Early versus delayed direct oral anticoagulant initiation in nonvalvular atrial fibrillation–associated acute ischemic stroke: A systematic review and meta-analysis

Background: Early initiation of direct oral anticoagulants (DOACs) after acute ischemic stroke (AIS) in patients with nonvalvular atrial fibrillation (NVAF) can prevent early recurrent AIS but may increase the risk of intracerebral hemorrhage (ICH). The appropriate DOAC initiation time remains uncertain. This systematic review and meta-analysis aimed to determine the optimal timing for DOAC initiation following NVAF-associated AIS. Methods: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library from inception to March 2025. Eligible studies were randomized controlled trials and prospective cohort studies examining the effects of DOAC initiation timing in patients with NVAF-associated AIS. The primary outcome was the pooled risk ratio for a composite measure of ischemic and hemorrhagic events. Secondary outcomes were the pooled risk ratios for symptomatic ICH, recurrent AIS, major extracranial bleeding, and mortality. Subgroup analyses examined patients initiating DOACs within 3 days of stroke onset and compared outcomes based on baseline stroke severity (NIHSS < 5 vs ≥ 5). Results: Eleven studies from ten cohorts (12,388 participants) met the inclusion criteria. No significant differences were found between early and delayed DOAC initiation for the composite outcomes or for any secondary endpoint. Subgroup analyses revealed a nonsignificant increase in ICH risk among patients with early treatment and higher stroke severity (NIHSS ≥ 5). No significant differences in early ischemic stroke rate were observed in both subgroups. Conclusions: Early DOAC initiation appears to be safe following NVAF-associated AIS, including in patients with moderate stroke severity. However, the rate of early recurrent ischemic stroke remains comparable between early and delayed initiation groups.