Abstract
The optimal timing for initiating oral anticoagulation in patients with atrial fibrillation (AF) following acute ischemic stroke (AIS) remains uncertain in specific subgroups and real-world settings. This study evaluates the association between early (≤2 days) versus later (>2 days) oral anticoagulation initiation and short-term clinical outcomes in patients with AF and mild to moderate AIS. We conducted a retrospective cohort study using the TriNetX global research network. Adult patients (≥18 years) diagnosed with both AF and AIS (National Institutes of Health Stroke Scale 0-15) between January 2010 and February 2025 were included. Patients were categorized into early and later initiation groups based on treatment start time. The primary outcome was a 30-day composite of tissue plasminogen activator (tPA) use, intracranial hemorrhage (ICH), and all-cause mortality. Propensity score matching (1:1) was used to adjust for baseline characteristics. Cox regression and Kaplan-Meier methods were used for analysis. A total of 5240 matched patients (2620 per group) were included. Early anticoagulation initiation was associated with a significantly lower risk of the primary composite outcome (hazard ratio (HR): 0.43; 95% CI: 0.30-0.60; P < .001). Each component of the composite outcome was also significantly reduced in the early group. Subgroup analyses showed consistent results across male sex, age over 75 years, paroxysmal AF, patients with heart failure, coronary artery disease, hypertension, and different anticoagulants (apixaban and rivaroxaban), though some subgroups had wide confidence intervals due to small sample sizes. Negative control outcomes, landmark analysis, and E-value analysis supported the robustness of the findings. In patients with mild to moderate AIS and AF, early initiation of oral anticoagulation within 2 days was associated with a significantly lower 30-day composite of tPA use, ICH, and all-cause mortality compared to the later initiation group. These findings support the safety and potential benefit of early anticoagulation initiation, though further randomized controlled trials are needed to confirm these results and inform clinical guidelines.