Once-daily oral rivaroxaban versus placebo in the long-term prevention of recurrent symptomatic venous thromboembolism (2010)


Extended thromboprophylaxis after completing a 6 or 12 months treatment of acute DVT or PE

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To evaluate the efficacy and safety of once-daily rivaroxaban for the secondary prevention of recurrent VTE versus placebo

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Trial design

Randomized, placebo-controlled phase III superiority study
Active treatment: rivaroxaban 20 mg once daily for 6 or 12 months (n=602)
Control treatment: placebo once daily (n=594)

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Primary efficacy endpoint: symptomatic recurrent VTE – the composite of recurrent DVT or fatal or non-fatal PE 
Secondary efficacy endpoint: all-cause mortality, vascular events (acute coronary syndrome, ischemic stroke, transient ischemic attack, or systemic embolism), and net clinical benefit (defined as the composite of the primary efficacy outcome or major bleeding), net clinical benefit (defined as the composite of the primary efficacy outcome or major bleeding)
Primary safety endpoint: major bleeding 
Secondary safety endpoint: adverse events, abnormal laboratory findings

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Trial participants

1197 patients who have previously completed 6 or 12 months of treatment for an acute episode of VTE

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Efficacy outcome: In the intent-to-treat population the primary efficacy endpoint occurred in 8 of 602 patients (1.3%) given rivaroxaban and in 42 of 594 patients (7.1%) given placebo. The outcome of net clinical benefit occurred in 12 (2.0%) of the patients who received rivaroxaban and in 42 (7.1%) of the patients who received placebo
Safety outcome: In the safety population major bleeding occurred in 4 of 598 patients given rivaroxaban (0.7%) and in none of the 590 placebo patients. Clinically relevant non-major bleeding was noted in 32 (5.4%) of the rivaroxaban and in 7 (1.2%) of the placebo recipients, respectively. No patients were observed to have an ALT rise above 3x ULN combined with a total bilirubin above 2x ULN

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Efficacy: Extended treatment with rivaroxaban was superior to placebo in preventing symptomatic recurrent VTE. A prespecified indicator of net clinical benefit (symptomatic recurrent VTE plus major bleeding) favored rivaroxaban
Safety: The incidence of major bleeding was similar in both groups. However, the rate of clinically relevant non-major bleeding was higher in the patients assigned to rivaroxaban

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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 for the EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010;363(26):2499-2510

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Corresponding author

Harry R. Buller, MD, Department of Vascular Medicine, Academic Medical Center, F4-275, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, 
e-mail: h.r.buller@amc.uva.nl

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