Stroke and Bleeding in Patients with Atrial Fibrillation and End-Stage Renal Disease Treated with Apixaban Versus Warfarin

Introduction: Treating patients with atrial fibrillation (AF) in patients with advanced chronic kidney disease (CKD) can be particularly challenging as CKD is associated with higher risk of both thrombotic and bleeding events. Direct oral anticoagulants (DOACs) are partially eliminated through the kidneys to varying extents and initial trials validating their effectiveness excluded individuals with advanced kidney disease (creatinine clearance <25). Among the DOACs, apixaban undergoes the least renal excretion, making it a preferred choice for numerous physicians when it comes to stroke prevention in dialysis patients with AF who are either unable or unwilling to take warfarin for any reason. Hence, in this study, we aim to describe the clinical outcomes and safety of apixaban therapy compared to warfarin among patients with end-stage renal disease (ESRD) and AF.

Methods: We conducted a retrospective cohort study through population data collected and analyzed through the multicentric platform TriNetX, across 75 health care organizations (HCOs). Using International Classification of Diseases, tenth revision (ICD-10) codes, we identified patients diagnosed with ESRD (N18.6 and Z99.2) and AF (I48.0, I48.1, I48.91) after the year 2000. Over the period of 5 years, the incidence of ischemic embolic stroke, nontraumatic intracranial bleeding, gastrointestinal (GI) bleeding, and hemorrhage were compared among patients treated with warfarin versus those treated with apixaban.

Results: Our search yielded 23447 patients that had been started on warfarin and 21466 that had been started on apixaban. After propensity score matching of demographics, 10037 patients remained in each group. The average age in our population was 69 years-old with a standard deviation of 12 years, 62% males and 38% females: 62% white, 22% black, 13% unknown, and 2% Asian. Compared with patients who were treated with warfarin over a 5-year period, patients with ESRD and AF treated with apixaban had a decreased risk of nontraumatic intracranial bleeding (161 events vs 205 events, risk ratio 0.777, confidence interval 0.633 to 0.953, p<0.05) and a decreased risk of hemorrhage (212 events vs 293 events, risk ratio 0.711, confidence interval 0.597 to 0.847, p<0.01). No significant difference was observed in the risk of ischemic embolic stroke (57 events vs 56 events, risk ratio 1.01, confidence interval 0.699 to 1.459, p=0.9567) or in the risk of GI bleed (705 events vs 723 events, risk ratio 0.935, confidence interval 0.847 to 1.033, p=0.1846).

Conclusions: Patients with ESRD are at an increased risk of bleeding and thrombotic events. In patients with ESRD and AF, the use of apixaban was associated with a slight reduction in the risk of intracranial bleeding and hemorrhage. Meanwhile, no significant difference was observed in the risk of ischemic stroke or GI bleed. Notably, bleeding events were far more common compared to stroke events in our study. However, the evidence comparing the safety profiles of these two anticoagulants remains limited, particularly concerning randomized double-blind prospective data. Recent studies, such as the RENAL-AF trial showed similar rates of bleeding and strokes in both drugs, however, the study stopped prematurely because of enrollment challenges in the End-stage renal disease (ESRD) population. These findings warrant further investigation in a controlled prospective trial.