''If platelets remained below 30 x 10<sup>9</sup>/L or bleeding by day 10, course is repeated once.''<br />
<br />
===Variant #2 {{#subobject:678fa4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy, part 1====<br />
*[[Prednisone (Sterapred)]] 1 mg/kg/day for 7 days<br />
<br />
====Immunosuppressive therapy, part 2====<br />
*[[Dexamethasone (Decadron)]] 0.6 mg/kg/day for days 1 to 4<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===Variant #3 {{#subobject:19f4e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa030254 Cheng et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''4-day course'''<br />
<br />
''Patients who had an initial response, but whose platelets dropped below 30 x 10<sup>9</sup>/L within 6 months received:''<br />
<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 15 mg PO once per day starting on day 5, "with gradual tapering"<br />
<br />
===Variant #4, monthly dexamethasone {{#subobject:f892de|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*Patients who had platelet counts of less than or equal to 20 x 10<sup>9</sup>/L between cycles received [[Prednisone (Sterapred)]] 0.25 mg/kg PO once per day "between courses"<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #5, bi-weekly dexamethasone {{#subobject:8ac5fe|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Adults: 40 mg IV or PO once per day on days 1 to 4<br />
**Patients less than 15 years old: 20 mg/m<sup>2</sup> (maximum dose: 40 mg per day) IV or PO once per day on days 1 to 4<br />
**Patients who had platelet counts of less than or equal to 30 x 10<sup>9</sup>/L between cycles and/or who had bleeding related to thrombocytopenia received 0.035 mg/kg PO once per day "between courses"<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003 Aug 28;349(9):831-6. [https://www.nejm.org/doi/full/10.1056/NEJMoa030254 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12944568 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31. [http://www.bloodjournal.org/content/109/4/1401.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17077333 PubMed]<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==Dexamethasone & Eltrombopag {{#subobject:910687|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:470504|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/123/25/3906.long Gómez-Almaguer et al. 2014]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts reported<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day on days 5 to 33<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<!-- Presented in an abstract form at the 55th meeting of the American Society of Hematology, New Orleans, LA, December 2013. --><br />
# Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, Gómez-De León A, Cantú-Rodríguez OG, Gutiérrez-Aguirre CH, Tarín-Arzaga L, Hernández-Reyes J, Ruiz-Arguelles GJ. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014 Jun 19;123(25):3906-8. Epub 2014 May 6. [http://www.bloodjournal.org/content/123/25/3906.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24802773 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:b9a6ee|Regimen=1}}==<br />
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===Regimen ("R+3Dex") {{#subobject:d05adc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract: Retrospective:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
==Intravenous immunoglobuin monotherapy {{#subobject:ea894c|Regimen=1}}==<br />
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IVIG: '''<u>I</u>'''ntra'''<u>V</u>'''enous '''<u>I</u>'''mmuno'''<u>G</u>'''lobulin<br />
===Regimen {{#subobject:9134b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2141.1999.01766.x Godeau et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|IVIG 0.5 g/kg<br />
| style="background-color:#1a9850" |Superior response rate<br />
|}<br />
====Therapy====<br />
*[[Intravenous immunoglobulin (IVIG)]] 1 gm/kg IV once on day 1<br />
<br />
'''One dose'''<br />
<br />
===References===<br />
# Imbach P, Wagner HP, Berchtold W, Gaedicke G, Hirt A, Joller P, Mueller-Eckhardt C, Müller B, Rossi E, Barandun S. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet. 1985 Aug 31;2(8453):464-8. [https://www.sciencedirect.com/science/article/pii/S0140673685904003 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/2863492 PubMed]<br />
# Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. [https://www.sciencedirect.com/science/article/pii/S0022347605804007 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8229536 PubMed]<br />
# Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. [https://www.sciencedirect.com/science/article/pii/S0140673694922055 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/7915773 PubMed]<br />
# Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 05 and 1 g/kg bw. Br J Haematol. 1999 Dec;107(4):716-9. [https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2141.1999.01766.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10606875 PubMed]<br />
# Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, Chèze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. 2002 Jan 5;359(9300):23-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)07275-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11809183 PubMed]<br />
# '''TIKI:''' Heitink-Pollé KMJ, Uiterwaal CSPM, Porcelijn L, Tamminga RYJ, Smiers FJ, van Woerden NL, Wesseling J, Vidarsson G, Laarhoven AG, de Haas M, Bruin MCA; TIKI Investigators. Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial. Blood. 2018 Aug 30;132(9):883-891. Epub 2018 Jun 26. [http://www.bloodjournal.org/content/132/9/883.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29945954 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:5f27f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
===Variant #1 {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 28<br />
**Afterwards, tapered over 4 to 6 weeks with a goal of maintenance dosing less than 15 mg/day or "complete termination"<br />
***Taper schedule determined by treating physician<br />
<br />
===Variant #2 {{#subobject:7c003e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 14<br />
**Afterwards, tapered over 19 weeks with a goal of maintenance dosing less than 7.5 mg/day at the end of week 19<br />
<br />
===References===<br />
# Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. [https://www.sciencedirect.com/science/article/pii/S0022347605804007 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/8229536 PubMed]<br />
# Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. [https://www.sciencedirect.com/science/article/pii/S0140673694922055 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/7915773 PubMed]<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==RhIG monotherapy {{#subobject:3ab9b6|Regimen=1}}==<br />
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RhIG: '''<u>Rh</u>'''o(D) '''<u>I</u>'''mmune '''<u>G</u>'''lobulin<br />
===Variant #1, 25 mcg/kg {{#subobject:8335a6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/77/9/1884 Bussel et al. 1991]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Eligibility: RhD-positive.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 25 mcg/kg IV once on day 1, repeated as needed on days 3 & 4<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 50 mcg/kg {{#subobject:487067|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (C)<br />
|Rho(D) 75 mcg/kg <br />
| style="background-color:#fc8d59" |Seems to have inferior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 50 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===Variant #3, 75 mcg/kg {{#subobject:b30788|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (E)<br />
|Rho(D) 50 mcg/kg <br />
| style="background-color:#91cf60" |Seems to have superior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 75 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===References===<br />
# Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;77(9):1884-93. [http://www.bloodjournal.org/content/77/9/1884 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1850307 PubMed] <br />
# Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/d of iv anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol. 2001 Mar;112(4):1076-8. [https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11298610 PubMed]<br />
<br />
==TT4 {{#subobject:d5ad89|Regimen=1}}==<br />
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<br />
TT4: '''<u>T</u>'''riple '''<u>T</u>'''herapy (4?)<br />
<br />
===Regimen {{#subobject:be2a8d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ Choi et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[:Category:Cyclosporines|Cyclosporine A]] 2.5 to 3 mg/kg/day on days 1 to 28<br />
**Dose adjusted for target trough of 200 to 400 mcg/L<br />
*[[Rituximab (Rituxan)]] 100 mg IV once per day on days 7, 14, 21, 28<br />
<br />
===References===<br />
# Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015 Jul 23;126(4):500-3. Epub 2015 May 13. [http://www.bloodjournal.org/content/126/4/500.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25972158 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==ATRA & Danazol {{#subobject:43e110|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:077574|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#Danazol_monotherapy|Danazol]]<br />
| style="background-color:#1a9850" |Superior 12-month sustained response<br />
|-<br />
|}<br />
====Therapy====<br />
*[[All-trans retinoic acid (ATRA)]] 10 mg PO BID<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Avatrombopag monotherapy {{#subobject:c8da29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:1aab54|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.15573 Jurczak et al. 2018]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior cumulative weeks of platelet response<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Avatrombopag (Doptelet)]]<br />
<br />
===References===<br />
# Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, Tang S, McIntosh J. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014 Jun 19;123(25):3887-94. Epub 2014 May 6. [http://bloodjournal.hematologylibrary.org/content/123/25/3887.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24802775 PubMed]<br />
# Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, Allen LF. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018 Nov;183(3):479-490. Epub 2018 Sep 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.15573 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30191972 PubMed]<br />
<br />
==Cyclosporine monotherapy {{#subobject:4d3847|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:df1b55|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/4/1482 Emilia et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[:Category:Cyclosporines|Cyclosporine A]] as follows:<br />
**5 mg/kg/day PO split into twice daily dosing for 6 days, then<br />
**2.5 to 3 mg/kg/day with dose adjusted for target trough of 200 to 400 mcg/L<br />
<br />
===References===<br />
# Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, Ferrara L, D'Apollo N, Potenza L, Bertesi M, Torelli G. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002 Feb 15;99(4):1482-5. [http://www.bloodjournal.org/content/99/4/1482 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11830504 PubMed]<br />
<br />
==Danazol monotherapy {{#subobject:e7bf80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9a63e6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198306093082306 Ahn et al. 1983]<br />
| style="background-color:#91cf61" |Pilot, >20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#ATRA_.26_Danazol|ATRA & Danazol]]<br />
| style="background-color:#d73027" |Inferior 12-month sustained response<br />
|-<br />
|}<br />
''Note: Ahn et al. 1983 gave a range of 200 mg PO from two to four times per day; the dose below is from Feng et al. 2017''<br />
====Endocrine therapy====<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983 Jun 9;308(23):1396-9. [https://www.nejm.org/doi/full/10.1056/NEJM198306093082306 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6682484 PubMed]<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Dexamethasone monotherapy {{#subobject:a6cd06|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8c260f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199406023302203 Andersen 1994]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles for 6 cycles'''<br />
<br />
===References===<br />
# Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994 Jun 2;330(22):1560-4. [https://www.nejm.org/doi/full/10.1056/NEJM199406023302203 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8177245 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:52f32|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen ("R+3Dex") {{#subobject:abae3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
==Eltrombopag monotherapy {{#subobject:170bd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:90336c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''This regimen was intended for pediatric patients.''<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] with starting dose as follows:<br />
**Age 6 to 17, weighing at least 27kg, non-east Asian: 50 mg PO once per day<br />
**Age 6 to 17, weighing at least 27kg, east Asian: 25 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, non-east Asian: 37.5 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, east Asian: 25 mg PO once per day<br />
**Age 1 to 5, non-east Asian: 1.2 mg/kg/day oral suspension<br />
**Age 1 to 5, east Asian: 0.8 mg/kg/day oral suspension<br />
<br />
'''Dose adjusted to a maximum of 75 mg/day, with temporary discontinuation for platelet count greater than 400 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #2 {{#subobject:5912e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa073275 Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior plt count of greater than or equal to 50 x 10<sup>9</sup>/L on day 43<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg (starting dose) PO once per day<br />
<br />
'''The dose could be increased from 50 mg to 75 mg after 3 weeks in patients whose platelet counts were less than 50 x 10<sup>9</sup>/L. Treatment was discontinued in patients who attained a platelet count greater than 200 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #3 {{#subobject:9ac7d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with dose modifications:<br />
**Increase to 75 mg PO once per day allowed after day 22 for patients with platelet counts lower than 50 x 10<sup>9</sup>/L<br />
**Decrease to 25 mg PO once per day required for platelets counts between 200 and 400 x 10<sup>9</sup>/L<br />
**Drug was held for platelet count greater than 400 x 10<sup>9</sup>/L, until platelet count dropped below 150 x 10<sup>9</sup>/L<br />
<br />
'''6-month course'''<br />
<br />
===Variant #4 {{#subobject:b1f517|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day<br />
<br />
'''Up to 6-week course'''<br />
<br />
===Variant #5 {{#subobject:55f69d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/121/3/537.long Saleh et al. 2012 (EXTEND)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with adjustments:<br />
<br />
''Dose and schedule were individualized with the goal of achieving and maintaining platelets between 50 and 200 x 10<sup>9</sup>/L.''<br />
<br />
===References===<br />
# Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa073275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18046028 PubMed] <br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''EXTEND:''' Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. Epub 2012 Nov 20. [http://www.bloodjournal.org/content/121/3/537.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23169778 PubMed]<br />
# '''PETIT2:''' Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Fostamatinib monotherapy {{#subobject:ddb228|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:85221f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25125 Bussel et al. 2018 (FIT1; FIT2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior stable response<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Fostamatinib (Tavalisse)]] 100 mg PO twice per day <br />
**Dose may be increased to 150 mg PO twice per day after 4 weeks if needed to achieve platelet count of at least 50<br />
<br />
'''24-week course'''<br />
===References===<br />
# '''FIT1; FIT2:''' Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, Hellmann A, Windyga J, Sivcheva L, Khalafallah AA, Zaja F, Cooper N, Markovtsov V, Zayed H, Duliege AM. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. Epub 2018 May 15. [https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25125 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29696684 PubMed].<br />
# Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018 Jan;10(1):9-25. [https://www.futuremedicine.com/doi/10.2217/imt-2017-0097?url_ver=Z39.88-2003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967793 PubMed]<br />
<br />
==Mycophenolate mofetil monotherapy {{#subobject:ddb338|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:850f1f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full Taylor et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Mycophenolate mofetil (CellCept)]] 1 gm per day<br />
<br />
===References===<br />
# '''Retrospective:''' Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, McGuckin S, Kothari J, Cooper N, Stasi R, Scully M. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol. 2015 Nov;171(4):625-30. Epub 2015 Aug 6. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26250874 PubMed]<br />
<br />
==Placebo== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rituximab_monotherapy|Rituximab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|}<br />
<br />
''No active treatment; used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
# Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Rituximab monotherapy {{#subobject:d7d211|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:128a52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/112/4/999.long Godeau et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Patients in Godeau et al. 2008 had "ITP lasting 6 or more months before inclusion; at least 1 previous treatment for ITP; and platelet count less than 30 × 10<sup>9</sup>/L at inclusion" and were candidates for splenectomy."''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week<br />
<br />
====Supportive medications====<br />
*(per Godeau et al. 2008):<br />
*Patients received Streptococcus pneumoniae and Haemophilus influenzae vaccination at least 2 weeks before the first dose of [[Rituximab (Rituxan)]]<br />
*[[Acetaminophen (Tylenol)]] 1 g prior to [[Rituximab (Rituxan)]]<br />
*[[Methylprednisolone (Solumedrol)]] 60 mg IV prior to [[Rituximab (Rituxan)]]<br />
<br />
'''4-week course'''<br />
<br />
===References===<br />
# Godeau B, Porcher R, Fain O, Lefrère F, Fenaux P, Cheze S, Vekhoff A, Chauveheid MP, Stirnemann J, Galicier L, Bourgeois E, Haiat S, Varet B, Leporrier M, Papo T, Khellaf M, Michel M, Bierling P. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008 Aug 15;112(4):999-1004. [http://www.bloodjournal.org/content/112/4/999.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18463354 PubMed]<br />
# '''Prospective cohort:''' Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, Kanter J, Neufeld E, Taube T, Ramenghi U, Shenoy S, Ward MJ, Mihatov N, Patel VL, Bierling P, Lesser M, Cooper N, Bussel JB. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012 Jun 21;119(25):5989-95. [http://www.bloodjournal.org/content/119/25/5989.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383014/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22566601 PubMed]<br />
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
<br />
==Romiplostim monotherapy {{#subobject:a6df46|Regimen=1}}== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:8b8d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''Patients in '''Kuter et al. 2008''' were adults; some had undergone splenectomy. Patients in '''Tarantino et al. 2016''' were less than 18 years old at time of study entry.''<br />
====Growth factor therapy====<br />
*[[Romiplostim (Nplate)]] 1 mcg/kg SC once per week, with subsequent dose titration; see papers for details<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
<br />
== Vinblastine-loaded platelets ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/565464 Ahn et al. 1978]<br />
|Phase I<br />
|None<br />
|CR in 6 of 11 patients<br />
|}<br />
<br />
=== Reference ===<br />
# Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM. New England Journal of Medicine. 1978; 298:1101-1107. [https://www.nejm.org/doi/full/10.1056/NEJM197805182982001?query=recirc_curatedRelated_article link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/565464 PubMed.]<br />
[[Category:Immune thrombocytopenia (ITP) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Bleeding disorders]]<br />
[[Category:Cytopenias]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=31318
Venous thromboembolism
2018-09-13T02:26:30Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
===Current===<br />
*'''2015:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Pulmonary Embolism Prevention (PEP) trial Collaborative Group 2000]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br> Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg q12h {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC q12h, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br> Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [http://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for 35 +/- 4 days<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [http://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg BID {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|Apixaban 5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg BID {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|Apixaban 2.5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Therapy====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [http://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [http://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [http://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [http://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [http://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 10 mg PO BID for 7 days, then 5 mg PO BID<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Therapy====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Therapy====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Therapy====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO BID<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Therapy====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subset analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Therapy====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/?term=16926353 Kearon et al. (FIDO) 2006]<br />
|Phase III<br />
|Dalteparin or Enoxaparin<br />
|No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Therapy====<br />
*[[Heparin]] administered subcutaneously, initial dose 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours<br />
===References===<br />
# Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/?term=16926353 PubMed].<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Therapy====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/d {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/d {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/d with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO BID for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Therapy====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC q12h until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subset analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism (VTE) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Venous_thromboembolism&diff=31317
Venous thromboembolism
2018-09-13T02:25:56Z
<p>Benjamintillman: /* Heparin monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
''Note that there is a considerable literature on using these agents in the prevention of thromboembolism associated with atrial fibrillation and mechanical heart valves. As these conditions are out of the purview of HemOnc.org, this page primarily focuses on the prevention and treatment of venous thromboembolism (VTE).''<br />
<br>'''Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:'''<br />
*[[Bleeding with anticoagulation]]<br />
*[[Deep veins and superficial veins in the arms and legs]]<br />
*[[Hypercoagulable state (thrombophilia)]] evaluation<br />
*[[Compression stockings and sleeves]] for management and prophylaxis against postphlebitic (postthrombotic) syndrome<ref>[http://circ.ahajournals.org/content/121/8/e217.full Circulation patient page about postthrombotic syndrome (PTS)]</ref><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==ACCP==<br />
*'''2012:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/ Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines]<br />
<br />
==[https://www.asco.org/ ASCO]==<br />
===Current===<br />
*'''2015:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881372/ ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update] <br />
*'''2013:''' [http://ascopubs.org/doi/abs/10.1200/JCO.2013.49.1118 Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
===Older===<br />
*'''2013:''' [http://jco.ascopubs.org/content/31/17/2189.long ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update] [https://www.ncbi.nlm.nih.gov/pubmed/23669224 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2010:''' [http://www.thrombosisresearch.com/article/S0049-3848(10)70028-1/pdf Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management] [https://www.ncbi.nlm.nih.gov/pubmed/20433989 PubMed]<br />
<br />
==IMWG==<br />
===Current===<br />
*'''2010:''' [http://imwg.myeloma.org/imwg-guidelines-for-the-prevention-of-thalidomide-and-lenalidomide-associated-thrombosis-in-myeloma/ IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma]<br />
<br />
===Older===<br />
*'''2007:''' [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]<br />
<br />
==ITAC-CME==<br />
*'''2016:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30369-2/fulltext International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27733271 PubMed]<br />
<br />
=VTE primary prophylaxis=<br />
==Apixaban monotherapy {{#subobject:9958a4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10-14 days {{#subobject:734aaa|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#91cf60" |Seems to have lower bleeding rate<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#d9ef8b" |Might have lower bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 35 days {{#subobject:15ab8c|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total hip replacement<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID, beginning 12 to 24 h after wound closure <br />
<br />
'''35-day course'''<br />
<br />
===References===<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:2b1389|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e721b6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext Pulmonary Embolism Prevention (PEP) trial Collaborative Group 2000]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior VTE rate<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035572 Landolfi et al. 2004 (ECLAP)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br> Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis Anderson et al. 2013 (EPCAT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Dalteparin<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Aspirin]] 81 to 160 mg PO once per day<br />
<br />
'''Various durations, see individual trials'''<br />
===References===<br />
# '''PEP:''' Pulmonary Embolism Prevention (PEP) trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295-302. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02110-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10776741 PubMed]<br />
# '''ECLAP:''' Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 8;350(2):114-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa035572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14711910 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''EPCAT:''' Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. [http://annals.org/aim/fullarticle/1692573/aspirin-versus-low-molecular-weight-heparin-extended-venous-thromboembolism-prophylaxis link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23732713 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
==Betrixaban monotherapy {{#subobject:834d5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70ffb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#d9ef8b" |Might have lower rates of VTE<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Betrixaban (Bevyxxa)]] 80 mg PO once per day<br />
===References===<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:f7bdac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30 mg q12h {{#subobject:a4d4d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810773 Lassen et al. 2009 (ADVANCE-1)]]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#fc8d59" |Seems to have higher bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Total knee replacement<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC q12h, beginning 12 to 24 h after wound closure <br />
<br />
'''10- to 14-day course'''<br />
<br />
===Variant #2, 40 mg daily {{#subobject:8e940e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext Lassen et al. 2010 (ADVANCE-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1006885 Lassen et al. 2010 (ADVANCE-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy|Apixaban]]<br />
| style="background-color:#d73027" |Inferior composite outcome<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 Palumbo et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br> Low-dose warfarin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/119/4/933.long Larocca et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 Cohen et al. 2016 (APEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Betrixaban_monotherapy|Betrixaban]]<br />
| style="background-color:#fee08b" |Might have higher rates of VTE<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*ADVANCE-2: Total knee replacement<br />
*ADVANCE-3: Total hip replacement<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''Various durations (see papers for details)'''<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [http://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''ADVANCE-1:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. [https://www.nejm.org/doi/10.1056/NEJMoa0810773 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19657123 PubMed]<br />
# '''ADVANCE-2:''' Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62125-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20206776 PubMed]<br />
# '''ADVANCE-3:''' Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. [https://www.nejm.org/doi/10.1056/NEJMoa1006885 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21175312 PubMed]<br />
# Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.6844 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21282540 PubMed]<br />
# Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9. Epub 2011 Aug 11. [http://www.bloodjournal.org/content/119/4/933.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21835953 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''APEX:''' Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016 Aug 11;375(6):534-44. Epub 2016 May 27. [http://www.nejm.org/doi/full/10.1056/NEJMoa1601747 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27232649 PubMed]<br />
<br />
==Rivaroxaban monotherapy {{#subobject:6a7fba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:828315|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext Kakkar et al. 2008 (RECORD2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 Erikkson et al. 2008 (RECORD1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa076016 Lassen et al. 2008 (RECORD3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#1a9850" |Superior composite outcome<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext Turpie et al. 2009 (RECORD4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#91cf60" |Seems to have superior composite outcome<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 Cohen et al. 2013 (MAGELLAN)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Enoxaparin_monotherapy|Enoxaparin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 10 days<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 Anderson et al. 2018 (EPCAT II)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy|Aspirin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE rate at 90 days<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day for 35 +/- 4 days<br />
===References===<br />
# '''RECORD2:''' Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60880-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18582928 PubMed]<br />
# '''RECORD1:''' Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. [http://www.nejm.org/doi/full/10.1056/NEJMoa0800374 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579811 PubMed]<br />
# '''RECORD3:''' Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. [http://www.nejm.org/doi/full/10.1056/NEJMoa076016 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18579812 PubMed]<br />
# '''RECORD4:''' Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60734-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19411100 PubMed]<br />
# '''MAGELLAN:''' Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. [http://www.nejm.org/doi/full/10.1056/NEJMoa1111096 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23388003 PubMed]<br />
# '''EPCAT II:''' Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. [http://www.nejm.org/doi/full/10.1056/NEJMoa1712746 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29466159 PubMed]<br />
<br />
=VTE secondary prevention=<br />
==Apixaban monotherapy {{#subobject:94eb02|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2.5 mg BID {{#subobject:969d50|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|Apixaban 5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 2.5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 5 mg BID {{#subobject:c7bfff0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 Agnelli et al. 2012 (AMPLIFY-EXT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|Apixaban 2.5 mg BID<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior composite endpoint<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Therapeutic anticoagulation x 6-12 mo<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 5 mg PO BID<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY-EXT:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. [http://www.nejm.org/doi/full/10.1056/NEJMoa1207541 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23216615 PubMed]<br />
<br />
==Aspirin monotherapy {{#subobject:eb5633|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e3079b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1114238 Becattini et al. 2012 (WARFASA)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1210384 Brighton et al. 2012 (ASPIRE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#d9ef8b" |Might have superior rate of VTE recurrence<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*WARFASA: [[#Warfarin_monotherapy|Warfarin]] x 6 to 18 months<br />
*ASPIRE: [[#Warfarin_monotherapy|Warfarin]] x 6 weeks to 24 months<br />
====Therapy====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''Two or more years'''<br />
<br />
===References===<br />
# '''WARFASA:''' Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573. [http://www.nejm.org/doi/full/10.1056/NEJMoa1114238 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22621626 PubMed]<br />
# '''ASPIRE:''' Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. [http://www.nejm.org/doi/full/10.1056/NEJMoa1210384 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23121403 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:57c5b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cbc29a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#1a9850" |Superior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**'''Month 1:''' 200 IU/kg SC once per day<br />
**'''Months 2 to 6:''' 150 IU/kg SC once per day<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [http://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
==Enoxaparin monotherapy {{#subobject:30d50d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a64a42|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy|Warfarin]]<br />
| style="background-color:#d9ef8b" |Might have superior combined VTE/bleeding outcome<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Enoxaparin (Lovenox)]] 1.5 mg/kg SC once per day<br />
<br />
'''3-month course'''<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard intensity {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://archinte.jamanetwork.com/article.aspx?articleid=754085 Meyer et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Enoxaparin_monotherapy_2|Enoxaparin]]<br />
| style="background-color:#fee08b" |Might have inferior combined VTE/bleeding outcome<br />
|<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa025313 Lee et al. 2003 (CLOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dalteparin_monotherapy|Dalteparin]]<br />
| style="background-color:#d73027" |Inferior rate of VTE at 6 months<br />
| style="background-color:#ffffbf" |No difference in bleeding rate<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
===Variant #2, low intensity {{#subobject:7c40af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa035029 Ridker et al. 2003 (PREVENT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior recurrent VTE rate<br />
| style="background-color:#ffffbf" |No difference in major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Warfarin with goal INR of 2.0 to 3.0 for median of 6.5 mo<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 1.5 to 2.0<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [http://archinte.jamanetwork.com/article.aspx?articleid=754085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12153376 PubMed]<br />
# '''PREVENT:''' Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Apr 10;348(15):1425-34. Epub 2003 Feb 24. [http://www.nejm.org/doi/full/10.1056/NEJMoa035029 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12601075 PubMed]<br />
# '''CLOT:''' Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. [http://www.nejm.org/doi/full/10.1056/NEJMoa025313 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12853587 PubMed]<br />
## '''Posthoc analysis:''' Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9. Epub 2005 Feb 7. [http://jco.ascopubs.org/content/23/10/2123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15699480 PubMed]<br />
<br />
=VTE treatment, all lines of therapy=<br />
==Apixaban monotherapy {{#subobject:f80057|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:856942|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Apixaban (Eliquis)]] 10 mg PO BID for 7 days, then 5 mg PO BID<br />
<br />
'''6-month course'''<br />
<br />
===References===<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
<br />
==Argatroban monotherapy {{#subobject:8171b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3f6d7f|Variant=1}}===<br />
====Therapy====<br />
*[[Argatroban (Acova)]]<br />
===References===<br />
To be completed<br />
<br />
==Aspirin monotherapy {{#subobject:0481f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0113df|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban 10 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban 20 mg]]<br />
| style="background-color:#d73027" |Inferior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
<br />
====Therapy====<br />
*[[Aspirin]] 100 mg PO once per day <br />
<br />
'''Up to 12-month course'''<br />
===References===<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
<br />
==Bivalirudin monotherapy {{#subobject:5a08f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5faf02|Variant=1}}===<br />
====Therapy====<br />
*[[Bivalirudin (Angiomax)]]<br />
===References===<br />
To be completed<br />
==Dabigatran monotherapy {{#subobject:4b48cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:518855|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dabigatran (Pradaxa)]] 150 mg PO BID<br />
<br />
'''6-month course'''<br />
===References===<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
<br />
==Dalteparin monotherapy {{#subobject:4a96a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbbc0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract Francis et al. 2015 (DALTECAN)]<br />
| style="background-color:#1a9851" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#fc8d59" |Seems to have inferior rate of VTE recurrence<br />
| style="background-color:#1a9850" |Superior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dalteparin (Fragmin)]] as follows:<br />
**First month: 200 IU/kg once per day<br />
**Subsequent months: 150 IU/kg once per day<br />
<br />
'''6- to 12-month course'''<br />
===References===<br />
# '''DALTECAN:''' Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. [https://onlinelibrary.wiley.com/doi/10.1111/jth.12923/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25827941 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Edoxaban monotherapy {{#subobject:d0ebe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, reduced dose {{#subobject:5c53d8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Superior rate of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
''Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup>, a body weight of up to 60 kg, or those taking "potent" [[P-glycoprotein_modifying_drugs#P-glycoprotein_inhibitors|P-glycoprotein inhibitors]].''<br />
====Therapy====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 30 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
<br />
===Variant #2, normal dosing {{#subobject:88a424|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#1a9850" |Lower rates of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 Raskob et al. 2017 (Hokusai VTE Cancer)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint of VTE/major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*Therapeutic dose [[:Category:Low molecular weight heparins|LMWH]] for at least 5 days, then:<br />
*[[Edoxaban (Savaysa)]] 60 mg PO once per day<br />
<br />
'''3- to 12-month course'''<br />
===References===<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subset analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''Hokusai VTE Cancer:''' Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1711948 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231094 PubMed]<br />
<br />
==Fondaparinux monotherapy {{#subobject:7a8cb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab5c25|Variant=1}}===<br />
====Therapy====<br />
*[[Fondaparinux (Arixtra)]]<br />
===References===<br />
To be completed<br />
<br />
==Heparin monotherapy {{#subobject:2a8be8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8cae03|Variant=1}}===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/?term=16926353 Kearon et al. (FIDO) 2006]<br />
|Phase III<br />
|Dalteparinor Enoxaparin<br />
|No difference in recurrent VTE or major bleeding<br />
|}<br />
<br />
====Therapy====<br />
*[[Heparin]] administered subcutaneously, initial dose 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours<br />
===References===<br />
# Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. JAMA. 2006 Aug23;296(8):935-42. [https://jamanetwork.com/journals/jama/fullarticle/203221 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/?term=16926353 PubMed].<br />
<br />
==Lepirudin monotherapy {{#subobject:b61e00|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:22918f|Variant=1}}===<br />
====Therapy====<br />
*[[Lepirudin (Refludan)]]<br />
===References===<br />
To be completed<br />
<br />
==Rivaroxaban monotherapy {{#subobject:f435a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 10 mg/d {{#subobject:4f1fdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|Rivaroxaban 20 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 10 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #2, 20 mg/d {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Weitz et al. 2017 (EINSTEIN CHOICE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Aspirin_monotherapy_2|Aspirin]]<br />
| style="background-color:#1a9850" |Superior symptomatic recurrent VTE rate<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|Rivaroxaban 10 mg<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 20 mg PO once per day<br />
<br />
'''Up to 12-month course'''<br />
<br />
===Variant #3, 20 mg/d with loading dose {{#subobject:ba11d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Warfarin_monotherapy_2|Warfarin]]<br />
| style="background-color:#eeee01" |Non-inferior symptomatic VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 Young et al. 2018 (SELECT-D)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Dalteparin_monotherapy_2|Dalteparin]]<br />
| style="background-color:#91cf60" |Seems to have superior rate of VTE recurrence<br />
| style="background-color:#d73027" |Inferior rates of clinically relevant non-major bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Rivaroxaban (Xarelto)]] 15 mg PO BID for 3 weeks, then 20 mg PO once per day<br />
<br />
'''3-, 6-, or 12-month course'''<br />
<br />
===References===<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''XALIA:''' Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900257-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26765643 PubMed]<br />
# '''EINSTEIN CHOICE:''' Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28316279 PubMed]<br />
# '''SELECT-D:''' Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.8034 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746227 PubMed]<br />
<br />
==Tinzaparin monotherapy {{#subobject:3d9d84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:24b40c|Variant=1}}===<br />
''Note: this agent has been withdrawn from the US market.''<br />
====Therapy====<br />
*[[Tinzaparin (Innohep)]]<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
==Warfarin monotherapy {{#subobject:76610c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd707c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 Schulman et al. 2009 (RE-COVER)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dabigatran_monotherapy|Dabigatran]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 Bauersachs et al. 2010 (EINSTEIN Acute DVT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 Büller et al. 2012 (EINSTEIN-PE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rivaroxaban_monotherapy_2|Rivaroxaban]]<br />
| style="background-color:#eeee01" |Non-inferior VTE recurrence<br />
| style="background-color:#ffffbf" |Similar major bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 Agnelli et al. 2013 (AMPLIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apixaban_monotherapy_3|Apixaban]]<br />
| style="background-color:#eeee01" |Non-inferior composite endpoint<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 Büller et al. 2013 (Hokusai-VTE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Edoxaban_monotherapy|Edoxaban]]<br />
| style="background-color:#eeee01" |Non-inferior recurrent VTE rate<br />
| style="background-color:#d73027" |Higher rates of bleeding<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] with goal INR between 2.0 and 3.0<br />
====Supportive medications====<br />
*Most protocols: [[Enoxaparin (Lovenox)]] 1 mg/kg SC q12h until INR greater than 2.0<br />
<br />
'''3-, 6-, or 12- month course (see individual papers)'''<br />
===References===<br />
# '''LITE:''' Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. [https://www.amjmed.com/article/S0002-9343(06)00263-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17145251 PubMed]<br />
# '''RE-COVER:''' Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. [http://www.nejm.org/doi/full/10.1056/NEJMoa0906598 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19966341 PubMed]<br />
# '''EINSTEIN Acute DVT:''' Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. [http://www.nejm.org/doi/full/10.1056/NEJMoa1007903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21128814 PubMed]<br />
# '''EINSTEIN-PE:''' Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113572 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22449293 PubMed]<br />
# '''RE-MEDY:''' Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113697 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23425163 PubMed]<br />
# '''AMPLIFY:''' Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1302507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23808982 PubMed]<br />
# '''Hokusai-VTE:''' Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. [http://www.nejm.org/doi/full/10.1056/NEJMoa1306638 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23991658 PubMed]<br />
## '''Subset analysis:''' Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30057-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27476789 PubMed]<br />
# '''RE-COVER II:''' Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. [http://circ.ahajournals.org/content/129/7/764.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24344086 PubMed]<br />
# '''CATCH:''' Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. [http://jama.jamanetwork.com/article.aspx?articleid=2428955 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26284719 PubMed]<br />
<br />
=Additional information=<br />
<references /><br />
*[http://journal.publications.chestnet.org/data/Journals/CHEST/934919/11026.pdf ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)]<br />
*[http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443&direction=P ACCP Chest Guidelines (2012)] - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)<br />
**[http://journal.publications.chestnet.org/article.aspx?articleID=1159399 Executive summary] [http://journal.publications.chestnet.org/data/Journals/CHEST/23443/chest_141_2_suppl_7S.pdf PDF]<br />
*Bleeding risk on anticoagulation: [http://www.globalrph.com/has-bled-score.htm HAS-BLED]; [http://www.globalrph.com/hemorr2hages-bleeding-risk.htm HEMORR2HAGES]<br />
<br />
[[Category:Venous thromboembolism (VTE) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31312
Heparin-induced thrombocytopenia
2018-09-13T02:12:05Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Lewis et al. 2003 (ARG-915)]<br />
| style="background-color:#91cf61" |Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
''Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT.''<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed]<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long Link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/11816702 Chong et al. 2001]<br />
| style="background-color:#1a9851" |Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
*[[Danaparoid (Orgaran)]] Bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed]<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long Link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/6/924.long Kang et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
To be completed<br />
====Anticoagulation====<br />
*[[Fondaparinux (Arixtra)]]<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ Treschan et al. 2014 (ALicia)] <br />
| style="background-color:#1a9851" |Randomized, double-blind<br />
|[[#Argatroban_monotherapy|Argatroban]]<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
''Note: Only 15 patients (23%) in the study had confirmed HIT.''<br />
==== Anticoagulation ====<br />
*[[Lepirudin (Refludan)]] as follows:<br />
**Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
**Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234853/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Linkins et al. 2016]<br />
| style="background-color:#91cf61" |Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27061271 PubMed]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31271
Heparin-induced thrombocytopenia
2018-09-11T16:50:48Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/12912723 Lewis et al. 2003 (ARG-915)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/11816702 Chong et al. 2001]<br />
|Phase III<br />
|Dextran 70<br />
|Improved complete clinical recovery with danaparoid<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
==== Anticoagulation ====<br />
Danaparoid: Bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed].<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31270
Heparin-induced thrombocytopenia
2018-09-11T16:49:15Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/12912723 Lewis et al. 2003 (ARG-915)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/11816702 Chong et al. 2001]<br />
|Phase III<br />
|Dextran 70<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
Anticoagulation<br />
<br />
Danaparoid: Bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2h, 300 units per hour for 2h, and then 200 units per hour for five days. <br />
<br />
=== References ===<br />
# Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Thromb Haemost. 2001 Nov;86(5):1170-5. [https://www.ncbi.nlm.nih.gov/pubmed/11816702 PubMed].<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31269
Heparin-induced thrombocytopenia
2018-09-11T16:43:31Z
<p>Benjamintillman: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/12912723 Lewis et al. 2003 (ARG-915)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. [https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/755826 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/12912723 PubMed]. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31268
Heparin-induced thrombocytopenia
2018-09-11T16:35:52Z
<p>Benjamintillman: /* Anticoagulation */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|Lewis et al. 2003 (ARG-915)<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. Link to original article. PubMed. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' [[Lepirudin (Refludan)]] paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* [[Rivaroxaban (Xarelto)]]: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31267
Heparin-induced thrombocytopenia
2018-09-11T16:34:13Z
<p>Benjamintillman: /* Argatroban monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|Lewis et al. 2003 (ARG-915)<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, or new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. Link to original article. PubMed. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* Rivaroxaban: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31266
Heparin-induced thrombocytopenia
2018-09-11T16:32:20Z
<p>Benjamintillman: /* Argatroban monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|Lewis et al. 2003 (ARG-915)<br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911, ARG-915:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ARG-915:''' Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. Link to original article. PubMed. <br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* Rivaroxaban: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=31235
Antiphospholipid antibody syndrome
2018-09-10T03:03:47Z
<p>Benjamintillman: /* Warfarin monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Rivaroxaban<br />
|Fewer events<br />
|}<br />
''Note: Pengo et al. 2018 was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffattia A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. Epub 2018 Jul 12. [Epub ahead of print] [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
|Phase III (C)<br />
|Warfarin<br />
|Seems inferior, excess events in rivaroxaban arm<br />
|}<br />
''Note: Pengo et al. 2018 was closed prematurely due to excess events in the rivaroxaban arm.''<br />
<br />
==== Therapy ====<br />
* [[Rivaroxaban (Xarelto)]] PO 20 mg PO once daily <br />
Continued indefinitely <br />
<br />
References<br />
# Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffattia A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. Epub 2018 Jul 12. [Epub ahead of print] [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Antiphospholipid_antibody_syndrome&diff=31234
Antiphospholipid antibody syndrome
2018-09-10T02:59:34Z
<p>Benjamintillman: /* Warfarin monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Warfarin monotherapy {{#subobject:acc688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3eda79|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa035241 Crowther et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|High-intensity Warfarin (INR 3.1 to 4.0)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Rivaroxaban<br />
|Fewer events<br />
|}<br />
''Note: Pengo et al. 2018 was closed prematurely due to excess events in the rivaroxaban arm.''<br />
====Therapy====<br />
*[[Warfarin (Coumadin)]] PO titrated to goal INR 2.0 to 3.0<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. [https://www.nejm.org/doi/full/10.1056/NEJMoa035241 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13679527 PubMed]<br />
# Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffattia A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. Epub 2018 Jul 12. [Epub ahead of print] [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long Pengo et al. 2018 (TRAPS)] <br />
|Phase III (C)<br />
|Warfarin<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
''Note: Pengo et al. 2018 was closed prematurely due to excess events in the rivaroxaban arm.''<br />
<br />
==== Therapy ====<br />
* Rivaroxaban (Xarelto) PO <br />
Continued indefinitely <br />
<br />
References<br />
# Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffattia A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. Epub 2018 Jul 12. [Epub ahead of print] [http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30002145 PubMed]<br />
[[Category:Antiphospholipid antibody syndrome regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31233
Heparin-induced thrombocytopenia
2018-09-10T02:52:42Z
<p>Benjamintillman: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Rivaroxaban monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract Linkins et al. 2016]<br />
|Prospective cohort<br />
|None<br />
|New thrombosis in one patient (4.5%)<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* Rivaroxaban: 15 mg PO BID until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20mg daily until day 30<br />
<br />
=== References ===<br />
# Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13330 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/27061271?dopt=Abstract PubMed].<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31232
Heparin-induced thrombocytopenia
2018-09-10T02:46:11Z
<p>Benjamintillman: /* Guidelines */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31231
Heparin-induced thrombocytopenia
2018-09-10T02:36:17Z
<p>Benjamintillman: /* Argatroban monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Danaparoid monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Fondaparinux<br />
|Similar efficacy and safety to fondaparinux<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity score-matched<br />
|Argatroban, Danaparoid<br />
|Similar efficacy and safety to argatroban, danaparoid<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=== References ===<br />
# Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015 Feb 5;125(6):924-9. [http://www.bloodjournal.org/content/125/6/924.long?sso-checked=true Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25515959 PubMed.]<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31230
Heparin-induced thrombocytopenia
2018-09-10T02:28:08Z
<p>Benjamintillman: /* Argatroban monotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25515959 Kang M et al. 2015]<br />
|Retrospective, propensity matched<br />
|Danaparoid, Fondaparinux<br />
|<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Fondaprinux monotherapy ==<br />
<br />
=== Regimen ===<br />
<br />
== Lepirudin monotherapy ==<br />
<br />
=== Regimen ===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014 (ALicia)] <br />
|Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
<br />
==== Anticoagulation ====<br />
* '''ALicia:''' Lepirudin paitents with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with moderate renal impairment (creatinine >=1.3 mg/dl): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
* '''ALicia:''' Lepirudin paitents with without renal impairment (creatinine <1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.<br />
<br />
=== References ===<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31226
Heparin-induced thrombocytopenia
2018-09-10T02:13:34Z
<p>Benjamintillman: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 Lewis et al. 2001 (ARG-911)]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014]<br />
|Randomized, double-blind<br />
|Lepirudin<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|}<br />
====Anticoagulation====<br />
*'''ARG-911:''' [[Argatroban (Acova)]] 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
*'''ALicia:''' [[Argatroban (Acova)]] with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value. <br />
<br />
===References===<br />
# '''ARG-911:''' Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]anja A Treschan[[Mailto:tanja.treschan@med.uni-duesseldorf.de|Email author]],<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
<br />
== Lepirudin monotherapy ==<br />
{| class="wikitable"<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/25344113 Treschan et al. 2014]<br />
!Randomized, double-blind<br />
|Argatroban<br />
|Suggests less bleeding in surgical patients with argatroban.<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|-<br />
|<br />
|<br />
|<br />
|<br />
|}<br />
# '''ALicia:''' Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina, T, Werner P, Golla, E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. [https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0588-8 link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed/25344113 PubMed.]<br />
#* Only 15 patients (23%) in the study had confirmed HIT.<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Heparin-induced_thrombocytopenia&diff=31210
Heparin-induced thrombocytopenia
2018-09-09T14:42:51Z
<p>Benjamintillman: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;" {|<br />
! colspan="4" style="color:white; font-size:125%; background-color:#31a354" align="center" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|} <br />
{| style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
To be completed<br />
=All lines of therapy=<br />
==Argatroban monotherapy==<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/11294800 Lewis et al. 2001]<br />
|Prospective, historical control<br />
|Multiple<br />
|Reduced all-cause death, all-cause amputation, and new thrombosis<br />
|}<br />
<br />
=== Anticoagulation ===<br />
* Argatroban 2 ug/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value. <br />
<br />
== References ==<br />
B.E. Lewis, D.E. Wallis, S.D. Berkowitz, W.H. Matthai, J. Fareed, J.M. Walenga, J. Bartholomew, R. Sham, R.G. Lerner, Z.R. Zeigler, P.K. Rustagi, I.K. Jang, S.D. Rifkin, J. Moran, M.J. Hursting, J.G. Kelton, for the ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with Heparin-induced thrombocytopenia. Circulation. 2001;103:1838-1843. [https://www.ahajournals.org/doi/abs/10.1161/circ.103.14.1838 link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/11294800 PubMed.]<br />
<br />
[[Category:Heparin-induced thrombocytopenia (HIT) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Thrombotic disorders]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Immune_thrombocytopenia&diff=28835
Immune thrombocytopenia
2018-07-20T00:17:46Z
<p>Benjamintillman: /* Fostamatinib monotherapy */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--> <br />
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! colspan="4" align="center" style="color:white; font-size:125%; background-color:#31a354" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==ASH==<br />
*'''2011:''' [http://www.bloodjournal.org/content/117/16/4190 The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia]<br />
<br />
=Initial therapy=<br />
<br />
==Dexamethasone monotherapy {{#subobject:7c8c62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:666055|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
<br />
'''One course'''<br />
<br />
''If platelets remained below 30 x 10<sup>9</sup>/L or bleeding by day 10, course is repeated once.''<br />
<br />
===Variant #2 {{#subobject:678fa4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy, part 1====<br />
*[[Prednisone (Sterapred)]] 1 mg/kg/day for 7 days<br />
<br />
====Immunosuppressive therapy, part 2====<br />
*[[Dexamethasone (Decadron)]] 0.6 mg/kg/day for days 1 to 4<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===Variant #3 {{#subobject:19f4e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa030254 Cheng et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''4-day course'''<br />
<br />
''Patients who had an initial response, but whose platelets dropped below 30 x 10<sup>9</sup>/L within 6 months received:''<br />
<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 15 mg PO once per day starting on day 5, "with gradual tapering"<br />
<br />
===Variant #4, monthly dexamethasone {{#subobject:f892de|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*Patients who had platelet counts of less than or equal to 20 x 10<sup>9</sup>/L between cycles received [[Prednisone (Sterapred)]] 0.25 mg/kg PO once per day "between courses"<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #5, bi-weekly dexamethasone {{#subobject:8ac5fe|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Adults: 40 mg PO/IV once per day on days 1 to 4<br />
**Patients less than 15 years old: 20 mg/m<sup>2</sup> (maximum dose: 40 mg per day) PO/IV once per day on days 1 to 4<br />
**Patients who had platelet counts of less than or equal to 30 x 10<sup>9</sup>/L between cycles and/or who had bleeding related to thrombocytopenia received 0.035 mg/kg PO once per day "between courses"<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003 Aug 28;349(9):831-6. [http://www.nejm.org/doi/full/10.1056/NEJMoa030254 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12944568 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31. [http://www.bloodjournal.org/content/109/4/1401.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17077333 PubMed]<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==Dexamethasone & Eltrombopag {{#subobject:910687|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:470504|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/123/25/3906.long Gómez-Almaguer et al. 2014]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts reported<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day on days 5 to 33<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<!-- Presented in an abstract form at the 55th meeting of the American Society of Hematology, New Orleans, LA, December 2013. --><br />
# Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, Gómez-De León A, Cantú-Rodríguez OG, Gutiérrez-Aguirre CH, Tarín-Arzaga L, Hernández-Reyes J, Ruiz-Arguelles GJ. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014 Jun 19;123(25):3906-8. Epub 2014 May 6. [http://www.bloodjournal.org/content/123/25/3906.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24802773 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:b9a6ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen ("R+3Dex") {{#subobject:d05adc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract: Retrospective:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
== Intravenous immunoglobuin ==<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|Godeau et al. 1999<br />
|Phase III<br />
|0.5g/kg IVIG<br />
|Higher response<br />
|}<br />
Therapy<br />
* Intravenous immunoglobulin (IVIG) 1gm/kg body weight on day 1<br />
References<br />
# Bertrand Godeau, Marie-Therese Caulier, Laurent Decuypere, Christian Rose, Annette Schaeffer, and Philippe Bierling for the Groupe d'Etude du Traitement du PTAI. British Journal of Hematology. 1999; 107: 716-719. [https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2141.1999.01766.x Link to article] [https://www.ncbi.nlm.nih.gov/pubmed?term=10606875 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:5f27f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 28<br />
**Afterwards, tapered over 4 to 6 weeks with a goal of maintenance dosing less than 15 mg/day or "complete termination"<br />
***Taper schedule determined by treating physician<br />
<br />
===Variant #2 {{#subobject:7c003e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 14<br />
**Afterwards, tapered over 19 weeks with a goal of maintenance dosing less than 7.5 mg/day at the end of week 19<br />
<br />
===References===<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==RhIG monotherapy {{#subobject:3ab9b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RhIG: '''<u>Rh</u>'''o(D) '''<u>I</u>'''mmune '''<u>G</u>'''lobulin<br />
===Variant #1, 25 mcg/kg {{#subobject:8335a6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/77/9/1884 Bussel et al. 1991]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Eligibility: RhD-positive.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 25 mcg/kg IV once on day 1, repeated as needed on days 3 & 4<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 50 mcg/kg {{#subobject:487067|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (C)<br />
|Rho(D) 75 mcg/kg <br />
| style="background-color:#fc8d59" |Seems to have inferior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 50 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===Variant #3, 75 mcg/kg {{#subobject:b30788|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (E)<br />
|Rho(D) 50 mcg/kg <br />
| style="background-color:#91cf60" |Seems to have superior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 75 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===References===<br />
# Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;77(9):1884-93. [http://www.bloodjournal.org/content/77/9/1884 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1850307 PubMed] <br />
# Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/d of iv anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol. 2001 Mar;112(4):1076-8. [https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11298610 PubMed]<br />
<br />
==TT4 {{#subobject:d5ad89|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
TT4: '''<u>T</u>'''riple '''<u>T</u>'''herapy (4?)<br />
<br />
===Regimen {{#subobject:be2a8d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ Choi et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[:Category:Cyclosporines|Cyclosporine A]] 2.5 to 3 mg/kg/day on days 1 to 28<br />
**Dose adjusted for target trough of 200 to 400 mcg/L<br />
*[[Rituximab (Rituxan)]] 100 mg IV once per day on days 7, 14, 21, 28<br />
<br />
===References===<br />
# Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015 Jul 23;126(4):500-3. Epub 2015 May 13. [http://www.bloodjournal.org/content/126/4/500.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25972158 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==ATRA & Danazol {{#subobject:43e110|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:077574|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#Danazol_monotherapy|Danazol]]<br />
| style="background-color:#1a9850" |Superior 12-month sustained response<br />
|-<br />
|}<br />
====Therapy====<br />
*[[All-trans retinoic acid (ATRA)]] 10 mg PO BID<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Cyclosporine monotherapy {{#subobject:4d3847|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:df1b55|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/4/1482 Emilia et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[:Category:Cyclosporines|Cyclosporine A]] as follows:<br />
**5 mg/kg/day PO split into twice daily dosing for 6 days, then<br />
**2.5 to 3 mg/kg/day with dose adjusted for target trough of 200 to 400 mcg/L<br />
<br />
===References===<br />
# Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, Ferrara L, D'Apollo N, Potenza L, Bertesi M, Torelli G. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002 Feb 15;99(4):1482-5. [http://www.bloodjournal.org/content/99/4/1482 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11830504 PubMed]<br />
<br />
==Danazol monotherapy {{#subobject:e7bf80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9a63e6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJM198306093082306 Ahn et al. 1983]<br />
| style="background-color:#91cf61" |Pilot, >20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#ATRA_.26_Danazol|ATRA & Danazol]]<br />
| style="background-color:#d73027" |Inferior 12-month sustained response<br />
|-<br />
|}<br />
''Note: Ahn et al. 1983 gave a range of 200 mg PO from two to four times per day; the dose below is from Feng et al. 2017''<br />
====Endocrine therapy====<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983 Jun 9;308(23):1396-9. [http://www.nejm.org/doi/full/10.1056/NEJM198306093082306 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6682484 PubMed]<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Dexamethasone monotherapy {{#subobject:a6cd06|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8c260f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJM199406023302203 Andersen et al. 1994]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles for 6 cycles'''<br />
<br />
===References===<br />
# Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994 Jun 2;330(22):1560-4. [http://www.nejm.org/doi/full/10.1056/NEJM199406023302203 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8177245 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:52f32|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen ("R+3Dex") {{#subobject:abae3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
==Eltrombopag monotherapy {{#subobject:170bd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:90336c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''This regimen was intended for pediatric patients.''<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] with starting dose as follows:<br />
**Age 6 to 17, weighing at least 27kg, non-east Asian: 50 mg PO once per day<br />
**Age 6 to 17, weighing at least 27kg, east Asian: 25 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, non-east Asian: 37.5 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, east Asian: 25 mg PO once per day<br />
**Age 1 to 5, non-east Asian: 1.2 mg/kg/day oral suspension<br />
**Age 1 to 5, east Asian: 0.8 mg/kg/day oral suspension<br />
<br />
'''Dose adjusted to a maximum of 75 mg/day, with temporary discontinuation for platelet count greater than 400 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #2 {{#subobject:5912e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa073275 Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior plt count of greater than or equal to 50 x 10<sup>9</sup>/L on day 43<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg (starting dose) PO once per day<br />
<br />
'''The dose could be increased from 50 mg to 75 mg after 3 weeks in patients whose platelet counts were less than 50 x 10<sup>9</sup>/L. Treatment was discontinued in patients who attained a platelet count greater than 200 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #3 {{#subobject:9ac7d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with dose modifications:<br />
**Increase to 75 mg PO once per day allowed after day 22 for patients with platelet counts lower than 50 x 10<sup>9</sup>/L<br />
**Decrease to 25 mg PO once per day required for platelets counts between 200 and 400 x 10<sup>9</sup>/L<br />
**Drug was held for platelet count greater than 400 x 10<sup>9</sup>/L, until platelet count dropped below 150 x 10<sup>9</sup>/L<br />
<br />
'''6-month course'''<br />
<br />
===Variant #4 {{#subobject:b1f517|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2007]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day<br />
<br />
'''Up to 6-week course'''<br />
<br />
===Variant #5 {{#subobject:55f69d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/121/3/537.long Saleh et al. 2012 (EXTEND)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with adjustments:<br />
<br />
''Dose and schedule were individualized with the goal of achieving and maintaining platelets between 50 and 200 x 10<sup>9</sup>/L.''<br />
<br />
===References===<br />
# Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. [http://www.nejm.org/doi/full/10.1056/NEJMoa073275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18046028 PubMed] <br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''EXTEND:''' Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. Epub 2012 Nov 20. [http://www.bloodjournal.org/content/121/3/537.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23169778 PubMed]<br />
# '''PETIT2:''' Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Fostamatinib monotherapy {{#subobject:ddb228|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:85221f|Variant=1}}===<br />
<br />
====Therapy====<br />
*[[Fostamatinib (Tavalisse)]] 100 mg PO twice per day <br />
**Dose may be increased to 150 mg PO twice per day after 4 weeks if needed to achieve platelet count of at least 50<br />
<br />
===References===<br />
# James Bussel, Donald M. Arnold, Elliot Grossbard, Jiri Mayer, Jacek Trelinski, Wojciech Homenda, Andrzej Hellmann, Jerzy Windyga, Liliya Sivcheva, Alhossain A. Khalafallah, Francesco Zaja, Nichola Cooper, Vadim Markovtsov, Hany Zayed, Anne-Marie Duliege. Fostamatinib for the treatment of adjult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. American Journal of Hematology. 2018; 93:921-930. [https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25125 Link to original article]. [https://www.ncbi.nlm.nih.gov/pubmed?term=29696684 PubMed].<br />
# [http://tavalisse.com/downloads/pdf/Full-Prescribing-Information.pdf Fostamatinib (Tavalisse) package insert]<br />
# Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018 Jan;10(1):9-25. [https://www.futuremedicine.com/doi/10.2217/imt-2017-0097?url_ver=Z39.88-2003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967793 PubMed]<br />
<br />
==Mycophenolate mofetil monotherapy {{#subobject:ddb338|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:850f1f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full Taylor et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Mycophenolate mofetil (CellCept)]] 1 gm per day<br />
<br />
===References===<br />
# Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, McGuckin S, Kothari J, Cooper N, Stasi R, Scully M. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol. 2015 Nov;171(4):625-30. Epub 2015 Aug 6. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26250874 PubMed]<br />
<br />
==Placebo== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Rituximab_monotherapy|Rituximab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|}<br />
<br />
''No active treatment; used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
# Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Rituximab monotherapy {{#subobject:d7d211|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:128a52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/112/4/999.long Godeau et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Patients in Godeau et al. 2008 had "ITP lasting 6 or more months before inclusion; at least 1 previous treatment for ITP; and platelet count less than 30 × 10<sup>9</sup>/L at inclusion" and were candidates for splenectomy."''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week<br />
<br />
====Supportive medications====<br />
*(per Godeau et al. 2008):<br />
*Patients received Streptococcus pneumoniae and Haemophilus influenzae vaccination at least 2 weeks before the first dose of [[Rituximab (Rituxan)]]<br />
*[[Acetaminophen (Tylenol)]] 1 g prior to [[Rituximab (Rituxan)]]<br />
*[[Methylprednisolone (Solumedrol)]] 60 mg IV prior to [[Rituximab (Rituxan)]]<br />
<br />
'''4-week course'''<br />
<br />
===References===<br />
# Godeau B, Porcher R, Fain O, Lefrère F, Fenaux P, Cheze S, Vekhoff A, Chauveheid MP, Stirnemann J, Galicier L, Bourgeois E, Haiat S, Varet B, Leporrier M, Papo T, Khellaf M, Michel M, Bierling P. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008 Aug 15;112(4):999-1004. [http://www.bloodjournal.org/content/112/4/999.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18463354 PubMed]<br />
# '''Prospective cohort:''' Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, Kanter J, Neufeld E, Taube T, Ramenghi U, Shenoy S, Ward MJ, Mihatov N, Patel VL, Bierling P, Lesser M, Cooper N, Bussel JB. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012 Jun 21;119(25):5989-95. [http://www.bloodjournal.org/content/119/25/5989.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383014/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22566601 PubMed]<br />
# Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
<br />
==Romiplostim monotherapy {{#subobject:a6df46|Regimen=1}}== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:8b8d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''Patients in '''Kuter et al. 2008''' were adults; some had undergone splenectomy. Patients in '''Tarantino et al. 2016''' were less than 18 years old at time of study entry.''<br />
====Growth factor therapy====<br />
*[[Romiplostim (Nplate)]] 1 mcg/kg SC once per week, with subsequent dose titration; see papers for details<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
<br />
[[Category:Immune thrombocytopenia (ITP) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Bleeding disorders]]<br />
[[Category:Cytopenias]]</div>
Benjamintillman
https://hemonc.org/w/index.php?title=Immune_thrombocytopenia&diff=28816
Immune thrombocytopenia
2018-07-19T23:12:59Z
<p>Benjamintillman: </p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--> <br />
<br />
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! colspan="4" align="center" style="color:white; font-size:125%; background-color:#31a354" |'''Section editors'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Shruti.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Shrutichaturvedi|Shruti Chaturvedi, MBBS, MSCI]]<br>Baltimore, MD</big><br>[https://www.linkedin.com/in/shruti-chaturvedi-bb83b126/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==ASH==<br />
*'''2011:''' [http://www.bloodjournal.org/content/117/16/4190 The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia]<br />
<br />
=Initial therapy=<br />
<br />
==Dexamethasone monotherapy {{#subobject:7c8c62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:666055|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
<br />
'''One course'''<br />
<br />
''If platelets remained below 30 x 10<sup>9</sup>/L or bleeding by day 10, course is repeated once.''<br />
<br />
===Variant #2 {{#subobject:678fa4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy, part 1====<br />
*[[Prednisone (Sterapred)]] 1 mg/kg/day for 7 days<br />
<br />
====Immunosuppressive therapy, part 2====<br />
*[[Dexamethasone (Decadron)]] 0.6 mg/kg/day for days 1 to 4<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===Variant #3 {{#subobject:19f4e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa030254 Cheng et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''4-day course'''<br />
<br />
''Patients who had an initial response, but whose platelets dropped below 30 x 10<sup>9</sup>/L within 6 months received:''<br />
<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 15 mg PO once per day starting on day 5, "with gradual tapering"<br />
<br />
===Variant #4, monthly dexamethasone {{#subobject:f892de|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*Patients who had platelet counts of less than or equal to 20 x 10<sup>9</sup>/L between cycles received [[Prednisone (Sterapred)]] 0.25 mg/kg PO once per day "between courses"<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #5, bi-weekly dexamethasone {{#subobject:8ac5fe|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Adults: 40 mg PO/IV once per day on days 1 to 4<br />
**Patients less than 15 years old: 20 mg/m<sup>2</sup> (maximum dose: 40 mg per day) PO/IV once per day on days 1 to 4<br />
**Patients who had platelet counts of less than or equal to 30 x 10<sup>9</sup>/L between cycles and/or who had bleeding related to thrombocytopenia received 0.035 mg/kg PO once per day "between courses"<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003 Aug 28;349(9):831-6. [http://www.nejm.org/doi/full/10.1056/NEJMoa030254 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12944568 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31. [http://www.bloodjournal.org/content/109/4/1401.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17077333 PubMed]<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==Dexamethasone & Eltrombopag {{#subobject:910687|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:470504|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/123/25/3906.long Gómez-Almaguer et al. 2014]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts reported<br />
|-<br />
|}<br />
====Therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day on days 5 to 33<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<!-- Presented in an abstract form at the 55th meeting of the American Society of Hematology, New Orleans, LA, December 2013. --><br />
# Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, Gómez-De León A, Cantú-Rodríguez OG, Gutiérrez-Aguirre CH, Tarín-Arzaga L, Hernández-Reyes J, Ruiz-Arguelles GJ. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014 Jun 19;123(25):3906-8. Epub 2014 May 6. [http://www.bloodjournal.org/content/123/25/3906.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24802773 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:b9a6ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen ("R+3Dex") {{#subobject:d05adc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract: Retrospective:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
== Intravenous immunoglobuin ==<br />
{| class="wikitable"<br />
!Study<br />
!Evidence<br />
!Comparator<br />
!Efficacy<br />
|-<br />
|Godeau et al. 1999<br />
|Phase III<br />
|0.5g/kg IVIG<br />
|Higher response<br />
|}<br />
Therapy<br />
* Intravenous immunoglobulin (IVIG) 1gm/kg body weight on day 1<br />
References<br />
# Bertrand Godeau, Marie-Therese Caulier, Laurent Decuypere, Christian Rose, Annette Schaeffer, and Philippe Bierling for the Groupe d'Etude du Traitement du PTAI. British Journal of Hematology. 1999; 107: 716-719. [https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2141.1999.01766.x Link to article] [https://www.ncbi.nlm.nih.gov/pubmed?term=10606875 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:5f27f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:d3c7eb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 28<br />
**Afterwards, tapered over 4 to 6 weeks with a goal of maintenance dosing less than 15 mg/day or "complete termination"<br />
***Taper schedule determined by treating physician<br />
<br />
===Variant #2 {{#subobject:7c003e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**1 mg/kg/day PO on days 1 to 14<br />
**Afterwards, tapered over 19 weeks with a goal of maintenance dosing less than 7.5 mg/day at the end of week 19<br />
<br />
===References===<br />
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]<br />
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26480931 PubMed]<br />
<br />
==RhIG monotherapy {{#subobject:3ab9b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RhIG: '''<u>Rh</u>'''o(D) '''<u>I</u>'''mmune '''<u>G</u>'''lobulin<br />
===Variant #1, 25 mcg/kg {{#subobject:8335a6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/77/9/1884 Bussel et al. 1991]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Eligibility: RhD-positive.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 25 mcg/kg IV once on day 1, repeated as needed on days 3 & 4<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 50 mcg/kg {{#subobject:487067|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (C)<br />
|Rho(D) 75 mcg/kg <br />
| style="background-color:#fc8d59" |Seems to have inferior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 50 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===Variant #3, 75 mcg/kg {{#subobject:b30788|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full Newman et al. 2001]<br />
| style="background-color:#91cf61" |Randomized Phase II, <20 pts (E)<br />
|Rho(D) 50 mcg/kg <br />
| style="background-color:#91cf60" |Seems to have superior platelet effect<br />
|-<br />
|}<br />
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''<br />
====Therapy====<br />
*[[Rho(D) immune globulin (RhoGAM)]] 75 mcg/kg IV once<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once prior to therapy<br />
*[[Prednisone (Sterapred)]] 20 mg PO once prior to therapy<br />
<br />
'''Can be repeated if required to increase platelet count'''<br />
<br />
===References===<br />
# Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;77(9):1884-93. [http://www.bloodjournal.org/content/77/9/1884 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1850307 PubMed] <br />
# Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/d of iv anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol. 2001 Mar;112(4):1076-8. [https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02627.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11298610 PubMed]<br />
<br />
==TT4 {{#subobject:d5ad89|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
TT4: '''<u>T</u>'''riple '''<u>T</u>'''herapy (4?)<br />
<br />
===Regimen {{#subobject:be2a8d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ Choi et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4<br />
*[[:Category:Cyclosporines|Cyclosporine A]] 2.5 to 3 mg/kg/day on days 1 to 28<br />
**Dose adjusted for target trough of 200 to 400 mcg/L<br />
*[[Rituximab (Rituxan)]] 100 mg IV once per day on days 7, 14, 21, 28<br />
<br />
===References===<br />
# Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015 Jul 23;126(4):500-3. Epub 2015 May 13. [http://www.bloodjournal.org/content/126/4/500.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25972158 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==ATRA & Danazol {{#subobject:43e110|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:077574|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#Danazol_monotherapy|Danazol]]<br />
| style="background-color:#1a9850" |Superior 12-month sustained response<br />
|-<br />
|}<br />
====Therapy====<br />
*[[All-trans retinoic acid (ATRA)]] 10 mg PO BID<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Cyclosporine monotherapy {{#subobject:4d3847|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:df1b55|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/4/1482 Emilia et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
<br />
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''<br />
====Immunosuppressive therapy====<br />
*[[:Category:Cyclosporines|Cyclosporine A]] as follows:<br />
**5 mg/kg/day PO split into twice daily dosing for 6 days, then<br />
**2.5 to 3 mg/kg/day with dose adjusted for target trough of 200 to 400 mcg/L<br />
<br />
===References===<br />
# Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, Ferrara L, D'Apollo N, Potenza L, Bertesi M, Torelli G. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002 Feb 15;99(4):1482-5. [http://www.bloodjournal.org/content/99/4/1482 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11830504 PubMed]<br />
<br />
==Danazol monotherapy {{#subobject:e7bf80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9a63e6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJM198306093082306 Ahn et al. 1983]<br />
| style="background-color:#91cf61" |Pilot, >20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext Feng et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#ATRA_.26_Danazol|ATRA & Danazol]]<br />
| style="background-color:#d73027" |Inferior 12-month sustained response<br />
|-<br />
|}<br />
''Note: Ahn et al. 1983 gave a range of 200 mg PO from two to four times per day; the dose below is from Feng et al. 2017''<br />
====Endocrine therapy====<br />
*[[Danazol (Danocrine)]] 200 mg PO BID<br />
<br />
'''16-week course'''<br />
<br />
===References===<br />
# Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983 Jun 9;308(23):1396-9. [http://www.nejm.org/doi/full/10.1056/NEJM198306093082306 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6682484 PubMed]<br />
# Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30170-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28917657 PubMed]<br />
<br />
==Dexamethasone monotherapy {{#subobject:a6cd06|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8c260f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJM199406023302203 Andersen et al. 1994]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles for 6 cycles'''<br />
<br />
===References===<br />
# Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994 Jun 2;330(22):1560-4. [http://www.nejm.org/doi/full/10.1056/NEJM199406023302203 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8177245 PubMed]<br />
<br />
==Dexamethasone & Rituximab {{#subobject:52f32|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen ("R+3Dex") {{#subobject:abae3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Dexamethasone (Decadron)]] 28 mg/m2/day (max dose of 40 mg) on days 1 to 4, repeated every 2 weeks for 3 cycles<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week on weeks 1 to 4<br />
<br />
===References===<br />
# '''Abstract:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]<br />
<br />
==Eltrombopag monotherapy {{#subobject:170bd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:90336c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''This regimen was intended for pediatric patients.''<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] with starting dose as follows:<br />
**Age 6 to 17, weighing at least 27kg, non-east Asian: 50 mg PO once per day<br />
**Age 6 to 17, weighing at least 27kg, east Asian: 25 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, non-east Asian: 37.5 mg PO once per day<br />
**Age 6 to 17, weighing less than 27kg, east Asian: 25 mg PO once per day<br />
**Age 1 to 5, non-east Asian: 1.2 mg/kg/day oral suspension<br />
**Age 1 to 5, east Asian: 0.8 mg/kg/day oral suspension<br />
<br />
'''Dose adjusted to a maximum of 75 mg/day, with temporary discontinuation for platelet count greater than 400 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #2 {{#subobject:5912e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa073275 Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior plt count of greater than or equal to 50 x 10<sup>9</sup>/L on day 43<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg (starting dose) PO once per day<br />
<br />
'''The dose could be increased from 50 mg to 75 mg after 3 weeks in patients whose platelet counts were less than 50 x 10<sup>9</sup>/L. Treatment was discontinued in patients who attained a platelet count greater than 200 x 10<sup>9</sup>/L'''<br />
<br />
===Variant #3 {{#subobject:9ac7d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with dose modifications:<br />
**Increase to 75 mg PO once per day allowed after day 22 for patients with platelet counts lower than 50 x 10<sup>9</sup>/L<br />
**Decrease to 25 mg PO once per day required for platelets counts between 200 and 400 x 10<sup>9</sup>/L<br />
**Drug was held for platelet count greater than 400 x 10<sup>9</sup>/L, until platelet count dropped below 150 x 10<sup>9</sup>/L<br />
<br />
'''6-month course'''<br />
<br />
===Variant #4 {{#subobject:b1f517|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2007]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RR<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day<br />
<br />
'''Up to 6-week course'''<br />
<br />
===Variant #5 {{#subobject:55f69d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/121/3/537.long Saleh et al. 2012 (EXTEND)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Growth factor therapy====<br />
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with adjustments:<br />
<br />
''Dose and schedule were individualized with the goal of achieving and maintaining platelets between 50 and 200 x 10<sup>9</sup>/L.''<br />
<br />
===References===<br />
# Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. [http://www.nejm.org/doi/full/10.1056/NEJMoa073275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18046028 PubMed] <br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''EXTEND:''' Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. Epub 2012 Nov 20. [http://www.bloodjournal.org/content/121/3/537.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23169778 PubMed]<br />
# '''PETIT2:''' Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Fostamatinib monotherapy {{#subobject:ddb228|Regimen=1}}==<br />
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|-<br />
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|}<br />
<br />
===Regimen {{#subobject:85221f|Variant=1}}===<br />
<br />
====Therapy====<br />
*[[Fostamatinib (Tavalisse)]] 100 mg PO twice per day <br />
**Dose may be increased to 150 mg PO twice per day after 4 weeks if needed to achieve platelet count of at least 50<br />
<br />
===References===<br />
# [http://tavalisse.com/downloads/pdf/Full-Prescribing-Information.pdf Fostamatinib (Tavalisse) package insert]<br />
# Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018 Jan;10(1):9-25. [https://www.futuremedicine.com/doi/10.2217/imt-2017-0097?url_ver=Z39.88-2003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967793 PubMed]<br />
# Publications describing results for the FIT-1 (NCT02076399) and FIT-2 (NCT02076412) trial could not be found<br />
<br />
==Mycophenolate mofetil monotherapy {{#subobject:ddb338|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:850f1f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full Taylor et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
*[[Mycophenolate mofetil (CellCept)]] 1 gm per day<br />
<br />
===References===<br />
# Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, McGuckin S, Kothari J, Cooper N, Stasi R, Scully M. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol. 2015 Nov;171(4):625-30. Epub 2015 Aug 6. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13622/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26250874 PubMed]<br />
<br />
==Placebo== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext Bussel et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext Cheng et al. 2010 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior RR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Rituximab_monotherapy|Rituximab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext Grainger et al. 2015 (PETIT2)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Eltrombopag_monotherapy|Eltrombopag]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Romiplostim_monotherapy|Romiplostim]]<br />
| style="background-color:#d73027" |Inferior durable platelet response<br />
|-<br />
|}<br />
<br />
''No active treatment; used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60402-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19231632 PubMed]<br />
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60959-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739054 PubMed]<br />
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
# Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61107-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26231455 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14380/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27734464 PubMed]<br />
<br />
==Rituximab monotherapy {{#subobject:d7d211|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:128a52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/112/4/999.long Godeau et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext Ghanima et al. 2015 (RITP)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Autoimmune_thrombocytopenic_purpura_(ITP)#Placebo|Placebo]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Patients in Godeau et al. 2008 had "ITP lasting 6 or more months before inclusion; at least 1 previous treatment for ITP; and platelet count less than 30 × 10<sup>9</sup>/L at inclusion" and were candidates for splenectomy."''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per week<br />
<br />
====Supportive medications====<br />
*(per Godeau et al. 2008):<br />
*Patients received Streptococcus pneumoniae and Haemophilus influenzae vaccination at least 2 weeks before the first dose of [[Rituximab (Rituxan)]]<br />
*[[Acetaminophen (Tylenol)]] 1 g prior to [[Rituximab (Rituxan)]]<br />
*[[Methylprednisolone (Solumedrol)]] 60 mg IV prior to [[Rituximab (Rituxan)]]<br />
<br />
'''4-week course'''<br />
<br />
===References===<br />
# Godeau B, Porcher R, Fain O, Lefrère F, Fenaux P, Cheze S, Vekhoff A, Chauveheid MP, Stirnemann J, Galicier L, Bourgeois E, Haiat S, Varet B, Leporrier M, Papo T, Khellaf M, Michel M, Bierling P. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008 Aug 15;112(4):999-1004. [http://www.bloodjournal.org/content/112/4/999.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18463354 PubMed]<br />
# '''Prospective cohort:''' Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, Kanter J, Neufeld E, Taube T, Ramenghi U, Shenoy S, Ward MJ, Mihatov N, Patel VL, Bierling P, Lesser M, Cooper N, Bussel JB. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012 Jun 21;119(25):5989-95. [http://www.bloodjournal.org/content/119/25/5989.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383014/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22566601 PubMed]<br />
# Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61495-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25662413 PubMed]<br />
<br />
==Romiplostim monotherapy {{#subobject:a6df46|Regimen=1}}== <br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:8b8d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract Kuter et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext Tarantino et al. 2016]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior durable platelet response<br />
|-<br />
|}<br />
''Patients in '''Kuter et al. 2008''' were adults; some had undergone splenectomy. Patients in '''Tarantino et al. 2016''' were less than 18 years old at time of study entry.''<br />
====Growth factor therapy====<br />
*[[Romiplostim (Nplate)]] 1 mcg/kg SC once per week, with subsequent dose titration; see papers for details<br />
<br />
===References===<br />
# Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60203-2/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18242413 PubMed]<br />
# Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00279-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27103127 PubMed]<br />
<br />
[[Category:Autoimmune thrombocytopenic purpura (ITP) regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Autoimmune hematologic conditions]]<br />
[[Category:Bleeding disorders]]<br />
[[Category:Cytopenias]]</div>
Benjamintillman