Int J Stroke. 2026 Apr 17:17474930261446363. doi: 10.1177/17474930261446363. Online ahead of print.
ABSTRACT
BackgroundCovert brain infarction (CBI) is a common neuroimaging-defined manifestation of covert cerebrovascular disease and is associated with increased risks of future stroke and cognitive decline. CBI has been included as an outcome in randomized trials evaluating coagulation-pathway-targeting strategies. However, whether these strategies consistently reduce incident CBI, and whether treatment effects on CBI parallel those for acute ischemic stroke (AIS), remains uncertain.MethodsFollowing PRISMA 2020 guidelines, we searched PubMed, Ovid MEDLINE, Embase, and Web of Science through November 10, 2025, for randomized controlled trials and MRI 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 CBI on follow-up MRI. Trial-level treatment effects for CBI, AIS, and their composite were compared. Exploratory cross-outcome comparisons were performed using the ratio of relative risks (RRR) with prespecified interpretability bounds.ResultsSix 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 CBI 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 (RR, 0.95; 95% CI, 0.81-1.12). Findings were consistent across CBI subtypes, including lacunar and non-lacunar lesions. In trials reporting all three outcomes, these strategies were not associated with significant reductions in CBI, AIS (RR, 0.85; 95% CI, 0.65-1.11), or their composite endpoint (RR, 0.97; 95% CI, 0.84-1.11). The composite endpoint was predominantly driven by CBI (~70% of events). Exploratory cross-outcome comparisons yielded point estimates favoring AIS over CBI, although confidence intervals crossed unity.ConclusionsIn clinical settings without a mandatory indication for anticoagulation, coagulation-pathway strategies were not associated with reduced incident CBI compared with antiplatelet therapy. Although effect estimates for CBI and AIS were broadly similar, uncertainty remains. Composite endpoints predominantly driven by CBI warrant cautious interpretation when inferring treatment effects on clinically manifest ischemic stroke.
PMID:41999065 | DOI:10.1177/17474930261446363
