The DIG trial was the only large randomised trial of digoxin in heart failure, and it reported a neutral effect on mortality and a significant reduction in heart failure hospitalisations, but more recent observational studies reported increased mortality with digoxin treatment. A recent review has argued that increases in mortality in patients treated with digoxin in observational data are most likely driven by ‘prescription bias’, i.e. clinical deterioration leads the treating physician to prescribe an additional drug and consequently sicker patients are more likely treated than healthier patients confounding data in observational studies.
This analysis of the RCT demonstrates that prognostic differences between patients pre-treated and not pre-treated with digoxin were so pronounced that they could not be appropriately addressed with statistical adjustment for baseline covariates. Given that the potential benefits of most treatments are likely to be moderate, biases in observational studies may far exceed these. The results of this analysis therefore may cast doubt on the recently presented observational analyses indicating harm from digoxin treatment.