Background: There is growing controversy regarding the association between digoxin and mortality in atrial fibrillation (AF). The aim of this analysis was to systematically review digoxin use and risk of mortality in patients with AF.

Methods: MEDLINE, EMBASE, GoogleScholar, CINAHL, meeting abstracts, presentations, and Cochrane central databases were searched from inception through December 2014, without language restrictions. For a study to be selected, it had to report the risk of mortality associated with digoxin use in AF patients as an outcome measure. Data were extracted by 2 independent authors. Evidence tables were created.

Results: A total of 16 studies (6 post hoc analyses of randomized controlled trials) with 111,978 digoxin users and 389,643 non-digoxin users were included. In a random effects model, patients treated with digoxin had a 27% increased risk of all-cause mortality (pooled HR 1.27; 95% CI 1.19–1.36) and 21% increased risk of cardiovascular mortality (pooled HR 1.21; 95% CI 1.12–1.30) compared with those who did not use digoxin. In a random effects model, the association of digoxin with all-cause mortality was stronger for AF patients without heart failure (pooled HR 1.47; 95% CI 1.25–1.73) than AF patients with heart failure (pooled HR 1.21; 95% CI 1.07–1.36, interaction p = 0.06).

Conclusions: Digoxin use in AF is associated with increased risk of all-cause and cardiovascular mortalities. The effect size was larger for AF patients without heart failure than AF patients with heart failure. The study suggests further directed analyses to study the effect that is suggested by this meta-analysis, especially in AF without heart failure.