A LATE-breaking ESC 2025 trial has demonstrated that digitoxin, an old cardiac glycoside, significantly reduces the risk of all-cause death and hospitalisation for worsening heart failure in patients with advanced heart failure and reduced ejection fraction (HFrEF).
Cardiac glycosides such as digoxin have been used for centuries in heart failure management, but robust randomised trial evidence has been largely limited to the 1997 DIG trial of digoxin. To address this gap, the DIGIT-HF trial enrolled 1,212 patients across 55 sites in Germany, Austria, and Serbia. Eligible participants had symptomatic HFrEF (NYHA class II with LVEF ≤30% or NYHA III–IV with LVEF ≤40%) and were already receiving contemporary guideline-directed therapy. Patients were randomised 1:1 to digitoxin or placebo using a simple titration protocol: starting at 0.07 mg once daily, adjusted to 0.05–0.1 mg to achieve a target concentration of 8–18 ng/mL. The primary outcome was a composite of all-cause death and hospitalisation for worsening HF, analysed on an intention-to-treat basis.
Over a median follow-up of 36 months, the primary endpoint occurred in 39.5% of patients receiving digitoxin versus 44.1% in the placebo group (hazard ratio [HR]: 0.82; 95% CI: 0.69–0.98; p=0.03). Death from any cause occurred in 27.2% versus 29.5% (HR: 0.86; 95% CI: 0.69–1.07), and first hospitalisation for worsening HF occurred in 28.1% versus 30.4% (HR: 0.85; 95% CI: 0.69–1.05). Benefits appeared consistent across prespecified subgroups, with particular efficacy in patients with heart rates ≥75 bpm or systolic blood pressure ≤120 mmHg. Serious adverse events occurred in 4.7% of the digitoxin group versus 2.8% for placebo, primarily cardiac disorders.
The findings confirm that digitoxin, when carefully titrated, can provide an additional therapeutic option for patients with advanced HFrEF, particularly those with atrial fibrillation, elevated heart rates, low blood pressure, or renal impairment. DIGIT-HF suggests that long-standing cardiac glycosides may regain relevance in modern heart failure management alongside contemporary therapies.
Reference
Bavendiek U. DIGIT-HF: Digitoxin in patients with heart failure and reduced ejection fraction. ESC Congress 2025, 29 August-1 September, 2025.
