BACKGROUND: Patients with noncardioembolic ischemic stroke or transient ischemic attack (TIA) are at risk for recurrent stroke. Low factor XI levels are associated with a reduced risk of ischemic stroke. Asundexian inhibits activated factor XI. Whether the addition of asundexian to antiplatelet therapy would be superior to antiplatelet therapy alone for the secondary prevention of ischemic stroke is unclear.

METHODS: In this phase 3, double-blind trial, we randomly assigned patients within 72 hours after the onset of a noncardioembolic ischemic stroke or high-risk TIA to receive asundexian (50 mg once daily) or placebo, in addition to planned dual or single antiplatelet therapy. Patients had at least one of the following: a nonlacunar infarct on imaging, a history of atherosclerosis, or evidence of atherosclerotic plaque at any location on cerebrovascular imaging. The primary efficacy outcome was ischemic stroke. The composite of death from cardiovascular causes, myocardial infarction, or stroke was a key secondary outcome. The primary safety outcome was major bleeding.

RESULTS: Among 12,327 patients who underwent randomization (6162 to the asundexian group and 6165 to the placebo group), the incidence of ischemic stroke was lower in the asundexian group than in the placebo group (6.2% vs. 8.4%; cause-specific hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.84; P<0.001). The incidence of the composite of death from cardiovascular causes, myocardial infarction, or stroke was lower in the asundexian group than in the placebo group. The incidence of major bleeding was similar in the asundexian group and the placebo group (1.9% and 1.7%, respectively; cause-specific hazard ratio, 1.10; 95% CI, 0.85 to 1.44). The incidence of adverse events was 69.3% in the asundexian group and 70.1% in the placebo group; the incidence of serious adverse events was 19.2% and 19.5%, respectively.

CONCLUSIONS: Among patients with noncardioembolic ischemic stroke or high-risk TIA treated with antiplatelet therapy, asundexian at a daily dose of 50 mg resulted in lower risks of ischemic stroke and major cardiovascular events than placebo, without a higher risk of major bleeding. (Funded by Bayer; OCEANIC-STROKE ClinicalTrials.gov number, NCT05686070.).

Emergency Medicine rater

This is a double-blind trial of patients at 702 centers in 37 countries within 72 hours after the onset of a non-cardioembolic ischemic stroke or high-risk TIA who were being treated with dual or single antiplatelet therapy and were randomized to receive asundexian (50 mg once daily; a factor XI inhibitor) or placebo. The asundexian group had fewer strokes (number needed to treat [NNT] of 44 [95% confidence interval (CI): 31,74]) but no statistically significant difference in mortality, major bleeding, symptomatic intracranial hemorrhage or serious adverse events.

Neurology rater

Although this drug is not (yet) approved by the governmental authorities, asundexian has demonstrated both efficacy and safety in this large phase 3 RCT for secondary stroke prevention. This would be a safe long-term addition to standard antiplatelet therapy in stroke prevention. Dual antithrombotic therapy, whether antiplatelet therapy or anticoagulant-anticoagulant combination, has not demonstrated safety in long-term stroke prevention. Asundexian, a Factor XI inhibitor, may be different.