Despite more than 200 years of research, the role of digoxin in contemporary medicine remains controversial. It is an old drug but with a remarkably sophisticated and rather modern pharmacological profile. It was the first neuroendocrine 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 controlled trials conducted in the pre–β-blocker era suggested that digoxin could improve symptoms and exercise capacity,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.
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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 antagonists6 and β-blockers7 and, subsequently, cardiac resynchronization therapy8 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, β-blockers, and aldosterone antagonists could simply be so overwhelming that any additional benefit from …