Factor XIa Inhibition Drives Down Recurrent Stroke Risk Without Rise in Bleeding

The investigational oral Factor XIa inhibitor asundexian has been shown to significantly reduce risk of repeat ischemic stroke without increasing bleeding risk in patients with recent noncardioembolic stroke. So reported investigators with the phase 3 OCEANIC-STROKE trial in a late-breaking science presentation at the International Stroke Conference 2026.

The relative risk reduction for recurrent stroke with asundexian was 26% when compared with placebo in the international study of more than 12,000 patients, all of whom also received standard antiplatelet therapy. The benefit was seen across a wide range of patient subgroups.

Stroke experts say the results represent a likely paradigm shift in secondary prevention of noncardioembolic ischemic events. “Up to now, we’ve been limited to antiplatelet medications like aspirin or clopidogrel for secondary stroke prevention in this setting,” says Andrew Russman, DO, Head of the Stroke Program at Cleveland Clinic and an OCEANIC-STROKE investigator. “But we’ve reached the limits of the stroke protection that can be achieved with antiplatelets, and we’re always concerned about increasing the risk of bleeding when we add other agents that act on the blood. What’s exciting about this study is that asundexian significantly lowered patients’ ischemic stroke risk without an increase in major bleeding risk. That’s an important advance.”

A pressing need for better secondary prevention

Secondary stroke prevention remains a primary concern for clinicians, as roughly one in four stroke survivors will face a subsequent stroke or stroke-like event. Despite the widespread use of antiplatelet regimens, the risk of recurrence remains substantial, often leading to more severe disability, higher mortality and a greater likelihood of post-stroke dementia.

Past efforts to improve these outcomes by adding traditional anticoagulants to antiplatelet therapy have been thwarted by bleeding concerns. While agents that inhibit Factor Xa or thrombin are effective at preventing clots, they also interfere with essential hemostasis, leading to unacceptably high rates of major bleeding. Inhibition of Factor XIa represents a biological breakthrough because the Factor XIa protein is essential for pathological thrombus growth but plays a negligible role in the normal physiological clotting required for healing.

“Factor XIa inhibitors represent an entirely new class of drugs that are relatively selective,” Dr. Russman explains. “That selectivity protects against harmful clots without impairing the clot formation that’s part of the body’s natural defense against excessive bleeding.”

OCEANIC-STROKE: Design at a glance

The OCEANIC-STROKE trial is one of the largest secondary prevention studies ever conducted, enrolling 12,327 patients across 702 international sites.

Participants were adults who had experienced a mild to moderate ischemic stroke (NIH Stroke Scale score ≤ 15) or a high-risk transient ischemic attack (TIA). Eligibility required that patients have noncardioembolic events, with exclusion of patients with atrial fibrillation, mechanical valves or other known cardiac sources of emboli.

Patients were randomized within 72 hours of index stroke onset to receive 50 mg of oral asundexian daily or a matching placebo. Randomization was done in a double-blind, parallel-group manner. Both groups continued their standard-of-care antiplatelet regimen, which was dual antiplatelet therapy for nearly 63% of the study population.

The trial was event-driven, with patients monitored for up to 31 months to assess the primary efficacy endpoint of recurrent ischemic stroke and the primary safety endpoint of major bleeding based on International Society on Thrombosis and Hemostasis criteria.

Results: Early and sustained efficacy with comparable bleeding rates

Mean patient age was 68 years, and two-thirds of patients were male. The index event was an ischemic stroke in 95% of participants and a high-risk TIA in 5%. The population was clinically diverse: 43% had large-artery atherosclerosis, 23% had small-vessel occlusion and 30% had strokes of undetermined etiology. Median drug exposure was 430 days.

The study met its primary goals with high levels of statistical significance. Among the key findings:

• Asundexian recipients had a 26% relative risk reduction, and a 2.2% absolute risk reduction, for recurrent ischemic stroke compared with placebo recipients (6.2% vs. 8.4%; hazard ratio [HR] = 0.74; 95% CI, 0.65-0.84). The divergence in event curves began early in the treatment course and was sustained throughout the study period.
• Despite the added antithrombotic effect, rates of major bleeding were nearly identical between the groups (1.9% with asundexian vs. 1.7% with placebo; HR = 1.10; 95% CI, 0.85-1.44).
• Asundexian was also associated with a significant reduction in disabling and fatal strokes (2.1% vs. 3.0%; HR = 0.69; 95% CI, 0.55-0.87).

The drug’s benefits were consistent across all analyzed subgroups, regardless of age, sex, stroke subtype, stroke risk factors, severity of index event, delivery of hyperacute treatment, geographic region and use of single or dual antiplatelet therapy.

“This suggests the benefits of FXIa inhibition are widely applicable to the varied presentations seen among noncardioembolic patients in a typical stroke center,” Dr. Russman notes.

Implications and next steps

The results of OCEANIC-STROKE suggest that FXIa inhibition could soon become a key component of secondary prevention in survivors of noncardioembolic stroke. “The ability to reduce the risk of ischemic stroke recurrence without an increase in bleeding is critically important for long-term management of these patients,” says Dr. Russman.

The investigators noted that the study is limited, however, by having a relatively small number of patients with severe stroke despite its broad inclusion criteria. Additional insights may emerge from ongoing monitoring of trial participants and from a substudy using standardized MRI to evaluate asundexian’s effect on subclinical clotting and micro-bleeding.

The agent has received FDA fast-track designation. If it receives approval, Dr. Russman says its exact role in practice won’t be clear until it sees wider clinical use. Additional assessment will be needed to address questions such as perioperative management and reversal in cases of bleeding emergencies.

He notes that studies of additional Factor XIa inhibitors are underway as well. “This class represents an exciting new era in secondary stroke prevention,” he concludes.

OCEANIC-STROKE was funded by Bayer, the commercial developer of asundexian.