Hot Line 1: DIGIT-HF
30 Aug 2025
Hot Line ESC Congress 2025 Can digitoxin improve outcomes in heart failure?
Yesterday, Professor Udo Bavendiek (Hannover Medical School - Hannover, Germany) presented results from the DIGIT-HF trial. “Evidence for the beneficial effects of cardiac glycosides in heart failure (HF) with reduced ejection fraction (HFrEF) comes mainly from a single randomised trial, the DIG trial published in 1997,1” he explained. “Digoxin had an overall neutral effect on the primary endpoint of mortality; however, lower serum digoxin levels seemed to be associated with improvements, while higher digoxin levels worsened prognosis. 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 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.”
In this double-blind trial conducted in Germany, Austria and Serbia, eligible patients with NYHA class II and LVEF ≤30% or NYHA class III–IV and LVEF ≤40% were randomised to digitoxin or placebo on top of standard-care. Patients in the digitoxin group initially received 0.07 mg once daily with double-blind dose adjustment to 0.05 mg or 0.1 mg once daily after 6 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 ITT population had a mean age of 66 years, with 20% being female. The mean LVEF was 29% and 70% of patients had NYHA class III or IV. Contemporary HF therapy was well implemented across the population.
Over a median of 36 months, the primary outcome was significantly lower with digitoxin vs. placebo.
Primary outcome events occurred in 39.5% of patients in the digitoxin group and 44.1% in the placebo group (hazard ratio [HR] 0.82; 95% CI 0.69 to 0.98; p=0.03). Results appeared positive in all prespecified subgroups.
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 (rate ratio 0.85; 95% CI 0.67 to 1.09), while 27.2% and 29.5% of patients, respectively, died (HR 0.86; 95% CI 0.69 to 1.07). Serious adverse events were reported in 4.7% of patients with digitoxin and 2.8% with placebo.
Prof. Bavendiek concluded: “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. Based on our findings, digitoxin represents an additional option for patients with HFrEF, particularly when current guideline-recommended therapies cannot be tolerated.”
References
- Digitalis Investigation Group. N Engl J Med. 1997;336:525–533.
