Venous thromboembolism

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN, USA LinkedIn

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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).

• We have moved How I Treat articles to a dedicated page.

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

24 regimens on this page 30 variants on this page

Living Interactive Systematic Reviews

• Direct oral anti-coagulants compared to dalteparin

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ACCP

• 2012: Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines PubMed

ASCO

• 2023: Key et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update PubMed

• 2019: Key et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. PubMed
• 2015: Lyman et al. ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update PubMed
• 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 PubMed
• 2020: Ortel et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism PubMed
• 2019: Anderson et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients PubMed
• 2018: Schünemann et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients PubMed
• 2018: Lim et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism PubMed
• 2018: Witt et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy PubMed
• 2018: Monagle et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism PubMed
• 2018: Bates et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy PubMed
• 2018: Cuker et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia PubMed

ESMO

• 2023: Falanga et al. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline PubMed
  • 2010: Mandalà et al. Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management PubMed
  • 2009: Mandalà et al. Management of venous thromboembolism in cancer patients: ESMO clinical recommendations PubMed

IMWG

Current

• IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma PubMed

• 2007: Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma PubMed

ITAC (International Initiative on Thrombosis and Cancer)

• 2022: Farge et al. 2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19 PubMed

• 2019: Farge et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer PubMed
• 2016: Farge et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer PubMed
• 2013: Farge et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer PubMed

NCCN

• NCCN Guidelines - Cancer-Associated Venous Thromboembolic Disease
  • 2015: Streiff et al. Cancer-Associated Venous Thromboembolic Disease, Version 1.2015 PubMed
  • 2013: Streiff et al. Venous thromboembolic disease. PubMed
  • 2011: Streiff et al. Venous thromboembolic disease. PubMed
  • 2008: Wagman et al. Venous thromboembolic disease. NCCN. Clinical practice guidelines in oncology. PubMed
  • 2006: Wagman et al. Venous thromboembolic disease. Clinical practice guidelines in oncology. PubMed

VTE primary prophylaxis

Apixaban monotherapy

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 3 (E-switch-ic)	Enoxaparin	Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment (primary endpoint)	Seems to have lower bleeding rate
Lassen et al. 2010 (ADVANCE-2)	Phase 3 (E-switch-ic)	Enoxaparin	Superior composite primary 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 3 (E-switch-ic)	Enoxaparin	Superior composite primary 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 3 (E-esc)	Placebo	Superior VTE rate over 180 days (primary endpoint)	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

1. 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 dosing details in abstract PubMed NCT00371683
2. 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 dosing details in abstract PubMed NCT00452530
3. 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
4. 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 dosing details in manuscript PubMed NCT02048865
5. PREVAPIX-ALL: O'Brien SH, Rodriguez V, Lew G, Newburger JW, Schultz CL, Orgel E, Derr K, Ranalli MA, Esbenshade AJ, Hochberg J, Kang HJ, Dinikina Y, Mills D, Donovan M, Dyme JL, Favatella NA, Mitchell LG; PREVAPIX-ALL investigators. Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024 Jan;11(1):e27-e37. Epub 2023 Nov 16. link to original article PubMed NCT02369653

Aspirin monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Rodgers et al. 2000 (PEP)	Phase 3 (E-esc)	Placebo	Superior VTE rate
Landolfi et al. 2004 (ECLAP)	Phase 3 (E-esc)	Placebo	Seems to have superior rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (primary endpoint)
Palumbo et al. 2011 (GIMEMA MM-03-05)	Phase 3 (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 (MPRvsMEL200VTE)	Phase 3 (E-de-esc)	Enoxaparin	Did not meet primary endpoint of VTE incidence
Anderson et al. 2013 (EPCAT)	Phase 3 (E-de-esc)	Dalteparin	Non-inferior VTE rate at 90 days (primary endpoint)
Anderson et al. 2018 (EPCAT II)	Phase 3 (E-de-esc)	Rivaroxaban	Non-inferior VTE rate at 90 days (primary endpoint)
O'Toole et al. 2023 (PREVENT CLOT)	Randomized (C)	Enoxaparin	Non-inferior death rate at 90 days

Note: Palumbo et al. 2011 was a substudy looking at thromboprophylaxis in the thalidomide arm. Larocca et al. 2011 was also a substudy looking at thromboprophylaxis in the lenalidomide arm.

Anticoagulation

• Aspirin 81 to 160 mg PO once per day

Various durations, see individual trials

References

1. 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
2. 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
3. GIMEMA MM-03-05: Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article contains dosing details in manuscript PubMed NCT01063179
   1. Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains dosing details in manuscript PubMed
   2. Subgroup analysis: 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
4. MPRvsMEL200_VTE: 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
5. 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
6. 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
7. PREVENT CLOT: O'Toole RV, Stein DM, O'Hara NN, Frey KP, Taylor TJ, Scharfstein DO, Carlini AR, Sudini K, Degani Y, Slobogean GP, Haut ER, Obremskey W, Firoozabadi R, Bosse MJ, Goldhaber SZ, Marvel D, Castillo RC. Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture. N Engl J Med. 2023 Jan 19;388(3):203-213. link to original article PubMed NCT02984384

Betrixaban monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Cohen et al. 2016 (APEX-VTE)	Phase 3 (E-switch-ic)	Enoxaparin	Might have lower rates of VTE (primary endpoint)

Note: this APEX trial should not be confused with the one in multiple myeloma.

Anticoagulation

• Betrixaban (Bevyxxa) 80 mg PO once per day

References

1. 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

Regimen variant #1, 30 mg every 12 hours

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Geerts et al. 1996	Phase 3 (E-switch-ic)	UFH	Superior DVT rates	No difference in major bleeding rate
Lassen et al. 2009 (ADVANCE-1)]	Phase 3 (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
O'Toole et al. 2023 (PREVENT CLOT)	Randomized (E-esc)	Aspirin	Non-inferior death rate at 90 days (primary endpoint)

Preceding treatment

• ADVANCE-1: Total knee replacement
• 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 3 (C)	1. Placebo 2. Enoxaparin; 20 mg daily	Superior VTE rates
Kakkar et al. 2008 (RECORD2)	Phase 3 (C)	Rivaroxaban	Inferior composite outcome
Erikkson et al. 2008 (RECORD1)	Phase 3 (C)	Rivaroxaban	Inferior composite outcome
Lassen et al. 2008 (RECORD3)	Phase 3 (C)	Rivaroxaban	Inferior composite outcome
Turpie et al. 2009 (RECORD4)	Phase 3 (C)	Rivaroxaban	Seems to have inferior composite outcome
Lassen et al. 2010 (ADVANCE-2)	Phase 3 (C)	Apixaban	Inferior composite primary endpoint
Hull et al. 2010 (EXCLAIM)	Phase 3 (E-esc)	Placebo	Superior composite VTE rate (primary endpoint)
Lassen et al. 2010 (ADVANCE-3)	Phase 3 (C)	Apixaban	Inferior composite primary endpoint
Palumbo et al. 2011 (GIMEMA MM-03-05)	Phase 3 (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 (MPRvsMEL200VTE)	Phase 3 (E-esc)	Aspirin	Did not meet primary endpoint of VTE incidence
Goldhaber et al. 2011 (ADOPT)	Phase 3 (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 3 (E-esc)	Placebo	Did not meet primary endpoint of death rate at 30 days
Cohen et al. 2013 (MAGELLAN)	Phase 3 (C)	Rivaroxaban	Non-inferior VTE rate at 10 days
Cohen et al. 2016 (APEX-VTE)	Phase 3 (C)	Betrixaban	Might have higher rates of VTE
Sidhu et al. 2022 (CRISTAL)	Phase 3 (C)	Aspirin	Superior rate of symptomatic VTE within 90 days

Note: the APEX trial here should not be confused with the one in multiple myeloma. Larocca et al. 2011 was a substudy looking at thromboprophylaxis in the lenalidomide arm.

Preceding treatment

• ADVANCE-2 & CRISTAL: Total knee replacement
• ADVANCE-3 & CRISTAL: Total hip replacement

Anticoagulation

• Enoxaparin (Lovenox) 40 mg SC once per day

Various durations (see papers for details)

References

1. 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
2. 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.
3. 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
4. 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
5. 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
6. 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
7. 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 dosing details in abstract PubMed NCT00371683
8. 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 dosing details in abstract PubMed NCT00452530
9. 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
10. 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 dosing details in abstract PubMed NCT00423319
11. 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
12. MPRvsMEL200_VTE: 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
13. 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
14. 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
15. 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
16. 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
17. CRISTAL: Sidhu VS, Kelly TL, Pratt N, Graves SE, Buchbinder R, Adie S, Cashman K, Ackerman I, Bastiras D, Brighton R, Burns AWR, Chong BH, Clavisi O, Cripps M, Dekkers M, de Steiger R, Dixon M, Ellis A, Griffith EC, Hale D, Hansen A, Harris A, Hau R, Horsley M, James D, Khorshid O, Kuo L, Lewis P, Lieu D, Lorimer M, MacDessi S, McCombe P, McDougall C, Mulford J, Naylor JM, Page RS, Radovanovic J, Solomon M, Sorial R, Summersell P, Tran P, Walter WL, Webb S, Wilson C, Wysocki D, Harris IA; CRISTAL Study Group. Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial. JAMA. 2022 Aug 23;328(8):719-727. link to original article link to PMC article contains dosing details in manuscript PubMed ACTRN12618001879257
18. PREVENT CLOT: O'Toole RV, Stein DM, O'Hara NN, Frey KP, Taylor TJ, Scharfstein DO, Carlini AR, Sudini K, Degani Y, Slobogean GP, Haut ER, Obremskey W, Firoozabadi R, Bosse MJ, Goldhaber SZ, Marvel D, Castillo RC. Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture. N Engl J Med. 2023 Jan 19;388(3):203-213. link to original article PubMed NCT02984384

Rivaroxaban monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Kakkar et al. 2008 (RECORD2)	Phase 3 (E-switch-ic)	Enoxaparin	Superior composite outcome (primary endpoint)
Erikkson et al. 2008 (RECORD1)	Phase 3 (E-switch-ic)	Enoxaparin	Superior composite outcome (primary endpoint)
Lassen et al. 2008 (RECORD3)	Phase 3 (E-switch-ic)	Enoxaparin	Superior composite outcome (primary endpoint)
Turpie et al. 2009 (RECORD4)	Phase 3 (E-switch-ic)	Enoxaparin	Seems to have superior composite outcome (primary endpoint)
Cohen et al. 2013 (MAGELLAN)	Phase 3 (E-switch-ic)	Enoxaparin	Non-inferior VTE rate at 10 days (co-primary endpoint)
Anderson et al. 2018 (EPCAT II)	Phase 3 (E-esc)	Aspirin	Non-inferior VTE rate at 90 days (primary endpoint)
Spyropoulos et al. 2018 (MARINER)	Phase 3 (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

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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

Regimen variant #1, 2.5 mg twice per day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Agnelli et al. 2012 (AMPLIFY-EXT)	2008-05 to 2011-07	Phase 3 (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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Agnelli et al. 2012 (AMPLIFY-EXT)	2008-05 to 2011-07	Phase 3 (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

1. 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 dosing details in manuscript PubMed

Aspirin monotherapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Becattini et al. 2012 (WARFASA)	Phase 3 (E-esc)	Placebo	Superior rate of VTE recurrence (primary endpoint)	No difference in bleeding rate
Brighton et al. 2012 (ASPIRE-VTE)	Phase 3 (E-esc)	Placebo	Might have superior rate of VTE recurrence (primary endpoint)	No difference in bleeding rate

Note: ASPIRE should not be confused with the multiple myeloma trial of the same name.

Preceding treatment

• WARFASA: Warfarin x 6 to 18 months
• ASPIRE: Warfarin x 6 weeks to 24 months

Anticoagulation

• Aspirin 100 mg PO once per day

Two or more years

References

1. 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 dosing details in abstract PubMed NCT00222677
2. 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

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Lee et al. 2003 (CLOT)	Phase 3 (E-switch-ic)	Warfarin	Superior rate of VTE at 6 months (primary endpoint)	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

1. 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
   1. Post-hoc 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

Regimen

Study	Evidence	Comparator	Efficacy
Meyer et al. 2002	Phase 3 (E-switch-ic)	Warfarin	Might have superior composite VTE/bleeding outcome (primary endpoint)

Anticoagulation

• Enoxaparin (Lovenox) 1.5 mg/kg SC once per day

3-month course

References

1. Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, Huet Y, Simonneau G; Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998 Feb 12;338(7):409-15. link to original article PubMed
2. 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 dosing details in abstract PubMed
3. Highlow: Bistervels IM, Buchmüller A, Wiegers HMG, Ní Áinle F, Tardy B, Donnelly J, Verhamme P, Jacobsen AF, Hansen AT, Rodger MA, DeSancho MT, Shmakov RG, van Es N, Prins MH, Chauleur C, Middeldorp S; Highlow Block writing committee; Highlow Investigators. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet. 2022 Oct 28:S0140-6736(22)02128-6. link to original article PubMed NCT01828697

Warfarin monotherapy

Regimen variant #1, standard intensity

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Meyer et al. 2002	Phase 3 (C)	Enoxaparin	Might have inferior composite VTE/bleeding outcome
Lee et al. 2003 (CLOT)	Phase 3 (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	Comparative Efficacy	Comparative Toxicity
Ridker et al. 2003 (PREVENT)	Phase 3 (E-esc)	Placebo	Superior recurrent VTE rate (primary endpoint)	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

1. 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
2. Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, MacKinnon B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M; Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Aug 14;349(7):631-9. link to original article PubMed
3. 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 dosing details in manuscript PubMed
4. 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
   1. Post-hoc 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

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Agnelli et al. 2013 (AMPLIFY)	2008-08 to 2012-08	Phase 3 (E-switch-ooc)	Warfarin	Non-inferior composite primary endpoint	Lower rates of bleeding
McBane et al. 2019 (ADAM VTE)	2015-11-20 to 2017-10-02	Phase 3 (E-switch-ooc)	Dalteparin		Might have lower rates of major bleeding (primary endpoint)
Angelli et al. 2020 (CARAVAGGIO)	2017-04 to 2019-06	Phase 3 (E-switch-ooc)	Dalteparin	Non-inferior recurrent VTE (primary endpoint)	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

1. 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 dosing details in manuscript PubMed NCT00643201
2. ADAM VTE: McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, Zemla T, Ashrani A, Tafur A, Perepu U, Anderson D, Gundabolu K, Kuzma C, Perez Botero J, Leon Ferre RA, Henkin S, Lenz CJ, Houghton DE, Vishnu P, Loprinzi CL. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. J Thromb Haemost. 2020 Feb;18(2):411-421. Epub 2019 Nov 28. link to original article contains dosing details in abstract PubMed NCT02585713
3. 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

Regimen

Anticoagulation

• Argatroban (Acova)

References

To be completed

Aspirin monotherapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	Phase 3 (C)	1. Rivaroxaban; 10 mg/day 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

1. 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 dosing details in manuscript PubMed NCT02064439

Bivalirudin monotherapy

Regimen

Anticoagulation

• Bivalirudin (Angiomax)

References

To be completed

Dabigatran monotherapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Schulman et al. 2009 (RE-COVER)	Phase 3 (E-switch-ic)	Warfarin	Non-inferior composite primary endpoint	Similar major bleeding

Anticoagulation

• Dabigatran (Pradaxa) 150 mg PO twice per day

6-month course

References

1. 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 dosing details in manuscript PubMed NCT00291330
2. 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
3. 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
4. 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

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Francis et al. 2015 (DALTECAN)	Non-randomized
Raskob et al. 2017 (Hokusai VTE Cancer)	Phase 3 (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 3 (C)	Rivaroxaban	Seems to have inferior rate of VTE recurrence	Superior rates of clinically relevant non-major bleeding
Angelli et al. 2020 (CARAVAGGIO)	Phase 3 (C)	Apixaban	Non-inferior recurrent VTE	Major bleeding similar in both groups

Anticoagulation

• Dalteparin (Fragmin) as follows:
  • Month 1: 200 IU/kg once per day
  • Months 2 to 6 up to 12: 150 IU/kg once per day

6- to 12-month course

References

1. 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
2. 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 dosing details in abstract PubMed NCT02073682
3. 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 dosing details in abstract PubMed ISRCTN86712308
4. ADAM VTE: McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, Zemla T, Ashrani A, Tafur A, Perepu U, Anderson D, Gundabolu K, Kuzma C, Perez Botero J, Leon Ferre RA, Henkin S, Lenz CJ, Houghton DE, Vishnu P, Loprinzi CL. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. J Thromb Haemost. 2020 Feb;18(2):411-421. Epub 2019 Nov 28. link to original article contains dosing details in abstract PubMed NCT02585713
5. 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

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Büller et al. 2013 (Hokusai-VTE)	Phase 3 (E-RT-switch-ic)	Warfarin	Non-inferior recurrent symptomatic VTE rate (primary endpoint) Symptomatic VTE rate: 3.2% vs 3.5% (HR 0.89, 95% CI 0.70-1.13)	Lower rates of bleeding
Raskob et al. 2017 (Hokusai VTE Cancer)	Phase 3 (E-RT-switch-ic)	Dalteparin	Non-inferior composite primary endpoint of VTE/major bleeding	Non-inferior composite primary 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

Dose and schedule modifications

• Edoxaban (Savaysa): Patients with CrCl 30 to 50 mL/min/1.73 m², a body weight of up to 60 kg, or those taking "potent" P-glycoprotein inhibitors: 30 mg PO once per day

References

1. 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 dosing details in manuscript PubMed NCT00986154
   1. 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
2. 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 dosing details in abstract PubMed NCT02073682

Enoxaparin monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Kearon et al. 2006 (FIDO)	Phase 3 (E-switch-ic)	1. Dalteparin 2. UFH	No difference in recurrent VTE or major bleeding

Anticoagulation

• Enoxaparin (Lovenox) 100 IU/kg SC once every 12 hours

References

1. 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 Aug 23;296(8):935-42. link to original article PubMed NCT00182403

Fondaparinux monotherapy

Regimen

Anticoagulation

• Fondaparinux (Arixtra)

References

To be completed

Heparin monotherapy

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 3 (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) 333 units/kg SC once, then 250 units/kg SC every 12 hours

References

1. Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. link to original article PubMed
2. 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 Aug 23;296(8):935-42. link to original article PubMed NCT00182403

Lepirudin monotherapy

Regimen

Anticoagulation

• Lepirudin (Refludan)

References

To be completed

Rivaroxaban monotherapy

Regimen variant #1, 10 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	2014-03 to 2016-03	Phase 3 (E-esc)	1. Aspirin	Superior symptomatic recurrent VTE rate (primary endpoint)	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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	2014-03 to 2016-03	Phase 3 (E-esc)	1. Aspirin	Superior symptomatic recurrent VTE rate (primary endpoint)	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	Comparative Efficacy	Comparative Toxicity
Bauersachs et al. 2010 (EINSTEIN Acute DVT)	Phase 3 (E-switch-ic)	Warfarin	Non-inferior VTE recurrence (primary endpoint)	Similar major bleeding
Büller et al. 2012 (EINSTEIN-PE)	Phase 3 (E-switch-ic)	Warfarin	Non-inferior symptomatic VTE recurrence (primary endpoint)	Similar major bleeding
Young et al. 2018 (SELECT-D)	Phase 3 (E-switch-ic)	Dalteparin	Seems to have superior rate of VTE recurrence over 6 months (primary endpoint)	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

1. 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 dosing details in manuscript PubMed NCT00440193; NCT00439725
2. 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 dosing details in abstract PubMed NCT00439777
3. 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
4. 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
5. 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 dosing details in abstract PubMed ISRCTN86712308
6. 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

Regimen

Note: this agent has been withdrawn from the US market.

Anticoagulation

• Tinzaparin (Innohep)

References

1. 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
2. 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

Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Schulman et al. 2009 (RE-COVER)	Phase 3 (C)	Dabigatran	Non-inferior composite endpoint	Similar major bleeding
Bauersachs et al. 2010 (EINSTEIN Acute DVT)	Phase 3 (C)	Rivaroxaban	Non-inferior VTE recurrence	Similar major bleeding
Büller et al. 2012 (EINSTEIN-PE)	Phase 3 (C)	Rivaroxaban	Non-inferior symptomatic VTE recurrence (primary endpoint)	Similar major bleeding
Agnelli et al. 2013 (AMPLIFY)	Phase 3 (C)	Apixaban	Non-inferior composite primary endpoint	Higher rates of bleeding
Büller et al. 2013 (Hokusai-VTE)	Phase 3 (C)	Edoxaban	Non-inferior recurrent VTE rate	Higher rates of bleeding
Lee et al. 2015 (CATCH)	Phase 3 (C)	Tinzaparin	Might have inferior composite outcome	Similar major bleeding

Anticoagulation

• Warfarin (Coumadin) with goal INR between 2 and 3.0

Supportive therapy

• Most protocols: Enoxaparin (Lovenox) 1 mg/kg SC once every 12 hours, given until INR greater than 2.0

3-, 6-, or 12- month course (see individual papers)

References

1. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Lärfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H; Duration of Anticoagulation Trial Study Group. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995 Jun 22;332(25):1661-5. link to original article PubMed
2. Schulman S, Granqvist S, Holmström M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Lärfars G, Leijd B, Linder O, Loogna E; The Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997 Feb 6;336(6):393-8. link to original article PubMed
3. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999 Mar 25;340(12):901-7. Erratum in: N Engl J Med 1999 Jul 22;341(4):298. link to original article PubMed
4. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med. 2001 Jul 19;345(3):165-9. link to original article PubMed
5. DOTAVK: Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I, Nony P, Sanson C, Boissel JP; Investigators of the "Durée Optimale du Traitement AntiVitamines K" (DOTAVK) Study. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001 May 22;103(20):2453-60. link to original article PubMed
6. Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, Imberti D, Poggio R, Ageno W, Pogliani E, Porro F, Zonzin P; Warfarin Optimal Duration Italian Trial Investigators. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003 Jul 1;139(1):19-25. link to original article PubMed
7. SOFAST: Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA, Mackinnon B, Demers C, Douketis J, Turpie AG, Van Nguyen P, Green D, Kassis J, Kahn SR, Solymoss S, Desjardins L, Geerts W, Johnston M, Weitz JI, Hirsh J, Gent M; SOFAST Investigators. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost. 2004 May;2(5):743-9. link to original article PubMed
8. 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
9. 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 dosing details in manuscript PubMed NCT00291330
10. 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 dosing details in manuscript PubMed NCT00440193; NCT00439725
11. 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 dosing details in abstract PubMed NCT00439777
12. 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
13. 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 dosing details in manuscript PubMed NCT00643201
14. 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 dosing details in manuscript PubMed NCT00986154
    1. 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
15. 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
16. 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)
  • Executive summary PDF
• Bleeding risk on anticoagulation: HAS-BLED; HEMORR2HAGES