Cardiovascular-Kidney-Metabolic Interplay in Patients with Atrial Fibrillation Receiving Direct Oral Anticoagulants

Background and aims: Cardiovascular-kidney-metabolic (CKM) syndrome reflects the interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic risk factors. We examined whether the number, components, and complexity of CKM domains influence outcomes and years of life lost (YLL) in patients with non-valvular atrial fibrillation (AF) receiving direct oral anticoagulants (DOACs). Methods: We included 17,378 AF patients (mean age 76.1±10.7 years; 40.9% women) on DOACs from a multicenter Taiwanese database (2012-2021). Patients were followed until outcomes, death, or study end. Results: Overall, 18.2%, 35.0%, 32.2%, and 14.6% of patients had 0, 1, 2, and 3 CKM domains. Women more often exhibited kidney, metabolic, or combined domains. Clinical risks rose stepwise with domain number; patients with 3 domains had the highest risks of ischemic stroke/systemic embolic event/acute coronary syndrome (adjusted hazard ratio (aHR) 1.60, 95% confidence interval (CI) 1.25-2.05), major bleeding (aHR 2.60, 95%CI 2.00-3.38), heart failure hospitalization (aHR 2.83, 95%CI 2.38-3.37), all-cause mortality (aHR 1.80, 95%CI 1.58-2.06), acute kidney injury (aHR 3.42, 95%CI 2.76-4.25), and major adverse renal events (aHR 20.84, 95%CI 14.14-30.71; all p<0.001). Domain-specific analysis showed kidney involvement conferred the strongest risks (except IS/SEE/ACS), while cardiovascular and metabolic domains were more associated with IS/SEE/ACS. YLL rose with more CKM domains, with females associated with greater reductions, especially in cardiovascular (-10.29 vs. -4.67) and metabolic (-4.98 vs. -0.80) domains (p<0.001). Conclusions: Increasing CKM burden was associated with progressively worse prognosis and shorter life expectancy in AF patients on DOACs, with more pronounced impacts in women.