Digitoxin reduced the risk of a composite of all-cause death and hospitalisation for worsening heart failure (HF) among patients with advanced HF and a reduced ejection fraction (HFrEF), according to a late-breaking trial presented at the 2025 European Society of Cardiology (ESC) congress (29 August–1 September, Madrid Spain).
Cardiac glycosides, such as digitoxin and digoxin have been used to treat heart failure for two centuries, Udo Bavendiek (Hannover Medical School, Hannover, Germany), an investigator on the DIGIT-HF trial told delegates at ESC 2025, noting that evidence for their beneficial effects in HFrEF comes mainly from a single randomised trial—DIG—which was published in 1997.
“Digoxin had an overall neutral effect on the primary endpoint of mortality in the DIG trial; however, lower serum digoxin levels seemed to be associated with improvements, while higher digoxin levels worsened prognosis,” Bavendiek said. “Notably, hospitalisations for worsening HF, a prespecified secondary outcome, were reduced with digoxin and the greatest benefits were seen in patients with pronounced HF symptoms and markedly reduced left ventricular ejection fraction (LVEF). We designed the DIGIT-HF trial with digitoxin—which has stable blood concentrations even in patients with renal dysfunction—and included patients with HF and a pronounced HF symptom burden.”
DIGIT-HF, a double-blind, placebo-controlled randomised trial conducted at 55 sites in Germany, Austria and Serbia, included patients with symptomatic HFrEF, namely a New York Heart Association (NYHA) functional class II and a left ventricular ejection fraction (LVEF) of ≤30% or NYHA class III–IV and LVEF ≤40%.
Patients were randomised 1:1 to digitoxin or placebo on top of standard-care treatment. Patients in the digitoxin group initially received 0.07mg once daily with double-blind dose adjustment to 0.05mg or 0.1mg once daily after six weeks to achieve a digitoxin target concentration of 8–18 ng/ml. The primary outcome was a composite of all-cause death and hospital admission for worsening HF (whichever occurred first), analysed according to the intention-to-treat (ITT) principle.
The 1,212 patients in the intention-to-treat (ITT) population had a mean age of 66 years, with 20% being female. The mean LVEF was 29% and the HF symptom burden was high —70% of patients had NYHA class III or IV. Contemporary pharmacological HF therapy was well implemented across the population, including high uptake of defibrillator-based devices (64%; cardiac resynchronisation therapy 25%).
Over a median of 36 months, the primary outcome occurred in 39.5% of patients in the digitoxin group and 44.1% in the placebo group, Bavendiek reported.
In total, 27.2% of patients in the digitoxin group and 29.5% in the placebo group died. A first hospital admission for worsening HF occurred in 28.1% of patients in the digitoxin group and 30.4% in the placebo group. The total number of deaths from any cause and hospitalisations for worsening HF was 537 in the digitoxin group and 531 in the placebo group.
The primary outcome appeared positive in all pre-specified subgroups, but those with heart rate ≥75bpm or systolic blood pressure ≤120mmHg appeared to be associated with particular benefit. Regarding safety, serious adverse events occurred in 4.7% of patients in the digitoxin group and 2.8% in the placebo group, predominantly cardiac disorders (3.4% and 1.8%, respectively).
“We were able to demonstrate that using a simple dose-titration protocol, digitoxin significantly reduced all-cause death and hospitalisation for worsening HF in patients with well-implemented HF therapy, despite lower-than-expected enrolment,” Bavendiek concluded. “Based on our findings, digitoxin represents an additional option for patients with HFrEF, particularly those with atrial fibrillation, higher heart rates, low blood pressure or impaired kidney function.”
Results of the trial were published simultaneously in the New England Journal of Medicine.
