Editorial Digoxin Quo Vadis? John G.F. Cleland, MD; Damien Cullington, MD D espite more than 200 years of research, the role of digoxin in contemporary medicine remains controver- sial. It is an old drug but with a remarkably sophisticated and rather modern pharmacological profile. It was the first neu- roendocrine modulator to enhance parasympathetic tone and possibly reduce sympathetic activity. 1 It is the only available oral inotropic agent. It is probably also a diuretic. 2 In common with many other agents for heart failure, good dose-ranging studies have not been conducted, and the optimal dose is uncertain. Well-designed randomized con- trolled trials conducted in the pre–-blocker era suggested that digoxin could improve symptoms and exercise capaci- ty, 3,4 but a large trial that enrolled patients mostly with mild symptoms suggested no overall effect on mortality, although it did report a substantial (28%) reduction in hospitalization for worsening heart failure. 5 A small increase in sudden death was balanced by a reduction in death from worsening heart failure. Whether these benefits were mediated by changes in autonomic tone, in heart rate, in sodium balance, or through inotropic effects is unclear. Article see p 90 At this time, the clinical community’s attention turned from the potential, but still equivocal, effects of digoxin on morbidity and mortality to the striking benefits of aldosterone receptor antagonists 6 and -blockers 7 and, subsequently, cardiac resynchronization therapy 8 on prognosis. Digoxin became largely ignored in discussions and debate, its use declined rapidly (Table and Figure), and the role of digoxin for managing heart failure was left unresolved. The benefits of angiotensin-converting enzyme inhibitors, -blockers, and aldosterone antagonists could simply be so overwhelming that any additional benefit from digoxin is swamped. However, in epidemiologically representative pop- ulations, the prognosis of heart failure remains poor. 34 –36 Most patients who have experienced an episode of worsening heart failure requiring hospitalization or who have an N-terminal prohormone brain natriuretic peptide that is per- sistently above 1500 pg/mL will be dead within 3 years. 37 We are simply not doing as well as some people would like to think. A combination of better monitoring, improved phar- macological interventions, more aggressive device strategies, and ultimately replacement of organ function or, alterna- tively, improved palliative care will be required to manage the growing size and complexity of the population with heart failure. Is the role of digoxin for the contemporary management of heart failure undervalued? One potential mechanism of ben- efit of digoxin is simply to reduce ventricular rate. This is regarded as its principal mode of action in patients with atrial fibrillation, the group of patients in whom the benefits of digoxin are most widely accepted. 38 The concept that -blockers might eliminate the need for digoxin in patients with atrial fibrillation and heart failure was the rationale for the Carvedilol Atrial Fibrillation Evaluation (CAFÉ) study. 1 However, rather than suggesting that digoxin was redundant, the study suggested that there might be synergistic benefits between digoxin and carvedilol. Circumstantial evidence of possible benefit mediated through a reduction in heart rate might come from a large ongoing trial named Systolic Heart Failure Treatment with I f Inhibitor Ivabradine Trial (SHIFT) that investigates the effects of ivabradine, a sinus node inhibitor causing further reduction in heart rate in patients with heart failure already treated with -blockers. 39 If this study shows that further reductions in heart rate are associ- ated with benefit, the question of whether digoxin or ivabra- dine is the preferred method to reduce heart rate or, indeed, whether all 3 rate-lowering agents should be used in combi- nation, at least for those patients with inadequate rate control in sinus rhythm, will arise. Subgroup analyses of studies of -blockers suggest that the benefits of carvedilol are similar in the presence or absence of digoxin, 40 although this seems not to be the case for 1-receptor selective agents. 41,42 There were too few patients on -blockers in the Digitalis Investi- gation Group (DIG) study to allow any insight into the potential benefits of adding -blockers to digoxin for patients in sinus rhythm. There are reasons other than heart rate control to suggest that digoxin might be more effective in the presence of a -blocker. -blockers, especially nonselective ones that attenuate stress-induced reductions in serum potas- sium, 43 might neutralize the increase in sudden death associ- ated with the use of digoxin. Aldosterone antagonists also increase serum potassium, which may also reduce the ar- rhythmogenic potential of digoxin. In the Randomized Al- dactone Evaluation Study (RALES) trial, spironolactone tended to exert a greater reduction in mortality among patients treated with digoxin. 6 Perhaps, concomitant therapy has at last evolved to the point where the full benefits of digoxin can be exploited, but final proof is still lacking. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Cardiology, University of Hull, Kingston- Upon-Hull, United Kingdom. Correspondence to John G.F. Cleland, MD, Department of Cardiology, University of Hull, Castle Hill Hospital, Kingston-Upon-Hull, Cotting- ham HU16 5JQ, United Kingdom. E-mail g.m.porter@hull.ac.uk (Circ Heart Fail. 2009;2:81-85.) © 2009 American Heart Association, Inc. Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.109.859322 81 by guest on March 26, 2015 http://circheartfailure.ahajournals.org/ Downloaded from