- The OCEANIC-Stroke trial (NCT05686070) was a placebo-controlled, double-blind, trial that randomized participants with ischemic stroke or high-risk TIA within 72 hours of onset, to receive either asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy.
- Adding asundexian to standard antiplatelet therapy reduces recurrent ischemic stroke by 26% with a safety profile comparable to placebo.
- OCEANIC-STROKE clearly marks a significant advance in secondary stroke prevention research.
Asundexian is a direct, potent small molecule inhibitor of Factor XIa (FXIa). Previously, in a randomized, placebo-controlled, double-blind, dose-finding trial of asundexian combined with antiplatelets in 1808 participants with acute non-cardioembolic ischemic stroke, there was no statistically significant increase in major or clinically relevant non-major bleeding (PACIFIC-STROKE; NCT04304508). The primary efficacy outcome of clinical stroke and MRI-determined covert infarct did not show a dose-response effect with asundexian, due to the absence of an effect on covert infarcts. Symptomatic ischemic stroke was numerically, but not significantly, less common in participants assigned asundexian 50 mg compared with placebo. Exploratory analyses showed that participants who received asundexian 50mg experienced a notable decrease in symptomatic ischemic stroke or TIA, especially among those with any type or location of intra- or extracranial atherosclerosis, compared to those given a placebo. There was no statistically significant increase in hemorrhagic transformation vs placebo of the index ischemic stroke or new microhemorrhages on study MRI after cerebral microbleeds. These promising results from phase II study led to OCEANIC -STROKE TRIAL.
The Oral faCtor Eleven A iNhibitor asundexIan as novel antithrom-botiC – OCEANIC-STROKE trial (NCT05686070) is an international, phase III, randomised, double-blind, placebo-controlled, event-driven clinical trial examining the efficacy and safety of asundexian 50 mg daily in participants with acute non-cardioembolic stroke or high-risk TIA. Adults were eligible for the study if they had a non-cardioembolic ischemic stroke with an NIHSS score of 15 or less, or a high-risk TIA (ABCD2 scores of 6 or 7), and could be randomized within 72 hours after symptoms began. All participants were required to have at least one of the following: (1) cerebrovascular imaging showing evidence of atherosclerosis at any location from the aortic arch to the intracranial vessels; (2) a history of atherosclerosis including coronary artery disease, peripheral vascular disease, asymptomatic carotid atherosclerosis or previous carotid revascularization and (3) brain imaging demonstrating an acute non-lacunar infarct. Individuals with lacunar infarcts could participate, provided they met at least one of the first two criteria. Participants needed an antiplatelet treatment plan, either single or dual, aligned with local guidelines and practices. Exclusion criteria included participants with atrial fibrillation, asymptomatic hemorrhagic transformation characterized by petechial hemorrhage (HI1 and HI2 according to the Heidelberg classification), a history of nontraumatic intracranial bleeding, and others. Although individuals with symptomless chronic macro-hemorrhages were not included, those with cerebral microbleeds or superficial siderosis were allowed. OCEANIC-STROKE was an event-driven trial that was designed to continue until 830 participants had a new ischemic stroke confirmed by the adjudication committee.
The primary results of the OCEANIC-STROKE trial were presented at the International Stroke Conference (ISC) 2026. The trial marks the first successful completion of a Phase III study for a FXIa inhibitor, demonstrating that this novel class of anticoagulants can significantly reduce recurrent stroke without the traditionally expected bleeding risk.
For over half a century, secondary stroke prevention for non-cardioembolic events has relied primarily on antiplatelet monotherapy, such as aspirin. While effective, clinicians have long sought more robust protection. Previous attempts to add traditional anticoagulants to these regimens often failed, not necessarily due to a lack of efficacy, but because of unacceptable rates of major bleeding. Concomitantly, Factor XIa is a unique target in the coagulation cascade- essential for the growth of pathological thrombosis but plays a minimal role in hemostasis.
The OCEANIC-STROKE trial, which enrolled 12,327 patients across thirty-seven countries, investigated the addition of 50 mg of asundexian (a once-daily oral) vs placebo to standard antiplatelet therapy. Mean age was 67 years, one third females, 21% had a prior history of stroke or TIA, 31% had diabetes, and 16% coronary artery disease. Most of the index events were ischemic strokes (94.7%). The distribution based on the TOAST classification was approximately 43% large artery atherosclerosis, 30% stroke of undetermined sources, 22% small vessel occlusion, almost 3% stroke of other etiology, and 1.6% cardioembolic strokes. Approximately 27.5% of the patients received either intravenous thrombolysis and /or endovascular therapy. Regarding antiplatelet treatment, 62.5% were in dual therapy.
Asundexian reduced the risk of recurrent ischemic stroke by 26% compared to placebo (csHR 0.74; 95% CI 0.65–0.84; p < .0001). This benefit was observed across all clinically relevant subgroups, including age, sex, stroke severity (NIHSS), and stroke subtype (e.g., large artery atherosclerosis or small vessel disease). The drug also achieved a 26% reduction in “all-cause” stroke (ischemic and hemorrhagic combined) and significantly lowered the composite of cardiovascular death, myocardial infarction, and stroke. During the trial, there was no increase in ISTH major bleeding with asundexian compared to placebo (1.9% vs. 1.7%), with similar rates of clinically relevant non major bleeding, and minor bleeding. Rates of intracranial hemorrhage and fatal bleeding matched those in the placebo group.
Principal investigator Dr. Mike Sharma described the result: “So very nicely, we saw this impressive reduction in the occurrence of stroke without a price to pay in terms of bleeding. After all these years, we finally got a free lunch. Benefit without a safety problem, a free lunch without catch-up, as I like to say.”
The success of OCEANIC-STROKE provides a significant boost to the Factor XIa inhibitor class, especially after the earlier termination of the OCEANIC-AF trial due to a lack of efficacy in atrial fibrillation. The results suggest that the role of Factor XI may vary significantly depending on the clinical setting.