Difference between revisions of "Venous thromboembolism"
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| style="background-color:#eeee01" |Non-inferior recurrent VTE rate | | style="background-color:#eeee01" |Non-inferior recurrent VTE rate | ||
| style="background-color:#d73027" |Higher rates of bleeding | | style="background-color:#d73027" |Higher rates of bleeding | ||
+ | |- | ||
+ | |[https://doi.org/10.1001/jama.2015.9243 Lee et al. 2015 (CATCH)] | ||
+ | | style="background-color:#1a9851" |Phase III (C) | ||
+ | |[[#Tinzaparin_monotherapy|Tinzaparin]] | ||
+ | | style="background-color:#fee08b" |Might have inferior composite outcome | ||
+ | | style="background-color:#ffffbf" |Similar major bleeding | ||
|- | |- | ||
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##'''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://pubmed.ncbi.nlm.nih.gov/27476789 PubMed] | ##'''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://pubmed.ncbi.nlm.nih.gov/27476789 PubMed] | ||
#'''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://pubmed.ncbi.nlm.nih.gov/24344086 PubMed] NCT00680186 | #'''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://pubmed.ncbi.nlm.nih.gov/24344086 PubMed] NCT00680186 | ||
− | #'''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. [ | + | #'''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. [https://doi.org/10.1001/jama.2015.9243 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26284719 PubMed] NCT01130025 |
=Additional information= | =Additional information= |
Revision as of 12:03, 14 September 2021
Section editor | |
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Benjamin Tillman, MD Vanderbilt University Nashville, TN |
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).
Other pages on HemOnc.org regarding management of deep vein thrombosis (DVT) and pulmonary embolism (PE) include:
- Bleeding with anticoagulation
- Deep veins and superficial veins in the arms and legs
- Hypercoagulable state (thrombophilia) evaluation
- Compression stockings and sleeves for management and prophylaxis against postphlebitic (postthrombotic) syndrome[1]
24 regimens on this page
30 variants on this page
|
Guidelines
ACCP
ASCO
- 2019: Key et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. PubMed
Older
- 2015: Lyman et al. ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update
- 2013: Lyman et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
- 2007: Lyman et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. PubMed
ASH
- 2021: Lyman et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer
- 2020: Ortel et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism
- 2019: Anderson et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients
- 2018: Schünemann et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients
- 2018: Lim et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism
- 2018: Witt et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy
- 2018: Monagle et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism
- 2018: Bates et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy
- 2018: Cuker et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia
ESMO
- 2010: Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management PubMed
"How I Treat"
- 2020: Klok & Huisman. How I assess and manage the risk of bleeding in patients treated for venous thromboembolism
- 2020: Middeldorp & Ganzevoort. How I treat venous thromboembolism in pregnancy
- 2020: Wang & Carrier. How I treat obese patients with oral anticoagulants
- 2019: Pabinger & Thaler. How I treat patients with hereditary antithrombin deficiency
IMWG
Current
- IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma
Older
ITAC-CME
- 2016: International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer PubMed
VTE primary prophylaxis
Apixaban monotherapy
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Regimen variant #1, 10-14 days post-op
FDA-recommended dose |
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Lassen et al. 2009 (ADVANCE-1)] | Phase III (E-switch-ic) | Enoxaparin | Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment | Seems to have lower bleeding rate |
Lassen et al. 2010 (ADVANCE-2) | Phase III (E-switch-ic) | Enoxaparin | Superior composite endpoint | Might have lower bleeding rate |
Preceding treatment
- Total knee replacement
Anticoagulation
- Apixaban (Eliquis) 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure
10- to 14-day course
Regimen variant #2, 35 days post-op
FDA-recommended dose |
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Lassen et al. 2010 (ADVANCE-3) | Phase III (E-switch-ic) | Enoxaparin | Superior composite endpoint | Did not meet endpoint of major and clinically relevant nonmajor bleeding |
Preceding treatment
- Total hip replacement
Anticoagulation
- Apixaban (Eliquis) 2.5 mg PO twice per day, beginning 12 to 24 h after wound closure
35-day course
Regimen variant #3, 180 days
FDA-recommended dose |
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Carrier et al. 2018 (AVERT) | Phase III (E-esc) | Placebo | Superior VTE rate | Seems to have higher rate of bleeding |
Anticoagulation
- Apixaban (Eliquis) 2.5 mg PO twice per day, beginning within 24 h of initiation of chemotherapy
6-month course
References
- 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. link to original article contains protocol PubMed NCT00371683
- 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. link to original article contains protocol PubMed NCT00452530
- 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. link to original article PubMed NCT00423319
- 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. link to original article contains verified protocol PubMed NCT02048865
Aspirin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Rodgers et al. 2000 (PEP) | Phase III (E-esc) | Placebo | Superior VTE rate |
Landolfi et al. 2004 (ECLAP) | Phase III (E-esc) | Placebo | Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes |
Palumbo et al. 2011 (GIMEMA MM-03-05) | Phase III (E-switch-ic) | 1. Enoxaparin 2. Warfarin; low-dose |
Did not meet primary endpoint of serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment |
Larocca et al. 2011 (MPRvsMEL200) | Phase III (E-de-esc) | Enoxaparin | Did not meet primary endpoint of VTE incidence |
Anderson et al. 2013 (EPCAT) | Phase III (E-de-esc) | Dalteparin | Non-inferior VTE rate at 90 days |
Anderson et al. 2018 (EPCAT II) | Phase III (E-de-esc) | Rivaroxaban | Non-inferior VTE rate at 90 days |
Anticoagulation
- Aspirin 81 to 160 mg PO once per day
Various durations, see individual trials
References
- 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. link to original article PubMed
- 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. link to original article PubMed
- GIMEMA MM-03-05: 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. link to original article PubMed NCT01063179
- MPRvsMEL200: 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. link to original article PubMed NCT00551928
- 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. link to original article PubMed ISRCTN11902170
- 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. link to original article PubMed NCT01720108
Betrixaban monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cohen et al. 2016 (APEX-VTE) | Phase III (E-switch-ic) | Enoxaparin | Might have lower rates of VTE |
Note: this APEX trial should not be confused with the one in multiple myeloma.
Anticoagulation
- Betrixaban (Bevyxxa) 80 mg PO once per day
References
- 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. link to original article PubMed NCT01583218
Enoxaparin monotherapy
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Regimen variant #1, 30 mg every 12 hours
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Geerts et al. 1996 | Phase III (E-switch-ic) | UFH | Superior DVT rates | No difference in major bleeding rate |
Lassen et al. 2009 (ADVANCE-1)] | Phase III (C) | Apixaban | Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment | Seems to have higher bleeding rate |
Preceding treatment
- Total knee replacement (ADVANCE-1)
- The study population in Geerts et. al. were trauma patients without intracranial hemorrhage. Prophylaxis was initiated within 36 hours of the injury.
Anticoagulation
- Enoxaparin (Lovenox) 30 mg SC every 12 hours, beginning 12 to 24 h after wound closure (ADVANCE-1), 10- to 14-day course
- The comparison arm in Geerts et al. used heparin 5000 units subcutaneous every 12 hours.
Regimen variant #2, 40 mg daily
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Samama et al. 1999 (MEDENOX) | Phase III (C) | 1. Placebo 2. Enoxaparin; 20 mg daily |
Superior VTE rates |
Kakkar et al. 2008 (RECORD2) | Phase III (C) | Rivaroxaban | Inferior composite outcome |
Erikkson et al. 2008 (RECORD1) | Phase III (C) | Rivaroxaban | Inferior composite outcome |
Lassen et al. 2008 (RECORD3) | Phase III (C) | Rivaroxaban | Inferior composite outcome |
Turpie et al. 2009 (RECORD4) | Phase III (C) | Rivaroxaban | Seems to have inferior composite outcome |
Lassen et al. 2010 (ADVANCE-2) | Phase III (C) | Apixaban | Inferior composite outcome |
Hull et al. 2010 (EXCLAIM) | Phase III (E-esc) | Placebo | Superior composite VTE rate |
Lassen et al. 2010 (ADVANCE-3) | Phase III (C) | Apixaban | Inferior composite outcome |
Palumbo et al. 2011 (GIMEMA MM-03-05) | Phase III (E-switch-ic) | 1. Aspirin 2. Warfarin; low-dose |
Did not meet primary endpoint of serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment |
Larocca et al. 2011 (MPRvsMEL200) | Phase III (E-esc) | Aspirin | Did not meet primary endpoint of VTE incidence |
Goldhaber et al. 2011 (ADOPT) | Phase III (C) | Apixaban | 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 |
Kakkar et al. 2011 (LIFENOX) | Phase III (E-esc) | Placebo | Did not meet primary endpoint of death rate at 30 days |
Cohen et al. 2013 (MAGELLAN) | Phase III (C) | Rivaroxaban | Non-inferior VTE rate at 10 days |
Cohen et al. 2016 (APEX-VTE) | Phase III (C) | Betrixaban | Might have higher rates of VTE |
Note: the APEX trial here should not be confused with the one in multiple myeloma.
Preceding treatment
- ADVANCE-2: Total knee replacement
- ADVANCE-3: Total hip replacement
Anticoagulation
- Enoxaparin (Lovenox) 40 mg SC once per day
Various durations (see papers for details)
References
- 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. link to original article PubMed
- 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. link to original article. PubMed.
- 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. link to original article PubMed NCT00332020
- 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. link to original article PubMed NCT00329628
- 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. link to original article PubMed NCT00361894
- 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. link to original article PubMed NCT00362232
- 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. link to original article contains protocol PubMed NCT00371683
- 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. link to original article contains protocol PubMed NCT00452530
- 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. link to original article PubMed NCT00077753
- 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. link to original article contains protocol PubMed NCT00423319
- GIMEMA MM-03-05: 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. link to original article PubMed NCT01063179
- MPRvsMEL200: 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. link to original article PubMed NCT00551928
- 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. link to original article PubMed NCT00457002
- 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. link to original article PubMed NCT00622648
- 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. link to original article PubMed NCT00571649
- 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. link to original article PubMed NCT01583218
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gärdlund et al. 1996 | Phase III (C) | UFH; SC | Did not meet primary endpoint of necropsy-verified pulmonary embolism of predefined clinical relevance |
Hull et al. 2010 (EXCLAIM) | Phase III (C) | Enoxaparin | Inferior composite VTE rate |
Kakkar et al. 2011 (LIFENOX) | Phase III (C) | Enoxaparin | Did not meet primary endpoint of death rate at 30 days |
Spyropoulos et al. 2018 (MARINER) | Phase III (C) | Rivaroxaban | Did not meet primary endpoint of symptomatic VTE or death due to VTE |
Khorana et al. 2019 (CASSINI) | Phase III (C) | Rivaroxaban | 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 |
No active treatment.
References
- 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. link to original article PubMed
- 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. link to original article PubMed NCT00077753
- 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. link to original article PubMed NCT00622648
- 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. link to original article PubMed NCT02111564
- 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. link to original article PubMed NCT02555878
Rivaroxaban monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kakkar et al. 2008 (RECORD2) | Phase III (E-switch-ic) | Enoxaparin | Superior composite outcome |
Erikkson et al. 2008 (RECORD1) | Phase III (E-switch-ic) | Enoxaparin | Superior composite outcome |
Lassen et al. 2008 (RECORD3) | Phase III (E-switch-ic) | Enoxaparin | Superior composite outcome |
Turpie et al. 2009 (RECORD4) | Phase III (E-switch-ic) | Enoxaparin | Seems to have superior composite outcome |
Cohen et al. 2013 (MAGELLAN) | Phase III (E-switch-ic) | Enoxaparin | Non-inferior VTE rate at 10 days |
Anderson et al. 2018 (EPCAT II) | Phase III (E-esc) | Aspirin | Non-inferior VTE rate at 90 days |
Spyropoulos et al. 2018 (MARINER) | Phase III (E-esc) | Placebo | Did not meet primary endpoint of symptomatic VTE or death due to VTE |
Anticoagulation
- Rivaroxaban (Xarelto) 10 mg PO once per day for varying durations (see individual studies)
References
- 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. link to original article PubMed NCT00332020
- 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. link to original article PubMed NCT00329628
- 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. link to original article PubMed NCT00361894
- 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. link to original article PubMed NCT00362232
- 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. link to original article PubMed NCT00571649
- 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. link to original article PubMed NCT01720108
- 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. link to original article PubMed NCT02111564
VTE secondary prevention
Apixaban monotherapy
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Regimen variant #1, 2.5 mg twice per day
FDA-recommended dose |
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Agnelli et al. 2012 (AMPLIFY-EXT) | Phase III (E-esc) | 1. Apixaban; 5 mg twice per day | Did not meet primary endpoint of symptomatic recurrent VTE or death from any cause |
2. Placebo | Superior symptomatic recurrent VTE or death from any cause |
Preceding treatment
- Therapeutic anticoagulation x 6-12 mo
Anticoagulation
- Apixaban (Eliquis) 2.5 mg PO twice per day
12-month course
Regimen variant #2, 5 mg twice per day
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Agnelli et al. 2012 (AMPLIFY-EXT) | Phase III (E-esc) | 1. Apixaban; 2.5 mg twice per day | Did not meet primary endpoint of symptomatic recurrent VTE or death from any cause |
2. Placebo | Superior symptomatic recurrent VTE or death from any cause |
Preceding treatment
- Therapeutic anticoagulation x 6-12 mo
Anticoagulation
- Apixaban (Eliquis) 5 mg PO twice per day
12-month course
References
- 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. link to original article contains verified protocol PubMed
Aspirin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Becattini et al. 2012 (WARFASA) | Phase III (E-esc) | Placebo | Superior rate of VTE recurrence | No difference in bleeding rate |
Brighton et al. 2012 (ASPIRE-VTE) | Phase III (E-esc) | Placebo | Might have superior rate of VTE recurrence | No difference in bleeding rate |
Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.
Preceding treatment
Anticoagulation
- Aspirin 100 mg PO once per day
Two or more years
References
- 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. link to original article contains protocol PubMed NCT00222677
- ASPIRE-VTE: 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. link to original article PubMed ACTRN12605000004662
Dalteparin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Lee et al. 2003 (CLOT) | Phase III (E-switch-ic) | Warfarin | Superior rate of VTE at 6 months | No difference in bleeding rate |
Anticoagulation
- Dalteparin (Fragmin) as follows:
- Month 1: 200 IU/kg SC once per day
- Months 2 to 6: 150 IU/kg SC once per day
6-month course
References
- 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. link to original article PubMed
- 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. link to original article PubMed
Enoxaparin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Meyer et al. 2002 | Phase III (E-switch-ic) | Warfarin | Might have superior combined VTE/bleeding outcome |
Anticoagulation
- Enoxaparin (Lovenox) 1.5 mg/kg SC once per day
3-month course
References
- 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. link to original article contains protocol PubMed
Warfarin monotherapy
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Regimen variant #1, standard intensity
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Meyer et al. 2002 | Phase III (C) | Enoxaparin | Might have inferior combined VTE/bleeding outcome | |
Lee et al. 2003 (CLOT) | Phase III (C) | Dalteparin | Inferior rate of VTE at 6 months | No difference in bleeding rate |
Anticoagulation
- Warfarin (Coumadin) PO titrated to goal INR 2 to 3.0
Regimen variant #2, low intensity
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Ridker et al. 2003 (PREVENT) | Phase III (E-esc) | Placebo | Superior recurrent VTE rate | No difference in major bleeding |
Preceding treatment
- Warfarin with goal INR of 2 to 3 for median of 6.5 mo
Anticoagulation
- Warfarin (Coumadin) PO titrated to goal INR 1.5 to 2.0
Continued indefinitely
References
- 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. link to original article PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article PubMed
- 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. link to original article PubMed
VTE treatment, all lines of therapy
Apixaban monotherapy
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Regimen
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Agnelli et al. 2013 (AMPLIFY) | Phase III (E-switch-ic) | Warfarin | Non-inferior composite endpoint | Lower rates of bleeding |
Angelli et al. 2020 (CARAVAGGIO) | Phase III (E-switch-ic) | Dalteparin | Non-inferior recurrent VTE | Major bleeding similar in both groups |
Anticoagulation
- Apixaban (Eliquis) 10 mg PO twice per day for 7 days, then 5 mg PO twice per day
6-month course
References
- 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. link to original article contains verified protocol PubMed NCT00643201
- CARAVAGGIO: Agnelli 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. Epub 2020 Mar 29. link to original article PubMed NCT03045406
Argatroban monotherapy
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Regimen
Anticoagulation
References
To be completed
Aspirin monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Weitz et al. 2017 (EINSTEIN CHOICE) | Phase III (C) | 1. Rivaroxaban; 10 mg/day | Inferior symptomatic recurrent VTE rate | Similar major bleeding |
2. Rivaroxaban; 20 mg/day | Inferior symptomatic recurrent VTE rate | Similar major bleeding |
Preceding treatment
- 6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant
Anticoagulation
- Aspirin 100 mg PO once per day
Up to 12-month course
References
- 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. link to original article contains verified protocol PubMed NCT02064439
Bivalirudin monotherapy
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Regimen
Anticoagulation
References
To be completed
Dabigatran monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Schulman et al. 2009 (RE-COVER) | Phase III (E-switch-ic) | Warfarin | Non-inferior composite endpoint | Similar major bleeding |
Anticoagulation
- Dabigatran (Pradaxa) 150 mg PO twice per day
6-month course
References
- 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. link to original article contains verified protocol PubMed NCT00291330
- 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. link to original article PubMed NCT00329238
- 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. link to original article PubMed NCT00680186
- DIVERSITY: Halton J, Brandão LR, Luciani M, Bomgaars L, Chalmers E, Mitchell LG, Nurmeev I, Sharathkumar A, Svirin P, Gorbatikov K, Tartakovsky I, Simetzberger M, Huang F, Sun Z, Kreuzer J, Gropper S, Reilly P, Brueckmann M, Albisetti M; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021 Jan;8(1):e22-e33. Epub 2020 Dec 5. link to original article PubMed NCT01895777
Dalteparin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Francis et al. 2015 (DALTECAN) | Non-randomized | |||
Raskob et al. 2017 (Hokusai VTE Cancer) | Phase III (C) | Edoxaban | Non-inferior composite endpoint of VTE/major bleeding | Non-inferior composite endpoint of VTE/major bleeding |
Young et al. 2018 (SELECT-D) | Phase III (C) | Rivaroxaban | Seems to have inferior rate of VTE recurrence | Superior rates of clinically relevant non-major bleeding |
Angelli et al. 2020 (CARAVAGGIO) | Phase III (C) | Apixaban | Non-inferior recurrent VTE | Major bleeding similar in both groups |
Anticoagulation
- Dalteparin (Fragmin) as follows:
- First month: 200 IU/kg once per day
- Subsequent months: 150 IU/kg once per day
6- to 12-month course
References
- 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. link to original article PubMed NCT00942968
- 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. link to original article contains protocol PubMed NCT02073682
- 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. link to original article contains protocol PubMed ISRCTN86712308
- CARAVAGGIO: Agnelli 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. Epub 2020 Mar 29. link to original article PubMed NCT03045406
Edoxaban monotherapy
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Regimen variant #1, reduced dose
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Büller et al. 2013 (Hokusai-VTE) | Phase III (E-switch-ic) | Warfarin | Non-inferior recurrent VTE rate | Superior rate of bleeding |
Raskob et al. 2017 (Hokusai VTE Cancer) | Phase III (E-switch-ic) | Dalteparin | Non-inferior composite endpoint of VTE/major bleeding | Non-inferior composite endpoint of VTE/major bleeding |
Note: this dose was used for patients with CrCl of 30 to 50 mL/min/1.73m2, a body weight of up to 60 kg, or those taking "potent" P-glycoprotein inhibitors.
Anticoagulation
- Therapeutic dose LMWH for at least 5 days, then:
- Edoxaban (Savaysa) 30 mg PO once per day
3- to 12-month course
Regimen variant #2, normal dosing
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Büller et al. 2013 (Hokusai-VTE) | Phase III (E-switch-ic) | Warfarin | Non-inferior recurrent VTE rate | Lower rates of bleeding |
Raskob et al. 2017 (Hokusai VTE Cancer) | Phase III (E-switch-ic) | Dalteparin | Non-inferior composite endpoint of VTE/major bleeding | Non-inferior composite endpoint of VTE/major bleeding |
Anticoagulation
- Therapeutic dose LMWH for at least 5 days, then:
- Edoxaban (Savaysa) 60 mg PO once per day
3- to 12-month course
References
- 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. link to original article contains verified protocol PubMed NCT00986154
- 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. link to original article PubMed
- 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. link to original article contains protocol PubMed NCT02073682
Enoxaparin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kearon et al. 2006 (FIDO) | Phase III (E-switch-ic) | 1. Dalteparin 2. UFH |
No difference in recurrent VTE or major bleeding |
Anticoagulation
- Enoxaparin (Lovenox) SC 100 IU/kg every 12 hours
References
- 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. link to original article PubMed NCT00182403
Fondaparinux monotherapy
back to top |
Regimen
Anticoagulation
References
To be completed
Heparin monotherapy
back to top |
UFH: UnFractionated Heparin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Loewe & Hirsch 1947 | Observational | None | 2.4% fatality rate due to pulmonary embolism |
Kearon et al. 2006 (FIDO) | Phase III (C) | 1. Dalteparin 2. Enoxaparin |
No difference in recurrent VTE or major bleeding |
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.
Anticoagulation
- Unfractionated heparin (UFH) SC 333 units/kg once, then 250 units/kg every 12 hours
References
- Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. link to original article PubMed
- 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. link to original article PubMed NCT00182403
Lepirudin monotherapy
back to top |
Regimen
Anticoagulation
References
To be completed
Rivaroxaban monotherapy
back to top |
Regimen variant #1, 10 mg/day
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Weitz et al. 2017 (EINSTEIN CHOICE) | Phase III (E-esc) | 1. Aspirin | Superior symptomatic recurrent VTE rate | Similar major bleeding |
2. Rivaroxaban; 20 mg/day | Did not meet primary endpoint of symptomatic recurrent VTE rate | Similar major bleeding |
Preceding treatment
- 6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant
Anticoagulation
- Rivaroxaban (Xarelto) 10 mg PO once per day
Up to 12-month course
Regimen variant #2, 20 mg/day
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Weitz et al. 2017 (EINSTEIN CHOICE) | Phase III (E-esc) | 1. Aspirin | Superior symptomatic recurrent VTE rate | Similar major bleeding |
2. Rivaroxaban; 10 mg/day | Did not meet primary endpoint of symptomatic recurrent VTE rate | Similar major bleeding |
Preceding treatment
- 6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant
Anticoagulation
- Rivaroxaban (Xarelto) 20 mg PO once per day
Up to 12-month course
Regimen variant #3, 20 mg/day with loading dose
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Bauersachs et al. 2010 (EINSTEIN Acute DVT) | Phase III (E-switch-ic) | Warfarin | Non-inferior VTE recurrence | Similar major bleeding |
Büller et al. 2012 (EINSTEIN-PE) | Phase III (E-switch-ic) | Warfarin | Non-inferior symptomatic VTE recurrence | Similar major bleeding |
Young et al. 2018 (SELECT-D) | Phase III (E-switch-ic) | Dalteparin | Seems to have superior rate of VTE recurrence | Inferior rates of clinically relevant non-major bleeding |
Anticoagulation
- Rivaroxaban (Xarelto) 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day
3-, 6-, or 12-month course
References
- 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. link to original article contains verified protocol PubMed NCT00440193; NCT00439725
- 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. link to original article contains protocol PubMed NCT00439777
- 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. link to original article PubMed NCT01619007
- 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. link to original article PubMed NCT02064439
- 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. link to original article contains protocol PubMed ISRCTN86712308
- EINSTEIN Junior: Male C, Lensing AWA, Palumbo JS, Kumar R, Nurmeev I, Hege K, Bonnet D, Connor P, Hooimeijer HL, Torres M, Chan AKC, Kenet G, Holzhauer S, Santamaría A, Amedro P, Chalmers E, Simioni P, Bhat RV, Yee DL, Lvova O, Beyer-Westendorf J, Biss TT, Martinelli I, Saracco P, Peters M, Kállay K, Gauger CA, Massicotte MP, Young G, Pap AF, Majumder M, Smith WT, Heubach JF, Berkowitz SD, Thelen K, Kubitza D, Crowther M, Prins MH, Monagle P; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e18-e27. Epub 2019 Nov 5. link to original article PubMed NCT02234843
Tinzaparin monotherapy
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Regimen
Note: this agent has been withdrawn from the US market.
Anticoagulation
References
- 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. link to original article PubMed
- 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. link to original article PubMed NCT01130025
Warfarin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Schulman et al. 2009 (RE-COVER) | Phase III (C) | Dabigatran | Non-inferior composite endpoint | Similar major bleeding |
Bauersachs et al. 2010 (EINSTEIN Acute DVT) | Phase III (C) | Rivaroxaban | Non-inferior VTE recurrence | Similar major bleeding |
Büller et al. 2012 (EINSTEIN-PE) | Phase III (C) | Rivaroxaban | Non-inferior VTE recurrence | Similar major bleeding |
Agnelli et al. 2013 (AMPLIFY) | Phase III (C) | Apixaban | Non-inferior composite endpoint | Higher rates of bleeding |
Büller et al. 2013 (Hokusai-VTE) | Phase III (C) | Edoxaban | Non-inferior recurrent VTE rate | Higher rates of bleeding |
Lee et al. 2015 (CATCH) | Phase III (C) | Tinzaparin | Might have inferior composite outcome | Similar major bleeding |
Anticoagulation
- Warfarin (Coumadin) with goal INR between 2 and 3.0
Supportive medications
- Most protocols: Enoxaparin (Lovenox) 1 mg/kg SC every 12 hours until INR greater than 2.0
3-, 6-, or 12- month course (see individual papers)
References
- 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. link to original article PubMed
- 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. link to original article contains verified protocol PubMed NCT00291330
- 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. link to original article contains verified protocol PubMed NCT00440193; NCT00439725
- 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. link to original article contains protocol PubMed NCT00439777
- 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. link to original article PubMed NCT00329238
- 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. link to original article contains verified protocol PubMed NCT00643201
- 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. link to original article contains verified protocol PubMed NCT00986154
- 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. link to original article PubMed
- 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. link to original article PubMed NCT00680186
- 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. link to original article PubMed NCT01130025
Additional information
- ACCP Chest guidelines for antithrombotic therapy for venous thromboembolic disease (2016)
- ACCP Chest Guidelines (2012) - Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (2012)
- Bleeding risk on anticoagulation: HAS-BLED; HEMORR2HAGES