Prescribing low-dose digoxin for patients with heart failure may reduce hospitalizations and cardiovascular complications when the drug is added to current guideline-directed therapy, according to three studies led by researchers at the University Medical Center Groningen (UMCG). The findings, published in Nature Medicine, showed that a meta-analysis combining data from the DECISION clinical trial with two earlier randomized studies found hospitalizations were reduced by 25% achieved by a reduction in worsening heart failure events.
Heart failure affects roughly 60 million people worldwide. Standard treatments currently rely on four medications commonly referred to as the “Fantastic Four.” The Groningen investigators examined whether digoxin, a drug that has been used for centuries in cardiovascular medicine, could serve as an additional therapy alongside those treatments.
The core study in the newly published research was the randomized, double-blind, placebo-controlled DECISION trial, which enrolled 1,000 patients with symptomatic chronic heart failure and a left ventricular ejection fraction of 50% or less at 43 centers in the Netherlands. Participants received either low-dose digoxin (600) or placebo (400) in addition to standard therapy with a median follow-up of 36.5 months.
The trial found that low-dose digoxin reduced the combined rate of worsening heart failure events and cardiovascular mortality by 19%, a figure that was not statistically significance. But when these data were then combined with two earlier randomized trials that evaluated digitalis glycosides—the same class of drugs as digoxin—in heart failure, the pooling of data from the three studies was able to demonstrate a statistically significant benefit.
The data from DECISION showed 238 primary outcome events among patients receiving digoxin compared with 291 events in the placebo group. The number of worsening heart failure events was also lower in the digoxin arm, with 155 events compared with 203 among placebo-treated patients.
One of the earlier studies, the DIG trial, published in 1997, had researched digoxin in patients receiving diuretics and angiotensin-converting enzyme inhibitors. While this combination did not reduce all-cause mortality, it demonstrated a 28% reduction in hospitalization for worsening heart failure. Subsequent analyses of the DIG data also suggested that lower serum digoxin concentrations were associated with more favorable outcomes, while higher concentrations above 1.2 ng ml−1 were linked to increased mortality.
The other earlier study, DIGIT-HF, had evaluated low-dose digitoxin added to contemporary heart failure therapy. In this study, the researchers reported a 15% reduction in the combined endpoint of all-cause death and first hospitalization for heart failure.
The third and current study from the Groningen researchers followed about 600 patients who had participated in the DECISION clinical trial after study treatment ceased. In this case, the team found that patients who discontinued digoxin experienced more problems during the first six weeks after withdrawal than patients who had never received the drug. Among 288 patients who stopped digoxin, 14 were hospitalized or died.
The studies all focused on low-dose digoxin because earlier analyses had suggested that lower serum concentrations of the drug produced benefit without the adverse effects created by higher dosing levels. In the past, higher doses were used to increase heart muscle contraction, but the researchers found that this approach was not beneficial in weakened hearts. Instead, lower doses appear to blunt adverse compensatory responses in heart failure.
The DECISION study also provided new randomized data regarding the safety of low-dose digoxin in women and in patients with atrial fibrillation, populations that had been considered at risk from higher doses. The investigators reported that low-dose digoxin did not increase adverse effects or pacemaker implantation and produced similar findings in men and women.
These new data could change heart failure guidelines in the future by including the use of digoxin as an additional therapy in patients with reduced or mildly reduced ejection fraction. Further, because digoxin therapy costs less than ten cents per day, it could offer a low-cost treatment option compared with newer therapies that cost several dollars daily.
The researchers said future work should further define which heart failure populations benefit most from low-dose digoxin and continue evaluating its role alongside contemporary guideline-directed therapies, including sodium-glucose cotransporter-2 inhibitors and other newer agents.
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