Download PDF
Thromb Haemost 2019; 119(05): 689-694
DOI: 10.1055/s-0039-1679906
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials

Jeffrey I. Weitz
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Noel C. Chan
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

21 September 2018

10 January 2019

Publication Date:
26 February 2019 (online)

   Permissions and Reprints

Abstract

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.

The non-VKA oral anticoagulants (NOACs)—apixaban, dabigatran, edoxaban and rivaroxaban—simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

Keywords

venous thromboembolism - anticoagulation - extended therapy - rivaroxaban - acetylsalicylic acid
 

  • References

  • 1 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 2 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA. ; Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14 (07) 1480-1483
    CrossrefPubMedGoogle Scholar
  • 3 Kuipers S, Schreijer AJ, Cannegieter SC, Büller HR, Rosendaal FR, Middeldorp S. Travel and venous thrombosis: a systematic review. J Intern Med 2007; 262 (06) 615-634
    CrossrefPubMedGoogle Scholar
  • 4 Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute stroke. Stroke 2001; 32 (01) 262-267
    CrossrefPubMedGoogle Scholar
  • 5 Goldhaber SZ, Grodstein F, Stampfer MJ. , et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277 (08) 642-645
    CrossrefPubMedGoogle Scholar
  • 6 Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375 (9715): 657-663
    CrossrefPubMedGoogle Scholar
  • 7 Nguyen GC, Bernstein CN, Bitton A. , et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology 2014; 146 (03) 835-848
    CrossrefPubMedGoogle Scholar
  • 8 Bauersachs RM, Lensing AWA, Prins MH. , et al. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J 2014; 12: 25-32
    CrossrefPubMedGoogle Scholar
  • 9 Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev 2006; (01) CD001367
    PubMedGoogle Scholar
  • 10 Simes J, Becattini C, Agnelli G. , et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 11 Gómez-Outes A, Lecumberri R, Suárez-Gea ML, Terleira-Fernández AI, Monreal M, Vargas-Castrillón E. Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther 2015; 20 (05) 490-500
    CrossrefPubMedGoogle Scholar
  • 12 Weitz JI, Lensing AWA, Prins MH. , et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
    CrossrefPubMedGoogle Scholar
  • 13 Bauersachs R, Berkowitz SD, Brenner B. , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 14 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 15 Schulman S, Kearon C, Kakkar AK. , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedGoogle Scholar
  • 16 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar
  • 17 Raskob G, Ageno W, Cohen AT. , et al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016; 3 (05) e228-e236
    PubMedGoogle Scholar
  • 18 Lee AY, Levine MN, Baker RI. , et al; 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; 349 (02) 146-153
    CrossrefPubMedGoogle Scholar
  • 19 Raskob GE, van Es N, Verhamme P. , et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
    CrossrefPubMedGoogle Scholar
  • 20 Young AM, Marshall A, Thirlwall J. , et al. 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; 36 (20) 2017-2023
    CrossrefPubMedGoogle Scholar
  • 21 Khorana AA, Noble S, Lee AYY. , et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1891-1894
    CrossrefPubMedGoogle Scholar
  • 22 Becattini C, Agnelli G, Schenone A. , et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366 (21) 1959-1967
    CrossrefPubMedGoogle Scholar
  • 23 Brighton TA, Eikelboom JW, Mann K. , et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367 (21) 1979-1987
    CrossrefPubMedGoogle Scholar
  • 24 Castellucci LA, Cameron C, Le Gal G. , et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ 2013; 347: f5133
    CrossrefPubMedGoogle Scholar
  • 25 Sobieraj DM, Coleman CI, Pasupuleti V, Deshpande A, Kaw R, Hernandez AV. Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: a network meta-analysis. Thromb Res 2015; 135 (05) 888-896
    CrossrefPubMedGoogle Scholar
  • 26 Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, Crowther M. Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2018; 16 (07) 1288-1295
    CrossrefPubMedGoogle Scholar
  • 27 Prandoni P, Lensing AWA, Prins MH. , et al. Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin. Thromb Res 2018; 168: 121-129
    CrossrefPubMedGoogle Scholar
  • 28 Kearon C, Ginsberg JS, Kovacs MJ. , et al; 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; 349 (07) 631-639
    CrossrefPubMedGoogle Scholar
  • 29 Bayer AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2018. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf . Accessed October 16, 2018
    PubMedGoogle Scholar
  • 30 Prins MH, Lensing AWA, Prandoni P. , et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018; 2 (07) 788-796
    CrossrefPubMedGoogle Scholar