Venous thromboembolism

Section editors
	Shruti Chaturvedi, MBBS, MSCI Johns Hopkins University Baltimore, MD LinkedIn		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

24 regimens on this page 30 variants on this page

Guidelines

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

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

• 2013: Lyman et al. ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2013 update PubMed

ASH

• 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

IMWG

Current

• 2010: IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma

Older

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

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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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)	Enoxaparin	Seems not superior	Seems to have lower bleeding rate
Lassen et al. 2010 (ADVANCE-2)	Phase III (E)	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

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)	Enoxaparin	Superior composite endpoint	Seems not superior

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

Variant #3, 180 days

FDA-recommended dose

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Carrier et al. 2018 (AVERT)	Phase III (E)	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

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 protocol PubMed
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 protocol PubMed
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
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 verified protocol PubMed

Aspirin monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Rodgers et al. 2000 (PEP)	Phase III (E)	Placebo	Superior VTE rate
Landolfi et al. 2004 (ECLAP)	Phase III (E)	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	Phase III (E)	1. Enoxaparin 2. Low-dose warfarin	Seems not superior
Larocca et al. 2011	Phase III (E)	Enoxaparin	Seems not superior
Anderson et al. 2013 (EPCAT)	Phase III (E)	Dalteparin	Non-inferior VTE rate at 90 days
Anderson et al. 2018 (EPCAT II)	Phase III (E)	Rivaroxaban	Non-inferior VTE rate at 90 days

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. 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. 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
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
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

Betrixaban monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Cohen et al. 2016 (APEX-VTE)	Phase III (E)	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

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

Enoxaparin monotherapy

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Variant #1, 30 mg every 12 hours

Study	Evidence	Comparator	Efficacy	Toxicity
Geerts et al. 1996	Phase III (E)	UFH	Superior DVT rates	No difference in major bleeding rate
Lassen et al. 2009 (ADVANCE-1)]	Phase III (C)	Apixaban	Seems not superior	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.

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)	Placebo	Superior composite VTE rate
Lassen et al. 2010 (ADVANCE-3)	Phase III (C)	Apixaban	Inferior composite outcome
Palumbo et al. 2011	Phase III (E)	1. Aspirin 2. Low-dose warfarin	Seems not superior
Larocca et al. 2011	Phase III (E)	Aspirin	Seems not superior
Goldhaber et al. 2011 (ADOPT)	Phase III (C)	Apixaban	Seems not superior
Kakkar et al. 2011 (LIFENOX)	Phase III (E)	Placebo	Seems not superior
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

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
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
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
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
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 protocol PubMed
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 protocol PubMed
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
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 protocol PubMed
11. 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
12. 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
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
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
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
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

Placebo

Regimen

Study	Evidence	Comparator	Efficacy
Gärdlund et al. 1996	Phase III (C)	UFH (SC)	Seems not superior
Hull et al. 2010 (EXCLAIM)	Phase III (C)	Enoxaparin	Inferior composite VTE rate
Kakkar et al. 2011 (LIFENOX)	Phase III (C)	Enoxaparin	Seems not superior
Spyropoulos et al. 2018 (MARINER)	Phase III (C)	Rivaroxaban	Seems not superior
Khorana et al. 2019 (CASSINI)	Phase III (C)	Rivaroxaban	Seems not superior

No active treatment.

References

1. Gärdlund B; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996 May 18;347(9012):1357-61. link to SD article PubMed
2. 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
3. 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
4. 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
5. 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

Rivaroxaban monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Kakkar et al. 2008 (RECORD2)	Phase III (E)	Enoxaparin	Superior composite outcome
Erikkson et al. 2008 (RECORD1)	Phase III (E)	Enoxaparin	Superior composite outcome
Lassen et al. 2008 (RECORD3)	Phase III (E)	Enoxaparin	Superior composite outcome
Turpie et al. 2009 (RECORD4)	Phase III (E)	Enoxaparin	Seems to have superior composite outcome
Cohen et al. 2013 (MAGELLAN)	Phase III (E)	Enoxaparin	Non-inferior VTE rate at 10 days
Anderson et al. 2018 (EPCAT II)	Phase III (E)	Aspirin	Non-inferior VTE rate at 90 days
Spyropoulos et al. 2018 (MARINER)	Phase III (E)	Placebo	Seems not superior

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
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
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
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
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
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
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

VTE secondary prevention

Apixaban monotherapy

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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)	1. Apixaban 5 mg twice per day	Seems not superior
		2. Placebo	Superior composite endpoint

Preceding treatment

• Therapeutic anticoagulation x 6-12 mo

Anticoagulation

• Apixaban (Eliquis) 2.5 mg PO twice per day

12-month course

Variant #2, 5 mg twice per day

Study	Evidence	Comparator	Comparative Efficacy
Agnelli et al. 2012 (AMPLIFY-EXT)	Phase III (E)	1. Apixaban 2.5 mg twice per day	Seems not superior
		2. Placebo	Superior composite endpoint

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 verified protocol PubMed

Aspirin monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Becattini et al. 2012 (WARFASA)	Phase III (E)	Placebo	Superior rate of VTE recurrence	No difference in bleeding rate
Brighton et al. 2012 (ASPIRE-VTE)	Phase III (E)	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

• 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 protocol PubMed
2. ASPIRE: Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. link to original article PubMed

Dalteparin monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Lee et al. 2003 (CLOT)	Phase III (E)	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

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. 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)	Warfarin	Might have superior combined VTE/bleeding outcome

Anticoagulation

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

3-month course

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 contains protocol PubMed

Warfarin monotherapy

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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 2.0 to 3.0

Variant #2, low intensity

Study	Evidence	Comparator	Efficacy	Toxicity
Ridker et al. 2003 (PREVENT)	Phase III (E)	Placebo	Superior recurrent VTE rate	No difference in major bleeding

Preceding treatment

• Warfarin with goal INR of 2.0 to 3.0 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. 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
3. 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. 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)	Warfarin	Non-inferior composite endpoint	Lower rates of bleeding

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 verified protocol PubMed

Argatroban monotherapy

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Regimen

Anticoagulation

• Argatroban (Acova)

References

To be completed

Aspirin monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	Phase III (C)	1. Rivaroxaban 10 mg	Inferior symptomatic recurrent VTE rate	Similar major bleeding
		2. Rivaroxaban 20 mg	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 verified protocol PubMed

Bivalirudin monotherapy

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Regimen

Anticoagulation

• Bivalirudin (Angiomax)

References

To be completed

Dabigatran monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Schulman et al. 2009 (RE-COVER)	Phase III (E)	Warfarin	Non-inferior composite 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 verified protocol PubMed
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
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

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

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

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
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 protocol PubMed
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 protocol PubMed

Edoxaban monotherapy

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Variant #1, reduced dose

Study	Evidence	Comparator	Efficacy	Toxicity
Büller et al. 2013 (Hokusai-VTE)	Phase III (E)	Warfarin	Non-inferior recurrent VTE rate	Superior rate of bleeding
Raskob et al. 2017 (Hokusai VTE Cancer)	Phase III (E)	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

Variant #2, normal dosing

Study	Evidence	Comparator	Efficacy	Toxicity
Büller et al. 2013 (Hokusai-VTE)	Phase III (E)	Warfarin	Non-inferior recurrent VTE rate	Lower rates of bleeding
Raskob et al. 2017 (Hokusai VTE Cancer)	Phase III (E)	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

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 verified protocol PubMed
   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 protocol PubMed

Enoxaparin monotherapy

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Regimen

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

Anticoagulation

• Enoxaparin (Lovenox) SC 100 IU/kg 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 Aug23;296(8):935-42. link to original article PubMed

Fondaparinux monotherapy

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Regimen

Anticoagulation

• Fondaparinux (Arixtra)

References

To be completed

Heparin monotherapy

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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

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 Aug23;296(8):935-42. link to original article PubMed

Lepirudin monotherapy

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Regimen

Anticoagulation

• Lepirudin (Refludan)

References

To be completed

Rivaroxaban monotherapy

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Variant #1, 10 mg/day

Study	Evidence	Comparator	Efficacy	Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	Phase III (E)	1. Aspirin	Superior symptomatic recurrent VTE rate	Similar major bleeding
		2. Rivaroxaban 20 mg	Seems not superior	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

Variant #2, 20 mg/day

Study	Evidence	Comparator	Efficacy	Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	Phase III (E)	1. Aspirin	Superior symptomatic recurrent VTE rate	Similar major bleeding
		2. Rivaroxaban 10 mg	Seems not superior	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

Variant #3, 20 mg/day with loading dose

Study	Evidence	Comparator	Efficacy	Toxicity
Bauersachs et al. 2010 (EINSTEIN Acute DVT)	Phase III (E)	Warfarin	Non-inferior VTE recurrence	Similar major bleeding
Büller et al. 2012 (EINSTEIN-PE)	Phase III (E)	Warfarin	Non-inferior symptomatic VTE recurrence	Similar major bleeding
Young et al. 2018 (SELECT-D)	Phase III (E)	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

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 verified protocol PubMed
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 protocol PubMed
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
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
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 protocol PubMed

Tinzaparin monotherapy

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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

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

Anticoagulation

• Warfarin (Coumadin) with goal INR between 2.0 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

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. 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
3. 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
4. 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
5. 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
6. 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
7. 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
   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
8. 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
9. 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

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