title: Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin--Insights From the ENGAGE AF-TIMI 48 Trial.
abstract: BACKGROUND
  In 21,105 patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial, edoxaban was non-inferior to warfarin in preventing thromboembolic events while reducing bleeding. We compared results in Japan with the rest of East Asia (EA), including China, Korea, and Taiwan.
  
  
  RESULTS
  We compared baseline characteristics, time-in-therapeutic range (TTR) for warfarin, and outcomes (efficacy: stroke or systemic embolic events [SEE], safety: major bleeding). Interaction P values were used to assess for effect modification of treatment (higher-dose edoxaban [HDE, 60 mg/30 mg] vs. warfarin; lower-dose edoxaban [LDE, 30 mg/15 mg] vs. warfarin) by region with adjustments for baseline characteristics. Fewer patients in Japan (n=1,010) were female, taking aspirin or amiodarone, naïve to warfarin (P<0.001 for each), had a history of stroke or transient ischemic attack (P=0.02), and more patients needed dose reduction (P<0.001) compared with EA (n=933). The mean TTR was higher in Japan (70% vs. 56%, P<0.001). Evidence for statistical interactions was observed for HDE vs. warfarin by region for stroke/SEE (adjusted P-int=0.052) and major bleeding (adjusted P-int=0.048) with greater relative efficacy and safety with HDE in EA compared with Japan. No interactions were observed for LDE vs. warfarin after adjustment.
  
  
  CONCLUSIONS
  HDE had a greater relative efficacy and safety in EA compared with Japan that was only partially explained by differences in baseline characteristics and TTR.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Shimada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Koretsune
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Shunichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Michele
authors.initials: M
authors.lastname: Mercuri
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
mesh_terms: D000368:Aged; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005202:Asia, Eastern / Q000453:epidemiology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013923:Thromboembolism / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D014859:Warfarin; D003520:Cyclophosphamide