June 29, 2016Open Access
View Full PaperImpact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial
Key Result
Higher-dose edoxaban showed consistent safety and net clinical benefit versus warfarin across renal function ranges, despite lower relative efficacy for stroke prevention at CrCl >95 mL/min (HR 1.36).
Study Design
Type
RCT (n=14,071)
Randomization
randomized
Structured PICO
Does edoxaban reduce stroke or systemic embolism compared to warfarin in patients with atrial fibrillation across the range of baseline creatinine clearance?
P
Population
14,071 patients with atrial fibrillation at moderate to high risk for stroke. Key exclusion: CrCl <30 mL/min.
I
Intervention
Edoxaban higher-dose regimen (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30-50 mL/min, body weight of ≤60 kg, or use of a potent phosphorylated glycoprotein inhibitor)
C
Comparator
Warfarin
O
Outcome
Stroke or systemic embolism (S/SE)hard clinical
Edoxaban maintains a consistent safety and net clinical benefit compared with warfarin across the range of renal function in patients with atrial fibrillation, despite a potential decrease in relative efficacy for stroke prevention at very high creatinine clearance (>95 mL/min).
Main Result
Effect estimate: HR 0.87 (95% CI 0.72-1.04)
Abstract
BACKGROUND: Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patients with atrial fibrillation. We evaluated the efficacy and safety of edoxaban versus warfarin across the range of baseline creatinine clearance (CrCl) in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) with a focus on the higher-dose edoxaban regimen (HDER) and the upper range of CrCl. METHODS: A total of 14 071 patients with atrial fibrillation at moderate to high risk for stroke were randomized to warfarin or HDER (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30-50 mL/min, body weight of ≤60 kg, or use of a potent phosphorylated glycoprotein inhibitor). CrCl 50 mL/min (hazard ratio HR, 0.87; 95% confidence interval CI, 0.72-1.04) was similar to that in patients with CrCl ≤50 mL/min (HR, 0.87; 95% CI, 0.65-1.18; P for interaction=0.94). Several exploratory analyses suggested lower relative efficacy for the prevention of S/SE with HDER compared with warfarin at higher levels of CrCl (CrCl ≤50 mL/min: HR, 0.87; 95% CI, 0.65-1.18; CrCl >50-95 mL/min: HR, 0.78; 95% CI, 0.64-0.96; CrCl >95 mL/min: HR, 1.36; 95% CI, 0.88-2.10; P for interaction=0.08). Bleeding rates were lower at all levels of CrCl with HDER (P for interaction=0.11). Because of the preserved effect on bleeding, the net clinical outcome was more favorable with HDER across the range of CrCl (P for interaction=0.73). Similar findings were observed in the sensitivity analysis using the CKD-EPI formula. CONCLUSIONS: Although there was an apparent decrease in relative efficacy to prevent arterial thromboembolism in the upper range of CrCl, the safety and net clinical benefit of HDER compared with warfarin are consistent across the range of renal function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
Cite This Study
Bohula et al. (Wed,) conducted a rct in atrial fibrillation at moderate to high risk for stroke (n=14,071). higher-dose edoxaban regimen (HDER) vs. warfarin was evaluated on stroke or systemic embolism (S/SE) (HR 0.87, 95% CI 0.72-1.04). Higher-dose edoxaban showed consistent safety and net clinical benefit versus warfarin across renal function ranges, despite lower relative efficacy for stroke prevention at CrCl >95 mL/min (HR 1.36).