Study title: DIGIT-HF: Digitoxin in Patients with Heart Failure and Reduced Ejection Fraction

Published in Congress: ESC Congress 2025

Link: https://www.nejm.org/doi/abs/10.1056/NEJMoa2415471

Prepared by: Dr. Serkan Bulguroğlu

Introduction

Cardiac glycosides have been used in the treatment of heart failure for many years, but their effect on mortality has not been clearly established. The most recent large study, conducted in 1997, did not use currently used first-line drugs such as beta-blockers and SGLT-2 inhibitors. Digitoxin, with its more stable pharmacokinetics and ability to remain stable even in the presence of renal dysfunction, is gaining prominence in the treatment of heart failure.

Objective

The aim of this study was to determine whether the cardiac glycoside digitoxin has therapeutic efficacy in patients with heart failure and reduced ejection fraction.

Methods

In this international, double-blind, placebo-controlled study, patients with chronic heart failure with a left ventricular ejection fraction of 40% or less and New York Heart Association (NYHA) functional class III or IV, or a left ventricular ejection fraction of 30% or less and NYHA functional class II, were randomly assigned in a 1:1 ratio to receive digitoxin (at a starting dose of 0.07 mg once daily) or matching placebo, in addition to guideline-assigned medical therapy. The primary outcome was the composite of death from any cause or hospitalization for worsening heart failure, whichever occurred first.

Results

Among the 1240 patients randomized, 1212 met inclusion criteria in the modified intent-to-treat population: 613 patients in the digitoxin group and 599 patients in the placebo group. During a median follow-up of 36 months, the primary outcome event occurred in 242 patients (39.5%) in the digitoxin group and 264 patients (44.1%) in the placebo group (hazard ratio for death or first hospitalization for worsening heart failure, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P=0.03). Death from any cause occurred in 167 patients (27.2%) in the digitoxin group and 177 patients (29.5%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.69 to 1.07). A first hospitalization for worsening heart failure occurred in 172 patients (28.1%) in the digitoxin group and 182 patients (30.4%) in the placebo group (hazard ratio 0.85; 95% CI 0.69-1.05). At least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 patients (2.8%) in the placebo group.

Conclusions

In patients with heart failure and reduced ejection fraction receiving guideline-based medical treatment, digitoxin treatment resulted in a lower risk of death from any cause or hospitalization for worsening heart failure compared with placebo.

Commentary

This study provides an important contribution by evaluating the effect of digitoxin compared to placebo on cardiac outcomes in patients with heart failure with reduced ejection fraction receiving current therapy. The findings suggest that digitoxin may significantly reduce the risk of death or hospitalization for worsening heart failure. However, the limited effect on mortality and the frequency of adverse events warrant cautious interpretation of the results when translating them into clinical practice.