Apixaban Bests Rivaroxaban for Bleeding in VTE: COBBRA

Patients treated with apixaban (Eliquis; Bristol Myers Squibb) for 3 months after acute venous thromboembolism (VTE) report more than half the rate of clinically relevant bleeding compared with those taking rivaroxaban (Xarelto; Bayer/Janssen), according to results from the COBRRA trial.

The lower risk of bleeding comes without any trade-off in efficacy, including risk of recurrent VTE. 

The findings, published in the March 12/19, 2026, issue of the New England Journal of Medicine, indicate a clear benefit of using one direct oral anticoagulant (DOAC) over another following years of uncertainty.

Among more than 2,700 patients randomized to either drug at one of 32 centers throughout three countries, the primary outcome of clinically relevant bleeding—including ISTH major or clinically relevant nonmajor bleeding—occurred in 3.3% of those taking apixaban and 7.1% of the rivaroxaban group (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,” lead author Lana A. Castellucci, MD (University of Ottawa/Ottawa Hospital, Canada), told TCTMD. “COBRRA adds a ton of valuable information for acute VTE, and I think that the best information that we could have hoped for was achieved.”

In an accompanying editorial, Lisa K. Moores, MD (Uniformed Services University of the Health Sciences, Bethesda, MD), writes that the findings should spur a review of current guidelines in this space. “For many patients with acute venous thromboembolism, the choice of anticoagulant is no longer a toss-up,” she says. “Apixaban is a safer first-line option than rivaroxaban for minimizing the risk of bleeding without compromising the prevention of recurrent thrombosis.”

Gregory Piazza, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the study, said COBRRA represents a trial that the community was “waiting on” to help make clinical decisions in this space. “Of course, this doesn’t mean we get rid of all the options because for some patients there may be a reason why one is preferred over the other,” he told TCTMD. “But I think for the general population in whom we’re starting anticoagulation, these types of data are critical.”

COBRRA Findings

For the trial, researchers randomized 2,760 patients (mean age 58.3 years; 43.5% female) with acute symptomatic pulmonary embolism (PE) or proximal deep vein thrombosis (DVT) to treatment with either apixaban (n = 1,345; 10 mg twice daily for 7 days followed by 5 mg twice daily) or rivaroxaban (n = 1,355; 15 mg twice daily for 21 days followed by 20 mg daily) between December 2017 and January 2025.

Most patients (77.3%) had an unprovoked VTE, and 15.9% had a history of VTE. The split was even between those who had DVT alone (52.2%) and patients who had PE with or without DVT (47.8%).

The rate of major bleeding was substantially lower in the apixaban-treated patients compared with those taking rivaroxaban (0.4% vs 2.4%; RR 0.16; 95% CI 0.06-0.40). A similar pattern emerged with clinically relevant nonmajor bleeding (2.9% vs 4.9%; RR 0.59; 95% CI 0.40-0.86).

There were no significant differences in the rates of recurrent symptomatic VTE (1.1% vs 1.0%; RR 1.08; 95% CI 0.52-2.23) and all-cause death (0.1% vs 0.3%; RR 0.25; 95% CI 0.03-2.26). No deaths were attributed to either bleeding or recurrent VTE.

Notably, complete adherence to the assigned drug was reported by 65.7% of those assigned to apixaban and 75.1% in the rivaroxaban group.

Dosing, Generalizability

Part of the motivation in conducting this head-to-head comparison in an academic fashion is that industry would likely never fund such a study, Castellucci said. “Many years ago, when rivaroxaban and apixaban were first approved for treatment of DVT and PE, these were very new trials that had been completed and [they] compared those anticoagulants to our standard anticoagulant, which was warfarin,” she said. “None of the information from these trials was really able to give us information about a preference for one direct oral anticoagulant over the other.”

It’s likely that the different dosing regimens played a role in the final outcome, according to Castellucci. “There was early separation of the number of bleeding events between the two arms with more events in the rivaroxaban group, where the dosing strategy is different,” she said.

Moores agreed. “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 writes. “The extended high-dose phase of rivaroxaban might have resulted in a higher burden of bleeding without a corresponding increase in protection against thrombosis.”

In Castellucci’s opinion, rivaroxaban is still an option for some preferring the convenience of a once-daily dosing regimen, “but I think for the most part if anybody is considering a direct oral anticoagulant for treatment of acute VTE, apixaban really is showing a safer profile, and I think the majority of patients will receive apixaban,” she said.

Also, she added, while the study was included almost 90% white patients, it’s likely the results still apply to other ethnicities. “For the most part, the principles of medication selection are fairly standard across different ethnic groups,” Castellucci said. “Looking at the individual patient, what their other medications are, and bleeding risk—we look at all of those factors combined.”

The ongoing COBRRA-AF trial will hopefully give more information on how these drugs can best be used for stroke prevention in a population of patients with atrial fibrillation, she added.

Piazza would also like to see more work done examining “patients that have malignancy and thrombosis and what’s the best DOAC management plan for them,” he said. “We’re happy to know that DOACs like apixaban are good options for them, but we really could benefit from these [other] types of head-to-head analyses.”