Robert P Giugliano1, Christian T Ruff2, Natalia S Rost2, Scott Silverman2, Stephen D Wiviott2, Cheryl Lowe2, Naveen Deenadayalu2, Sabina A Murphy2, Laura T Grip2, Joshua M Betcher2, Anil Duggal2, Jay Dave2, Minggao Shi2, Michele Mercuri2, Elliott M Antman2, Eugene Braunwald2. 1. From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (R.P.G., C.T.R., S.D.W., C.L., N.D., S.A.M., L.T.G., E.M.A., E.B.); Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., S.S.); Biostatistics, Quintiles, Inc, Durham, NC (J.M.B.); and Daiichi Sankyo, Inc, Pharma Development, Edison, NJ (A.D., J.D., M.S., M.M.). rgiugliano@partners.org. 2. From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (R.P.G., C.T.R., S.D.W., C.L., N.D., S.A.M., L.T.G., E.M.A., E.B.); Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., S.S.); Biostatistics, Quintiles, Inc, Durham, NC (J.M.B.); and Daiichi Sankyo, Inc, Pharma Development, Edison, NJ (A.D., J.D., M.S., M.M.).
Abstract
BACKGROUND AND PURPOSE: The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously. METHODS: We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events. RESULTS: Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91-1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds. CONCLUSIONS: In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
RCT Entities:
BACKGROUND AND PURPOSE: The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously. METHODS: We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events. RESULTS:Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91-1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds. CONCLUSIONS: In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
Authors: Andrew M Demchuk; Patrick Yue; Elena Zotova; Juliet Nakamya; Lizhen Xu; Truman J Milling; Tomoyuki Ohara; Joshua N Goldstein; Saskia Middeldorp; Peter Verhamme; Jose Luis Lopez-Sendon; Pamela B Conley; John T Curnutte; John W Eikelboom; Mark Crowther; Stuart J Connolly Journal: Stroke Date: 2021-05-10 Impact factor: 10.170