Clinical trajectories of heart failure and atrial fibrillation onset influence multi-organ risks: an analysis from a global federated research network

Background The temporal sequence of heart failure (HF) and atrial fibrillation (AF) onset may represent different pathophysiological trajectories. Whether this chronology is associated with multi-organ outcomes has not been well defined. Methods Using a large federated electronic health record network (TriNetX), patients with both HF and non-valvular AF were categorized according to onset sequence (HF→AF or AF→HF). Two temporal cohorts were constructed requiring ≥1-month separation between HF and AF diagnoses to minimize misclassification of concurrent events. Propensity score matching (PSM) was performed for demographics and major comorbidities. Five-year outcomes were evaluated using Cox proportional hazards models. Landmark sensitivity analyses (3 months–5 years and 1–5 years) were conducted to account for early competing risk. Stratified analyses were performed by anticoagulant class (direct oral anticoagulant [DOAC] vs vitamin K antagonist [VKA]).The primary endpoint was all-cause mortality. Secondary endpoints included major adverse cardiovascular events (MACE), major adverse kidney events (MAKE), stroke, and overall dementia (including Alzheimer’s disease, vascular dementia, and unspecified dementia). Results Before PSM, 111,254 patients were HF-first (72.9 ±12.7 years; 42.5% female) and 222,938 were AF-first (75.8 ± 11.2 years; 57.3% female). After PSM, in the primary 0–5-year analysis, the HF→AF trajectory was associated with higher risks of all-cause death (aHR 1.180, 95% CI 1.161-1.200), MACE (1.080, 1.049-1.111), and MAKE (1.198, 1.130-1.270), whereas the association with overall dementia was modest (1.026, 0.984-1.069). Estimates remained consistent after exclusion of early deaths and landmark restriction [Figure1]. In anticoagulant-stratified analyses, chronology-associated risk gradients for stroke, vascular dementia, and MAKE were attenuated among DOAC users (vascular dementia aHR 0.929, 95% CI 0.796-1.085) but more pronounced among VKA users (1.747, 1.351-2.258) [Figure 2]. Conclusion The clinical chronology of HF and AF onset is associated with distinct multi-organ risk profiles. These trajectory-associated gradients appear attenuated among DOAC users but more pronounced among VKA users, indicating differential modification of trajectory-associated risk by anticoagulant class.