In 1785, Sir William Withering first described the leaves from the common foxglove plant, Digitalis purpurea, as a treatment for heart failure (HF) and arrhythmia in his monograph “An Account of the Foxglove and Some of Its Medicinal Uses.”¹ More than 200 years later, digoxin remains in contemporary use for the treatment of HF with reduced systolic function, albeit with increasing scrutiny and controversy. In 1997, the landmark Digitalis Investigation Group (DIG) trial showed that while digoxin did reduce total and HF-related hospitalizations, there was no survival benefit.² Over the next decade, a change in practice patterns would lead to a significant reduction in digoxin use, but ultimately no change in the burden of digoxin-related adverse events.^3,4 In patients with persistently symptomatic heart failure with reduced ejection fraction (HFrEF) on guideline-directed medical therapy, the addition of digoxin may help ameliorate signs and symptoms of HF, improve quality of life, and reduce overall and HF-specific hospitalizations. Thus, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the management of HF recommends digoxin as an adjuvant agent in select patient populations.⁵

Digoxin is a purified steroid cardiac glycoside. Cardiac glycosides directly and reversibly inhibit the sodium-potassium-activated adenosine triphosphate transporter (Na⁺K⁺-ATPase) on the plasma membrane of the cardiac myocyte, preventing the influx of potassium and expulsion of intracellular sodium (Figure 26-1).⁶ The net increase in intracellular sodium disrupts the sodium-calcium antiporter (Na^+-Ca²⁺ exchange), effectively increasing intracellular calcium concentrations, and as a result, increases cardiac contractility and augments systolic function.⁶

In addition to augmentation of cardiac inotropy, cardiac glycosides also have an important role in neurohormonal regulation, having effects on both vascular smooth muscle tone and the sympathetic nervous system.⁶ In patients with advanced systolic HF, digitalis has been shown to reduce plasma renin concentrations and promote peripheral vasodilation, likely due to down-regulation of hypersensitized baroreceptors.⁷ By increasing vagal tone and attenuating the sympathetic nervous system, cardiac glycosides also work to slow conduction through the SA and AV nodes.⁷ The increased intracellular calcium levels also work to shorten cardiac repolarization time, increasing the propensity for automaticity and arrhythmias.⁷ In the setting of cardiac glycoside toxicity, one can see that these dual effects of increased automaticity and nodal block can create dangerous exit blocks and arrhythmias.

Digitalis is primarily renally cleared. Due to its large molecular weight and volume distribution, hemodialysis or other methods of extracorporeal elimination are generally ineffective. Digoxin also serves as a substrate for the P-glycoprotein efflux pump, which excretes select drugs into the intestine or proximal renal tubule in exchange for increasing the serum concentration of digoxin.⁸ Common classes of drugs that inhibit the P-glycoprotein pump and significantly increase digoxin concentrations include antiarrhythmics such as amiodarone and quinidine (the latter rarely used in contemporary clinical practice), nondihydropyridine calcium channel blockers, as well as certain antibiotics. Care should always be taken to monitor for potential drug interactions when prescribing digoxin. Recommendations are to reduce the dose of digoxin by at least 50% when using these agents.⁹

Digoxin is the only inotrope that has not been associated with long-term mortality when used in chronic HF.^10,11 While there is a significant risk of adverse events when used at higher doses or in the setting of drug-drug interactions, digoxin can be a safe medication when used within a narrow therapeutic window. While digoxin itself does not cause renal dysfunction or electrolyte abnormalities, the presence of either condition can dangerously potentiate the effects of digoxin.

THE DIGITALIS INVESTIGATION GROUP TRIAL

The Digitalis Investigation Group (DIG) trial was the first randomized controlled trial designed to investigate the impact of digoxin on mortality and morbidity in patients with chronic HF.² Published in 1997, this large double-blind randomized controlled trial enrolled almost 6800 ambulatory adult patients with HFrEF (<45% in the trial), and normal sinus rhythm, who were randomized to receive digoxin or placebo.² The study failed to reach its primary endpoint, showing no statistically significant effect on all-cause mortality (34.8% in the digoxin arm vs 35.1% in the placebo group; RR 0.99 p = 0.8), although there was a 28% reduction in hospitalizations in the digoxin arm.² While this study has had an undeniable impact on contemporary practice patterns in the management of HFrEF, it should be cautioned that this study occurred in an era prior to the use of beta blockers and aldosterone-receptor antagonists for HFrEF, thus impacting its generalizability to current HF management.

There have been multiple post hoc analyses from the DIG trial suggesting that certain subgroups within the digoxin arm may experience a greater benefit from the use of digoxin. For example, patients with more advanced HF, with New York Heart Association (NYHA) class III to IV functional class, left ventricular ejection fraction (LVEF) less than 25%, or cardiomegaly had a modest survival benefit (HR 0.88, P = 0.012) with digoxin use compared to placebo.¹² Similarly, a subgroup analysis of various serum digoxin concentrations (SDCs) in the DIG trial found a 6.8% reduction in mortality among patients with an SDC of 0.5 to 0.9 ng/mL compared to placebo, whereas patients with an SDC of 1.2 to 2 ng/mL had an 11.8% absolute increase in mortality compared to patients receiving placebo.¹³ The study authors hypothesized that a lower SDC may predominantly affect neurohormonal modulation, whereas higher plasma concentrations may have more inotropic effects that may lead to increased myocardial oxygen demand and the promotion of arrhythmic complications.¹³ Based on these findings, the current AHA/ACC guidelines recommend maintaining SDC between 0.5 and 0.9 ng/mL when using digoxin in the treatment of HFrEF.⁵

It should be noted that only 22% of patients enrolled in the DIG trial were women and fewer women had serum digoxin levels drawn during the study.^2,13-14 In a post hoc analysis of sex-based differences in the DIG trial, digoxin was associated with an increased risk of all-cause mortality in women but not in men.¹⁴ A subgroup analysis of SDC among women in the DIG trial was insufficiently powered to determine if there is a safe therapeutic range for digoxin use in women.¹³ To date, there is insufficient evidence to support the use of digoxin in women and further studies are needed to evaluate the effect of digitalis on women with chronic HF.

Almost one-third of patients with HF with reduced systolic function have atrial fibrillation (AF).^11,15 Digoxin may help control the rate of ventricular response in AF by increasing vagal tone; however, this effect may be best seen in resting well-compensated HF states with minimal adrenergic stimulation.¹⁶ While the DIG trial excluded patients with AF, subsequent smaller studies have found that the combined use of digoxin and a beta blocker leads to improved rate control, systolic function, and NYHA functional class compared to either agent alone.^17,18 A recent retrospective study of AF in a non-HF population found an increased risk of death among patients taking digoxin, once again raising the controversy of contemporary digoxin use.¹⁹