Objective:

To assess whether low-dose digoxin reduces worsening heart failure events and cardiovascular mortality in patients with symptomatic heart failure and LVEF of 50% or less receiving guideline-directed treatment.

Approach:

• Design and participants: Double-blind, placebo-controlled DECISION trial randomized 1,001 adults to low-dose digoxin or placebo. Mean LVEF was 33%; most participants had NYHA class II symptoms.
• Treatment and follow-up: Digoxin was started at 0.1 or 0.2 mg daily, targeting serum concentrations of 0.5–0.9 ng/mL. Median follow-up was 36.5 months.
• Primary outcome: The primary endpoint combined recurrent hospitalizations and urgent visits for worsening heart failure with cardiovascular mortality.

Key Findings:

• The primary endpoint was not significantly different: 238 events among 500 digoxin-assigned patients versus 291 among 501 placebo-assigned patients; rates were 15.7 and 19.3 per 100 patient-years, respectively.
• Worsening heart failure events numbered 155 with digoxin and 203 with placebo. Cardiovascular deaths were 83 (17%) and 88 (18%), respectively; all-cause mortality was also similar.
• No statistically significant treatment-effect differences were found across 11 prespecified subgroups. Subgroup analyses were exploratory and did not establish efficacy in a specific population.
• Low-dose digoxin was generally well tolerated, although treatment-related serious adverse events occurred in 8% with digoxin and 5% with placebo; this difference was not statistically significant.

Interpretation:

The researchers concluded that low-dose digoxin did not significantly reduce the primary composite endpoint when added to contemporary guideline-directed treatment.

Limitations:

• The study population was predominantly male, and most participants had class II heart failure, limiting generalizability to populations with different characteristics.
• Treatment discontinuation was greater than anticipated; at the end-of-study visit, 24% of assessed digoxin patients and 21% of placebo patients had discontinued medication for reasons other than mortality.
• SGLT2 inhibitor use at the end of follow-up was higher with placebo than digoxin (80% vs. 72%), which the researchers noted could have influenced results.
• An exploratory on-treatment sensitivity analysis showed lower event rates with digoxin, but it did not change the nonsignificant result of the primary randomized comparison.

Conclusion:

The researchers noted that the primary outcome difference was smaller than the 22% reduction assumed in the trial’s sample-size calculation. They suggested low-dose digoxin may be an easy, simple, and inexpensive treatment option for patients with reduced or mildly reduced ejection fraction.

Sources:

• Nature Medicine