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The comeback of digitalis (digitoxin): the DIGIT-HF trial
Edoardo Sciatti1, Emilia D'Elia1, Mauro Gori1
1Department of Cardiovascular Medicine, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy.
Insights
The DIGIT-HF trial found that digitoxin benefits patients with heart failure with reduced ejection fraction (HFrEF) in the modern treatment era. This cardiac glycoside significantly reduced mortality and hospitalizations, reviving interest in digitalis therapy.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Cardiac glycosides, like digitalis, have a long history in medicine but their use in heart failure (HF) declined with modern therapies.
- The Digitalis Investigation Group (DIG) trial in 1997 led to a long gap in randomized clinical trials for this drug class, with subsequent studies yielding mixed results.
Purpose of the Study:
- To evaluate the efficacy of digitoxin in patients with heart failure with reduced ejection fraction (HFrEF) within the current guideline-directed medical therapy (GDMT) landscape.
- To address the unmet need for updated evidence on cardiac glycoside use in contemporary HF management.
Main Methods:
- The DIGIT-HF trial was a randomized clinical trial conducted in the modern era of HF treatment.
- It assessed the impact of digitoxin on clinical outcomes in patients with HFrEF receiving GDMT.
Main Results:
- Digitoxin treatment demonstrated favorable outcomes in the studied HFrEF population.
- A significant reduction was observed in the composite endpoint of all-cause mortality and HF hospitalizations.
Conclusions:
- The DIGIT-HF trial re-establishes a favorable role for digitoxin in managing HFrEF patients on contemporary GDMT.
- These findings reopen the discussion on the clinical utility of digitalis, which had been marginalized for decades.
Abstract:
Cardiac glycosides represent one of the oldest therapeutic pillars in medicine, although their role has progressively diminished in the modern era of neurohormonal therapy for heart failure (HF). Following publication of the Digitalis Investigation Group (DIG) trial in 1997, no randomized clinical trials evaluating this drug class were conducted for almost three decades, while observational studies and meta-analyses accumulated, often yielding conflicting results. The DIGIT-HF randomized clinical trial (2025) addressed a major unmet need by evaluating digitoxin in patients with HF with reduced ejection fraction in the contemporary era of guideline-directed medical therapy. Treatment with digitoxin was associated with favourable outcomes, including a reduction in the composite endpoint of all-cause mortality and hospitalizations for HF, thereby reopening a long-standing debate on the role of digitalis, which had remained marginal for many years. This article reviews the history of digitalis, the main evidence generated over recent decades, the evolution of clinical guidelines from 1997 to 2022, and the conceptual and clinical implications of the DIGIT-HF trial.
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