PMID- 32920808 OWN - NLM STAT- MEDLINE DCOM- 20211008 LR - 20211008 IS - 2567-689X (Electronic) IS - 0340-6245 (Linking) VI - 121 IP - 2 DP - 2021 Feb TI - Edoxaban versus Warfarin in Patients with Atrial Fibrillation at the Extremes of Body Weight: An Analysis from the ENGAGE AF-TIMI 48 Trial. PG - 140-149 LID - 10.1055/s-0040-1716540 [doi] AB - 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, 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. CI - Thieme. All rights reserved. FAU - Boriani, Giuseppe AU - Boriani G AD - Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Modena University Hospital, Modena, Italy. FAU - Ruff, Christian T AU - Ruff CT AD - TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States. FAU - Kuder, Julia F AU - Kuder JF AD - TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States. FAU - Shi, Minggao AU - Shi M AD - Daiichi Sankyo Inc., Basking Ridge, New Jersey, United States. FAU - Lanz, Hans J AU - Lanz HJ AD - Daiichi Sankyo Europe GmbH, Munich, Germany. FAU - Antman, Elliott M AU - Antman EM AD - TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States. FAU - Braunwald, Eugene AU - Braunwald E AD - TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States. FAU - Giugliano, Robert P AU - Giugliano RP AD - TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States. LA - eng PT - Clinical Trial PT - Journal Article PT - Randomized Controlled Trial DEP - 20200913 PL - Germany TA - Thromb Haemost JT - Thrombosis and haemostasis JID - 7608063 RN - 0 (Anticoagulants) RN - 0 (Factor Xa Inhibitors) RN - 0 (Pyridines) RN - 0 (Thiazoles) RN - 5Q7ZVV76EI (Warfarin) RN - NDU3J18APO (edoxaban) SB - IM CIN - Thromb Haemost. 2021 Feb;121(2):118-120. PMID: 32942314 CIN - Thromb Haemost. 2021 Feb;121(2):115-117. PMID: 33086398 MH - Aged MH - Aged, 80 and over MH - Anticoagulants/pharmacokinetics/*therapeutic use MH - Atrial Fibrillation/*drug therapy MH - Body Weight MH - Double-Blind Method MH - Factor Xa Inhibitors/pharmacokinetics/*therapeutic use MH - Female MH - Humans MH - Male MH - Middle Aged MH - Pyridines/pharmacokinetics/*therapeutic use MH - Thiazoles/pharmacokinetics/*therapeutic use MH - Treatment Outcome MH - Warfarin/pharmacokinetics/*therapeutic use COIS- G.B. reports personal fees from Boehringer, Boston, Biotronik, and Medtronic, outside the submitted work; C.T.R. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences; J.F.K. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, and Zora Biosciences; M.S. reports to be an employee of Daiichi Sankyo Inc.; H.J.L. reports to be an employee of Daiichi Sankyo Inc.; E.M.A. reports grants from Daiichi Sankyo, during the conduct of the ENGAGE study; E.B. reports grants from Daiichi Sankyo during the conduct of the ENGAGE study, grants from Astra Zeneca, Daiichi Sankyo, Merck, Novartis, and personal fees from Amgen, Cardurion, MyoKardia, Novo Nordisk, Verve, outside the submitted work; R.P.G. reports grants from Merck, during the conduct of the study; personal fees from Akcea, grants and personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees from Angel Med, Beckman-Coulter, Boehringer-Ingelheim, Bristol Myers Squibb, CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, Janssen, Lexicon, grants and personal fees from Merck, personal fees from Portola, Pfizer, St. Jude, Stealth Peptide, outside the submitted work; and institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research he is not directly involved in from AstraZeneca, Bayer, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, and Takeda. EDAT- 2020/09/14 06:00 MHDA- 2021/10/09 06:00 CRDT- 2020/09/13 20:42 PHST- 2020/09/14 06:00 [pubmed] PHST- 2021/10/09 06:00 [medline] PHST- 2020/09/13 20:42 [entrez] AID - 10.1055/s-0040-1716540 [doi] PST - ppublish SO - Thromb Haemost. 2021 Feb;121(2):140-149. doi: 10.1055/s-0040-1716540. Epub 2020 Sep 13.