The oldest cardiac drug still in contemporary use, digoxin was prescribed to an estimated 80% of heart failure (HF) patients at its peak. However, as beta-blockers and angiotensin-converting enzyme inhibitors became available, its use declined. While HF management guidelines recommend digoxin as a secondary treatment for HF patients with reduced ejection fraction (HFrEF), Ambrosy et al. suggest that the drug should be reconsidered in patients with worsening chronic HF who remain at high risk for hospital admission or death.

In the main trial of the pivotal Digitalis Investigation Group (DIG) study, patients with reported New York Heart Association class II or III symptoms experienced a trend towards lower risk of HF-specific mortality, while the incidence of allcause, cardiovascular-, and HF-related hospitalization was significantly lower. Digoxin, a cardiac glycoside, was thought to exert these effects in both cardiac and noncardiac tissues (acting as a neurohormonal modulator).

DIG investigators considered serum digoxin concentration (SDC) levels of 0.5-2.0 ng/mL therapeutic; today, guidelines put those levels at 0.5-0.9 ng/ml. Notably, nearly half of patients enrolled in the DIG trial had a supratherapeutic SDC by modern standards, but digoxin therapy did not adversely impact survival. Additionally, many modern medical and device therapies were not yet a part of background therapy when the trial was conducted—potentially limiting the applicability of these data to contemporary clinical practice.

A review of several retrospective studies of consecutive patients, clinical trial databases, and prospective cohort studies revealed that, in patients with HFrEF:

• digoxin therapy held no long-term deleterious consequences
• digoxin's hemodynamic effects were not attenuated by chronic administration
• the drug worked synergistically with beta-blockers (as an adjunct for reducing heart rate) and mineralocorticoid receptor antagonists (for its putative antifibrotic properties)
• digoxin therapy did not decrease blood pressure or worsen renal function

So, can you teach an old drug new tricks? According to Ambrosy and colleagues, future research trials designed specifically to evaluate digoxin in patients with worsening HF should include stable, ambulatory HF patients who are unable to take modern HF management drugs, as well as the 30–40% of HF patients with comorbid atrial fibrillation in whom the combination of carvedilol and digoxin has been shown to improve rate control. Overall, they noted that given safety concerns regarding supratherapeutic levels and digoxin toxicity, future studies should also investigate a dosing algorithm accounting for age, gender, ideal body weight, and renal function. "With appropriate dosing, it may not be necessary to routinely measure SDC in most patients in order to achieve a safe and efficacious level."

Perhaps, the authors suggest, there also needs to be a recalibration of outcome measures. While the "gold standard" for efficacy and safety will always be all-cause mortality, they wrote, "There is growing recognition that the 'patient journey' may include impairments in the day-to-day experience that are not fully captured by traditional outcome measures." Revisiting existing and novel interventions through a set of validated, patient-centered supplementary endpoints, such as hospitalization- free survival, functional capacity, and quality of life, may open up new possibilities for clinical benefit in new subsets of patients.

Ambrosy AP, Butler J, Ahmed A, et al. J Am Coll Cardiol. 2014 February 21. [Epub ahead of print]