Warfarin and direct-acting oral anticoagulants (DOACs) increase the risk of major bleeding and other complications among patients with stage 3 or higher chronic kidney disease (CKD) and nonvalvular atrial fibrillation (AFib) and lower the net benefit of treatment, study findings suggest.
In a post hoc analysis, investigators pooled data from 3 large randomized clinical trials involving approximately 57,000 patients: The RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy), ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events) trial, and ENGAGE AF-TIMI 8 (The Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial. These trials compared dabigatran, apixaban, and edoxaban, respectively, against warfarin. The 4-variable Modification of Diet in Renal Disease (MDRD) Study equation was used to calculate estimated glomerular filtration rate (eGFR; in mL/min/1.73 m2). Of the trial participants, 25%-29% had an eGFR of 45-59 and 9.5%-12.6% had an eGFR less than 45. Patients with an eGFR less than 30 made up approximately 1% of the populations.
The primary efficacy outcome was stroke or systemic embolism (stroke/SEE). A key secondary outcome was death from any cause. The primary safety end point was major bleeding.
Compared with patients with an eGFR of 60 or more, warfarin users with an eGFR of 45-59 and less than 45 had a significant 1.4- to 1.8-fold and 1.5- to 2.8-fold higher incidence of major bleeding, respectively, across trials, Nita A. Limdi, PharmD, PhD, of the University of Alabama at Birmingham and colleagues reported in Clinical Pharmacology & Therapeutics. Warfarin users in the ARISTOTLE and ENGAGE trials with an eGFR of 45 to 59 had a significant 40% higher incidence of stroke/SEE.
Dabigatran users with an eGFR of 45-59 and less than 45 had a significant 1.5- to 1.9-fold and 1.8-fold higher incidence of stroke/SEE, depending on dose, compared with patients with an eGFR of 60 or more. Dabigatran users, however, also had a significant 1.7- to 1.8-fold and 2.7- to 2.8-fold higher incidence of hemorrhage, depending on dose, at the respective levels of kidney function compared with patients with an eGFR of 60 or more.
Apixaban users with an eGFR of 45-59 and less than 45 had a significant 1.4-fold higher incidence of major bleeding, compared with patients with an eGFR of 60 or more. Edoxaban users with an eGFR 45-59 and less than 45 had a significant 1.3- to 1.5 fold and 1.5- to 1.6-fold higher incidence of hemorrhage, respectively, depending on dose.
In adjusted analyses, compared with patients with an eGFR of 60 or more, warfarin users with an eGFR of less than 60 in the ARISTOTLE and RE-LY trials had a significantly higher risk of hemorrhage, as did dabigatran and edoxaban users, whereas apixaban users did not, the investigators found. This study adds important new information for clinical practice. Although the ORBIT risk score for bleeding in patients with atrial fibrillation assigns risk points for GFR less than 60, HAS-BLED and ATRIA currently assign risk points only for GFR less than 30, they pointed out.
“Given the current American Heart Association and European Cardiology Society recommendations on the preferential use of DOACs over warfarin in patients with [atrial fibrillation], the use of DOACs is expected to continue to rise,” Dr Limdi’s team stated. “The increasing prevalence of CKD and its co-prevalence with [cardiovascular disease] calls for comparative effectiveness research to assess risk/benefit tradeoff and enable personalized treatment decisions in patients with compromised kidney function.”
Limdi NA, Beasley TM, Sun J, Stockbridge N, Pacanowski M, Florian J. Thromboembolic and hemorrhagic outcomes in the direct oral anticoagulant trials across the spectrum of kidney function. Clin Pharmacol Ther. 2021:1-13. doi:10.1002/cpt.2131