Early vs Delayed Direct Oral Anticoagulant (DOAC) Resumption After Ischemic Stroke in Patients with Atrial Fibrillation: A MetaAnalysis

Abstract

Background: For patients with atrial fibrillation (AF) who experience acute ischemic stroke, clinicians must balance prevention of early recurrent embolism against the risk of intracranial hemorrhage (ICH) when restarting direct oral anticoagulants (DOACs). The optimal timing for DOAC resumption remains uncertain.

Methods: We conducted a systematic review and meta-analysis (PRISMA-aligned) of randomized controlled trials, registry-based randomized trials, and prospective cohorts comparing early versus delayed DOAC initiation after ischemic stroke in adults with AF. Databases (PubMed, Embase, Web of Science, Scopus, Cochrane Library) were searched from inception to June 2024. Two reviewers performed independent screening, data extraction, and risk-of-bias assessment (RoB 2.0 for RCTs; Newcastle–Ottawa Scale for the cohort). Random-effects models (DerSimonian–Laird) were prespecified for pooled analyses; heterogeneity was assessed with I² and χ². Primary outcomes were recurrent ischemic stroke and ICH; secondary outcomes included major bleeding, all-cause mortality, and composite endpoints.

Results: Three studies (n = 4028) met eligibility: one prospective cohort (RAF-NOAC, 2017) and two randomized trials (TIMING, 2022; ELAN, 2023). Definitions of “early” ranged from ≤48 h (minor/moderate strokes) to ≤4 days; “delayed” ranged from day 5–10 or >14 days, with follow-up to 90 days (ELAN also reported 30- day outcomes). Across studies, early DOAC initiation was not associated with increased ICH; symptomatic ICH was rare (e.g., 0% in TIMING; ~0.2% in both ELAN arms). Efficacy signals favored early treatment: composite endpoints were numerically lower with early initiation in TIMING (6.9% vs 8.7%) and ELAN (2.9% vs 4.1%), with similar or lower major bleeding (e.g., 1.4% vs 2.5% in ELAN). Observational data (RAF-NOAC) suggested the most favorable outcomes when treatment began 3–14 days after stroke, with slightly higher events at ≤2 days. Subgroup analyses in RCTs showed no significant effect modification by age, sex, stroke severity, or reperfusion status.

Conclusions: In AF-related ischemic stroke, early DOAC resumption appears safe and at least non-inferior to delayed strategies, with signals of reduced recurrent ischemia and no excess ICH. A tailored, severity-informed approach—especially leveraging imaging—seems appropriate, while very-early initiation (≤48 h) may warrant caution in large infarcts. These findings support guideline evolution toward earlier anticoagulation in suitable patients and underscore the need for longerterm outcomes and refined risk-stratification tools.