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

BACKGROUND  The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48. METHODS AND RESULTS  We analyzed three BW groups: low BW (LBW: 95th percentile, ≥120 kg, N = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, Ptrend < 0.001), major bleeding (MB: 9.3 vs. 7.7 vs. 6.5%, Ptrend = 0.08), and worse net clinical outcome of systemic embolic event, MB, or death (31.5 vs. 19.1 vs. 16.0%, Ptrend < 0.0001). The time-in-therapeutic range with warfarin was lowest in LBW patients (63.0 vs. 69.3 vs. 70.1% patients, Ptrend < 0.001). The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across BW groups. The risk of SSE was similar between HDER and warfarin for each of the three weight groups (Pint = 0.52, Pint-trend = 0.86). MB was reduced by LDER versus warfarin (Pint = 0.061, Pint-trend = 0.023), especially in LBW patients. Net clinical outcomes were improved by HDER versus warfarin (Pint = 0.087, Pint-trend = 0.027), especially in LBW patients. CONCLUSION  Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients.