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

Abstract

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/1.73m2 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.