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Gorlin R, et al. "The effect of digoxin on mortality and morbidity in patients with heart failure". The New England Journal of Medicine. 1997. 336(8):525-533.
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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 (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.

Further Reading

  1. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.