Key Points:
- Factor XIa inhibition may reduce stroke risk while causing bleeding.
- In this phase III trial, asundexian, a factor XIa inhibitor, was associated with a higher incidence of stroke or systemic embolism than apixaban but had fewer bleeding events.
Among patients with atrial fibrillation (AF) and an annual stroke risk of at least 2.2%, the guideline-recommended first-line treatment is a direct oral anticoagulant (DOAC) for stroke prevention. However, patients on DOACs have an annual bleeding risk between 2.7% and 3.5%, which may contribute to the underuse of anticoagulation in patients with AF. In the phase II PACIFIC-AF trial, asundexian, a new oral factor XIa inhibitor, showed a significant reduction in bleeding compared to apixaban.1 Building on these findings, the OCEANIC AF trial, a large phase III study, tested whether asundexian could prevent stroke and systemic embolism to the same extent as apixaban.
The trial sponsor, Bayer, announced the early termination of the trial in November 2023 based on the recommendation of the study’s Independent Data Monitoring Committee (IDMC) after ongoing surveillance showed inferior efficacy of asundexian compared to the control arm. On September 1, 2024, Dr. Manesh Patel from Duke University Medical Center, USA, presented the results of the OCEANIC-AF trial in a Hot Lines session with simultaneous publication in NEJM.
In this double-blind, randomized trial, patients with AF who met guideline recommendations for anticoagulation (CHA2DS2-VASc score ≥2 for men or ≥3 for women) were randomized 1:1 to receive asundexian 50 mg once daily or standard dosing with apixaban (5 mg or 2.5 mg twice daily based on dose-reduction criteria). The primary efficacy and safety endpoints were the prevention of stroke or systemic embolism and the reduction of major bleeding, respectively.
At the time of trial termination, 14,830 patients (out of a planned 18,000) had been randomized (mean age 73.9 years, 35% women). The average CHA2DS2-VASc score was 4.3, and 17% had previously taken an oral anticoagulant for 6 weeks or less. Compared to apixaban, patients on asundexian had a significantly higher risk of stroke or systemic embolism (1.3% vs. 0.4%; HR 3.79 [95% CI 2.46–5.83]). Cardiovascular and all-cause death rates were similar in both arms. In the safety population (at the end of treatment plus 2 days), ISTH major bleeding (the primary safety end point) occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55).
Primary investigator Dr. Patel commented, “Our results show that the dose of asundexian tested was inferior for preventing stroke or systemic embolism compared with apixaban. We could speculate that near-total factor XIa suppression may be needed to prevent thrombus formation. We also noted a lower-than-expected rate of stroke or systemic embolism in the apixaban group, which may reflect prior use of oral anticoagulants and improved medical therapy. Finally, we demonstrated lower bleeding rates with asundexian, which has to be put into context with the stroke findings. There remains a need for better antithrombotic therapy for AF with a lower bleeding risk than current DOACs.”
References:
- Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399(10333):1383-1390. doi:10.1016/S0140-6736(22)00456-1