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
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 . 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.
- Plasma concentration, exogenous anti-FXa activity and inhibition of baseline endogenous FXa with HDER were similar across the three weight groups, at both peak and at day 29. Pharmacodynamic measurement with LDER were also consistent across weight groups.
- Proportion of time with an INR in the therapeutic range (2.0-3.0) differed according to weight categories, with 63% (49.0-73.0) (median and IQR) for LBW patients, 69.3% (55.9-77.8) for MBW and 70.1% (61.0-79.9) for HBS (Ptrend<0.001).
- In the warfarin group, risk of SSE, major bleeding and net clinical outcome differed across the 3 weight groups. Patients in the LBW group had higher rates of SSE, higher rates of major bleeding and worse net clinical outcome.
- Risk of SSE were similar between HDER and warfarin across weight groups (Pinteraction=0.52). LDER compared with warfarin on risk of SSE across weight groups gave similar results (Pinteraction=0.61).
- No differences in major bleeding were seen across weight groups with HDER vs. warfarin (Pinteraction=0.35). Major bleeding was reduced by LDER compared to warfarin, independent of weight (Pinteraction=0.061). HDER and LDER reduced major or clinically relevant nonmajor bleeding compared to warfarin, with no difference across weight groups (Pinteraction=0.055 and 0.064, respectively).
- Net clinical outcome showed no difference across weight groups for the effect of HDER compared to warfarin (Pinteraction=0.087). Also, not when effect of LDER was compared to warfarin across body weight groups (Pinteraction=0.21).
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).