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Meta-Analysis
. 2015 Aug 30:351:h4451.
doi: 10.1136/bmj.h4451.

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

Oliver J Ziff  1 , Deirdre A Lane  2 , Monica Samra  3 , Michael Griffith  4 , Paulus Kirchhof  2 , Gregory Y H Lip  2 , Richard P Steeds  4 , Jonathan Townend  5 , Dipak Kotecha  6
Affiliations
Meta-Analysis

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

Oliver J Ziff et al. BMJ. .

Erratum in

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.

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Conflict of interest statement

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.

Figures

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Fig 1 Selection of studies flowchart (after duplicates removed) on safety and efficacy of digoxin. *Primary outcome (all cause mortality) includes data from 41 studies
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Fig 2 Summary of meta-analyses for all cause mortality in observational and randomised studies on safety and efficacy of digoxin, comprising 999 994 participants across 75 study analyses. (See fig 4 and figs A, C, D, and E in appendix 3 for study level results)
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Fig 3 Meta-regression of all cause mortality according to risk of bias and efficacy of digoxin. Risk of bias in each study was summed across all six domains (low risk=0, unclear risk=1, high risk=2; excluding “other threats to validity” domain from Cochrane risk of bias tool). All analyses that provided data on rates of death were included, regardless of study design. Each circle represents particular study, with circle size dependent on precision of each estimate in random-effects model (inverse of its variance)
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Fig 4 Meta-analyses of all cause mortality in randomised controlled trials on safety and efficacy of digoxin
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Fig 5 Overview of evidence base for digoxin versus placebo/no treatment
See this image and copyright information in PMC

Comment in

References

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