Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function

Chronic kidney disease is a common comorbidity among patients taking direct‐acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism (SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR) ≥ 60 (reference), 45–59, and < 45mL/min/1.73 m 2 for participants in the Randomized Evaluation of Long‐Term Anticoagulant Therapy (RE‐LY) ( n  = 18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) ( n  = 18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) ( n  = 20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention‐to‐treat analysis adjusting for known predictors. A large proportion of participants had GFR < 60 (25–29% had 45 ≤ GFR < 60 and 9.5–12.6% with GFR < 45). Compared with patients with GFR ≥ 60, warfarin users across the trials with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage ( P values < 0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE ( P values ≤ 0.05). Compared with patients with GFR ≥ 60, dabigatran users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of stroke/SEE ( P  ≤ 0.02), hemorrhage ( P  < 0.001), and both composite end points ( P  < 0.0001). Compared with patients with GFR ≥ 60, apixaban and edoxaban users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage ( P values ≤ 0.05) and composite end points ( P values ≤ 0.05). After adjustment, compared with patients with GFR ≥ 60, warfarin users with GFR < 60 in the ARISTOTLE and RE‐LY trials had a higher risk of hemorrhage ( P  < 0.05), as did dabigatran ( P  < 0.001) and edoxaban ( P  ≤ 0.005) users, while apixaban users did not exhibit an increased risk ( P  = 0.08 GFR ≥ 45–59; P  = 0.71 GFR < 45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.