Oral Factor XIa Inhibitors for Secondary Prevention After Noncardioembolic Ischemic Stroke or High‐Risk Transient Ischemic Attack: Systematic Review and Meta‐Analysis

Introduction Patients with recent noncardioembolic ischemic stroke or high‐risk transient ischemic attack (TIA) remain at risk of recurrent events despite antiplatelet therapy. Oral factor XIa (FXIa) inhibitors may reduce thrombotic risk while limiting bleeding, but their adjunctive efficacy and safety require clarification. Methods PubMed, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov were searched through May 2026 for randomized, double‐blind, placebo‐controlled trials of oral FXIa inhibitors added to antiplatelet therapy. Primary efficacy and safety outcomes were recurrent ischemic stroke and major bleeding. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random‐effects models. Results Three trials randomized 16,501 participants overall, of whom 14,239 contributed to the primary selected‐dose efficacy analysis. FXIa inhibition reduced recurrent ischemic stroke (413/6927 vs. 579/7312; RR 0.74, 95% CI 0.65–0.84; I 2 = 0%; p < 0.00001). No statistically significant differences were observed in major bleeding (RR 1.12, 95% CI 0.87–1.44), major or clinically relevant non‐major bleeding (RR 1.40, 95% CI 0.91–2.15), clinically relevant non‐major bleeding (RR 1.49, 95% CI 0.85–2.60), minor or non‐actionable bleeding (RR 0.94, 95% CI 0.84–1.05), intracranial or intracerebral hemorrhage (RR 1.16, 95% CI 0.75–1.79), or fatal bleeding (RR 1.75, 95% CI 0.74–4.17); however, confidence intervals for several bleeding outcomes were wide and did not exclude clinically important harm. Findings remained consistent in the all‐dose sensitivity analysis (RR 0.77, 95% CI 0.68–0.86; I 2 = 0%). Conclusions In patients with recent noncardioembolic ischemic stroke or high‐risk TIA receiving antiplatelet therapy, pooled randomized evidence showed a reduction in recurrent ischemic stroke with oral FXIa inhibition; however, the estimate was predominantly driven by the phase 3 asundexian trial, limiting certainty regarding generalization across individual FXIa inhibitors. Major bleeding and other safety outcomes were not significantly increased, although rare‐event estimates were imprecise and clinically important harm cannot be excluded.