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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\u2010sparing anticoagulation. Three pharmacological classes are being studied, with distinct pharmacokinetic, pharmacodynamic, and drug\u2010drug interaction profiles: small\u2010molecule 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\u2010Stroke, AXIOMATIC\u2010SSP) showed neutral primary endpoints with reassuring safety, the phase III OCEANIC\u2010STROKE 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\u20130.84) without significant bleeding excess in non\u2010cardioembolic stroke; the ongoing LIBREXIA\u2010STROKE is testing milvexian 25 mg twice daily in a similar setting. Conversely, OCEANIC\u2010AF showed that FXIa inhibition alone is insufficient versus apixaban in atrial fibrillation, indicating dependence upon clinical setting and suggesting the need for a precision\u2010medicine approach integrating clinical, imaging, and biomarker\u2010based patient stratification. This narrative review integrates pathophysiological rationale, comparative pharmacology of all FXI\u2010targeting classes, trial evidence, and patient stratification, providing an up\u2010to\u2010date reference for FXI\/FXIa inhibition in secondary ischemic stroke prevention.<\/jats:p>","DOI":"10.1002\/jcph.70266","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:30:46Z","timestamp":1786710646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Factor XI Inhibition for Ischemic Stroke Secondary Prevention: Pharmacology, Clinical Evidence, and Future Directions"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-5997","authenticated-orcid":false,"given":"Federica","family":"Ferrari","sequence":"first","affiliation":[{"name":"Department of Health Sciences School of Medicine Univ ersit\u00e0 del Piemonte Orientale \u201cAmedeo 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