Physicians' Academy for Cardiovascular Education

Factor Xa inhibitor efficacious and safe in AF patients with extreme body weight

Edoxaban versus Warfarin in Patients with Atrial Fibrillation at the Extremes of Body Weight: An Analysis from the ENGAGE AF-TIMI 48 Trial

Literature - Boriani G, Ruff CT, Kuder JF et al. - Thromb Haemost 2020;

Introduction and methods

Specific criteria for dose reduction of NOACs are based on weight and/or renal function [1-4]. However, there is limited data on efficacy and safety of NOACS in patients with extreme body weight, both very low and very high weight. There are concerns about use of NOACS at fixed-dosing schedules in these patients, as higher of lower drug concentrations may results in increased bleeding or thrombosis [5,6]. Indeed, the ISTH guidelines recommend to be cautious with use of NOACs in patients ≥120 kg, but there is no recommendation for those with low body weight [7]. The Working Group on Thrombosis of the ESC has also raised caution for use of NOACs in obese patients. There is a need for additional assessments on pharmacokinetics and pharmacodynamics of NOACs at the extremes of body weight.

This posthoc analysis of the ENGAGE AF-TIMI 48 trial analyzed the pharmacokinetics, pharmacodynamics and clinical outcomes in patients treated with edoxaban vs warfarin, who were at extremes of body weight (≥120 kg or ≤55 kg) compared to those with middle body weight.

The ENGAGE AF-TIMI 48 trial enrolled 21105 AF patients with a CHADS₂ score ≥2, who were followed for a median of 2.8 years [8,9]. Patients were randomized in a 1:1:1 ratio to warfarin, higher dose edoxaban (HDER, 60 mg), or lower dose edoxaban (LDER, 30 mg) regimens. Dose was halved if estimated CrCl ≤50 mL/min, weight ≤60 kg or concomitant use of a potent P-glycoprotein inhibitor. Three weight groups were prespecified: low body weight (LBW, bottom 5th percentile: ≤55 kg) middle body weight (MBW, 45th-55th percentile: 79.8-84 kg), high body weight (HBW, top 5th percentile: ≥120 kg). There were 1082 LBW, 2153 MBW and 1093 HBW patients. Primary efficacy endpoint was the composite of stroke or systemic embolic events (SEE). Principal safety endpoint was ISTH major bleeding. Additional endpoints included ischemic stroke/SEE, mortality, major or clinically relevant nonmajor bleeding and primary net clinical outcome was a composite of stroke, SEE, major bleeding or death.

Main results


AF patients with at extremes of body weight (≥120 kg or ≤55 kg) had similar efficacy and safety with edoxaban vs. warfarin compared to those with middle weight (79.8-84 kg).


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