Venous thromboembolism

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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) syndromeCirculation patient page about postthrombotic syndrome (PTS)
Last updated on 2024-07-23:24 regimens on this page
31 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 EuroPMC
==ASCO==
*2023: Key et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update EuroPMC
*2019: Key et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. EuroPMC
*2015: Lyman et al. ASCO Clinical Practice Guideline on VTE prophylaxis and treatment 2014 update EuroPMC
*2013: Lyman et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update EuroPMC
*2007: Lyman et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. EuroPMC
==ASH==
*2021: Lyman et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer link to PMC article EuroPMC
*2020: Ortel et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism link to PMC article EuroPMC
*2019: Anderson et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients link to PMC article EuroPMC
*2018: Schünemann et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients link to PMC article EuroPMC
*2018: Lim et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism link to PMC article EuroPMC
*2018: Witt et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy link to PMC article EuroPMC
*2018: Monagle et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism link to PMC article EuroPMC
*2018: Bates et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy link to PMC article EuroPMC
*2018: Cuker et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia link to PMC article EuroPMC
==ESMO==
*2023: Falanga et al. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline EuroPMC
**2010: Mandalà et al. Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management EuroPMC
**2009: Mandalà et al. Management of venous thromboembolism in cancer patients: ESMO clinical recommendations EuroPMC
==IMWG==
===Current===
*IMWG guidelines for the prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma EuroPMC
*2007: Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma EuroPMC
==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 link to PMC article EuroPMC
*2019: Farge et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer EuroPMC
*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 EuroPMC
*2013: Farge et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer EuroPMC
==NCCN==
*NCCN Guidelines - Cancer-Associated Venous Thromboembolic Disease
**2015: Streiff et al. Cancer-Associated Venous Thromboembolic Disease, Version 1.2015 EuroPMC
**2013: Streiff et al. Venous thromboembolic disease. EuroPMC
**2011: Streiff et al. Venous thromboembolic disease. link to PMC article EuroPMC
**2008: Wagman et al. Venous thromboembolic disease. NCCN. Clinical practice guidelines in oncology. EuroPMC
**2006: Wagman et al. Venous thromboembolic disease. Clinical practice guidelines in oncology. EuroPMC
=VTE primary prophylaxis=
==Apixaban monotherapy==
===Regimen variant #1, 10-14 days post-op===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Lassen et al. 2009 (ADVANCE-1)	Not reported 	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)Primary endpoint rate: 9.0% vs 8.8%(RR 1.02, 95% CI 0.78-1.32)	Seems to have lower bleeding rate
Lassen et al. 2010 (ADVANCE-2)	2007-06-29 to 2008-11-12	Phase 3 (E-switch-ic)	Enoxaparin	Lower rate of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment (composite primary endpoint)Rate: 15% vs 24%(RR 0.62, 95% CI 0.51-0.74)	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 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Lassen et al. 2010 (ADVANCE-3)	2007-03 to 2009-05 	Phase 3 (E-switch-ic)	Enoxaparin	Lower rate of asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause during the treatment period (composite primary endpoint)Rate: 1.4% vs 3.9%(RR 0.36, 95% CI 0.22-0.54)	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 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Carrier et al. 2018 (AVERT)	2014-02 to 2018-04 	Phase 3 (E-esc)	Placebo 	Lower 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===
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00371683
#ADVANCE-2: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00452530
#ADVANCE-3: Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. link to original article EuroPMC NCT00423319
#AVERT: Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. Epub 2018 Dec 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02048865
#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 EuroPMC NCT02369653
==Aspirin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rodgers et al. 2000 (PEP) 	1992-1998 	Phase 3 (E-esc) 	Placebo 	Lower VTE rate
Landolfi et al. 2004 (ECLAP) 	Not reported 	Phase 3 (E-esc) 	Placebo 	Seems to have higher 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)	2006-05 to 2009-01 	Phase 3 (E-switch-ic)	1. Enoxaparin2. 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) 	2007-11 to 2009-06 	Phase 3 (E-de-esc) 	Enoxaparin 	Did not meet primary endpoint of VTE incidence
Anderson et al. 2013 (EPCAT) 	2007-2010 	Phase 3 (E-de-esc) 	Dalteparin 	Non-inferior VTE rate at 90 days (primary endpoint)
Anderson et al. 2018 (EPCAT II) 	2013-01 to 2016-04 	Phase 3 (E-de-esc) 	Rivaroxaban 	Non-inferior VTE rate at 90 days (primary endpoint)
O'Toole et al. 2023 (PREVENT CLOT) 	2017-04 to 2021-08 	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===
#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 EuroPMC
#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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01063179
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
#MPRvsMEL200VTE: 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 EuroPMC NCT00551928
#EPCAT: Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli PA. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. link to original article EuroPMC ISRCTN11902170
#EPCAT II: Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. link to original article EuroPMC NCT01720108
#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 EuroPMC NCT02984384
==Betrixaban monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cohen et al. 2016 (APEX-VTE)	2012-03 to 2015-11 	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) 160 mg PO once on day 1, then 80 mg PO once per day
35- to 42-day course
===References===
#APEX-VTE: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01583218
==Enoxaparin monotherapy==
===Regimen variant #1, 30 mg every 12 hours===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Geerts et al. 1996 	1992-11 to 1994-11 	Phase 3 (E-switch-ic)	UFH 	Lower DVT rates 	No difference in major bleeding rate
Lassen et al. 2009 (ADVANCE-1)] 	Not reported 	Phase 3 (C) 	Apixaban 	Inconclusive whether non-inferior asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment Primary endpoint rate: 8.8% vs 9.0%(RR 0.98, 95% CI 0.76-1.28)	Seems to have higher bleeding rate
O'Toole et al. 2023 (PREVENT CLOT)	2017-04 to 2021-08 	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
===Regimen variant #2, 40 mg daily===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Samama et al. 1999 (MEDENOX) 	1996-12 to 1998-07 	Phase 3 (C) 	1. Placebo2. Enoxaparin; 20 mg daily	Lower VTE rates
Hull et al. 2010 (EXCLAIM) 	2002-02 to 2006-03 	Phase 3 (E-esc) 	Placebo 	Lower composite VTE rate (primary endpoint)
Erikkson et al. 2008 (RECORD1) 	2006-02 to 2007-03 	Phase 3 (C) 	Rivaroxaban 	Higher rate of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (composite primary endpoint)Rate: 3.7% vs 1.1%
Kakkar et al. 2008 (RECORD2) 	2006-02 to 2007-04 	Phase 3 (C) 	Rivaroxaban 	Higher rate of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30 to 42 (composite primary endpoint)Rate: 9.3% vs 2%
Lassen et al. 2008 (RECORD3) 	2006-02 to 2006-11 	Phase 3 (C) 	Rivaroxaban 	Higher rate of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery (composite primary endpoint)Rate: 18.9% vs 9.6%
Palumbo et al. 2011 (GIMEMA MM-03-05)	2006-05 to 2009-01 	Phase 3 (E-switch-ic)	1. Aspirin2. 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
Turpie et al. 2009 (RECORD4) 	2006-06 to 2007-10 	Phase 3 (C) 	Rivaroxaban 	Seems to have higher rate of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery (composite primary endpoint)Rate: 10.1% vs 6.9%
Lassen et al. 2010 (ADVANCE-3) 	2007-03 to 2009-05 	Phase 3 (C) 	Apixaban 	Higher rate of asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause during the treatment period (composite primary endpoint)Rate: 3.9% vs 1.4%(RR 2.78, 95% CI 1.85-4.55)
Goldhaber et al. 2011 (ADOPT) 	2007-06 to 2011-02 	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
Lassen et al. 2010 (ADVANCE-2) 	2007-06-29 to 2008-11-12	Phase 3 (C) 	Apixaban 	Higher rate of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment (composite primary endpoint)Rate: 24% vs 15%(RR 1.61, 95% CI 1.35-1.96)
Larocca et al. 2011 (MPRvsMEL200VTE) 	2007-11 to 2009-06 	Phase 3 (E-esc) 	Aspirin 	Did not meet primary endpoint of VTE incidence
Cohen et al. 2013 (MAGELLAN) 	2007-12 to 2010-07 	Phase 3 (C) 	Rivaroxaban 	Non-inferior VTE rate at 10 days
Kakkar et al. 2011 (LIFENOX) 	2008-01 to 2010-09 	Phase 3 (E-esc) 	Placebo 	Did not meet primary endpoint of death rate at 30 days
Cohen et al. 2016 (APEX-VTE) 	2012-03 to 2015-11 	Phase 3 (C) 	Betrixaban 	Might have higher rates of VTE
Sidhu et al. 2022 (CRISTAL) 	2019-04-20 to 2020-12-18	Phase 3 (C) 	Aspirin 	Higher 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: 6 to 14 days (APEX-VTE); other (see papers for details)
===References===
#Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996 Sep 5;335(10):701-7. link to original article EuroPMC
#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. EuroPMC.
#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 EuroPMC NCT00332020
#RECORD1: Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. link to original article EuroPMC NCT00329628
#RECORD3: Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. link to original article EuroPMC NCT00361894
#RECORD4: Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. link to original article EuroPMC NCT00362232
#ADVANCE-1: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009 Aug 6;361(6):594-604. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00371683
#ADVANCE-2: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00452530
#EXCLAIM: Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AG, Yusen RD; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18. link to original article EuroPMC NCT00077753
#ADVANCE-3: Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00423319
#GIMEMA MM-03-05: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article EuroPMC NCT01063179
#MPRvsMEL200VTE: 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 EuroPMC NCT00551928
#ADOPT: Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. Epub 2011 Nov 13. link to original article EuroPMC NCT00457002
#LIFENOX: Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. link to original article EuroPMC NCT00622648
#MAGELLAN: Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. link to original article EuroPMC NCT00571649
#APEX-VTE: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01583218
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ACTRN12618001879257
#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 EuroPMC NCT02984384
==Rivaroxaban monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Erikkson et al. 2008 (RECORD1) 	2006-02 to 2007-03 	Phase 3 (E-switch-ic)	Enoxaparin	Lower rate of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (composite primary endpoint)Rate: 1.1% vs 3.7%
Kakkar et al. 2008 (RECORD2) 	2006-02 to 2007-04 	Phase 3 (E-switch-ic)	Enoxaparin	Lower rate of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30 to 42 (composite primary endpoint)Rate: 2% vs 9.3%
Lassen et al. 2008 (RECORD3) 	2006-02 to 2006-11 	Phase 3 (E-switch-ic)	Enoxaparin	Lower rate of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery (composite primary endpoint)Rate: 9.6% vs 18.9%
Turpie et al. 2009 (RECORD4) 	2006-06 to 2007-10 	Phase 3 (E-switch-ic)	Enoxaparin	Seems to have lower rate of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery (composite primary endpoint)Rate: 6.9% vs 10.1%
Cohen et al. 2013 (MAGELLAN) 	2007-12 to 2010-07 	Phase 3 (E-switch-ic)	Enoxaparin	Non-inferior VTE rate at 10 days (co-primary endpoint)
Anderson et al. 2018 (EPCAT II) 	2013-01 to 2016-04 	Phase 3 (E-esc) 	Aspirin 	Non-inferior VTE rate at 90 days (primary endpoint)
Spyropoulos et al. 2018 (MARINER)	2014-06 to 2018-01 	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
Continue for varying durations: 10 to 14 days (RECORD3, RECORD4); 31 to 39 days (MAGELLAN, RECORD1); 35 days (RECORD2); 45 days (MARINER)
===References===
#RECORD2: Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. Epub 2008 Jun 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00332020
#RECORD1: Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00329628
#RECORD3: Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00361894
#RECORD4: Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. Epub 2009 May 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00362232
#MAGELLAN: Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00571649
#EPCAT II: Anderson DR, Dunbar M, Murnaghan J, Kahn SR, Gross P, Forsythe M, Pelet S, Fisher W, Belzile E, Dolan S, Crowther M, Bohm E, MacDonald SJ, Gofton W, Kim P, Zukor D, Pleasance S, Andreou P, Doucette S, Theriault C, Abianui A, Carrier M, Kovacs MJ, Rodger MA, Coyle D, Wells PS, Vendittoli PA. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. link to original article EuroPMC NCT01720108
#MARINER: Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Epub 2018 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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
Agnelli et al. 2012 (AMPLIFY-EXT)	2008-05 to 2011-07 	Phase 3 (E-esc)	2. Placebo 	Lower 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
Agnelli et al. 2012 (AMPLIFY-EXT)	2008-05 to 2011-07 	Phase 3 (E-esc)	2. Placebo 	Lower symptomatic recurrent VTE or death from any cause
====Preceding treatment====
*Therapeutic anticoagulation x 6-12 mo
====Anticoagulation====
*Apixaban (Eliquis) 5 mg PO twice per day
12-month course
===References===
#AMPLIFY-EXT: Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. Epub 2012 Dec 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Aspirin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Brighton et al. 2012 (ASPIRE-VTE)	2003-05 to 2011-08 	Phase 3 (E-esc)	Placebo 	Might have higher rate of VTE recurrence (primary endpoint)	No difference in bleeding rate
Becattini et al. 2012 (WARFASA) 	2004-05 to 2010-08 	Phase 3 (E-esc)	Placebo 	Higher 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===
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00222677
#ASPIRE-VTE: Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979-87. Epub 2012 Nov 4. link to original article EuroPMC ACTRN12605000004662
==Dalteparin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Lee et al. 2003 (CLOT)	1999-05 to 2001-10 	Phase 3 (E-switch-ic)	Warfarin 	Higher 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===
#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 EuroPMC
##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 EuroPMC
==Enoxaparin monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Meyer et al. 2002	1995-04-02 to 1999-03-31	Phase 3 (E-switch-ic)	Warfarin 	Might have lower composite VTE/bleeding outcome (primary endpoint)
====Anticoagulation====
*Enoxaparin (Lovenox) 1.5 mg/kg SC once per day
3-month course
===References===
#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 EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 EuroPMC NCT01828697
==Warfarin monotherapy==
===Regimen variant #1, standard intensity===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Meyer et al. 2002 	1995-04-02 to 1999-03-31	Phase 3 (C)	Enoxaparin	Might have lower composite VTE/bleeding outcome	
Lee et al. 2003 (CLOT)	1999-05 to 2001-10 	Phase 3 (C)	Dalteparin	Lower 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 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Ridker et al. 2003 (PREVENT)	1998-07-06 to 2002-12-04	Phase 3 (E-esc)	Placebo 	Lower 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===
#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 EuroPMC
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC
##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 EuroPMC
=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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00643201
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT02585713
#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 EuroPMC NCT03045406
==Argatroban monotherapy==
===Regimen===
====Anticoagulation====
*Argatroban (Acova)
===References===
To be completed
==Aspirin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Weitz et al. 2017 (EINSTEIN CHOICE)	2014-03 to 2016-03 	Phase 3 (C)	1. Rivaroxaban; 10 mg/day2. Rivaroxaban; 20 mg/day	Higher symptomatic recurrent VTE rate	Similar major bleeding
====Preceding treatment====
*6 to 12 months of a vitamin K antagonist or a direct oral anticoagulant
====Anticoagulation====
*Aspirin 100 mg PO once per day
Up to 12-month course
===References===
#EINSTEIN CHOICE: Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02064439
==Bivalirudin monotherapy==
===Regimen===
====Anticoagulation====
*Bivalirudin (Angiomax)
===References===
To be completed
==Dabigatran monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Schulman et al. 2009 (RE-COVER)	2006-04 to 2008-11 	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00291330
#RE-MEDY: Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. link to original article EuroPMC NCT00329238
#RE-COVER II: Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. Epub 2013 Dec 16. link to original article EuroPMC NCT00680186
#DIVERSITY: Halton J, Brandão LR, Luciani M, Bomgaars L, Chalmers E, Mitchell LG, Nurmeev I, Sharathkumar A, Svirin P, Gorbatikov K, Tartakovsky I, Simetzberger M, Huang F, Sun Z, Kreuzer J, Gropper S, Reilly P, Brueckmann M, Albisetti M; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021 Jan;8(1):e22-e33. Epub 2020 Dec 5. link to original article EuroPMC NCT01895777
==Dalteparin monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Francis et al. 2015 (DALTECAN) 	2009-06 to 2011-03 	Non-randomized	 	 	
Young et al. 2018 (SELECT-D) 	2013-09-06 to 2016-12-22	Phase 3 (C) 	Rivaroxaban	Seems to have lower rate of VTE recurrence 	Higher rates of clinically relevant non-major bleeding
Raskob et al. 2017 (Hokusai VTE Cancer)	2015-07 to 2016-12 	Phase 3 (C) 	Edoxaban 	Non-inferior composite primary endpoint of VTE/major bleeding	Non-inferior composite primary endpoint of VTE/major bleeding
Angelli et al. 2020 (CARAVAGGIO) 	2017-04 to 2019-06 	Phase 3 (C) 	Apixaban 	Non-inferior recurrent VTE 	Major bleeding similar in both groups
====Anticoagulation====
*Dalteparin (Fragmin) as follows:
**Month 1: 200 IU/kg SC once per day
**Months 2 to 6 up to 12: 150 IU/kg SC once per day
6- to 12-month course
===References===
#DALTECAN: Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. Epub 2015 May 10. link to original article EuroPMC NCT00942968
#Hokusai VTE Cancer: Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Epub 2017 Dec 12. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02073682
#SELECT-D: Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. link to original article dosing details in abstract have been reviewed by our editors EuroPMC ISRCTN86712308
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT02585713
#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 EuroPMC NCT03045406
==Edoxaban monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Büller et al. 2013 (Hokusai-VTE) 	2010-01 to 2012-10 	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)	2015-07 to 2016-12 	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00986154
##Subgroup analysis: Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. link to original article EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT02073682
==Enoxaparin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kearon et al. 2006 (FIDO)	1998-09 to 2004-02 	Phase 3 (E-switch-ic)	1. Dalteparin2. UFH	No difference in recurrent VTE or major bleeding
====Anticoagulation====
*Enoxaparin (Lovenox) 100 IU/kg SC once every 12 hours
One course
===References===
#FIDO: Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, Jackson S, Turpie AG, MacKinnon B, Hirsh J, Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug 23;296(8):935-42. link to original article EuroPMC NCT00182403
==Fondaparinux monotherapy==
===Regimen===
====Anticoagulation====
*Fondaparinux (Arixtra)
===References===
To be completed
==Heparin monotherapy==
UFH: UnFractionated Heparin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Loewe & Hirsch 1947 	Not reported 	Observational	None 	2.4% fatality rate due to pulmonary embolism
Kearon et al. 2006 (FIDO)	1998-09 to 2004-02 	Phase 3 (C) 	1. Dalteparin2. 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
One course
===References===
#Loewe L, Hirsch E. Heparin in the treatment of thromboembolic disease. JAMA. 1947;133(17):1263-1268. link to original article EuroPMC
#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 EuroPMC 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 	Lower symptomatic recurrent VTE rate (primary endpoint) 	Similar major bleeding
Weitz et al. 2017 (EINSTEIN CHOICE)	2014-03 to 2016-03 	Phase 3 (E-esc)	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 	Lower symptomatic recurrent VTE rate (primary endpoint) 	Similar major bleeding
Weitz et al. 2017 (EINSTEIN CHOICE)	2014-03 to 2016-03 	Phase 3 (E-esc)	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 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Bauersachs et al. 2010 (EINSTEIN Acute DVT)	2007-03 to 2009-09 	Phase 3 (E-switch-ic)	Warfarin 	Non-inferior VTE recurrence (primary endpoint) 	Similar major bleeding
Büller et al. 2012 (EINSTEIN-PE) 	2007-03 to 2011-03 	Phase 3 (E-switch-ic)	Warfarin 	Non-inferior symptomatic VTE recurrence (primary endpoint) 	Similar major bleeding
Young et al. 2018 (SELECT-D) 	2013-09-06 to 2016-12-22	Phase 3 (E-switch-ic)	Dalteparin	Seems to have higher rate of VTE recurrence over 6 months (primary endpoint)	Lower rates of clinically relevant non-major bleeding
====Anticoagulation====
*Rivaroxaban (Xarelto) 15 mg PO twice per day for 3 weeks, then 20 mg PO once per day
3-, 6-, or 12-month course
===References===
#EINSTEIN Acute DVT: Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00440193; NCT00439725
#EINSTEIN-PE: Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00439777
#XALIA: Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol. 2016 Jan;3(1):e12-21. Epub 2015 Dec 8. link to original article EuroPMC NCT01619007
#EINSTEIN CHOICE: Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. Epub 2017 Mar 18. link to original article EuroPMC NCT02064439
#SELECT-D: Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Epub 2018 May 10. link to original article dosing details in abstract have been reviewed by our editors EuroPMC ISRCTN86712308
#EINSTEIN Junior: Male C, Lensing AWA, Palumbo JS, Kumar R, Nurmeev I, Hege K, Bonnet D, Connor P, Hooimeijer HL, Torres M, Chan AKC, Kenet G, Holzhauer S, Santamaría A, Amedro P, Chalmers E, Simioni P, Bhat RV, Yee DL, Lvova O, Beyer-Westendorf J, Biss TT, Martinelli I, Saracco P, Peters M, Kállay K, Gauger CA, Massicotte MP, Young G, Pap AF, Majumder M, Smith WT, Heubach JF, Berkowitz SD, Thelen K, Kubitza D, Crowther M, Prins MH, Monagle P; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e18-e27. Epub 2019 Nov 5. link to original article EuroPMC NCT02234843
==Tinzaparin monotherapy==
===Regimen===
Note: this agent has been withdrawn from the US market.
====Anticoagulation====
*Tinzaparin (Innohep)
===References===
#LITE: Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006 Dec;119(12):1062-72. link to original article EuroPMC
#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 EuroPMC NCT01130025
==Warfarin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Schulman et al. 2009 (RE-COVER) 	2006-04 to 2008-11 	Phase 3 (C)	Dabigatran 	Non-inferior composite endpoint 	Similar major bleeding
Bauersachs et al. 2010 (EINSTEIN Acute DVT)	2007-03 to 2009-09 	Phase 3 (C)	Rivaroxaban	Non-inferior VTE recurrence 	Similar major bleeding
Büller et al. 2012 (EINSTEIN-PE) 	2007-03 to 2011-03 	Phase 3 (C)	Rivaroxaban	Non-inferior symptomatic VTE recurrence (primary endpoint) 	Similar major bleeding
Agnelli et al. 2013 (AMPLIFY) 	2008-08 to 2012-08 	Phase 3 (C)	Apixaban 	Non-inferior composite primary endpoint 	Higher rates of bleeding
Büller et al. 2013 (Hokusai-VTE) 	2010-01 to 2012-10 	Phase 3 (C)	Edoxaban 	Non-inferior recurrent VTE rateSymptomatic VTE rate: 3.5% vs 3.2% untimed rate(HR 1.12, 95% CI 0.88-1.43) 	Higher rates of bleeding
Lee et al. 2015 (CATCH) 	2010-08 to 2013-11 	Phase 3 (C)	Tinzaparin 	Might have higher recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE (composite primary outcome)	Similar major bleeding
====Anticoagulation====
*Warfarin (Coumadin) PO with goal INR between 2 and 3
====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===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00291330
#EINSTEIN Acute DVT: Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00440193; NCT00439725
#EINSTEIN-PE: Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Epub 2012 Mar 26. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00439777
#RE-MEDY: Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18. link to original article EuroPMC NCT00329238
#AMPLIFY: Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. Epub 2013 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00643201
#Hokusai-VTE: Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00986154
##Subgroup analysis: Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI, Zhang G, Lanz H, Mercuri MF, Büller HR; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016 Aug;3(8):e379-87. Epub 2016 Jul 1. link to original article EuroPMC
#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 EuroPMC NCT00680186
#CATCH: Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015 Aug 18;314(7):677-86. link to original article EuroPMC 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
Category:Venous thromboembolism regimens
Category:Disease-specific pages
Category:Thrombotic disorders