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

Giuseppe Boriani; Christian T. Ruff; Julia F. Kuder; Minggao Shi; Hans J. Lanz; Elliott M. Antman; Eugene Braunwald; Robert P. Giugliano

doi:10.1055/s-0040-1716540

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2021; 121(02): 140-149
DOI: 10.1055/s-0040-1716540

Coagulation and Fibrinolysis

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

Giuseppe Boriani

¹Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Modena University Hospital, Modena, Italy

,

Christian T. Ruff

²TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States

,

Julia F. Kuder

²TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States

,

Minggao Shi

³Daiichi Sankyo Inc., Basking Ridge, New Jersey, United States

,

Hans J. Lanz

⁴Daiichi Sankyo Europe GmbH, Munich, Germany

,

Elliott M. Antman

²TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States

,

Eugene Braunwald

²TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States

,

Robert P. Giugliano

²TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States

› Author Affiliations

Abstract

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: <5th percentile, ≤55 kg, N = 1,082), middle BW (MBW: 45th–55th percentile, 79.8–84 kg, N = 2,153), and high BW (HBW: >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, P _trend < 0.001), major bleeding (MB: 9.3 vs. 7.7 vs. 6.5%, P _trend = 0.08), and worse net clinical outcome of systemic embolic event, MB, or death (31.5 vs. 19.1 vs. 16.0%, P _trend < 0.0001). The time-in-therapeutic range with warfarin was lowest in LBW patients (63.0 vs. 69.3 vs. 70.1% patients, P _trend < 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 (P _int = 0.52, P _int-trend = 0.86). MB was reduced by LDER versus warfarin (P _int = 0.061, P _int-trend = 0.023), especially in LBW patients. Net clinical outcomes were improved by HDER versus warfarin (P _int = 0.087, P _int-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.

Keywords

anticoagulation - atrial fibrillation - edoxaban - factor Xa - pharmacokinetics - weight - underweight

Full Text

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Supplementary Material

Supplementary Material