FXIa inhibitors and secondary stroke prevention

Patients with noncardioembolic ischemic stroke face a substantial residual risk of recurrence despite antiplatelet therapy, while conventional anticoagulation is unsuitable due to an unacceptably high bleeding risk. Activated factor XI (FXIa) inhibition promises anticoagulant efficacy while sparing hemostasis. We appraise the evidence of FXIa-inhibitors in secondary stroke prevention considering the pivotal OCEANIC-STROKE trial.

Phase-2 trials of asundexian and milvexian were reassuring on safety but neutral on imaging-based endpoints, establishing that covert infarcts are a poor surrogate. In the phase-3 OCEANIC-STROKE trial, asundexian added to single or dual antiplatelet therapy reduced recurrent ischemic stroke by 26%, consistently across subtypes, without any excess of major bleeding or intracranial hemorrhage. By contrast, asundexian was inferior to apixaban in atrial fibrillation, a result attributable to dose, comparator, and setting. Consistent with this, the monoclonal antibody abelacimab, which achieves near-complete FXIa-inhibition, reduced bleeding relative to rivaroxaban in atrial fibrillation, though its effect on thromboembolic events has not been established.

FXIa-inhibition is the first anticoagulant strategy preventing recurrent stroke after noncardioembolic ischemic stroke without a bleeding penalty. Confirmation of a class effect from further trials is awaited, alongside questions of duration, deeper inhibition, and use in other cardiovascular indications.