- Clinicians lack rigorous trial data regarding whether low-dose digoxin improves outcomes for patients with symptomatic chronic heart failure.
- The DECISION trial randomized 1,001 patients with reduced ejection fraction to receive either low-dose digoxin or a placebo.
- Digoxin did not significantly reduce composite events compared to placebo, yielding a rate ratio of 0.81 (95% CI 0.61-1.07, P=0.133).
- The researchers concluded that low-dose digoxin fails to significantly lower cardiovascular mortality or total worsening heart failure events.
- These findings suggest that low-dose digoxin should not be routinely added to standard heart failure regimens to improve survival.
Reassessing the Clinical Utility of Digoxin in Modern Heart Failure Management
Digoxin, one of the oldest agents in cardiovascular medicine, occupies a contested space in contemporary heart failure management [1, 2]. This uncertainty is fueled by conflicting evidence; large-scale observational data have associated the drug with increased all-cause mortality (hazard ratio 1.19, 95% confidence interval 1.14 to 1.25) and cardiovascular mortality, particularly in patients with atrial fibrillation [3, 4, 5, 6]. In contrast, meta-analyses of randomized controlled trials suggest a neutral effect on mortality (risk ratio 0.99, 95% confidence interval 0.93 to 1.05), coupled with a potential reduction in hospital admissions [7, 8]. To resolve this discrepancy, the DECISION trial was designed to test a specific hypothesis: whether maintaining low serum concentrations (0.5 to 0.9 ng ml-1) of this digitalis glycoside, a medication that inhibits the sodium-potassium pump to increase cardiac contractility, could improve outcomes in patients with reduced ejection fraction [9].
Trial Design and Patient Characteristics
The DECISION trial was a double-blind, placebo-controlled randomized clinical trial that enrolled 1,001 patients with symptomatic chronic heart failure and a left ventricular ejection fraction of 50% or less. This inclusion criterion captured patients with both heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF). The intervention was rigorously defined, with a target serum digoxin concentration of 0.5-0.9 ng ml-1 in the treatment arm. This specific range was chosen to explore potential efficacy while minimizing the well-documented risk of digitalis toxicity seen at higher concentrations. The study cohort reflected a typical clinical population, with a mean age of 72 ± 9 years and 28% of participants being women.
Crucially, 29% of the enrolled patients had atrial fibrillation, a common comorbidity where digoxin is often used for its rate-controlling effects. The inclusion of this substantial subgroup allowed the investigators to assess outcomes in a population representative of real-world practice. The baseline characteristics were well-balanced between the digoxin and placebo groups, providing a solid foundation for comparing the primary outcome, a composite of worsening heart failure events and cardiovascular mortality.
Primary Composite Outcomes and Mortality Data
The trial's primary efficacy measure was a composite of total worsening heart failure events (defined as hospitalizations or urgent visits) and cardiovascular mortality. Over a median follow-up of 36.5 months, the event burden was numerically lower in the treatment group. In the digoxin arm (n = 500), 131 patients experienced 238 primary-outcome events, while in the placebo arm (n = 501), 152 patients experienced 291 such events. However, this difference did not translate into a statistically significant benefit. The final analysis yielded a rate ratio for the primary outcome of 0.81 (95% confidence interval [CI] 0.61-1.07, P = 0.133), indicating the result could not be confidently distinguished from chance.
When the components of the primary endpoint were analyzed separately, the findings remained consistent. The data on mortality showed no significant difference between the groups. Cardiovascular mortality occurred in 83 patients (17%) in the digoxin group compared to 88 patients (18%) in the placebo group, corresponding to a hazard ratio of 0.93 (95% CI 0.69-1.26). These results demonstrate that for patients with a reduced or mildly reduced ejection fraction, a strategy of targeting low-dose digoxin did not significantly reduce the combined risk of worsening heart failure or death from cardiovascular causes.
Safety Profile and Clinical Implications
A closer look at morbidity alone revealed a trend toward fewer clinical deteriorations with the study drug. The total number of worsening heart failure events was 155 in the digoxin group versus 203 in the placebo group, resulting in a rate ratio of 0.76 (95% confidence interval [CI] 0.54-1.05). While suggestive, this finding did not achieve statistical significance, as the confidence interval crossed 1.0. On the matter of safety, the investigators reported that low-dose digoxin was generally well tolerated, an important finding given the trial's elderly population (mean age 72 years), which is often at higher risk for adverse drug events. Furthermore, the results were similar between men and women, addressing historical concerns about potential sex-based differences in digoxin's effects.
For the practicing physician, the DECISION trial provides important clarity. The study concludes that in patients with heart failure and a left ventricular ejection fraction of 50% or less, low-dose digoxin did not significantly reduce the composite endpoint of total worsening heart failure events or cardiovascular mortality. While the drug appears safe at these low concentrations, these findings do not support its use for the primary purpose of improving major clinical outcomes in this population. The decision to use digoxin may therefore continue to be guided by other considerations, such as symptom control or rate management in atrial fibrillation, rather than an expectation of reducing hospitalizations or mortality.
References
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2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. European Journal of Heart Failure. 2016. doi:10.1002/ejhf.592
3. Gazzaniga G, Menichelli D, Scaglione F, Farcomeni A, Pani A, Pastori D. Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses.. European journal of clinical pharmacology. 2023. doi:10.1007/s00228-023-03470-y
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7. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015. doi:10.1136/bmj.h4451
8. Virgadamo S, Charnigo R, Darrat Y, Morales G, Elayi CS. Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction.. World journal of cardiology. 2015. doi:10.4330/wjc.v7.i11.808
9. Veldhuisen DJV, Rienstra M, Mosterd A, et al. Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial.. Nature medicine. 2026. doi:10.1038/s41591-026-04406-6