Digoxin–mortality: randomized vs. observational comparison in the DIG trial

AIMS: The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons despite extensive statistical adjustments. METHODS AND RESULTS: Forty-four percent of the 6800 patients in the DIG trial had been treated with digoxin before randomization, and half of them were randomly withdrawn from digoxin treatment. We contrast the main randomization-based result of the DIG trial with the observational non-randomized comparison of patients pre-treated or not pre-treated with digoxin. Mortality [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.12-1.34; P < 0.001] and heart failure hospitalizations (HR 1.47, 95% CI 1.33-1.61; P < 0.001) were significantly higher in patients pre-treated with digoxin even after adjustment for baseline population differences. The higher risks for both outcomes in those who had previously received digoxin persisted even if they received placebo during the trial (HR 1.24, 95% CI 1.10-1.40; P < 0.001). This sharply contradicts the neutral effect on mortality and the significant reduction in heart failure hospitalizations observed in the randomized comparison. CONCLUSION: Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.