The cardiac glycoside digitoxin significantly reduced the risk of death or hospitalization for worsening heart failure in patients with heart failure with reduced ejection fraction (HFrEF), according to results from the DIGIT-HF trial presented at the European Society of Cardiology Congress and published simultaneously in The New England Journal of Medicine.
The double-blind, placebo-controlled randomized trial enrolled 1,212 patients across 55 sites in Germany, Austria, and Serbia, demonstrating that digitoxin reduced the primary composite endpoint by 18% compared to placebo over a median follow-up of 36 months.
Trial Design and Patient Population
The DIGIT-HF study included patients with symptomatic HFrEF defined as NYHA functional class II with left ventricular ejection fraction (LVEF) ≤30% or NYHA class III-IV with LVEF ≤40%. Patients were randomized 1:1 to receive digitoxin starting at 0.07 mg once daily or placebo, with dose adjustments after 6 weeks to achieve target digitoxin concentrations of 8-18 ng/ml.
The study population had a mean age of 66 years, with 20% being female and a mean LVEF of 29%. Notably, 70% of patients had NYHA class III or IV symptoms, indicating advanced heart failure. Contemporary pharmacological therapy was well-implemented, with 95% of patients receiving beta-blockers, over 90% on renin-angiotensin system blockers, and 64% having implantable cardioverter defibrillators.
Primary Efficacy Results
The primary outcome of all-cause death or first hospitalization for worsening heart failure occurred in 39.5% of patients in the digitoxin group compared with 44.1% in the placebo group (HR = 0.82; 95% CI, 0.69-0.98; P = 0.03). This represented an absolute risk reduction of 4.6% and a number needed to treat of 22 to prevent one event.
"Importantly, we showed this on top of very well-implemented guideline-directed medical therapy," said Principal Investigator Professor Udo Bavendiek from Hannover Medical School, Germany, during the press conference. "Almost all the patients, 95%, had beta-blockers, renin-angiotensin system blockers were far above 90%, and [some patients were taking] mineralocorticoid receptor agonists and SGLT2 inhibitors."
Secondary Endpoints and Subgroup Analysis
Individual components of the primary endpoint showed consistent trends favoring digitoxin. All-cause death occurred in 27.2% of the digitoxin group versus 29.5% of the placebo group (HR = 0.86; 95% CI, 0.69-1.07), while first hospitalization for worsening heart failure occurred in 28.1% versus 30.4% respectively (HR = 0.85; 95% CI, 0.69-1.05).
The primary outcome appeared positive across all pre-specified subgroups, with patients having heart rates ≥75 bpm or systolic blood pressure ≤120 mmHg showing particular benefit from digitoxin therapy.
Safety Profile
Regarding safety, serious adverse events occurred in 4.7% of patients in the digitoxin group compared to 2.8% in the placebo group. Serious cardiac disorders were reported in 3.4% of digitoxin patients versus 1.8% of placebo patients. The percentage of patients discontinuing study drug due to adverse events was similar between groups at 9.1% for digitoxin and 10.2% for placebo.
"Also important was that the treatment appeared to be safe, as there were a lot of reports in the last year from post hoc analyses and nonrandomized trials claiming cardiac glycosides such as digitoxin are harmful for patients," Bavendiek noted.
Clinical Implications
The DIGIT-HF trial provides the first randomized controlled evidence for digitoxin in heart failure, addressing a significant gap in cardiac glycoside research. Previous evidence for cardiac glycosides in heart failure came primarily from the DIG trial with digoxin published in 1997, which showed neutral effects on mortality but reduced hospitalizations for worsening heart failure.
Digitoxin offers potential advantages over digoxin, including stable blood concentrations even in patients with renal dysfunction, making it particularly suitable for heart failure patients who often have compromised kidney function.
"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," Bavendiek concluded.
The results suggest digitoxin could be implemented in clinical practice as the study had no special exclusion criteria and was conducted on top of contemporary guideline-directed medical therapy, making the findings broadly applicable to real-world heart failure populations.
