Factor XI Inhibition for Ischemic Stroke Secondary Prevention: Pharmacology, Clinical Evidence, and Future Directions

Ischemic stroke remains a leading cause of death and disability worldwide, and bleeding (particularly intracranial hemorrhage) continues to limit conventional antithrombotic therapy in secondary prevention, even with direct oral anticoagulants. Factor XI (FXI) has emerged as a promising target: it amplifies thrombin generation and stabilizes pathological thrombi while contributing only marginally to physiological hemostasis, as illustrated by the mild bleeding phenotype of congenital FXI deficiency. This biological dissociation underpins the concept of hemostasis-sparing anticoagulation. Three pharmacological classes are being studied, with distinct pharmacokinetic, pharmacodynamic, and drug-drug interaction profiles: small-molecule oral FXIa inhibitors (asundexian and milvexian), FXI antisense oligonucleotides (fesomersen), and monoclonal antibodies targeting FXI/FXIa (abelacimab and osocimab). Oral small molecules offer rapid, reversible target engagement particularly suited to chronic cerebrovascular prevention. While phase II trials (PACIFIC-Stroke, AXIOMATIC-SSP) showed neutral primary endpoints with reassuring safety, the phase III OCEANIC-STROKE trial demonstrated that asundexian 50 mg once daily, added to antiplatelet therapy, reduced recurrent ischemic stroke by 26% (HR 0.74; 95% CI 0.65-0.84) without significant bleeding excess in non-cardioembolic stroke; the ongoing LIBREXIA-STROKE is testing milvexian 25 mg twice daily in a similar setting. Conversely, OCEANIC-AF showed that FXIa inhibition alone is insufficient versus apixaban in atrial fibrillation, indicating dependence upon clinical setting and suggesting the need for a precision-medicine approach integrating clinical, imaging, and biomarker-based patient stratification. This narrative review integrates pathophysiological rationale, comparative pharmacology of all FXI-targeting classes, trial evidence, and patient stratification, providing an up-to-date reference for FXI/FXIa inhibition in secondary ischemic stroke prevention.