DECISION

Population

• Adults with symptomatic chronic heart failure and left ventricular ejection fraction of 50% or less.
• Mean age was 72 years, 28% were women, 29% had atrial fibrillation, and most patients had NYHA class II symptoms.

Intervention

Algorithm-guided low-dose digoxin targeting a serum concentration of 0.5-0.9 ng/mL.

Comparator

Matching placebo.

Key results

• The primary outcome totaled 238 events in 131 of 500 patients receiving digoxin and 291 events in 152 of 501 patients receiving placebo; rate ratio 0.81 (95% CI 0.61-1.07; P=0.133).
• Total worsening heart failure events numbered 155 with digoxin and 203 with placebo; rate ratio 0.76 (95% CI 0.54-1.05).
• Cardiovascular mortality occurred in 83 patients (17%) with digoxin and 88 (18%) with placebo; hazard ratio 0.93 (95% CI 0.69-1.26).
• Results were similar in men and women.

Harms

• Serious adverse event rates excluding trial endpoints were similar between groups: 19.9 versus 18.3 events per 100 patient-years; rate ratio 1.09 (95% CI 0.86-1.37).
• Treatment-related serious adverse events occurred in 40 patients receiving digoxin and 25 receiving placebo, a nonsignificant difference; rate ratio 1.53 (95% CI 0.91-2.55).
• Patient-reported side effects and new device implantation did not differ significantly between groups.

Practice impact

• Provides modern placebo-controlled evidence for low-dose digoxin added to contemporary guideline-directed therapy.
• Offers reassurance about monitored low-dose digoxin safety but does not establish a significant reduction in major heart failure outcomes.

Applicability

• Patients with symptomatic HFrEF or HFmrEF despite contemporary therapy when adjunctive digoxin is being considered.
• Includes patients in sinus rhythm and those with atrial fibrillation.

Limitations

• The trial enrolled a mostly male, predominantly NYHA class II population in the Netherlands, limiting extrapolation to other populations and more advanced heart failure.
• Study treatment discontinuation was relatively common and may have reduced statistical power.
• Only 41% of participants used an SGLT2 inhibitor at baseline, reflecting therapy uptake during the enrollment period rather than universal contemporary quadruple therapy.

Common misinterpretations

• A numerically favorable rate ratio with P=0.133 is not evidence that digoxin significantly reduced the primary outcome.
• The generally reassuring safety findings do not establish mortality benefit or make digoxin a foundational HFrEF therapy.
• The trial does not prove no benefit is possible; its confidence interval includes both clinically meaningful benefit and no effect.