title: Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial.
abstract: BACKGROUND
  Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin.
  
  
  OBJECTIVE
  This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.
  
  
  METHODS
  Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization.
  
  
  RESULTS
  In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant.
  
  
  CONCLUSIONS
  Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone.
authors.affiliation: University of Missouri, Columbia, Missouri. Electronic address: flakerg@missouri.edu.
authors.forename: Greg
authors.initials: G
authors.lastname: Flaker
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hylek
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Wojdyla
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Laine
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Sana M
authors.initials: SM
authors.lastname: Al-Khatib
authors.affiliation: University of Missouri, Columbia, Missouri.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Sullivan
authors.affiliation: J.W. Goethe-University, Frankfurt, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Hohnloser
authors.affiliation: Division of Hematology, University of Washington, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Garcia
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Geelong Cardiology Research Center, Deakin University, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Amerena
authors.affiliation: Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Harjola
authors.affiliation: St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Dorian
authors.affiliation: Danta Pazzanese Institute of Cardiology, São Paulo, Brazil.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avezum
authors.affiliation: Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary.
authors.forename: Matyas
authors.initials: M
authors.lastname: Keltai
authors.affiliation: Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
mesh_terms: D000368:Aged; D000638:Amiodarone / Q000008:administration & dosage*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D000925:Anticoagulants / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001938:Brazil / Q000453:epidemiology; D002423:Cause of Death / Q000639:trends; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005060:Europe / Q000453:epidemiology; D065427:Factor Xa Inhibitors / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009864:Ontario / Q000453:epidemiology; D011720:Pyrazoles / Q000008:administration & dosage; D011728:Pyridones / Q000008:administration & dosage; D020521:Stroke / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D015996:Survival Rate / Q000639:trends; D013923:Thromboembolism / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014859:Warfarin / Q000008:administration & dosage
chemical_list: D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000638:Amiodarone
keywords: antiarrhythmia agents; anticoagulants; antithrombotic agents; factor Xa; stroke; thromboembolism; warfarin