Will Asundexian Change Secondary Stroke Prevention?

The FDA-approval of the first factor XIa inhibitor could mark a major advance in secondary stroke prevention, but questions remain about its clinical use, long-term safety, and how broadly it will be adopted.On November 9, the FDA approved asundexian (Sunharbo, Bayer) 50 mg tablets, the first factor XIa inhibitor, for use in combination with antiplatelet therapy to reduce the risk for stroke in adults following a recent mild-to-moderate noncardioembolic ischemic stroke or a high-risk transient ischemic attack (TIA).In October, China became the first country to approve the drug, marking the first regulatory approval for this new class of anticoagulants.In the phase 3 OCEANIC-STROKE trial, adding asundexian to standard antiplatelet therapy reduced recurrent ischemic stroke by 26% compared with antiplatelet therapy alone, without a statistically significant increase in major bleeding.The OCEANIC-STROKE findings are “practice changing,” Joseph Broderick, MD, a stroke neurologist at the University of Cincinnati in Cincinnati, told Medscape Medical News.How Does Asundexian Work?Genetically lower levels of factor XI are associated with reduced risk for ischemic stroke. Asundexian selectively inhibits activated factor XI (XIa), a protein involved in clot formation but believed to be less essential to normal hemostasis than factor Xa or thrombin, the targets of current direct oral anticoagulants (DOACs).The goal is to prevent harmful clots while preserving much of the body’s ability to stop bleeding — a longstanding challenge in anticoagulant development.Unlike patients with atrial fibrillation (AF)-related stroke, those with noncardioembolic ischemic stroke generally receive antiplatelet therapy rather than DOACs because conventional anticoagulation has not demonstrated a favorable balance of benefit and risk for bleeding. In OCEANIC-STROKE, asundexian was added to antiplatelet therapy, not used as a replacement for it.What Did OCEANIC-STROKE Show?The pivotal OCEANIC-STROKE trial randomly assigned12,327 patients within 72 hours of symptom onset following a noncardioembolic ischemic stroke or high-risk TIA. First presented at the International Stroke Conference (ISC) 2026 and subsequently published in The New England Journal of Medicine, participants received asundexian 50 mg once daily or placebo, added to planned single or dual antiplatelet therapy. Eligibility required evidence of a nonlacunar infarct or atherosclerotic disease. The median follow-up was approximately 19 months.Recurrent ischemic stroke occurred in 6.2% of patients receiving asundexian vs 8.4% receiving placebo (hazard ratio [HR], 0.74; P < .001), which represents an absolute risk reduction of 2.2 percentage points or a number needed to treat of approximately 46 over the trial’s follow-up period.The benefit appeared broadly consistent across stroke subtypes, including large-artery atherosclerosis, small-vessel occlusion, and strokes of undetermined cause.Exploratory analyses suggested that the benefit was maintained over time. Asundexian also reduced disabling strokes (2.1% vs 3.0%; HR, 0.69), suggesting that its clinical impact may extend beyond simply reducing the number of recurrent events. The composite of cardiovascular death, myocardial infarction, or stroke was also lower with asundexian.Asundexian is a “game changer” for secondary stroke prevention, said Andrew Russman, DO, head of the Cleveland Clinic Stroke Program in Cleveland.How Safe Is It?Major bleeding occurred in 1.9% of patients receiving asundexian and 1.7% receiving placebo (HR, 1.10), a difference that was not statistically significant.A more detailed analysis published in October in Circulation showed similar rates of symptomatic intracranial hemorrhage (0.7% vs 0.6%) and major or clinically relevant nonmajor bleeding (5.5% vs 5.0%). However, gastrointestinal bleeding was more frequent with asundexian (3.0% vs 2.4%), particularly lower gastrointestinal bleeding (1.7% vs 1.0%).In its approval announcement, the FDA noted that major bleeding rates with asundexian were higher in patients older than 75 years and during the first 90 days of treatment.Unanswered questions include longer-term safety and management of serious bleeding. No specific reversal agent is currently available for asundexian, although FDA labeling provides recommendations for withholding the drug around elective surgery and thrombolysis.Why Did It Work in Stroke but Not AF?The success of asundexian in OCEANIC-STROKE contrasts with results in other cardiovascular settings.In November 2023, the OCEANIC-AF trial was stopped early after asundexian proved substantially less effective than apixaban in preventing stroke or systemic embolism in patients with AF. The event rates were 1.3% with asundexian vs 0.4% with apixaban (HR, 3.79), although major bleeding was less frequent with asundexian.In another setback for factor XIa inhibition, the phase 3 LIBREXIA-ACS trial showed that milvexian failed to reduce cardiovascular death, myocardial infarction, or ischemic stroke after acute coronary syndrome when added to standard antiplatelet therapy (5.4% vs 5.1%; HR, 1.05).Why the divergent results? Russman suggested that the importance of factor XI-mediated thrombosis may differ across cardiovascular conditions. “Patients with FXI deficiency have similar rates of heart attack, but a reduced risk of stroke,” he said.Russman suggested that asundexian’s failure in AF may reflect, in part, the challenge of matching the efficacy of apixaban and potentially insufficient factor XIa inhibition at the evaluated dose.Whether differences in dosing, underlying biology, or background treatment explain the divergent findings remain uncertain. Notably, both OCEANIC-AF and OCEANIC-STROKE evaluated the same 50-mg daily dose of asundexian.What Else Is in the Pipeline?Other factor XI/XIa inhibitors are in late-stage development, including milvexian, an oral factor XIa inhibitor developed by Bristol Myers Squibb and Johnson & Johnson.The phase 3 LIBREXIA-STROKE trial is evaluating milvexian 25 mg twice daily, added to antiplatelet therapy, for preventing recurrent ischemic stroke after noncardioembolic stroke or high-risk TIA. Enrollment is complete, but efficacy results have not yet been reported.Broderick said positive results for milvexian in LIBREXIA-STROKE would reinforce confidence in factor XIa inhibition as a stroke prevention strategy and predicted that stroke neurologists would “adopt quickly.”Another approach involves abelacimab, a long-acting monoclonal antibody administered by monthly subcutaneous injection that inhibits factor XI activation. In the phase 2b AZALEA-TIMI 71 trial involving patients with AF, abelacimab substantially reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban.However, the trial was designed primarily to assess safety, not to establish efficacy for stroke prevention. The phase 3 LILAC-TIMI 76 trial is evaluating abelacimab in patients with AF considered unsuitable for conventional oral anticoagulation.The results of these ongoing trials should help determine whether factor XI/XIa inhibition represents a broadly useful anticoagulant strategy or one whose benefits depend heavily on the clinical setting.Broderick said the OCEANIC-STROKE findings are already influencing future stroke research.“We are already designing our trials of other medications for stroke prevention expecting that patients would already be on a factor XIa medication,” he said.What Could Slow Uptake?Other unanswered questions with asundexian include the optimal duration of treatment and which patients would derive the greatest benefit from long-term therapy. The FDA has advised against combining asundexian with certain drugs, including carbamazepine, which may reduce its effectiveness.Cost may also limit uptake. Broderick noted that cost was “a major issue for DOACs when they were first approved,” particularly for patients with inadequate or no prescription drug coverage.Guideline committees will also need to determine how factor XIa inhibition fits alongside established secondary prevention strategies.Russman reported financial relationships with Bayer and Boston Scientific. Broderick had no relevant disclosures.