Factor XIa Inhibition for Secondary Prevention of Ischemic Stroke and TIA

Background: There is a high risk of recurrent ischemic stroke (IS) or transient ischemic attack (TIA) for patients with a recent history of IS or high-risk TIA. FXIa inhibition is a novel antithrombotic agent with the potential to reduce thrombosis while preserving hemostasis. However, the clinical evidence from randomized controlled trials of FXIa inhibitors has yet to be pooled systematically. Research Question: The primary objective was to evaluate whether FXIa inhibition reduces recurrent ischemic stroke and vascular events without increasing major bleeding, intracranial hemorrhage, or mortality compared with placebo in patients with recent ischemic stroke or high-risk TIA. Methods: We systematically searched PubMed, Embase, and Cochrane Library Central through April 2026 for studies comparing FXIa with placebo for secondary prevention of IS and TIA. Risk ratios with 95% confidence intervals were calculated for each study and pooled using the Mantel-Haenszel method in a random-effects model with R. The degree of heterogeneity in the studies was evaluated with the I 2 statistic. Results: Six studies including 16,501 patients were analyzed, with 9,189 patients (55.7%) assigned to FXIa inhibitors, including 7,514 receiving asundexian and 1,675 receiving milvexianFXIa inhibition was associated with a significant reduction in the number of patients with recurrent IS (5.8% vs 8.0%; RR 0.76, 95% CI 0.68-0.86, p < 0.0001, I 2 = 0%) and the major vascular composite outcome (8.8% vs 10.9%; RR 0.84, 95% CI 0.76-0.93, p = 0.0006, I 2 = 0%). There was no significant difference in the number of patients with major bleeding (RR 1.13, 95% CI 0.89-1.45, p = 0.32, I 2 =0%), major or clinically relevant nonmajor bleeding (RR 1.16, 95% CI 0.91-1.48, p = 0.24, I 2 =17.8%), symptomatic intracranial hemorrhage (RR 1.11, 95% CI 0.73-1.70, p = 0.62, I 2 =0%), or all-cause mortality (RR 1.00, 95% CI 0.85-1.18, p = 0.97, I 2 =0%) Conclusions: FXIa inhibition is associated with a significant reduction in the number of patients with recurrent IS or vascular events after an initial diagnosis of IS or high-risk TIA, but not with a significant increase in major bleeding, intracranial hemorrhage, or mortality. Therefore, FXIa inhibition may present a promising new agent for the secondary prevention of stroke. However, the main evidence supporting this conclusion comes from only one trial, thereby limiting its strength. Additionally, differences in agents, doses, follow-up periods, and definitions of bleeding events across trials should be considered when interpreting these results.