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Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4451 (Published 30 August 2015) Cite this as: BMJ 2015;351:h4451
  1. Oliver J Ziff, academic foundation doctor12,
  2. Deirdre A Lane, lecturer in cardiovascular health13,
  3. Monica Samra, foundation doctor2,
  4. Michael Griffith, consultant electrophysiologist4,
  5. Paulus Kirchhof, professor of cardiovascular medicine13,
  6. Gregory Y H Lip, professor of cardiovascular medicine13,
  7. Richard P Steeds, consultant cardiologist4,
  8. Jonathan Townend, professor of cardiology14,
  9. Dipak Kotecha, clinician scientist in cardiovascular medicine1345
  1. 1University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK
  2. 2Royal Free London NHS Foundation Trust, London, UK
  3. 3Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK
  4. 4University Hospitals Birmingham NHS Trust, Birmingham, UK
  5. 5Monash Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia
  1. Correspondence to: D Kotecha, University of Birmingham Centre for Cardiovascular Sciences, Medical School, Edgbaston, Birmingham B15 2TT d.kotecha{at}bham.ac.uk
  • Accepted 13 August 2015

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.

Data sources and study selection Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (PROSPERO: CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment).

Data extraction and synthesis Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias.

Main outcome measures 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.

Footnotes

  • Contributors: DK designed the study concept, led the study group, performed statistical analysis, drafted the manuscript, and is guarantor. OJZ developed eligibility criteria, performed the primary literature search, contributed to data extraction, and drafted the manuscript. DAL, MS, MG, PK, GYHL, RPS, and JT contributed to data extraction and critical revision of the manuscript.

  • Funding: The study was funded by a grant from the Arthur Thompson Trust, University of Birmingham.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form (www.icmje.org/coi_disclosure.pdf) and declare: DAL has received investigator initiated grants from Boehringer Ingelheim, Bayer Healthcare, and Bristol-Myers Squibb; personal fees from Bristol-Myers Squibb, Boehringer Ingelheim, and Bayer; non-financial support from Boehringer Ingelheim; and is a steering committee member of a phase IV study sponsored by Bristol-Myers Squibb. PK has received grants and personal fees from several research funders including European Union, British Heart Foundation, German Research Foundation, Leducq Foundation, German Ministry of Education and Research, NIHR, and from medical device and pharmaceutical companies. PK also has patents pending for atrial fibrillation therapy and markers. GYHL has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, Bristol-Myers Squibb-Pfizer, Biotronik, Portola, and Boehringer Ingelheim, and has been on the speakers’ bureau for Bayer, Bristol-Myers Squibb-Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. JT has received research funding and travel grants from AstraZeneca. DK is the lead for the Beta-blockers in Heart Failure Collaborative Group (BB-meta-HF), has received honorariums from Menarini and professional development support from Daiichi-Sankyo.

  • Ethical approval: Not required.

  • Transparency: The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

  • Data sharing: No additional data are available, though details on statistical analysis are available from the corresponding author on request.

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