Factor XI/XIa Inhibitors for Secondary Prevention After Stroke and TIA

Background: Factor XI/Xia inhibitors have gained attention as an innovative anticoagulant strategy which may reduce thrombosis without substantially impairing hemostasis. Their role in secondary prevention following non-cardioembolic stroke and high-risk transient ischemic attack (TIA) remains uncertain. We conducted an updated systematic review and meta-analysis of Randomized Controlled Trial (RCTs) assessing the efficacy and safety of factor XI/Xia inhibition in patient with these conditions. Research Question: Does treatment with factor XI/XIa inhibitors improve clinical outcomes while minimizing bleeding complications compared with conventional therapy in patients with non-cardioembolic stroke or high-risk TIA? Methods: A thorough search was performed on PubMed, Scopus, Embase, ClinicalTrials.gov and the Cochrane library from inception until May 2025 comparing Factor XI/XIa inhibitors, primarily asundexian and milvexian, with placebo or standard antithrombotic therapy in patients with non-cardioembolic ischemic stroke or high-risk TIA. Pooled Risk Ratios (RRs) with 95% confidence intervals (CIs) were computed using random-effects models. Results: Five RCTs involving 18,603 participants were included. Factor XI/XIa inhibitors were associated with a significant reduction in symptomatic ischemic stroke compared with control therapy (RR 0.77, 95% CI 0.68-0.86; p<0.00001; I 2 =0%). No significant differences were observed for the composite of symptomatic ischemic stroke and covert infarction (RR 1.01, 95% CI 0.87-1.18; p=0.89; I 2 =0%) or the composite of symptomatic ischemic stroke and TIA (RR 0.78, 95% CI 0.61-1.01; p=0.06; I 2 =0%). Similarly, Factor XI/XIa inhibition did not significantly affect major adverse cardiovascular events (MACE) (RR 0.93, 95% CI 0.78-1.10; p=0.39; I 2 =36%) or all-cause mortality (RR 1.01, 95% CI 0.86-1.18; p=0.93; I 2 =0%). Safety outcomes were comparable between groups, with no significant differences in the composite of major bleeding or clinically relevant non-major bleeding (RR 1.06, 95% CI 0.80-1.40; p=0.70; I 2 =44%), major bleeding alone (RR 1.11, 95% CI 0.87-1.41; p=0.40; I 2 =0%), or intracranial hemorrhage (RR 1.11, 95% CI 0.73-1.69; p=0.62; I 2 =0%). Conclusion: Factor XI/XIa inhibitors reduced the risk of symptomatic ischemic stroke in patients with non-cardioembolic ischemic stroke and high-risk TIA without increasing major bleeding, clinically relevant non-major bleeding, or intracranial hemorrhage. These findings support continued investigation of factor XI/XIa inhibition as a potential strategy for secondary stroke prevention.