DIGIT-HF: Digitoxin Achieves Superiority to Placebo in Treating HFrEF

Digitoxin, an as-yet-unapproved cardiac glycoside, has proven its superiority to placebo in the phase 4 DIGIT-HF trial in patients with chronic heart failure with reduced ejection fraction (HFrEF) who had been treated with current medical and cardiac device therapies.1

Presented at the European Society of Cardiology Congress 2025 in Madrid, DIGIT-HF highlighted a significantly lower risk of all-cause mortality and hospitalization for HF in patients assigned to digitoxin versus placebo.1

Unlike its counterpart digoxin, which exhibits a shorter half-life and lower protein binding, digitoxin is a highly lipophilic drug which extensively binds to plasma proteins and is mainly eliminated in the metabolized state. Digitoxin also does not accumulate in kidney dysfunction, resulting in an apparently lower incidence of toxic side effects compared to digoxin.2

“However, the lack of double-blind, randomized, clinical trials that use digitoxin underscores the need for further investigation,” Udo Bavendiek, MD, department of cardiology and angiology, Hannover Medical School, and colleagues wrote. “The DIGIT-HF (Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure) trial was conducted to evaluate the efficacy and safety of digitoxin at low concentrations in patients with chronic heart failure and reduced ejection fraction that had been treated with current medical and cardiac device therapies.”1

The double-blind, randomized, placebo-controlled trial was conducted at 65 sites in Austria, Germany, and Serbia. It included patients who were ≥18 years old, had symptomatic chronic HF (specified as a left ventricular ejection fraction of ≤40% and an NYHA functional class of III or IV, or a left ventricular ejection fraction of ≤30% and an NYHA functional class of II), and had received evidence-based therapy for HF for ≥6 months.1

The team randomly assigned patients in a 1:1 ratio to either digitoxin at a starting dose of 0.07 mg daily or matching placebo. Adjustments were made based on an algorithm: digitoxin serum concentration was measured 6 weeks post-randomization, and if the level was outside the predefined target range of 8 to 18 ng/mL, the dosage was adjusted accordingly, up to 0.1 mg or down to 0.05 mg daily.1

The trial’s primary outcome was a composite of all-cause mortality and hospital admission for worsening HF, whichever occurred first. Secondary outcomes included all-cause mortality, which was tested for noninferiority to exclude a detriment from digitoxin as compared with placebo, and a composite of all-cause mortality and any hospitalization due to HF. Investigators also highlighted the safety outcomes of serum digitoxin concentrations and adverse and serious adverse events.1

An initial total of 1240 patients were included in the study; 25 were removed after never taking a dose of digitoxin or placebo post-randomization. Additionally, 3 were excluded from 1 trial site due to the closure of the site, leaving a final total of 1212. 613 were assigned to digitoxin and 590 received placebo.1

At baseline, characteristics of the patients and therapies appeared well-balanced. However, by the end of the trial, the primary-outcome event had occurred in 242 patients (39.5%; 12.8 events per 100 patient-years) in the digitoxin group and 264 (44.1%; 15.7 events per 100 patient-years) in the placebo group (hazard ratio [HR] 0.82; 95% CI, 0.69-0.98; P = .03). All-cause mortality occurred in 167 patients (27.2%; 7.8 deaths per 100 patient-years) in the digitoxin group and 177 (29.5%; 8.9 deaths per 100 patient-years) in the placebo group.1

Regarding safety, mean (+/- Standard Deviation [SD]) serum digitoxin concentration at the dose-adjustment visit was 17 +/- 5.9 ng/mL in 550 patients in the digitoxin group. At 12 months, this was down to 13.5 +/- 5.1 ng/mL in 398 patients. At least 1 serious adverse event occurred in 29 patients in the digitoxin group and 17 in the placebo group.1

Ultimately, investigators noted a significantly lower incidence of primary-outcome events among the digitoxin group compared to placebo.

“Our findings can be readily implemented into clinical practice, as shown by the simple digitoxin dosage protocol and by the fact that patient selection in our trial was based primarily on the burden of heart failure symptoms and the left ventricular ejection fraction rather than threshold levels of the brain natriuretic peptide biomarker,” Bavendiek and colleagues wrote.1

References

1. 1: Bavendiek U, Großhennig A, Schwab J, et al. Digitoxin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine. Published online August 29, 2025. doi:10.1056/nejmoa2415471

2. 2: Belz GG, Breithaupt-Grögler K, Osowski U. Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-17. doi:10.1046/j.1365-2362.2001.0310s2010.x