title: Edoxaban versus warfarin in patients with atrial fibrillation.
abstract: BACKGROUND
  Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.
  
  
  METHODS
  We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.
  
  
  RESULTS
  The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32).
  
  
  CONCLUSIONS
  Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).
authors.affiliation: From Brigham and Women's Hospital and Harvard Medical School, Boston (R.P.G., C.T.R., E.B., S.A.M., S.D.W., L.T.G., E.M.A.); Mount Sinai Medical Center, New York (J.L.H.); University Hospitals Case Medical Center, Cleveland (A.L.W.); Thomas Jefferson Medical College, Philadelphia (M.D.E.); McMaster University, Hamilton, ON, Canada (J.I.W.); University Hospital, Jihlavska, Brno, Czech Republic (J.S.); Institute of Cardiology, Warsaw, Poland (W.R.); Cardiology Research Center, Moscow (M.R.); National Hospital Organization, Osaka National Hospital, Osaka, Japan (Y.K.); Quintiles, Durham, NC (J.B., S.P.P.); and Daiichi Sankyo Pharma Development, Edison, NJ (M.S., I.P., J.J.H., M.M.).
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
authors.forename: Albert L
authors.initials: AL
authors.lastname: Waldo
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ezekowitz
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
authors.forename: Jindřich
authors.initials: J
authors.lastname: Špinar
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ruda
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Koretsune
authors.forename: Joshua
authors.initials: J
authors.lastname: Betcher
authors.forename: Minggao
authors.initials: M
authors.lastname: Shi
authors.forename: Laura T
authors.initials: LT
authors.lastname: Grip
authors.forename: Shirali P
authors.initials: SP
authors.lastname: Patel
authors.forename: Indravadan
authors.initials: I
authors.lastname: Patel
authors.forename: James J
authors.initials: JJ
authors.lastname: Hanyok
authors.forename: Michele
authors.initials: M
authors.lastname: Mercuri
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control; D004311:Double-Blind Method; D004617:Embolism / Q000517:prevention & control*; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke / Q000517:prevention & control*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban