OCEANIC-AF: Asundexian Patients Have Nearly 4x Stroke, Embolism Risk vs Apixaban Patients

Manesh Patel, MD
Credit: Duke Heart

The OCEANIC-AF trial has missed its primary endpoint, with use of asundexian nearly quadrupling the risk of stroke or systemic embolism compared with apixaban among high-risk patients with atrial fibrillation.

Presented at the European Society of Cardiology (ESC) Congress 2024, results of the study demonstrate the factor XIa inhibitor failed to achieve its primary endpoint but was associated with a reduction in major bleeding events relative to apixaban.

“Our results show that the dose of asundexian tested was inferior for stroke or systemic embolism compared with apixaban,” said principal investigator Manesh Patel, MD, Chief of the Division of Cardiology and the Division of Clinical Pharmacology. 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 were able to demonstrate lower bleeding rates with asundexian, which has to be put into context with the stroke findings.”

After proving successful in its phase 2 PACIFIC-AF trial, in addition to movement from the therapeutic pipeline for other factor XI inhibitors, many in cardiology looked ahead with optimism that phase 3 readouts might signal the age of a new era in antithrombotic therapy. Born out of the wake of the PACIFIC-AF trial, OCEANIC-AF was a phase 3, international, double-blind trial conducted at 1035 sites in 38 countries.

For inclusion in the trial, patients needed to be at least 18 years of age, have atrial fibrillation documented by electrocardiography with an indicate for indefinite treatment with an oral anticoagulant. Additional inclusion criteria required patients to have a CHA2 DS2-VASc score of 3 or more for men or 4 or more for women. Per trial protocol, eligible patients underwent randomization within 14 days of screening and were randomized in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or a standard dose of apixaban.

The primary efficacy outcome was the noninferiority of asundexian for stroke or systemic embolism, which investigators assessed in randomly assigned patients on an intention-to-treat basis. The primary safety outcome was ISTH major bleeding. Investigators noted the use of a net clinical benefit measure, which was a composite of stroke, systemic embolism, or ISTH major bleeding.

Overall, 14,810 patients underwent randomization and were included in the trial’s intention-to-treat population. This cohort had a mean age of 73.9 (SD, 7.7) years, 35.2% were women, and the mean CHA2DS2-VASc score was 4.3 (SD, 1.3). Baseline characteristics also indicated 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, and 16.8% had received oral anticoagulants for no more than 6 weeks.

Designed as an event-driven trial, OCEANIC-AF was stopped early at the recommendation of the independent data monitoring committee.

Results of the trial indicated the primary efficacy outcome occurred among 98 (1.3%) in the asundexian group and 26 (0.4%) in the apixaban group (Hazard Ratio [HR], 3.79; 95% Confidence Interval [CI], 2.46 to 5.83).

Analysis of the safety outcome revealed major bleeding occurred among 17 (0.2%) in the asundexian group and among 53 (0.7%) in the apixaban group (HR, 0.32; 95% CI, 0.18 to 0.55). When assessing the composite net clinical benefit endpoint, investigators found a 61% relative risk increase for asundexian relative to apixaban for stroke, systemic embolism, or ISTH major bleeding (HR, 1.61; 95% CI, 1.21 to 2.15).

Further safety analyses revealed adverse events occurred among 34.9% of each group, with adverse events leading to discontinuation occurring among 2.0% and 1.6% of the asundexian and apixaban groups, respectively.

“There remains a need for better antithrombotic therapy for AF with lower bleeding risk than current DOACs,” Patel added.

References:

1. JP Piccini, MR Patel, J Steffel, et al. Asundexian versus Apixaban in Patients with Atrial Fibrillation. Presented at: European Society of Cardiology Congress 2024. August 30 - September 2, 2024. London, UK.
2. 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