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Reduced-Intensity Rivaroxaban for the Prevention of Recurrent Venous Thromboembolism

New England Journal of Medicine, Ahead of Print. <br/>
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Editorial

Mark A. Crowther, M.D., and Adam Cuker, M.D.

March 18, 2017DOI: 10.1056/NEJMe1701628

Article

Warfarin and direct oral anticoagulant agents prevent recurrent venous thromboembolism. When a first episode of venous thromboembolism occurs in association with a transient risk factor (e.g., surgery), treatment can be stopped after 3 months. With persistent and strong risk factors, such as cancer, therapy should be continued indefinitely.1 Prolonged anticoagulation therapy is now suggested for most patients with unprovoked venous thromboembolism. Cessation of therapy after 3 to 6 months may be recommended in some female patients who are judged to be at low risk for recurrence,2 in patients at high risk for bleeding, and in patients with poor adherence or an aversion to anticoagulation therapy.

Various strategies have been studied to reduce the cost, complexity, and toxicity of long-term anticoagulation therapy. Reduced-intensity warfarin proved to be less efficacious than standard-intensity warfarin in randomized, controlled trials.3,4 Aspirin reduces the risk of recurrent venous thromboembolism, as compared with placebo, but recurrence rates remain substantial (5.1% per year) with aspirin.5

The direct oral anticoagulant agents do not require routine laboratory monitoring or dose adjustment, have fewer interactions with other drugs or food than warfarin, and are associated with a lower risk of most forms of bleeding.6 These advantages render this class of drugs attractive for long-term secondary prevention of venous thromboembolism.

Agnelli and colleagues assigned patients with venous thromboembolism who had received 6 to 12 months of anticoagulation therapy to receive apixaban at a dose of 2.5 mg or 5 mg twice daily or placebo.7 Symptomatic recurrent fatal or nonfatal venous thromboembolism occurred in 1.7% of the patients who received either of the two doses of apixaban and in 8.8% of those who received placebo. Major bleeding was numerically more common in the placebo group but was infrequent in all three groups.

Weitz and colleagues now report in the Journal additional information on a reduced-dose direct oral anticoagulant agent for the prevention of recurrent venous thromboembolism.8 They enrolled 3365 patients who had undergone 6 to 12 months of initial anticoagulation therapy and in whom there was equipoise with respect to the need for ongoing treatment. Patients were randomly assigned to receive once-daily rivaroxaban at doses of 20 mg or 10 mg or aspirin. After a median of 351 days, symptomatic recurrent fatal or nonfatal venous thromboembolism or unexplained death occurred in 17 of the 1107 patients (1.5%) who were assigned to receive 20 mg of rivaroxaban, in 13 of 1127 (1.2%) who were assigned to receive 10 mg of rivaroxaban, and in 50 of 1131 (4.4%) who were assigned to receive aspirin. Major or clinically relevant nonmajor bleeding occurred in 3.3%, 2.4%, and 2.0% of the patients, respectively.

How should clinicians interpret the results of this trial? First, after an initial treatment course at usual therapeutic doses, clinicians now have good-quality evidence to support the use of long-term, reduced-intensity anticoagulation therapy with rivaroxaban. Such treatment reduces the risk of recurrent venous thromboembolism, as compared with low-dose aspirin, without increasing major bleeding. Second, the favorable safety and efficacy profile of reduced-intensity rivaroxaban may lead to questions about how patients with provoked venous thromboembolism should be treated. After a first provoked event, recurrent venous thromboembolism occurred in 9 of 666 patients (1.4%) who were assigned to receive 20 mg of rivaroxaban, in 6 of 647 (0.9%) who were assigned to receive 10 mg of rivaroxaban, and in 24 of 663 (3.6%) who were assigned to receive aspirin. Given the protection from recurrent venous thromboembolism afforded by reduced-dose rivaroxaban, extending treatment beyond 3 months could be considered in patients with provoked venous thromboembolism who are at average risk for bleeding and who are strongly averse to having another episode of venous thromboembolism. In light of the safety profile of low-dose rivaroxaban, the benefit of this strategy does not need to be large in order to justify the extension of therapy. Third, this trial suggests that it would be helpful to evaluate the effect of reduced doses of rivaroxaban within 6 months after an episode of venous thromboembolism.

The results of this trial cannot be extended to patients who have an unequivocal indication for long-term anticoagulation therapy and who thus were ineligible to participate in the trial. Such patients are an important group in whom the efficacy of reduced-intensity therapy remains untested. For patients who are unable to afford direct oral anticoagulant agents, adjusted-dose warfarin remains an acceptable alternative for long-term secondary prevention of venous thromboembolism.

The emergence of rivaroxaban and other direct oral anticoagulant agents has altered the standard of care among patients with venous thromboembolism. For patients without cancer, the use of direct oral anticoagulant agents might be considered as first-line treatment for those with acute venous thromboembolism.1 Full-dose treatment could be continued for a minimum of 3 to 6 months. In patients in whom there is equipoise with respect to continuing anticoagulant therapy beyond this period, the use of a reduced-intensity direct oral anticoagulant agent might be considered. Clinicians who choose this strategy can be confident of excellent efficacy and low bleeding risk similar to that observed with aspirin or placebo.

Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.

This editorial was published on March 18, 2017, at NEJM.org.

Source Information

From the Departments of Pathology and Molecular Medicine, Medicine, and Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada (M.A.C.); and the Departments of Medicine and Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.C.).

References

References

  1. 1

    Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-352
    CrossRef | Web of Science | Medline

  2. 2

    Rodger MA, Scarvelis D, Kahn SR, et al. Long-term risk of venous thrombosis after stopping anticoagulants for a first unprovoked event: a multi-national cohort. Thromb Res 2016;143:152-158
    CrossRef | Web of Science | Medline

  3. 3

    Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-639
    Free Full Text | Web of Science | Medline

  4. 4

    Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434
    Free Full Text | Web of Science | Medline

  5. 5

    Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014;130:1062-1071
    CrossRef | Web of Science | Medline

  6. 6

    Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450-2458
    CrossRef | Web of Science | Medline

  7. 7

    Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708
    Free Full Text | Web of Science | Medline

  8. 8

    Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. DOI: 10.1056/NEJMoa1700518

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