For patients undergoing treatment for acute venous thromboembolism (VTE), a new study offers clearer guidance on anticoagulant selection. Results from the COBRRA trial demonstrate that apixaban (Eliquis; Bristol Myers Squibb) significantly reduces the risk of clinically relevant bleeding compared to rivaroxaban (Xarelto; Bayer/Janssen), without compromising efficacy in preventing recurrent VTE. This finding addresses a long-standing question regarding the safety profiles of these commonly used medications.
The landmark study, published in the March 12/19, 2026, issue of the New England Journal of Medicine, provides the first head-to-head comparison of the two direct oral anticoagulants (DOACs). For years, clinicians have faced uncertainty in choosing between apixaban and rivaroxaban, both proven effective but with lingering questions about bleeding risk. The COBRRA trial now suggests apixaban is a safer first-line option for minimizing bleeding without increasing the risk of thrombosis.
Researchers randomized over 2,700 patients with acute symptomatic pulmonary embolism (PE) or proximal deep vein thrombosis (DVT) across 32 centers in three countries. The primary outcome – clinically relevant bleeding, encompassing both major and non-major bleeding events – occurred in 3.3% of patients treated with apixaban, compared to 7.1% in the rivaroxaban group, representing a relative risk reduction of 54% (RR 0.46; 95% CI 0.33-0.65). “As much as we were expecting to see a bleeding difference, I don’t think any of us expected to see that much of a bleeding difference,” said lead author Lana A. Castellucci, MD, of the University of Ottawa/Ottawa Hospital, as reported by TCTMD.
COBRRA Trial Details and Findings
The COBRRA trial involved 2,760 participants (mean age 58.3 years; 43.5% female) who received either apixaban (10 mg twice daily for 7 days, then 5 mg twice daily) or rivaroxaban (15 mg twice daily for 21 days, then 20 mg daily) between December 2017 and January 2025. A majority of patients (77.3%) had an unprovoked VTE, while 15.9% had a prior history of VTE. The study population was evenly split between those with DVT alone (52.2%) and those with PE, with or without DVT (47.8%).
The rate of major bleeding was substantially lower with apixaban (0.4%) compared to rivaroxaban (2.4%; RR 0.16; 95% CI 0.06-0.40). Clinically relevant nonmajor bleeding also occurred less frequently in the apixaban group (2.9% vs. 4.9%; RR 0.59; 95% CI 0.40-0.86). Importantly, there were no statistically significant differences observed in rates of recurrent symptomatic VTE (1.1% vs. 1.0%; RR 1.08; 95% CI 0.52-2.23) or all-cause death (0.1% vs. 0.3%; RR 0.25; 95% CI 0.03-2.26) between the two treatment groups. No deaths were attributed to bleeding or recurrent VTE.
Dosing Regimen and Implications for Guidelines
The difference in bleeding risk appears to be linked to the dosing regimens of the two medications. Lisa K. Moores, MD, of the Uniformed Services University of the Health Sciences, wrote in an accompanying editorial that the prolonged high-dose phase of rivaroxaban may have contributed to the increased bleeding risk. “Data from the trial suggest that this prolongation of the loading-dose phase by 2 weeks in the rivaroxaban group was a primary driver of the disparity in safety outcomes,” she noted.
While rivaroxaban remains a viable option, particularly for patients who prefer a once-daily regimen, Dr. Castellucci suggests that apixaban’s safer profile makes it a preferable choice for most patients initiating anticoagulant treatment for acute VTE. Gregory Piazza, MD, of Brigham and Women’s Hospital, who was not involved in the study, echoed this sentiment, stating that the COBRRA trial provides critical data to inform clinical decision-making. He cautioned, however, that individual patient factors may still influence treatment selection.
The findings from the COBRRA trial are expected to prompt a review of current clinical practice guidelines for the management of VTE. Researchers are also continuing to investigate the optimal use of these medications in other contexts, such as stroke prevention in atrial fibrillation through the ongoing COBRRA-AF trial.
Disclaimer: This article provides informational content and should not be considered medical advice. Always consult with a qualified healthcare professional for diagnosis and treatment of any medical condition.
What are your thoughts on these new findings? Share your perspective in the comments below and please share this article with your network.
