title: Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study.
abstract: BACKGROUND
  Despite endorsement of digoxin in clinical practice guidelines, there exist limited data on its safety in atrial fibrillation/flutter (AF).
  
  
  OBJECTIVE
  The goal of this study was to evaluate the association of digoxin with mortality in AF.
  
  
  METHODS
  Using complete data of the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study from the U.S. Department of Veterans Affairs (VA) healthcare system, we identified patients with newly diagnosed, nonvalvular AF seen within 90 days in an outpatient setting between VA fiscal years 2004 and 2008. We used multivariate and propensity-matched Cox proportional hazards to evaluate the association of digoxin use with death. Residual confounding was assessed by sensitivity analysis.
  
  
  RESULTS
  Of 122,465 patients with 353,168 person-years of follow-up (age 72.1 ± 10.3 years, 98.4% male), 28,679 (23.4%) patients received digoxin. Cumulative mortality rates were higher for digoxin-treated patients than for untreated patients (95 vs. 67 per 1,000 person-years; p < 0.001). Digoxin use was independently associated with mortality after multivariate adjustment (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23 to 1.29, p < 0.001) and propensity matching (HR: 1.21, 95% CI: 1.17 to 1.25, p < 0.001), even after adjustment for drug adherence. The risk of death was not modified by age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin.
  
  
  CONCLUSIONS
  Digoxin was associated with increased risk of death in patients with newly diagnosed AF, independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies. These findings challenge current cardiovascular society recommendations on use of digoxin in AF.
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California. Electronic address: mintu@stanford.edu.
authors.forename: Mintu P
authors.initials: MP
authors.lastname: Turakhia
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California; Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Santangeli
authors.affiliation: Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Wolfgang C
authors.initials: WC
authors.lastname: Winkelmayer
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Xiangyan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Aditya J
authors.initials: AJ
authors.lastname: Ullal
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Claire T
authors.initials: CT
authors.lastname: Than
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Stanford Center for Sleep Sciences & Medicine, Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
authors.forename: Tyson H
authors.initials: TH
authors.lastname: Holmes
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Division of General Internal Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Frayne
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
authors.forename: Ciaran S
authors.initials: CS
authors.lastname: Phibbs
authors.affiliation: Maimonides Heart & Vascular Center, New York, New York.
authors.forename: Felix
authors.initials: F
authors.lastname: Yang
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Hoang
authors.affiliation: Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado; Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Denver, Colorado.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Ho
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Heidenreich
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000401:mortality*; D002423:Cause of Death / Q000639:trends; D016001:Confidence Intervals; D004077:Digoxin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010045:Outpatients; D011379:Prognosis; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology
chemical_list: D000889:Anti-Arrhythmia Agents; D004077:Digoxin
keywords: atrial fibrillation; digoxin; mortality; safety