Results of prematurely stopped OCEANIC-AF trial on asundexian in AF

ESC 2024 – In AF patients at high stroke risk, the factor XIa inhibitor asundexian was associated with a higher risk of stroke or systemic embolism than apixaban, leading to premature termination of the trial. Asundexian did lead to fewer major bleeding events than apixaban.

This summary is based on the presentation of Manesh Patel, MD (Durham, NC, USA) at the ESC Congress 2024 - OCEANIC-AF - Asundexian versus apixaban in patients with atrial fibrillation.

Introduction and methods

Many patients with AF do not receive anticoagulation therapy because of bleeding events or fear thereof. In the AF population, there is a need for effective anticoagulation that prevents stroke but has a lower bleeding risk than DOACs or VKAs. A potential candidate is asundexian, an oral, direct, selective small-molecule inhibitor of activated factor XI (XIa). Previously, the phase 2 PACIFIC-AF trial showed treatment with asundexian was associated with a decreased incidence of bleeding events compared with apixaban treatment.

The OCEANIC-AF trial was an international, double-blind, double-dummy, parallel-group, event-driven, phase 3 RCT in which 14,810 AF patients with increased risk of stroke (CHA₂DS₂-VASc score ≥3 in men and ≥4 in women) were randomized to asundexian 50 mg once daily or apixaban at standard dose (5 or 2.5 mg twice daily). The target study population size was 18,000 patients based on reaching 340 primary efficacy endpoint events within 33 months at an incidence rate of 1.5 (90% power).

The primary efficacy endpoint was the occurrence of stroke or systemic embolism. The primary safety endpoint was the incidence of major bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH). The primary net clinical benefit endpoint was a composite outcome of stroke, systemic embolism, or ISTH major bleeding. The study was powered to assess the noninferiority of asundexian compared with apixaban for the prevention of primary efficacy endpoint and the superiority of asundexian with respect to the primary safety and primary net clinical benefit endpoints.

At the recommendation of the Independent Data Monitoring Committee, the trial was stopped prematurely because of an increased incidence of the primary efficacy endpoint in the asundexian arm compared with the apixaban arm. Median-follow-up time was 155 days.

Main results

• The primary efficacy endpoint of stroke or systemic embolism occurred in 98 patients (1.3%) receiving asundexian (n=7415) and 26 patients (0.4%) assigned to apixaban (n=7395) (HR: 3.79; 95%CI: 2.46–5.83).
• The incidence of the primary safety endpoint of major bleeding was lower in the asundexian group than in the apixaban group (0.2% vs. 0.7%; HR: 0.32; 95%CI: 0.18–0.55).
• The rate of the primary net clinical benefit endpoint was increased in the asundexian group compared with the apixaban group (1.6% vs. 1.0%; HR: 1.61; 95%CI: 1.21–2.15).
• The all-cause mortality rate did not differ between the asundexian and apixaban groups (0.8% vs. 1.0%; HR: 0.84; 95%CI: 0.60–1.19).
• The frequency of any adverse event was 34.9% in either treatment group.
• A pharmacodynamics analysis indicated factor XIa inhibition at trough was similar in patients who had a primary efficacy endpoint event and those who did not, and it was also similar in patients in the OCEANIC-AF trial and those in the PACIFIC-AF trial (~92%).
• The majority of the OCEANIC-AF trial patients (83%) had previously received OAC treatment. A prespecified post-hoc hypothesis-generating analysis showed the incidence rate of the primary efficacy endpoint was rather similar in OAC-naïve patients in the asundexian and apixaban groups. In patients who had previously been treated with OACs, there was a larger difference in the incidence rate between the 2 treatment groups.

Conclusion

In the large OCEANIC-AF trial, treating AF patients at high stroke risk with asundexian 50 mg once daily was associated with an increased incidence of stroke or systemic embolism compared with standard-dose apixaban, leading to premature termination of the trial. However, there were fewer major bleeding events with asundexian than with apixaban.

Dr. Patel pointed out several implications of this study. Importantly, more research is needed to determine the degree of factor XIa inhibition required to prevent stroke in AF patients. 

- Our reporting is based on the information provided at the ESC Congress 2024 -

The findings of this study were simultaneously published in N Engl J Med.