Clinical question: In patients with chronic heart failure with reduced ejection fraction (HFrEF, defined as left ventricular ejection fraction of up to 40% with New York Heart Association class III–IV symptoms, or left ventricular ejection fraction of up to 30% with New York Heart Association class II symptoms) receiving guideline-directed medical therapy, does the addition of digitoxin reduce the risk of death or first hospitalization for worsening heart failure compared with placebo?
Background: Cardiac glycosides like digoxin and digitoxin have been used for centuries to manage heart failure and atrial fibrillation. Their positive inotropic effects and neurohormonal modulation improve symptoms and exercise tolerance in heart failure. The earlier DIG trial demonstrated that digoxin reduced hospitalizations for worsening heart failure without impacting overall mortality. A post hoc analysis suggested increased mortality at higher serum digoxin levels, particularly with renal impairment, as digoxin is primarily renally cleared.
The clinical benefit of digitoxin in the modern era of guideline-directed therapy is uncertain. Digitoxin has more stable pharmacokinetics than digoxin and is less dependent on renal clearance, potentially making it useful in advanced heart failure. However, evidence from modern randomized trials has been limited.
Study design: International, randomized, double-blind, placebo-controlled trial (DIGIT-HF)
Setting: Multicenter international trial conducted at 65 sites primarily in Europe with a median follow-up of 36 months
Synopsis: The DIGIT-HF trial evaluated whether digitoxin added to guideline-directed therapy improves outcomes in patients with advanced HFrEF. Patients were randomized to digitoxin or placebo and followed for clinical outcomes. The primary endpoint was a composite of death from any cause or first hospitalization for worsening heart failure.
The study demonstrated that digitoxin therapy reduced the risk of the composite endpoint, largely driven by fewer hospitalizations for heart failure but also some reduction in mortality. These benefits were observed despite patients receiving contemporary heart failure therapy, albeit with fewer participants being on newer agents like angiotensin receptor-neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors, limiting generalizability to future cohorts.
Bottom line: In patients with advanced HFrEF receiving guideline-directed therapy, digitoxin reduced the risk of death or hospitalization for worsening heart failure compared with placebo, suggesting that this older cardiac glycoside may still have a role as adjunct therapy in selected patients.
Citation: Bavendiek U, et al. Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2025;393(12):1155-1165. doi:10.1056/NEJMoa2415471.
Dr. Asmi
Dr. Asmi is a hospitalist and assistant professor of internal medicine at the University of North Carolina in Chapel Hill, N.C.