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

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.

Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data by Oliver J Ziff, et al. BMJ2015; 351 (Published 30 August 2015)

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