The comeback of digitalis (digitoxin): the DIGIT-HF trial

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.