DIG
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Clinical Question
Among patients with HFrEF, does digoxin impact mortality or hospitalization rate compared to placebo?
Bottom Line
Digoxin reduces hospitalization rate, but does not impact mortality, among patients with HFrEF.
Major Points
Digoxin had been a mainstay of therapy for patients with HF, and according to some epidemiologic studies was the most commonly prescribed agent for HF until fairly late in the 20th century. There was of course strong data demonstrating the mortality benefit of ACE inhibitors, beta-blockers, and other agents in HFrEF, but little data supported a survival benefit to digoxin. The 1997 DIG trial sought to investigate whether digoxin improved survival or reduced hospitalizations among individuals with chronic compensated HFrEF. Digoxin reduced hospitalizations by 28%, but had no statistically significant effect on all-cause mortality. However, a subgroup analysis of those with severe HFrEF had a trend towards a survival benefit.
Guidelines
AHA/ACCF Heart Failure Guidelines (2013, adapted)[1]
- Digoxin can be beneficial in reducing HF hospitalizations in HFrEF unless contraindicated (class IIa, level B)
Design
- Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- N=6,800 patients with HF
- Digoxin (n=3,397)
- Placebo (n=3,403)
- Primary outcome: All-cause mortality
- Setting: 302 centers in US and Canada
- Mean follow-up: 3.1 years
Population
Inclusion Criteria
- Chronic compensated HF
- LVEF ≤45% (although patients with LVEF >45% were included in a parallel analysis)
- Normal sinus rhythm
Exclusion Criteria
- Age < 21 years
- Cardiac surgery or PCI within previous 4 weeks or need for cardiac surgery or PCI in near future
- ACS within 4 weeks
- Second or third degree AV block without pacemaker
- Atrial fibrillation or atrial flutter
- Pre-excitation syndromes
- Sick sinus syndrome without pacemaker
- Cor pulmonale
- Constrictive pericarditis
- Acute myocarditis
- Hypertrophic cardiomyopathy
- Amyloid cardiomyopathy
- Complex congenital heart disease
- Current treatment with IV inotropic agents
- Potassium <3.2 mmol/L or >5.5 mmol/L
- On heart transplant list
- CKD (creatinine >3.0 mg/dl) or severe liver disease
- Life expectancy <3 years (e.g., malignancy)
- Unlikely to be compliant or adherent to medications (e.g., chronic alcoholism, no fixed address)
Interventions
- HF was diagnosed by:
- Symptoms: limitation of activity, fatigue, dyspnea, orthopnea
- Signs: edema, elevated JVP, rales, an S3 gallop, pulmonary congestion on CXR
- LVEF assessed by radionuclide left ventriculography, LV contrast angiography, or TTE
- Patients randomized to receive digoxin or placebo, stratified by center and by EF (≤45% or >45%)
- Providers were strongly encouraged to put patients on an ACE inhibitor
- Patients returned for follow-up visits at 4 weeks, 16 weeks, and then every 4 months
- With worsening HF symptoms, patients were placed on optimal heart failure treatments
- Patients remaining symptomatic could be placed on digoxin and have their trial drug discontinued
Outcomes
Comparisons are digoxin vs. placebo.
Primary Outcome
- All-cause mortality
- 34.8% vs. 35.1% (RR 0.99; 95% CI 0.91-1.07; P=0.80)
Secondary Outcomes
- Hospitalization for HF
- 26.8% vs. 34.7% (RR 0.72; 95% CI 0.66-0.79; P<0.001)
- Mortality from cardiovascular causes
- 29.9% vs. 29.5% (RR 1.01; 95% CI 0.93-1.10; P=0.78)
- Death from worsening heart failure
- 11.6% vs. 13.2% (RR 0.88; 95% CI 0.77-1.01; P=0.06)
- Hospitalizations
- All-cause hospitalization: favored digoxin (P=0.01)
- CV hospitalization: favored digoxin (P<0.001)
- Digoxin-toxicity hospitalization: 2% vs. 0.9% (P<0.001)
Additional Anlyses
- Combined all-cause mortality or HF hospitalization
- RR 0.85; 95% CI 0.79-0.91; P<0.001
- Combined HF mortality or HF hospitalization
- RR 0.75; 95% CI 0.69-0.82; P<0.001
- Parallel trial in LVEF >45%
- No difference in all-cause mortality or in the combined outcome of all-cause mortality and HF hospitalization
Subgroup Analyses
Individuals with worse HF (lower EF, cardiomegaly, and those with NYHA class III or IV) had a non-significant trend towards a decrease in the combined endpoints of death or hospitalizations for worsening HF when treated with digoxin.
Funding
The drug and placebo were provided by Glaxo Wellcome.