Secondary Atrial Fibrillation in Critically Ill Sepsis Patients: Evaluating the Role of Early Oral Anticoagulants in a Retrospective Multi-Center Study

Background: New-onset atrial fibrillation (AF) is a common complication of sepsis, affecting 5–25% of patients, and is associated with increased mortality and ischemic stroke. With limited high-quality evidence, the net clinical benefit of early oral anticoagulant (OAC) initiation in this high-risk setting remains uncertain. Methods: Adults ≥18 hospitalized with sepsis who developed new-onset AF within 3 days were identified from the TriNetX database. Cohort one included patients who received at least three doses of OAC within 3 days after AF onset and was compared to those who did not receive OAC (cohort two). Propensity score matching (1:1; 90 covariates; caliper 0.1) was employed to balance the groups. The primary outcomes assessed were evaluated at 7, 14, and 30 days. Risk ratios and risk differences with 95% confidence intervals were estimated using intention-to-treat analysis. Results: Among 136,172 eligible patients, 10,773 were matched per group. Early OAC use was associated with significantly lower mortality at 7, 14, and 30 days (RR 0.19-0.35; all p < 0.001) and reduced ischemic stroke risk across the same intervals (RR 0.74-0.83; p ≤ 0.004). Major bleeding rates were also lower (RR 0.40-0.49; all p < 0.001). MACEs showed a modest reduction at 7 days (RR 0.92; p = 0.001) but not afterward. Thromboembolic events were similar beyond the first week. The need for thrombolytics (RR 0.55-0.59) and anti-hemorrhagic therapy (RR≈0.69) consistently remained lower with OACs (all p < 0.001). Falsification outcomes were neutral, except for a minimal late increase for osteoarthritis at 30 days (RR 1.16; p = 0.03). Conclusion: In sepsis-associated NOAF, early OAC initiation was associated with reduced short-term mortality and ischemic stroke without excess bleeding or thromboembolic risk. The large magnitude of mortality benefit and paradoxical reduction in bleeding likely reflect residual confounding by clinical stability and patient selection. Findings warrant cautious interpretation given the observational design; prospective trials are needed.