Background: Apixaban and rivaroxaban are the oral anticoagulants most frequently used to treat acute venous thromboembolism. However, uncertainty remains about the difference in bleeding risk between the two medications.

Methods: In an international trial with a prospective, randomized, open-label, blinded end-point design, we assigned, in a 1:1 ratio, eligible patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis to receive apixaban or rivaroxaban for 3 months. Apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily, and rivaroxaban was given at a dose of 15 mg twice daily for 21 days followed by 20 mg daily. The primary outcome was clinically relevant bleeding, a composite of major bleeding or clinically relevant nonmajor bleeding, as defined according to the International Society on Thrombosis and Haemostasis, during the 3-month trial period. Secondary outcomes included death from any cause.

Results: A total of 2760 patients underwent randomization: 1370 to the apixaban group and 1390 to the rivaroxaban group. A primary-outcome event occurred in 44 of 1345 patients (3.3%) in the apixaban group and 96 of 1355 patients (7.1%) in the rivaroxaban group (relative risk, 0.46; 95% confidence interval [CI], 0.33 to 0.65; P<0.001). Death from any cause occurred in 1 patient (0.1%) in the apixaban group and in 4 patients (0.3%) in the rivaroxaban group (relative risk, 0.25; 95% CI, 0.03 to 2.26). Serious adverse events unrelated to bleeding or venous thrombosis occurred in 36 patients (2.7%) in the apixaban group and in 30 patients (2.2%) in the rivaroxaban group.

Conclusions: Among patients with acute venous thromboembolism, the risk of clinically relevant bleeding was significantly lower with apixaban than with rivaroxaban during the 3-month treatment period. (Funded by the Canadian Institutes of Health Research and others; COBRRA ClinicalTrials.gov number, NCT03266783.).