Oral Factor XIa Inhibitors for Non-Cardioembolic Ischemic Stroke and Transient Ischemic Attack

Introduction: Patients with non-cardioembolic ischemic stroke or transient ischemic attack (TIA) remain at high risk for recurrent vascular events despite standard antiplatelet therapy. Factor XIa inhibitors offer a novel dual-pathway antithrombotic approach by uncoupling thrombosis from hemostasis, potentially reducing ischemic events without proportionally increasing bleeding risk. Hypothesis: We hypothesized that adjunctive Factor XIa inhibitors added to background antiplatelet therapy improve cerebrovascular and cardiovascular outcomes without unacceptable bleeding risks compared to antiplatelet therapy alone. Methods: A systematic search of PubMed, Scopus, Embase, and Cochrane CENTRAL identified 157 records. Three randomized controlled trials (n=16,501) comparing Factor XIa inhibitors (asundexian and milvexian) versus placebo in adults with recent non-cardioembolic ischemic stroke or high-risk TIA on antiplatelet therapy met inclusion criteria. The primary outcomes were recurrent ischemic stroke and major bleeding. Secondary outcomes included any stroke, major adverse cardiovascular events (MACE), and serious adverse events. Outcomes were pooled using a random-effects model. The study protocol was registered (PROSPERO CRD420261417784). Results: A total of three RCTs comprising 16,501 patients were included in the quantitative synthesis. Adjunctive Factor XIa inhibition was associated with a highly significant reduction in the risk of any stroke (RR 0.75; 95% CI 0.66-0.84; p<0.0001; I 2 =0%) and MACE (RR 0.84; 95% CI 0.76-0.93; p=0.0005; I 2 =0%). The primary efficacy outcome of recurrent ischemic stroke demonstrated a numerical reduction that did not achieve statistical significance and exhibited substantial heterogeneity (RR 0.86; 95% CI 0.69-1.08; p=0.20; I 2 =66.5%). For the primary safety outcome, major bleeding showed a non-significant trend toward increased risk (RR 1.38; 95% CI 0.86-2.22; p=0.18; I 2 =36.1%). Overall tolerability remained comparable between groups, with no difference in the incidence of serious adverse events (RR 0.99; 95% CI 0.92-1.06; p=0.69; I 2 =0%). Conclusions: Factor XIa inhibitors added to standard antiplatelet therapy significantly reduce the composite risk of any stroke and MACE in patients with non-cardioembolic ischemic stroke or TIA, demonstrating robust systemic cardiovascular protection. While the specific reduction in isolated recurrent ischemic stroke was not statistically significant and major bleeding showed a trend toward harm, the overall incidence of serious adverse events remained neutral. These findings support expedited Phase 3 investigation to optimize dosing strategies and identify patient subgroups most likely to derive net clinical benefit from adjunctive Factor XIa inhibition in cerebrovascular disease