The DIGIT-HF trial and the Mihai Gheorghiade legacy: time to reconsider cardiac glycosides as effective therapy in HFrEF

Cardiac glycosides have been used for more than two centuries in patients with heart failure with reduced ejection fraction (HFrEF), but their use has steadily declined in recent decades, largely due to safety concerns raised by observational studies and the availability of outcome-modifying therapies with more favorable safety profiles. Evidence from earlier randomized trials suggested that digoxin improves symptoms and reduces heart-failure hospitalizations without affecting survival, but these studies were conducted before the widespread adoption of contemporary guideline-directed medical therapy (GDMT). Digitoxin is a cardiac glycoside that differs from digoxin through its hepatic clearance and more stable pharmacokinetics, diminishing the impact of renal dysfunction and serum concentration fluctuations, thereby improving safety and facilitating long-term use in routine care. Here, we critically discuss in the context of available evidence the findings of the recently published DIGIT-HF (Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure) trial, which for the first time evaluated the efficacy and safety of digitoxin in contemporary patients with HFrEF.