Digoxin in chronic heart failure: possibility of a second chance?

The cardiac glycoside digoxin is one of the oldest and probably the least expensive drug for the treatment of chronic heart failure (CHF). But still treatment with this drug in patients with CHF and sinus rhythm remains highly controversial. Despite the fact that the use of digoxin in CHF is considered to be effective and safe, its use has significantly declined due to the belief that digoxin is not able to favourably affect the natural history of CHF.1 Another important fact is the occurrence of its well-known toxic side effects, although the incidence of digoxin toxicity seems to have diminished in the first years of the 21st century.2 The European Society of Cardiology guidelines for the diagnosis and treatment of acute and CHF recommend the administration of digoxin in symptomatic patients with impaired left ventricular ejection fraction (LVEF) and sinus rhythm despite its lack of effect on survival.3 This recommendation is based on level B of evidence in view of the fact that only one meta-analysis of a single randomized controlled trial, the Digoxin Investigation Group (DIG) trial, could demonstrate a reduction in CHF-associated hospital admissions.3 The DIG trial is the most relevant study investigating the long-term effects of a median daily dose of 0.25 mg of digoxin in CHF and showed no evidence of decreased mortality but a reduced rate of hospitalizations both overall and for worsening CHF.4 Nevertheless, in more recent studies the use of digoxin has been associated with increased mortality not only in advanced CHF5 but also after hospitalization due to acute decompensated heart failure.6 On the other hand, post hoc and propensity-matched analyses of the DIG trial have delivered some evidences of a potentially beneficial effect in patients with CHF also on mortality.7–10 In a post hoc re-analysis of the DIG data, differences in outcome have been demonstrated for diverse ranges of serum concentrations of the drug. While serum digoxin concentrations (SDCs) between 0.5 and 0.9 ng/ml were related to lower mortality, all-cause hospitalization and CHF-specific hospitalization, a SDC above 1 ng/ml was associated with lower CHF hospitalizations but did not affect mortality, the latter regardless of LVEF.7 Moreover, a further post hoc analysis of the DIG trial has found analogous results in geriatric CHF patients aged ≥65 years.8 In a more recent retrospective propensity-matched study of the DIG trial, low concentrations of digoxin reduced major endpoints including mortality and hospitalization in ambulatory, systolic and diastolic patients with CHF.9 In these studies, a low digoxin dose (≤0.125 mg/day) was the strongest predictor of a low serum concentration of the drug, which is thought to be the most important predictor of beneficial clinical outcome.8,9 Furthermore, a retrospective analysis of two digoxin withdrawal studies, the Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme (RADIANCE), found a lower risk of worsening CHF in patients taking digoxin (independent of the dosage) and, in particular, patients with low SDC (0.5–0.9 ng/ml) were less likely to experience worsening of CHF.11 Digoxin is a potent inhibitor of the cellular sodium pump activity in cardiac and non-cardiac tissues, also involving vagal afferent fibers and the kidneys. By inhibiting the sodium–potassium adenosine triphosphatase, digoxin suppresses both the renin–angiotensin–aldosterone and the sympathetic nervous system,9,12 what may explain the favourable effects of this drug also in CHF patients with preserved LVEF.12,13 Of interest, improvements in the neurohormonal profile have been achieved with low doses and low SDC.14 Close monitoring of electrocardiographic changes, SDC, and in particular calculation of the target dosage are important observations concerning this point, since the safety window of digoxin is relatively narrow. With this objective, numerous equations and nomograms to calculate digoxin dosages have been developed.15–17 Importantly, most of these equations were employed to target higher SDC than the ones recommended now due to safety concerns.18 Against this background, Bauman and colleagues15 developed in 2006 a method to accurately calculate the initial dose of digoxin corresponding to a low SDC in CHF patients. Similarly, Konishi et al.19 had formulated a simple equation to determine the daily dose of digoxin based only on creatinine clearance and SDC. Muzzarelli et al.20 in their manuscript published in the current issue of this journal, have tested the Konishi equation, which had only been validated in Asian subjects before, and have also compared it with several equations for determining digoxin dosages including the one from Bauman. Digoxin doses were first calculated using the Konishi equation for a target SDC of 0.6–0.8 ng/ml. Digoxin compliance was then assessed in 40 CHF patients by means of a validated questionnaire and SDC was measured after 1 and 6 months. The relationship between the predicted SDC using the different equations and the measured SDC was assessed by linear regression analysis. The authors obtained the best correlation with the Konishi equation. Thus, given the intriguing retrospective evidence and the low costs of digoxin, the most important question arises of whether digoxin given in adequately small dosages on top of standard therapy, allowing to achieve and maintain low serum concentrations, may become first-line therapy in patients with CHF and, thereby, resembles a second chance of digoxin to enter mainstream heart failure drug therapy. Considering the lack of prospective trials showing a positive effect on mortality and hospitalization by using low doses of digoxin in CHF with sinus rhythm and left ventricular systolic dysfunction, the clinical use and optimization of equations and nomograms to determine the most appropriate administration of digoxin based on safety and efficacy aspects should be continued and tested prospectively in real-world CHF patients. Therefore, we certainly hope that a prospective randomized trial exploring the potential beneficial effects of low dose digoxin will be performed in the near future. By saying this, we speculate about the second chance of digoxin to enter first-line therapy in CHF—providing evidence-based benefit for our patients with the oldest known drug to treat heart failure. Competence Network Heart Failure, funded by the German Federal Ministry of Education and Research (FKZ 01GI0205 to A.V.P.).