title: Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.
abstract: BACKGROUND
  In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban.
  
  
  RESULTS
  At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use.
  
  
  CONCLUSIONS
  Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Steffel
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Department of Cardiology B, Oslo University Hospital Ulleval, University of Oslo, Oslo, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Atar
authors.affiliation: Hasselt University and Heart Center, Jessa Hospital, Hasselt, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Heidbuchel
authors.affiliation: Division of Clinical Sciences, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Camm
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA cruff@partners.org.
authors.forename: C T
authors.initials: CT
authors.lastname: Ruff
mesh_terms: D000368:Aged; D000638:Amiodarone / Q000627:therapeutic use*; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D005260:Female; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000627:therapeutic use*; D020521:Stroke / Q000209:etiology; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; D000638:Amiodarone; C552171:edoxaban
keywords: Amiodarone; Anticoagulation; Atrial fibrillation; Edoxaban