Apixaban Snags a Win in Head-to-Head Trial of Direct Oral Anticoagulants

One winner emerged from a direct comparison of direct oral anticoagulants (DOACs) for patients with acute venous thromboembolism, based on the COBRRA randomized trial.

Safety events favored apixaban (Eliquis) over rivaroxaban (Xarelto), as apixaban was associated with significantly less clinically relevant bleeding over 3 months (a composite of major bleeding or clinically relevant nonmajor bleeding events; 3.3% vs 7.1%, relative risk [RR] 0.46, 95% CI 0.33-0.65), according to a team led by Lana Castellucci, MD, of Ottawa Hospital in Ontario.

The secondary endpoint of all-cause death was also lower with apixaban (0.1% vs 0.3%, RR 0.25, 95% CI 0.03-2.26), while recurrent symptomatic venous thromboembolism was about the same between groups (1.1% vs 1.0%, RR 1.08, 95% CI 0.52-2.23). No deaths attributed to recurrent venous thromboembolism occurred in the trial’s 3 months.

The 2,700-person COBRRA trial was published in the New England Journal of Medicine. Results had previously been presented at the International Society on Thrombosis and Haemostasis annual meeting.

“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,” according to Lisa Moores, MD, of Uniformed Services University of the Health Sciences in Bethesda, Maryland, who is also president-elect of the American College of Chest Physicians.

“By confirming the safety advantage of apixaban over rivaroxaban in a randomized trial, these results should prompt a reevaluation of current guidelines. For many patients with acute venous thromboembolism, the choice of anticoagulant is no longer a toss-up. Apixaban is a safer first-line option than rivaroxaban for minimizing the risk of bleeding without compromising the prevention of recurrent thrombosis,” she wrote in an accompanying editorial.

Anticoagulation therapy is recommended for a minimum 3 months after venous thromboembolism to prevent recurrent thrombotic events. While DOACs are strongly endorsed by clinical guidelines, there has been no clear preference for one DOAC over another due to a lack of direct comparison trials.

The observed lower bleeding risk of apixaban shouldn’t be taken at face value, however.

In COBRRA, apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily, whereas rivaroxaban was given at 15 mg twice daily for 21 days followed by 20 mg daily. Complete adherence to study treatment was reported by 65.7% of apixaban users and by 75.1% of the rivaroxaban group.

“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,” Moores commented. “Essentially, the extra 14 days of high-intensity therapy in the rivaroxaban group appears to have intensified the antithrombotic effect, leading to an increased risk of bleeding without enhancing efficacy.”

She also cited pharmacokinetics as another potential driver of increased bleeding after rivaroxaban use, with the 20-mg once-daily maintenance dose of rivaroxaban associated with higher peak plasma concentrations than the 5-mg twice-daily maintenance dose of apixaban.

“Further evaluation in clinical trials is needed to confirm whether the rivaroxaban dosing regimen contributed to the observed bleeding risks,” Castellucci and colleagues acknowledged.

Their COBRRA open-label trial was conducted in Canada, Australia, and Ireland.

There were 2,760 adult patients randomized to apixaban or rivaroxaban treatment for 3 months for venous thromboembolism. Candidates were excluded if they had received therapeutic anticoagulation therapy for more than 72 hours immediately before the enrollment visit, had more severe renal insufficiency, or weighed over 120 kg (265 lbs), among other exclusion criteria.

Study authors reported that apixaban and rivaroxaban groups were ultimately well balanced at baseline. Mean age was 58.3 years, 43.5% were women, and 10% were non-white. Nearly 16% had a history of venous thromboembolism.

The index venous thromboembolism event was unprovoked in 77.3% of cases. Additionally, 52.2% of participants had deep vein thrombosis alone, and 47.8% had pulmonary embolism.

Serious adverse events unrelated to bleeding or venous thrombosis reached 2.7% in the apixaban group versus 2.2% of rivaroxaban group.

Castellucci and colleagues acknowledged that COBRRA’s open-label design could have introduced some bias to their analysis. Additionally, the study was limited by the exclusion of certain patients and the total follow-up lasting just 3 months.

COBRRA-AF, a separate trial comparing apixaban and rivaroxaban in atrial fibrillation, is currently underway.