title: Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data.
abstract: OBJECTIVE
  To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods.
  
  
  METHODS
  Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (
  CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment).
  
  
  METHODS
  Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias.
  
  
  METHODS
  Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling.
  
  
  RESULTS
  52 studies were systematically reviewed, comprising 621,845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4,006,210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P<0.001; n=29,525).
  
  
  CONCLUSIONS
  Digoxin is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types. Regardless of statistical analysis, prescription biases limit the value of observational data.
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Royal Free London NHS Foundation Trust, London, UK.
authors: Oliver J
authors: OJ
authors: Ziff
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK.
authors: Deirdre A
authors: DA
authors: Lane
authors: Royal Free London NHS Foundation Trust, London, UK.
authors: Monica
authors: M
authors: Samra
authors: University Hospitals Birmingham NHS Trust, Birmingham, UK.
authors: Michael
authors: M
authors: Griffith
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK.
authors: Paulus
authors: P
authors: Kirchhof
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK.
authors: Gregory Y H
authors: GY
authors: Lip
authors: University Hospitals Birmingham NHS Trust, Birmingham, UK.
authors: Richard P
authors: RP
authors: Steeds
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK University Hospitals Birmingham NHS Trust, Birmingham, UK.
authors: Jonathan
authors: J
authors: Townend
authors: University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK University Hospitals Birmingham NHS Trust, Birmingham, UK Monash Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia d.kotecha@bham.ac.uk.
authors: Dipak
authors: D
authors: Kotecha
mesh_terms: D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000401:mortality; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004077:Digoxin / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization; D006801:Humans; D017063:Outcome Assessment, Health Care; D016896:Treatment Outcome
chemical_list: D002316:Cardiotonic Agents; D004077:Digoxin