Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Martin H Prins, Anthonie Wa Lensing, Rupert Bauersachs, Bonno van Bellen, Henri Bounameaux, Timothy A Brighton, Alexander T Cohen, Bruce L Davidson, Hervé Decousus, Gary E Raskob, Scott D Berkowitz, Philip S Wells, EINSTEIN Investigators, Martin H Prins, Anthonie Wa Lensing, Rupert Bauersachs, Bonno van Bellen, Henri Bounameaux, Timothy A Brighton, Alexander T Cohen, Bruce L Davidson, Hervé Decousus, Gary E Raskob, Scott D Berkowitz, Philip S Wells, EINSTEIN Investigators

Abstract

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.

Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75.

Results: A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy.

Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups.

Trial registration einstein-pe: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.

Figures

Figure 1
Figure 1
Enrolment and outcomes. VKA, Vitamin K antagonist.
Figure 2
Figure 2
Kaplan–Meier curves. a. Primary efficacy outcome, b. Principal safety outcome and c. Major bleeding. VKA, Vitamin K antagonist.
Figure 3
Figure 3
Efficacy and safety outcomes in fragile patients and subgroups. a. Primary efficacy. b. Major bleeding. CI, Confidence interval; HR, Hazard ratio; VKA, Vitamin K antagonist.

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