title: Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48).
abstract: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA.
  
  
  
  ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin.
  
  
  
  Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28).
  
  
  
  Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.). nrost@partners.org.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Crompton
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Scott
authors.initials: S
authors.lastname: Silverman
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Aneesh B
authors.initials: AB
authors.lastname: Singhal
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: José C
authors.initials: JC
authors.lastname: Nicolau
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Bhupathi
authors.initials: B
authors.lastname: SomaRaju
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Michele F
authors.initials: MF
authors.lastname: Mercuri
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000627:therapeutic use*; D012008:Recurrence; D055502:Secondary Prevention; D020521:Stroke / Q000188:drug therapy / Q000517:prevention & control*; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban
keywords: atrial fibrillation; clinical trial; risk factors; stroke