title: Cerebrovascular events in 21 105 patients with atrial fibrillation randomized to edoxaban versus warfarin: Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
authors.affiliation: 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.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: 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.).
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.affiliation: 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.).
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.affiliation: 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.).
authors.forename: Scott
authors.initials: S
authors.lastname: Silverman
authors.affiliation: 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.).
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: 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.).
authors.forename: Cheryl
authors.initials: C
authors.lastname: Lowe
authors.affiliation: 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.).
authors.forename: Naveen
authors.initials: N
authors.lastname: Deenadayalu
authors.affiliation: 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.).
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: 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.).
authors.forename: Laura T
authors.initials: LT
authors.lastname: Grip
authors.affiliation: 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.).
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Betcher
authors.affiliation: 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.).
authors.forename: Anil
authors.initials: A
authors.lastname: Duggal
authors.affiliation: 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.).
authors.forename: Jay
authors.initials: J
authors.lastname: Dave
authors.affiliation: 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.).
authors.forename: Minggao
authors.initials: M
authors.lastname: Shi
authors.affiliation: 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.).
authors.forename: Michele
authors.initials: M
authors.lastname: Mercuri
authors.affiliation: 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.).
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: 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.).
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke / Q000139:chemically induced*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban
keywords: anticoagulant; atrial fibrillation; cerebral hemorrhage; stroke