Declining creatinine clearance was linked to increased ischemic and bleeding risks.

Risk patterns by renal function differed among individual anticoagulants.

Apixaban showed no significant association between event risk and renal function.

These findings highlight the importance of renal function–based risk assessment in the management of anticoagulation therapy.

Renal function influences the pharmacokinetics of oral anticoagulants in atrial fibrillation (AF), potentially affecting both efficacy and bleeding risk. However, its differential impact across specific agents remains unclear. In this study, we aimed to evaluate the association between renal function and ischemic and bleeding risks in patients with AF, with analyses stratified by anticoagulant type.

We analyzed 7239 patients with non-valvular AF from the DIRECT-Extend registry, a pooled dataset of three large-scale registries. Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault formula and categorized into ≥50, 30 to <50, and 15 to <30 mL/min. The primary ischemic endpoint was stroke or systemic embolism, and the primary bleeding endpoint was major bleeding. Cox proportional hazard models and restricted cubic spline analyses assessed associations between CrCl and outcomes, with subgroup analyses by anticoagulant type.

Lower CrCl was associated with older age, female sex, and greater comorbidity burden. Impaired renal function was significantly associated with higher ischemic and bleeding risks. Spline analysis demonstrated a continuous increase in both risks with declining CrCl, with a nonlinear relationship for bleeding. Subgroup analyses revealed significant associations between reduced CrCl and ischemic risk in patients on dabigatran, rivaroxaban, edoxaban, and warfarin. Increased bleeding risk was evident for edoxaban and warfarin at lower CrCl levels. No significant association was observed between CrCl and either endpoint in patients receiving apixaban.

In this large real-world cohort, declining renal function was associated with increased ischemic and bleeding risks, highlighting the importance of renal function–based risk assessment in the management of anticoagulation therapy.

Atrial fibrillation

Renal function

Anticoagulation

Ischemic events

Bleeding risk

Direct oral anticoagulants

© 2025 The Authors. Published by Elsevier B.V.