Effects of digoxin in modern heart failure treatment: Rationale and design of the DIG-Mod HF trial

AIMS: Even though it is the oldest heart failure (HF) medication still in use, digoxin has not been evaluated alongside the updated algorithm for treating HF with reduced ejection fraction patients. This could help explain the low use of digoxin in recent HF studies. The main objective is to assess the effectiveness of digoxin in functional capacity and cardiac function when combined with modern HF therapy. METHODS: An interventional, open-label, randomised, crossover trial among adults with chronic Heart Failure and reduced ejection fraction (≤ 45%) was designed to allocate 50 patients for 24 weeks in each arm (48 weeks of study). The arms are daily intake of digoxin 0.125mg plus standard of care versus standard of care alone. Both patients with sinus rhythm and atrial fibrillation were enrolled. At the end of each 24-week arm, patients will undergo the co-primary outcome measurement of the peak oxygen consumption, evaluated through cardiopulmonary exercise test, and the global work index, measured by transthoracic echocardiography. Key secondary outcome includes a safety composite of death, need for urgent heart transplantation or mechanical assist device, total hospitalizations and sustained ventricular arrhythmias. The study completed recruitment in April 2025 and will complete follow up in March 2026. CONCLUSIONS: The use of digoxin could be significantly affected by evidence that it still has a considerable effect on functional capacity and cardiac function in HF patients. EU CT Number: 2024-513448-26-00.