BACKGROUND: Digoxin is a widely used drug for ventricular rate control in 
patients with atrial fibrillation (AF), despite a scarcity of randomised trial 
data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban 
Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism 
for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
METHODS: For this retrospective analysis, we included and classified patients 
from ROCKET AF on the basis of digoxin use at baseline and during the study. 
Patients in ROCKET AF were recruited from 45 countries and had AF and risk 
factors putting them at moderate-to-high risk of stroke, with or without heart 
failure. We used Cox proportional hazards regression models adjusted for 
baseline characteristics and drugs to investigate the association of digoxin 
with all-cause mortality, vascular death, and sudden death. ROCKET AF was 
registered with ClinicalTrials.gov, number NCT00403767.
FINDINGS: In 14,171 randomly assigned patients, digoxin was used at baseline in 
5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) 
and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and 
persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, 
digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events 
per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular 
death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and 
sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, 
p=0·0076).
INTERPRETATION: Digoxin treatment was associated with a significant increase in 
all-cause mortality, vascular death, and sudden death in patients with AF. This 
association was independent of other measured prognostic factors, and although 
residual confounding could account for these results, these data show the 
possibility of digoxin having these effects. A randomised trial of digoxin in 
treatment of AF patients with and without heart failure is needed.
FUNDING: Janssen Research & Development and Bayer HealthCare AG.