Low-Dose Digoxin Fails to Meet Primary Endpoint in Largest Heart Failure Trial Despite Hospitalization Benefits

The largest randomized controlled trial of low-dose digoxin in heart failure patients has failed to meet its primary endpoint, despite showing numerical reductions in heart failure hospitalizations. The DECISION trial, published in Nature Medicine, enrolled 1,001 patients with heart failure and reduced or mildly reduced ejection fraction, representing the most rigorous test of precision-dosed digoxin therapy to date.

Trial Design and Patient Population

The double-blind, placebo-controlled trial randomized patients 1:1 to receive low-dose digoxin or matching placebo, targeting serum digoxin concentrations between 0.5-0.9 ng/mL. This narrow therapeutic window was selected based on post-hoc analyses suggesting optimal benefit-to-risk ratios at these concentrations, avoiding the toxicity associated with higher levels.

The study population had a mean age of 72 years, with 28% women and 29% having atrial fibrillation. Patients had a mean left ventricular ejection fraction of 33%, with 21% having heart failure with mildly reduced ejection fraction. Importantly, patients received contemporary guideline-directed therapy, with over 85% on beta-blockers and renin-angiotensin blockers, 70% on mineralocorticoid receptor antagonists, and 41% on SGLT2 inhibitors.

Primary Outcome Results

The primary composite endpoint of total worsening heart failure events and cardiovascular death occurred in 238 events among 131 patients in the digoxin group versus 291 events in 152 patients receiving placebo, yielding a rate ratio of 0.81 (95% CI 0.61-1.07, P = 0.133). While numerically favoring digoxin, this result failed to achieve statistical significance.

Secondary analyses revealed more granular insights into digoxin's effects. Worsening heart failure events specifically showed 155 events in the digoxin group compared to 203 in the placebo group (rate ratio 0.76, 95% CI 0.54-1.05). Cardiovascular deaths occurred in 83 patients (17%) in the digoxin group versus 88 patients (18%) in the placebo group (hazard ratio 0.93, 95% CI 0.69-1.26).

Precision Dosing Success

The trial demonstrated successful implementation of precision dosing protocols. Using a simple algorithm based on age, kidney function, and interacting medications, 75% of patients started with 0.1 mg daily and 25% with 0.2 mg daily. At the 4-week visit, 63.6% of patients achieved target serum concentrations, increasing to 83.6% after dose adjustments. The median serum digoxin concentration was 0.6 ng/mL, with only 17 patients exceeding 0.9 ng/mL.

Safety Profile and Subgroup Analyses

The trial provided important safety data, particularly for women and patients with atrial fibrillation. Previous post-hoc analyses of the original DIG trial had suggested increased mortality risk in women, but DECISION found no differential effects between sexes (rate ratio 0.71 in women versus 0.85 in men, P for interaction 0.61). Similarly, patients with atrial fibrillation showed comparable responses to those in sinus rhythm.

Serious adverse events occurred at similar rates between groups (19.9 versus 18.3 events per 100 patient-years). Treatment-related serious adverse events were reported in 40 digoxin patients versus 25 placebo patients, though this difference was not statistically significant.

Impact of Study Discontinuation

A notable challenge was the high discontinuation rate, with 24% of digoxin patients and 21% of placebo patients stopping study medication for reasons other than death. The COVID-19 pandemic significantly impacted discontinuation rates during the first year (hazard ratio 1.47, 95% CI 1.13-1.91, P = 0.016).

An as-treated sensitivity analysis, including only patients who remained on study medication, showed more pronounced effects. This analysis yielded 135 primary outcome events in the digoxin group versus 212 in the placebo group, with a rate ratio of 0.66 (95% CI 0.47-0.92, P = 0.015).

Clinical Context and Implications

The DECISION results must be interpreted within the broader context of heart failure therapeutics. During the trial's 8-year duration, SGLT2 inhibitors emerged as standard therapy, with the DAPA-HF and EMPEROR-Reduced trials demonstrating clear mortality benefits. This evolution in background therapy may have influenced the ability to detect incremental benefits from digoxin.

The trial's investigators noted that their effect size assumptions were based on analyses of approximately 600 patients from the original DIG trial who maintained target concentrations. However, the contemporary heart failure population receives more intensive background therapy, potentially reducing the incremental impact of additional agents.

Regulatory and Development Considerations

The DECISION trial highlights important considerations for cardiovascular drug development. The FDA's heart failure endpoints guidance explicitly supports hospitalization rate as a standalone approvable endpoint, yet DECISION's composite design may have diluted a genuine hospitalization signal with a null mortality effect.

The trial's extended recruitment period, from the planned 36 months to 84 months, reflects the challenges of conducting cardiovascular outcomes trials in an era of increasingly effective standard care. With contemporary therapy already reducing mortality by 30-40% through SGLT2 inhibitors and sacubitril/valsartan, detecting incremental mortality benefits requires either enormous sample sizes or populations deliberately under-treated on background therapy.

Future Perspectives

Despite the negative primary endpoint, the totality of evidence across three major digitalis trials (DIG, DIGIT-HF, and DECISION) shows consistent effects on heart failure hospitalizations. The DECISION investigators suggest that low-dose digoxin may remain "an easy, simple and cheap treatment option" for selected patients with heart failure and reduced or mildly reduced ejection fraction.

The trial's success in maintaining target serum concentrations through algorithmic dosing provides a template for precision medicine approaches in heart failure. However, the results underscore the importance of endpoint selection that aligns with a drug's mechanism of action, particularly for agents more likely to affect hospitalizations and quality of life than survival curves.