The DIG trial: Digoxin associated with significant decrease in hospitalizations in patients with systolic heart failure [Classics Series]

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1. Digoxin significantly reduced hospitalizations but had no significant effect on mortality when used to treat patients with systolic heart failure

2. Digoxin was most beneficial in patients with low ejection fractions (<0.25) and poor functional status (NYHA III-IV)

Original Date of Publication: February 20, 1997

Study Rundown: The DIG trial provided evidence that digoxin significantly reduces the number of hospitalizations in patients with heart failure, and this effect is greatest for those with low ejections fractions and poor functional status. Although the study did not show any mortality benefit, digoxin did not increase mortality, as had been demonstrated with other positive inotropes.

To reduce hospitalizations, the addition of digoxin should be considered for patients with systolic heart failure (EF<0.45) who continue to have poor functional status (NYHA III-IV) and are already optimized on a beta-blocker and ACE-I inhibitor.

Click to read study in NEJM

Primer: Digoxin, a cardiac glycoside derived from the extracts of the foxglove plant Digitalis purpurea, is one of the longest used medications in the treatment of heart disease. It acts primarily as a positive inotrope by inhibiting the sacrolemmal Na-K ATPase pump and consequently increasing myocardial intracellular calcium concentrations.

Prior the DIG trial, digoxin was commonly prescribed for patients with heart failure with the intention of improving contractility and thus, cardiac output. There was no substantial evidence, however, suggesting that the use of digoxin improved long-term outcomes in patients with heart failure. The DIG trial was published in NEJM in 1997. This landmark randomized controlled trial enrolled 6,800 patients and sought to examine the long-term effects of digoxin on mortality and hospitalization in patients suffering from systolic heart failure.

Relevant Reading:

1. Lee DC, Johnson RA, Bingham JB, et al. Heart failure in outpatients: A randomized trial of digoxin versus placebo. N Engl J Med 1982;306:699-705.
2. Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of the PROVED trial. J Am Coll Cardiol 1993;22(4):955-962.
3. Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol 2005;46(3):497-504.

In-Depth [randomized, controlled study]: This trial was conducted at 302 clinical centers in the United States and Canada. Patients were randomized to either receive digoxin or placebo.  The primary outcome studied was death from any cardiovascular cause. Secondary outcomes included hospitalization or death from worsening of heart failure.

There was no significant difference in mortality from any cause between the digoxin and placebo groups. Patients in the digoxin group, however, were significantly less likely to be hospitalized for worsening of heart failure. Subgroup analysis showed that the benefit of digoxin on a combined outcome of mortality and hospitalization for heart failure was greatest in patients with low ejection fractions (EF <0.25) and functional status (NYHA III-IV).

By Aimee Li, M.D. and Andrew Cheung, M.D.

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