Digoxin and Mortality in Patients With Atrial Fibrillation

Study Questions:

Is digoxin use associated with increased mortality in patients with atrial fibrillation (AF), and is the association modified by the presence of heart failure (HF) and/or serum digoxin concentration?


The association between digoxin use and mortality was assessed post hoc in 17,897 patients who had participated in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.


At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR], 1.09; p = 0.19). Patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR, 1.56; 95% confidence interval [CI], 1.20–2.04). When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5 ng/ml increase (p = 0.0010); these results were similar for patients with and without HF. Compared with propensity-score matched controls, the risk of death (adjusted HR, 1.78; 95% CI, 1.37–2.31) and sudden death (adjusted HR, 2.14; 95% CI, 1.11–4.12) was significantly higher in new digoxin users.


In patients with AF taking digoxin, the risk of death is independently related to serum digoxin concentration and is highest in patients with concentrations ≥1.2 ng/ml. Initiating digoxin is independently associated with higher mortality in patients with AF, regardless of HF.


Several observational analyses have suggested increased risk of mortality in patients with AF who are prescribed digoxin, although other similar studies failed to confirm this. The present study is also observational, but it provides the strongest evidence yet of the association between digoxin use and risk of death in AF. There was a direct association between serum digoxin concentration and mortality, and there was an increase in sudden (presumably arrhythmic) death among new digoxin users. In the absence of a definitive randomized trial, the findings of the present analysis suggest that, in general, digoxin should be avoided in patients with AF, at least until other therapeutic options are exhausted. If digoxin is used, its levels should be monitored carefully.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Death, Sudden, Digoxin, Heart Failure, Mortality, Risk, Secondary Prevention

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