The cardiac glycoside digitoxin, derived from digitalis purpurea, can reduce the risk of all-cause death and hospitalisation for worsening heart failure in patients with advanced heart failure and reduced ejection fraction (HFrEF), an international randomised trial has found.
Led by researchers from Hannover Medical School in Germany, the findings from the DIGIT-HF trial were presented at the European Society of Cardiology Congress 2025, with the results simultaneously published in the New England Journal of Medicine.
They found treatment with digitoxin led to a lower combined risk of death from any cause and hospital admission for worsening heart failure, suggesting that digitoxin may represent an additional treatment option to current guideline-recommended therapies, particularly when these cannot be tolerated.
Previous evidence for digoxin
Although cardiac glycosides have been used for many years as part of heart failure treatment, previous randomised trial evidence only exists for the more common digoxin, and this was conducted more than 25 years ago.
Indeed, the single randomised Digitalis Investigation Group (DIG) trial, published in 1997, found digoxin had an overall neutral effect on the primary endpoint of mortality, and that lower serum digoxin levels seemed to be associated with improvements, while higher digoxin levels worsened prognosis.
Hospitalisations for worsening heart failure, a prespecified secondary outcome, were reduced with digoxin and the greatest benefits were seen in patients with pronounced heart failure symptoms and markedly reduced left ventricular ejection fraction (LVEF).
The recent DIGIT-HF trial is a 10-year double-blind, placebo-controlled, randomised trial, conducted across 55 sites in Germany, Austria and Serbia. It compared digitoxin, dosed using a simple titration protocol with placebo, for treatment of HFrEF, on top of standard care.
Principal investigator Professor Udo Bavendiek, professor of internal medicine at Hannover Medical School, explained that his team designed the trial ‘with digitoxin, which has stable blood concentrations, even in patients with renal dysfunction, and included patients with heart failure, and a pronounced heart failure symptom burden.’
DIGIT-HF outcomes
Patients were eligible for inclusion if they had symptomatic HFrEF, New York Heart Association (NYHA) functional class II and a LVEF of <30% or NYHA class III-IV and LVEF <40%.
They were randomised 1:1 to digitoxin or placebo on top of standard care treatment. A total of 613 patients were in the digitoxin group and 599 in the placebo group.
Those 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 8-18ng/ml.
The primary outcome was a composite of all-cause death and hospital admission for worsening heart failure – whichever occurred first – analysed according to the intention-to-treat (ITT) principle.
A total of 1,212 patients made up the ITT population, with a mean age of 66 years and 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 heart failure therapy was well implemented across the ITT population, including high uptake of defibrillator-based devices (64%), and cardiac resynchronisation therapy (25%).
Over a median of 36 months, the primary outcome occurred in 242 patients (39.5%) in the digitoxin group, and 264 (44.1%) in the placebo group (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.69 to 0.98; p=0.03).
Serious adverse events occurred in 4.7% of patients in the digitoxin group and 2.8% in the placebo group, which were predominately cardiac disorders (3.4% and 1.8% respectively).
Death from any cause occurred in 167 patients (27.2%) in the digitoxin group and 177 patients (29.5%) in the placebo group (HR 0.86, 95% CI 0.69 to 1.07).
In addition, a first hospital admission for worsening heart failure occurred in 28.1% of patients in the digitoxin group, and 30.4% in the placebo group (HR 0.85, 95% CI 0.69 to 1.05).
Digitoxin ‘an additional option’ for HFrEF treatment
The primary outcome appeared positive in all prespecified subgroups, the trial authors noted, but those with heart rate of more than 75bpm or systolic blood pressure less than 120mmHg appeared to be associated with particular benefit.
‘We were able to demonstrate that using a simple dose-titration protocol, digitoxin significantly reduced all-cause death and hospitalisation for worsening heart failure in patients with well-implemented heart failure therapy, despite lower-than-expected enrolment,’ Professor Bavendiek said.
‘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.’
