Influence of renal dysfunction on clinical outcomes in elderly patients with atrial fibrillation: a subanalysis of the phase 3, randomized, placebo-controlled ELDERCARE-AF trial

Abstract

Abstract Background Renal dysfunction is common in elderly patients with atrial fibrillation (AF) and is thought to be associated with increased risk of thromboembolic and bleeding events. Once-daily low-dose (15 mg) edoxaban was superior to placebo in preventing stroke or systemic embolic events (S/SEE) without significantly increasing major bleeding events in very elderly (≥80 years) non-valvular AF (NVAF) patients in whom standard oral anticoagulant therapy at approved doses was inappropriate (ELDERCARE-AF trial). Little is known about how renal dysfunction affects the effects of low-dose edoxaban in these patients. Purpose We used prespecified subgroup analysis to investigate the relation between renal function (assessed by creatinine clearance, CrCl) and the efficacy and safety of edoxaban in elderly NVAF patients. Methods ELDERCARE-AF patients were divided into 3 subgroups according to baseline CrCl: normal renal function/mild dysfunction (CrCl >50 mL/min), moderate renal dysfunction (CrCl ≥30 to ≤50 [“30–50”] mL/min) and severe renal dysfunction (CrCl ≥15 to <30 [“15–30”] mL/min). Primary efficacy and safety endpoints were annualized incidence of S/SEE and ISTH-defined major bleeding, respectively. Results Of 984 patients randomized to edoxaban 15 mg or placebo (each group N=492), 681 completed the trial. The 303 discontinuations were due to withdrawal of consent (n=158), death (n=135), or other causes (n=10). Discontinuation rate was the same in the edoxaban and placebo groups. S/SEE incidence in patients with CrCl >50, 30–50 and 15–30 mL/min was 2.0%, 1.3% and 3.5%, respectively, in edoxaban, and 4.4%, 4.6% and 9.7%, respectively, in placebo. In those with CrCl 30–50 and 15–30 mL/min, it was significantly lower in edoxaban than in placebo (adjusted hazard ratio [HR], 0.30 [95% CI, 0.10–0.91], p=0.03; and 0.33 [95% CI, 0.16–0.71], p<0.01, respectively). Incidence of major bleeding in patients with CrCl >50, 30–50 and 15–30 mL/min was 1.0%, 1.8% and 6.2%, respectively, in edoxaban, and 0.9%, 1.5% and 2.4%, respectively, in placebo. Incidence of major bleeding in those with CrCl 15–30 mL/min was higher in edoxaban but not significantly (adjusted HR, 2.53 [95% CI, 0.96–6.72], p=0.062). Incidence of gastrointestinal bleeding in patients with CrCl 15–30 mL/min was 4.3% in edoxaban and 1.6% in placebo (adjusted HR, 2.61 [95% CI, 0.79–8.68], p=0.12). Incidence of all-cause death in patients with CrCl >50, 30–50 and 15–30 mL/min was 5.8%, 6.8% and 15.2%, respectively, in edoxaban, and 7.0%, 6.3% and 15.5%, respectively, in placebo (no significant intergroup differences). Conclusions Incidence of S/SEE, major bleeding and all-cause death increased with declining renal function in elderly NVAF patients. Edoxaban 15 mg remained superior to placebo in preventing S/SEE, even in those with moderate to severe renal dysfunction. Incidence of major bleeding in patients with severe renal dysfunction was higher (non-significantly) with edoxaban than with placebo. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi-Sankyo Co., Ltd.