Perspective:

The following are 10 points to remember pertaining to this article, which reviews the role of digoxin therapy in heart failure (HF):

1. Currently, digoxin is offered as a secondary recommendation in guidelines for patients with HF and reduced ejection fraction (EF) in normal sinus rhythm experiencing persistent symptoms despite optimal medical therapy.

2. Due to its mechanism of action, digoxin not only affects the myocardium, but also acts as a neurohormonal modulator by increasing parasympathetic tone and decreasing activation of the sympathetic system and the renin-angiotensin-aldosterone system.

3. Starting in 1995, in a pooled retrospective analysis of the PROVED (Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin) and RADIANCE (Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme) trials, triple therapy with digoxin, in addition to an angiotensin-converting enzyme inhibitor and diuretic, was associated with the lowest incidence of worsening HF, and found that digoxin therapy reduced overall hospital costs.

4. In 1996, the DIG (Digitalis Investigation Group) trial was designed to study the effects of digoxin on mortality and hospitalization in 6,800 stable ambulatory HF patients with an EF ≤45% in normal sinus rhythm.

5. Results of the DIG trial demonstrated a trend toward lower risk of HF-specific mortality in patients randomized to digoxin, as well a lower incidence of all-cause cardiovascular and HF-related hospitalization.

6. It is important to note that in the DIG trial, a younger population with few women and few racial minorities were included.

7. Although women only made up 20% of total enrollment in the DIG trial, initial data suggested that all-cause mortality may have increased in women randomized to digoxin. However, a subsequent analysis of the DIG trial found that women with a serum digoxin concentration (SDC) >1.0 ng/ml to be at higher risk for mortality.

8. Overall, digoxin is known to reduce all-cause HF-specific hospitalizations, and at lower SDC (i.e., 0.5-0.9 ng/ml) and in certain high-risk groups, may improve survival.

9. Despite safety concerns regarding supertherapeutic levels and fatal arrhythmias, the incidence of digoxin toxicity requiring hospitalization is low.

10. Existing and future clinical trial databases may provide useful information, but the efficacy and safety of these treatments should be interpreted with caution.