The Effect of Digoxin on Mortality and Morbidity in Patients With Chronic Heart Failure: A Secondary Survival Analysis of the Digitalis Investigation Group (DIG) Trial

Background The long-term efficacy and safety of cardiac glycosides in the treatment of chronic heart failure with normal sinus rhythm remain topics of clinical debate. This study assessed the impact of digoxin on overall mortality and hospitalization rates in patients with heart failure and reduced ejection fraction. This is a retrospective secondary survival analysis of the multi-center Digitalis Investigation Group (DIG) trial dataset, undertaken to clarify digoxin’s effect on mortality and hospitalizations for worsening heart failure over a 37‑month follow-up period. Methods A survival analysis was conducted using the Digitalis Investigation Group (DIG) trial dataset. Patients with a left ventricular ejection fraction of 0.45 or less were randomly assigned to receive either digoxin (n=3,397) or placebo (n=3,403). Digoxin was administered at an average dose of 0.25 mg per day over a 37-month follow-up period. Kaplan-Meier survival curves and log-rank tests were used to evaluate time-to-event outcomes, and Cox proportional hazards regression was applied to derive risk ratios and 95% confidence intervals for mortality and hospitalization endpoints. Results Digoxin therapy demonstrated no statistically significant effect on overall mortality. Death occurred in 34.8% of the digoxin group (1,181 deaths) compared to 35.1% of the placebo group (1,194 deaths), and this difference is reported as a risk ratio (RR=0.99; 95% CI: 0.91 to 1.07; P=0.80) based on the observed event proportions in each arm. However, hospitalizations were reduced in the treatment group, with a significant reduction specifically in hospitalizations for worsening heart failure, presented as a risk ratio (RR=0.72; 95% CI: 0.66 to 0.79; P=0.001) derived from the cumulative proportions of patients hospitalized in the digoxin and placebo groups. Conclusion Digoxin did not improve overall survival but significantly reduced hospitalizations for worsening heart failure in patients with chronic heart failure and reduced ejection fraction. These findings reinforce digoxin’s role as an adjunct therapy focused on morbidity reduction and symptom stabilization, rather than as a primary mortality‑reducing agent, and provide additional context for its use alongside contemporary guideline‑directed heart failure treatments.