Digitoxin in addition to guideline-directed medical therapy, reduced the risk of a composite of all-cause death and hospitalization for worsening heart failure (HF) among patients with advanced HF and a reduced ejection fraction (HFrEF), according to findings from the DIGIT-HF trial presented at ESC Congress 2025 and simultaneously published in NEJM.

Researchers randomly assigned 1,240 patients from 55 sites in Germany, Austria and Serbia to receive digitoxin (starting dose of 0.07 mg once daily) or matching placebo in addition to guideline-directed medical therapy. All participants had chronic HF and 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 a NYHA functional class of II. The primary outcome was a composite of death from any cause or hospital admission for worsening HF, whichever occurred first.

Over a median of 36 months, the primary outcome occurred in 39.5% of patients in the digitoxin group compared with 44.1% in the placebo group. In total, 27.2% of patients in the digitoxin group and 29.5% in the placebo group died, while a first hospital admission for worsening HF occurred in 28.1% of patients in the digitoxin group vs. 30.4% in the placebo group. The total number of deaths from any cause and hospitalizations for worsening HF was 537 in the digitoxin group and 531 in the placebo group.

According to study investigators, the primary outcome appeared positive across all pre-specified subgroups, but the results should be interpreted with caution due to lack of statistical power. In terms of safety, serious adverse events (predominantly cardiac disorders) occurred in 4.7% of patients in the digitoxin group compared with 2.8% in the placebo group.

"We were able to demonstrate that using a simple dose-titration protocol, digitoxin significantly reduced all-cause death and hospitalization for worsening HF in patients with well-implemented HF therapy, despite lower-than-expected enrollment," said Principal Investigator Udo Bavendiek, MD. "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."

According to Bavendiek and colleagues, the results from DIGIT-HF cannot be generalized to other cardiac glycosides like digoxin, which is available in more countries than digitoxin. A separate study, DECISION, evaluating digoxin in chronic HF is currently ongoing.