Apixaban reduced the risk for bleeding compared with rivaroxaban in the treatment of acute venous thromboembolism (VTE), the randomized COBRRA trial found, confirming observational and indirect signals of greater safety without a decrement in efficacy.

“This landmark trial provides the first evidence from a randomized, head-to-head comparison to guide clinicians in choosing between the two most prescribed anticoagulants for acute venous thromboembolism,” said Lisa K. Moores, MD, of the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

Clinically relevant bleeding occurred in 3.3% of apixaban-treated patients vs 7.1% of rivaroxaban-treated patients — a 54% relative reduction in risk at 3 months (P < .001).

This difference favoring apixaban held for both major and clinically relevant nonmajor bleeding (0.4% vs 2.4%; relative risk [RR], 0.16; 95% CI, 0.06-0.40) and clinically relevant nonmajor bleeding (2.9% vs 4.9%; RR, 0.59; 95% CI, 0.40-0.86).

In terms of efficacy, though, apixaban and rivaroxaban presented nearly identical risk for recurrent symptomatic VTE (1.1% vs 1.0%; RR, 1.08; 95% CI, 0.52-2.23). Mortality and other adverse events were also similar between groups, reported researchers led by Lana Castellucci, MD, of The Ottawa Hospital in Ottawa, Ontario, Canada.

Settling a Long-Running Question

Which direct oral anticoagulant (DOAC) is the safest has been a clinical question for over a decade, she wrote in an editorial accompanying the paper, which was published online on March 11 in The New England Journal of Medicine.

“Until now, the preference for one direct oral anticoagulant over another was based largely on indirect comparisons,” Moores wrote.

Pivotal trials pitting the DOACs against vitamin K antagonists showed a 4.3% risk for clinically relevant bleeding with apixaban in the AMPLIFY trial for initial VTE treatment and an 8.1% and 10.3% risk with rivaroxaban in the EINSTEIN-DVT and EINSTEIN-PE trials, respectively. However, differences in the trial designs and heterogeneity in the patient populations precluded direct comparison, Moores wrote.

Observational data and meta-analyses reinforced this apparent difference but faced likely confounding in the types of patients selected for one treatment vs another, Castellucci told Medscape Medical News. Thus, clinical guidelines remained neutral as to DOAC selection.

Changes Likely to Come

But that probably will change now along with a shift in insurance coverage, speculated Behnood Bikdeli, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston. Bikdeli was not involved in the trial.

“Simply put, I think it’s very difficult to make a case to put patients on the current regimen of rivaroxaban” in this setting, he told Medscape Medical News.

Even if guideline uptake takes a year or two, “I do think that it is practice-changing research that…lends itself well to immediate uptake,” Castellucci said.

After the initial presentation of the findings in July 2025 at the International Society on Thrombosis and Haemostasis Congress, Castellucci said she saw an immediate response: “People’s order sets have started to change, and they are preferentially using apixaban when they can. It is simply a matter of time before that shift becomes almost complete.”

COBRRA Data and Limitations

The COBRRA trial enrolled 2760 participants treated at 32 sites across Canada, Australia, and Ireland for acute symptomatic pulmonary embolism or proximal deep vein thrombosis.

Participants were randomly assigned to receive 3 months of treatment with either apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily) or rivaroxaban (15 mg twice daily for 21 days followed by 20 mg daily).

And it’s that difference in dosing — with an extended high-dose phase for rivaroxaban and a once-daily schedule that might lead to more peaks and troughs in drug concentration — that might be to blame for the risk for excess bleeding, argued Bikdeli.

Although the trial was limited by its short 3-month follow-up period, that probably was the right period to show a difference as many patients transition to lower-intensity anticoagulation long term after the acute phase of VTE treatment, Bikdeli said.

The overwhelmingly White population was a limitation as well.

The question now is how the DOACs stack up in other settings, particularly in thromboembolic prevention in atrial fibrillation, where there is no loading dose for these drugs as a potential driver of difference, Bikdeli said. The randomized COBRRA-AF trial is underway by Castellucci’s group to guide practice in that setting.

The study was supported by grants from the Canadian Institutes of Health Research and the Medical Research Future Fund International Clinical Trial Collaborations in Australia, by in-kind support from the Royal College of Surgeons in Ireland, and by the International Network of Venous Thromboembolism Clinical Research Networks.

Castellucci disclosed having relationships with Bayer, Bristol Myers Squibb/Pfizer, Inari Medical, Valeo Pharma, The Ottawa Hospital, and Medscape. Bikdeli disclosed having no relevant relationships with industry. Moores disclosed having relationships with CHEST and the American College of Chest Physicians, as well as having served on the Data Safety Monitoring Board for the NAIL-IT trial.

Crystal Phend is an award-winning medical journalist with decades of experience reporting on clinical research and healthcare developments across specialties. When not walking the halls at a medical conference, she can be found at a keyboard in upstate New York.