Factor XIa Inhibitor Reduces Stroke Recurrence Without Increasing Bleeding Risk in Phase 3 Trial

The phase 3 OCEANIC-STROKE trial demonstrated that asundexian, an oral Factor XIa inhibitor, reduced recurrent ischemic stroke by approximately 26% compared with standard antiplatelet therapy alone in patients with non-cardioembolic ischemic stroke or high-risk transient ischemic attack. The study enrolled 12,327 patients and found no increase in major bleeding events with the investigational drug.

OCEANIC-STROKE was a multicenter, international, randomized, placebo-controlled, double-blind, event-driven trial. Patients with mild to moderate ischemic stroke or high-risk TIA received asundexian 50 mg once daily or placebo on top of standard antiplatelet therapy, with stratification by single versus dual antiplatelet use. Participants were randomized within 72 hours of symptom onset and required evidence of atherosclerotic disease or a non-lacunar infarct on imaging. Patients requiring anticoagulation or with prior non-traumatic intracranial hemorrhage were excluded.

The primary efficacy endpoint was time to first ischemic stroke, and the primary safety endpoint was ISTH major bleeding. Asundexian was associated with a 2.2% absolute risk reduction in ischemic stroke over the study period, translating to approximately a 26% relative risk reduction compared with standard therapies alone. From a safety standpoint, there was no increase in major bleeding in the asundexian group compared with placebo.

The development of Factor XIa inhibitors is based on the observation that individuals naturally deficient in Factor XI tend to have fewer thrombotic events and do not appear to have a dramatically increased risk of bleeding. This led to the hypothesis that a medication reducing pathologic clot formation without interfering with normal hemostasis and healing could theoretically reduce stroke risk without increasing bleeding risk.

The trial population consisted of non-atrial fibrillation-associated stroke patients. Patients could have a lacunar infarct, but there needed to be some identified history of atherosclerosis. The study represents one of the larger contemporary secondary stroke prevention trials.

The ability to reduce ischemic events without increasing major bleeding differentiates this approach from traditional anticoagulant strategies, as intensifying antithrombotic strategies has historically come at the cost of increased bleeding. Genetic deficiency of Factor XI has been associated with lower rates of ischemic stroke without a corresponding rise in intracerebral hemorrhage.