title: Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
abstract: BACKGROUND
  Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF--TIMI 48 trial.
  
  
  METHODS
  The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years.
  
  
  RESULTS
  Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023).
  
  
  CONCLUSIONS
  In the FDA-approved cohort of the ENGAGE AF--TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA.
authors: Alon
authors: A
authors: Eisen
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA.
authors: Robert P
authors: RP
authors: Giugliano
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA.
authors: Christian T
authors: CT
authors: Ruff
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA.
authors: Francesco
authors: F
authors: Nordio
authors: Anaheim Regional Medical Center, Anaheim, CA.
authors: Harinder S
authors: HS
authors: Gogia
authors: Marion General Hospital, Marion, OH.
authors: Vivek R
authors: VR
authors: Awasty
authors: Florida Hospital Memorial Medical Center, Daytona Beach, FL.
authors: David A
authors: DA
authors: Henderson
authors: Daiichi Sankyo Pharma Development, Edison, NJ.
authors: Michele F
authors: MF
authors: Mercuri
authors: Daiichi Sankyo Inc, Parsippany, NJ.
authors: Howard
authors: H
authors: Rutman
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA.
authors: Elliott M
authors: EM
authors: Antman
authors: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA. Electronic address: ebraunwald@partners.org.
authors: Eugene
authors: E
authors: Braunwald
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000150:complications* / Q000628:therapy; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017277:Drug Approval; D015951:Factor Xa / Q000187:drug effects* / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage*; D020521:Stroke / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D013844:Thiazoles / Q000008:administration & dosage*; D015912:Thrombolytic Therapy / Q000379:methods*; D014481:United States; D014486:United States Food and Drug Administration; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; D015951:Factor Xa; C552171:edoxaban