Antithrombotic strategies targeting the coagulation pathway and incident covert brain infarction: A systematic review and meta-analysis of randomized trials

BACKGROUND: Covert brain infarction is a common neuroimaging-defined manifestation of covert cerebrovascular disease and is associated with increased risks of future stroke and cognitive decline. Covert brain infarction has been included as an outcome in randomized trials evaluating coagulation-pathway-targeting strategies. However, whether these strategies consistently reduce incident covert brain infarction and whether treatment effects on covert brain infarction parallel those for acute ischemic stroke remain uncertain. METHODS: Following PRISMA 2020 guidelines, we searched PubMed, Ovid MEDLINE, Embase, and Web of Science through 10 November 2025, for randomized controlled trials and magnetic resonance imaging substudies enrolling patients without an established indication for anticoagulation. Eligible trials compared antithrombotic strategies targeting the coagulation pathway (oral anticoagulation or direct factor inhibition, with or without background antiplatelet therapy) with antiplatelet-based regimens and reported incident covert brain infarction on follow-up magnetic resonance imaging. Trial-level treatment effects for covert brain infarction, acute ischemic stroke, and their composite were compared. Exploratory cross-outcome comparisons were performed using the ratio of relative risks with prespecified interpretability bounds. RESULTS: Six randomized trials met the inclusion criteria, encompassing diverse clinical populations and varying antiplatelet regimens in the control arms. In stratified analyses according to treatment structure, coagulation-pathway strategies were not associated with a statistically significant reduction in incident covert brain infarction compared with antiplatelet therapy alone, with similar estimates across treatment strata and no evidence of interaction (P_interaction = 0.249). An exploratory pooled estimate was similar (risk ratio, 0.95; 95% confidence interval, 0.81-1.12). Findings were consistent across covert brain infarction subtypes, including lacunar and non-lacunar lesions. In trials reporting all three outcomes, these strategies were not associated with significant reductions in covert brain infarction, acute ischemic stroke (risk ratio, 0.85; 95% confidence interval, 0.65-1.11), or their composite endpoint (risk ratio, 0.97; 95% confidence interval, 0.84-1.11). The composite endpoint was predominantly driven by covert brain infarction (~70% of events). Exploratory cross-outcome comparisons yielded point estimates favoring acute ischemic stroke over covert brain infarction, although confidence intervals crossed unity. CONCLUSION: In clinical settings without a mandatory indication for anticoagulation, coagulation-pathway strategies were not associated with reduced incident covert brain infarction compared with antiplatelet therapy. Although effect estimates for covert brain infarction and acute ischemic stroke were broadly similar, uncertainty remains. Composite endpoints predominantly driven by covert brain infarction warrant cautious interpretation when inferring treatment effects on clinically manifest ischemic stroke.