Oral Factor XIa Inhibitors for Secondary Prevention After Ischemic Stroke

Background: Ischemic stroke remains a major contributor to global disease burden, with an estimated recurrence risk of approximately 12% within five years following an initial event. Despite standard antiplatelet therapy, a substantial residual thromboembolic risk persists. Oral factor XIa inhibitors, including milvexian and asundexian, selectively target the intrinsic coagulation pathway and may provide a favorable balance between thrombotic risk reduction and bleeding complications. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of oral factor XIa inhibitors for secondary prevention after ischemic stroke. Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidelines. A comprehensive literature search of PubMed, Google Scholar, the Cochrane Library, and ScienceDirect was performed. Statistical analysis of the extracted data was conducted using Review Manager (RevMan) version 5.4. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Heterogeneity among studies was assessed using the I 2 statistic. A random-effects model was applied when heterogeneity was high (I 2 ≥ 50%), whereas a fixed-effect model was used when heterogeneity was low (I 2 ≤ 50%). Risk of bias was assessed using the Cochrane RoB 2.0 tool. Results: Three double-blind, placebo-controlled randomized controlled trials published between 2022 and 2026-AXIOMATIC-SSP (phase 2), PACIFIC-STROKE (phase 3), and OCEANIC-STROKE (phase 3)-comprising 15,596 participants were included. Oral factor XIa inhibitors were significantly associated with a reduction in ischemic stroke (OR = 0.73, 95% CI: 0.64-0.83, p < 0.00001; I 2 = 0%) and any stroke (OR = 0.73, 95% CI: 0.64-0.83, p < 0.00001; I 2 = 0%). No significant differences were observed in ischemic stroke or covert infarcts (p = 0.71), transient ischemic attack (TIA) (p = 0.13), or all-cause mortality (p = 0.93). No statistically significant increase in major bleeding (p = 0.26) or hemorrhagic stroke (p = 0.42) was noted. All included studies demonstrated a low risk of bias across all RoB 2.0 domains. Conclusion: Oral factor XIa inhibitors may be associated with a reduction in ischemic and any stroke without a statistically significant increase in bleeding risk, suggesting a potentially favorable efficacy-safety profile in secondary stroke prevention. However, given the limited number of available randomized trials, these findings should be interpreted with caution. Further large-scale, adequately powered studies are needed to better establish the efficacy and safety of oral factor XIa inhibitors in routine clinical practice.