2024, Volume 31, Supplement 3: Digoxin: its history, modern-day clinical use and toxicity management

Digoxin is one of the oldest drugs still used in cardiovascular medicine and yet one of the most controversial. Ever since its medical use was popularised by the British physician William Withering in 1785, it has been the subject of lingering debate within the medical community. In this issue of the British Journal of Cardiology, we explore the evolution of this seemingly timeless drug from its historical origins to modern day clinical use....

More than 200 years have passed since William Withering’s ground-breaking work on the medical use of foxglove for the treatment of dropsy. Its derivative, digoxin, remains one of the most heavily debated drugs in cardiovascular medicine. While its use predated the era of randomised control trial evidence or even a complete understanding of its mechanism of action, it has endured against a changing scientific and therapeutic landscape. In this historical review, we explore its journey from ancient wisdom to becoming a cornerstone of heart failure (HF) therapy, including discovery of its pharmacological properties and an appraisal of early clinical studies. The development of newer therapies for HF during the late twentieth century, alongside concerns regarding digoxin’s toxicity, impact on mortality, and comparative efficacy, have led to a decrease in its use. Nevertheless, digoxin remains a useful treatment option for selected patients with atrial fibrillation and HF....

Digoxin has been used in the management of chronic heart failure (HF) and atrial fibrillation (AF) for over 250 years. It is the only drug that combines an inotropic effect with a reduction in ventricular rate in AF. Therefore, in theory it should be an ideal treatment for HF, especially when there is co-existent AF. However, due to concerns about arrhythmia and toxicity, its use has declined dramatically over recent decades. In the only large, randomised trial of patients with HF with reduced ejection fraction (HFrEF), digoxin demonstrated a reduction in hospitalisation with no adverse effect on total mortality but patients in AF were excluded. In patients with both AF and mild HF (mainly HF with preserved ejection fraction [HFpEF]), the much smaller RATE-AF (Rate Control Therapy Evaluation in Permanent Atrial Fibrillation) trial showed that in comparison to a beta blocker, digoxin did not differ in its impact on quality of life and heart rate control but had superior effects on symptoms, N-terminal of the prohormone of B-type natriuretic peptide (NT-proBNP) and treatment-related adverse events. Meta-analysis also indicates that for patients with HF and AF, digoxin does not cause excess mortality; previous indications of mortality were almost certainly explained by prescription bias in non-randomised trials. It appears that digoxin is far from being redundant and might be the treatment of choice for older patients with AF and stable mild HF. It may also reduce the need for admission in patients with HFrEF without AF. As meta-analysis suggests that beta blockers may not confer prognostic benefit in patients with AF and HFrEF, it is also a reasonable choice in this group to achieve rate control....

Digoxin is widely used in the management of atrial fibrillation (AF) and the heart failure (HF) syndrome. Significant numbers of people are prescribed digoxin every year; 2,560,941 prescriptions for digoxin were issued by general practitioners in England in 2023.1 Digoxin predominantly acts by increasing vagal tone. This reduces heart rate and increases diastolic filling of the left ventricle (LV), resulting in an improvement in LV function. Coronary artery perfusion, which predominantly occurs during diastole, also increases. Digoxin increases intracellular Ca2+ concentrations as a result of inhibition of the Na+/K+ adenosine triphosphatase, and so myocardial contractility increases. However, it has limitations, which include a narrow therapeutic index, and interactions with drugs with which it is commonly co-prescribed. Moreover, it can cause problematic side effects. In acute overdose, or acute-on-chronic accumulation causing toxicity, digoxin presents some unique challenges – we will briefly consider some of these issues here....