DECISION

Rationale: Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To confirm these retrospective analyses, a prospective, randomized, placebo-controlled trial is necessary to establish the position of digoxin in the contemporary treatment of HF. Therefore, we investigate whether low-level, aiming for serum concentrations 0.5-0.9ng/mL, digoxin on top of standard treatment (guideline-recommended therapy), is beneficial in HF patients with reduced or mid-range ejection fractions (LVEF ≤50%).

Objective: The primary objective is to study whether in chronic HF compared to placebo, low-level digoxin reduces (repeated) HF hospitalizations, (repeated) urgent HF hospital visits and cardiovascular mortality, on top of guideline-recommended therapies.

Study design: The proposed trial is a national, multicenter, randomized, double-blind placebo controlled, clinical trial. We include 982 chronic HF patients with LVEF ≤50%, with at least one-third of patients with atrial fibrillation (AF), and one-third women, to ensure a sample of the real-life HF population.

Study population: Patients aged ≥18 years, with chronic HF NYHA II to ambulatory IV, LVEF ≤50%, serum NT-proBNP concentrations ≥400pg/mL if in sinus rhythm; ≥800pg/mL if in AF if recent prior HF hospitalization, (in the absence of (recent) HF hospitalizations ≥600pg/mL if sinus rhythm; ≥1000pg/mL if AF), and on guideline-recommended therapies are included.

Intervention: Patients will be randomized to low-level digoxin or placebo in double-blinded fashion. Digoxin Teva will be given orally starting at doses of 0.2mg, or 0.1mg, based on age, renal function and concomitant medication. No loading dose is given. After 4 weeks study medication (digoxin or placebo) concentrations will be measured. Dose adjustments will be made to reach the target serum digoxin concentration range of 0.5-0.9ng/mL.

Main study endpoint: The primary endpoint is the composite of (repeated) HF hospitalizations, (repeated) urgent HF hospital visits and cardiovascular death.