Factor XIa Inhibitors for Secondary Prevention After Noncardioembolic Stroke

OBJECTIVES: Patients with noncardioembolic ischemic stroke or transient ischemic attack (TIA) remain at substantial risk of recurrent ischemic events, despite guideline-recommended antithrombotic therapy. Factor XIa (FXIa) inhibitors may reduce thrombotic risk while preserving hemostasis. METHODS: We systematically searched MEDLINE and Scopus for randomized-controlled clinical trials (RCTs) comparing FXIa inhibitors with placebo in patients with acute noncardioembolic ischemic stroke or TIA. Primary efficacy outcome was first stroke (ischemic, hemorrhagic, or undefined), and primary safety outcome was first major bleeding event during follow-up. Risk ratios (RRs) with 95% CIs were pooled using random-effects models. RESULTS: Three RCTs recruiting 14,239 participants (6,927 assigned to FXIa inhibitors and 7,312 to placebo) were included. Effect estimates were largely driven by a single phase 3 trial, recruiting 12,327 participants. FXIa inhibitors reduced the risks for any stroke (RR = 0.75; 95% CI 0.66-0.84), ischemic stroke (RR = 0.74; 95% CI 0.66-0.84), and composite cardiovascular events (RR = 0.83; 95% CI 0.75-0.92), when compared with placebo. FXIa inhibitors did not increase the risks for major bleeding (RR = 1.12; 95% CI 0.87-1.44), hemorrhagic stroke, intracranial hemorrhage, any bleeding, or all-cause mortality. DISCUSSION: The addition of a FXIa inhibitor to standard antiplatelet therapy after an acute noncardioembolic ischemic stroke or TIA reduces the risk of stroke recurrence without evidence of an increased bleeding risk.