Digitoxin improves outcomes in heart failure with reduced ejection fraction
1. Among patients with symptomatic chronic heart failure already on guideline-directed medical therapy (GDMT), digitoxin lowered all-cause mortality and hospital admission for heart failure progression compared to placebo.
2. Digitoxin was associated with a small increase in serious adverse events compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Cardiac glycosides, namely digoxin and digitoxin, are longstanding parts of heart failure therapies. Although evidence for their benefits in patients with heart failure and reduced ejection is limited, this evidence arose before the arrival of advanced GDMT agents and cardiac devices. Additionally, while digoxin, which is cleared renally and can reach high serum levels in those with impaired renal function, is eliminated by enterohepatic excretion, digitoxin levels remain stable without dose adjustments. This study assessed digitoxin in adult patients with symptomatic chronic heart failure, stratified by left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class. Compared to placebo, digitoxin resulted in a lower composite risk of death from any cause or hospital admission from heart failure progression by 36 months, overall and across prespecified subgroups. The number needed to treat to prevent one primary outcome was 22. Overall, despite lacking statistical power for its subgroup analyses, digitoxin lowered the composite risk of all-cause mortality and hospital admission from heart failure progression among patients with symptomatic chronic heart failure.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: This double-blind, randomized, placebo-controlled trial evaluated the efficacy of digitoxin in the treatment of symptomatic heart failure. Adult patients with heart failure, who had a LVEF ≤40% with NYHA functional class III or IV, or a LVEF ≤30% with NYHA functional class II, and had been receiving stable GDMT, were eligible for inclusion. 1240 patients were randomized 1:1 to receive either daily digitoxin (starting dose 0.07mg) or a matching placebo. The primary outcome was a composite of death from any cause or hospital admission for worsening heart failure, whichever occurred first. Secondary outcomes included components of the primary outcome, as well as death from cardiovascular causes, death from heart failure, any hospitalization, and hospitalization for cardiovascular causes. A primary-outcome event occurred in 39.5% of patients in the digitoxin group compared to 44.1% in the placebo group (hazard ratio [HR] 0.82, 95% confidence Interval [CI] 0.69-0.98; P=0.03). Secondary outcomes, however, did not meet statistical significance. Death from any cause occurred in 27.2% of the digitoxin group and 29.5% of the placebo group (HR 0.86, 95% CI 0.69-1.07); whereas first hospital admission for worsening heart failure occurred in 28.1% of the digitoxin group vs. 30.4% in the placebo group (HR 0.85, 95% CI 0.69-1.05). Similarly, the risk of death from cardiovascular causes (HR 0.87, 95% CI 0.67-1.11), death from heart failure (HR 0.86, 95% CI 0.57-1.31), any hospitalization (HR 0.90, 95% CI 0.78-1.03), and hospitalization for cardiovascular causes (HR 0.89, 95% CI 0.77-1.04). The effects of digitoxin on the primary outcome were consistent in patients with impaired renal function. At least one serious adverse event occurred in 4.7% of the digitoxin group and 2.8% of the placebo group, including cardiac disorders in 3.4% and 1.8% of patients, respectively. Although these results cannot be generalized to other cardiac glycosides, they suggest that digitoxin lowered the composite risk of death from any cause and hospitalization from heart failure progression among patients with symptomatic heart failure with reduced ejection fraction already receiving stable GDMT.
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