digitoxin in heart failure with reduced ejection fraction (HFrEF)

Study design

• double-blind, placebo-controlled trial
  • randomly assigned patients with chronic heart failure who had a left ventricular ejection fraction of 40% or less and a New York Heart Association (NYHA) functional class of III or IV or a left ventricular ejection fraction of 30% or less and an NYHA functional class of II 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-directed medical therapy
  • primary outcome was a composite of death from any cause or hospital admission for worsening heart failure, whichever occurred first

Study results

• over a median follow-up of 36 months, a primary-outcome event occurred in 242 patients (39.5%) in the digitoxin group and 264 (44.1%) in the placebo group (hazard ratio for death or first hospital admission 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 (29.5%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.69 to 1.07)
• a first hospital admission for worsening heart failure occurred in 172 patients (28.1%) in the digitoxin group and 182 (30.4%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.69 to 1.05)
• at least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 (2.8%) in the placebo group

Study conclusions

• treatment with digitoxin led to a lower combined risk of death from any cause or hospital admission for worsening heart failure than placebo among patients with heart failure and reduced ejection fraction who received guideline-directed medical therapy
• efficacy of digitoxin observed in the overall trial population appeared to be consistent among patients who were taking an angiotensin receptor–neprilysin inhibitor or sodium–glucose cotransporter 2 inhibitor at baseline and among patients who were taking triple or quadruple combinations of guideline-recommended medications

Notes:

• digitoxin is a cardiac glycoside
  • concentrations in blood can remain stable without dose adjustments, even among patients with progressive renal dysfunction

Reference:

1. Bavendiek U et al; for the DIGIT-HF Study Group. Digitoxin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM 29th August 2025.