Factor XIa Inhibitors for Secondary Prevention after Ischemic Stroke or Transient Ischemic Attack: A Meta-Analysis of Randomized Clinical Trials

Background: Factor XIa inhibition is an emerging antithrombotic strategy intended to reduce recurrent thrombotic events while preserving physiological hemostasis. Its role in secondary prevention after non-cardioembolic ischemic stroke or high-risk transient ischemic attack (TIA) remains uncertain. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched from inception through May 1, 2026. Randomized controlled trials (RCTs) evaluating factor XIa inhibitors added to background antiplatelet therapy in adults with recent non-cardioembolic ischemic stroke or high-risk TIA were included. The primary efficacy outcome was recurrent ischemic stroke, and the primary safety outcome was major bleeding. Random-effects meta-analyses were performed using odds ratios (ORs) and 95% confidence intervals (CIs). Results: Three RCTs involving 13,889 participants were included; 6,937 received a factor XIa inhibitor and 6,952 received placebo. Two trials evaluated asundexian and one evaluated milvexian. Compared with placebo, factor XIa inhibition was associated with a significant reduction in recurrent ischemic stroke (OR, 0.66; 95% CI, 0.58–0.76; I2 = 0%). Although the effect estimate for TIA favored factor XIa inhibition, it was not statistically significant (OR, 0.44; 95% CI, 0.15–1.35; I2 = 60.9%). No significant differences were observed in all-cause mortality (OR, 1.14; 95% CI, 0.73–1.77; I2 = 6.6%) or major bleeding (OR, 1.16; 95% CI, 0.90–1.49; I2 = 7.4%). Conclusions: In patients with recent non-cardioembolic ischemic stroke or high-risk TIA, factor XIa inhibition added to antiplatelet therapy was associated with a lower risk of recurrent ischemic stroke without a significant increase in major bleeding. The effects on TIA and all-cause mortality remain uncertain; further adequately powered trials are needed to establish long-term safety and agent-specific efficacy.