The factor XIa inhibitor asundexian combined with standard antiplatelet therapy reduced the risk for recurrent ischemic stroke compared to antiplatelet therapy alone, without increasing bleeding, phase 3 trial data show.

In the OCEANIC-STROKE randomized controlled trial of more than 12,000 patients with recent noncardioembolic ischemic stroke or high-risk transient ischemic attack (TIA), those treated with antiplatelet therapy plus 50 mg/d oral asundexian were 26% less likely to have recurrent ischemic stroke than those in a placebo group.

There was no significant increase in bleeding including major, minor, or intracranial hemorrhage. Rates of intracranial hemorrhagic stroke and fatal bleeding were also similar between groups.

“The observed lower risk of ischemic stroke without a significant increase in bleeding validates factor XIa as a therapeutic target with the potential to uncouple pathologic thrombosis from hemostasis,” lead investigator Mukul Sharma, MD, professor of neurology at McMaster University in Hamilton, Ontario, Canada, and colleagues wrote.

Researchers presented initial findings at the International Stroke Conference 2026. The full study was published online on April 15 in The New England Journal of Medicine.

Assessing Factor XI Inhibitors

Epidemiologic data suggest factor XI plays a greater role in pathologic thrombosis than in normal hemostatic function. Asundexian is an oral factor XIa inhibitor developed to selectively block this pathway.

For the phase 3, multicenter, double-blind, randomized controlled trial, investigators enrolled 12,327 patients (mean age, 68 years; 33.3% women) across 37 countries within 72 hours of symptom onset after noncardioembolic ischemic stroke or high-risk TIA.

Patients were randomly assigned in a 1:1 ratio to 50 mg/d asundexian or placebo, in addition to standard antiplatelet therapy. Randomization was stratified by planned antiplatelet regimen, either single or dual therapy.

Stroke severity was generally mild, with 94.7% of patients presenting with ischemic stroke and 5.3% with high-risk TIA. Approximately 62.6% of patients were expected to receive dual antiplatelet therapy, and 27.4% received acute reperfusion therapies, including intravenous thrombolysis and/or endovascular thrombectomy.

The primary efficacy outcome was recurrent ischemic stroke. Secondary efficacy outcomes included a composite of cardiovascular death, myocardial infarction (MI), or stroke. The primary safety outcome was major bleeding.

Favorable Outcomes

After a median 567-day follow-up, recurrent ischemic stroke occurred in 6.2% of patients in the asundexian group compared with 8.4% of those in the placebo group (hazard ratio [HR], 0.74; P < .001).

Secondary efficacy outcomes also favored asundexian. Any stroke, defined as ischemic or hemorrhagic, occurred in 6.6% of patients with asundexian vs 8.8% with placebo (HR, 0.74; P < .001). The composite of death from cardiovascular causes, MI, or stroke occurred in 9.2% vs 11.1% of patients, respectively (HR, 0.83; P < .001).

Early ischemic stroke within 90 days did not differ significantly between groups, suggesting that treatment effects may emerge with longer follow-up, researchers noted.

Major bleeding was not significantly different between groups (1.9% with asundexian vs 1.7% with placebo), with findings consistent across bleeding categories. Adverse event rates were also similar.

Study limitations included predominantly mild stroke severity, limited representation of some demographic subgroups including Black patients, and treatment discontinuation in approximately 25% of patients in both groups.

“Until now, reducing stroke risk has often been associated with higher bleeding risk. These findings give us hope for a safer way to prevent recurrent strokes,” Ashkan Shoamanesh, co‑principal investigator and senior scientist at Population Health Research Institute, Hamilton, said in a statement. “That’s something physicians, patients, and families have been waiting for.”

Longer Follow-Up Needed

While other, more intensive antithrombotic agents have been investigated to reduce recurrent stroke among patients with noncardioembolic ischemic stroke or TIA, they have largely been unsuccessful, wrote Marion Boulanger, MD, PhD, Université de Caen Normandie and the Centre Hospitalier Universitaire de Caen Normandie, Caen, France, in an accompanying editorial.

Looking at factor XI, Boulanger highlighted that its predominant role in thrombosis, with limited involvement in hemostasis, supports its potential as a strategy to reduce ischemic events without increasing bleeding risk.

However, she highlighted that earlier phase 2 studies of factor XIa inhibitors did not demonstrate clear efficacy, leaving questions about timing, duration, and patient selection. There are also practical considerations, including the lack of a specific reversal agent.

“One minor concern is that no antidote to factor XI inhibitors is currently available,” Boulanger noted. She also commented on the high discontinuation rate with asundexian in the current trial, which was similar to placebo.

Studies with longer follow-up, such as 5 or 10 years, will need to be conducted to assess whether the observed benefits persist and translate into sustained net clinical benefit over time, she concluded.

The study was supported by Bayer AG. Disclosure information for study authors is available in the original study publication. Boulanger reported no relevant financial disclosures.