Cardiac glycosides derived from the foxglove plant have been used in cardiology for two centuries, but digoxin and digitoxin have gradually fallen out of favor and are now considered controversial in heart failure treatment.<\/p>\n
The early rationale for the use of glycosides in heart failure stemmed from the 1997 DIG trial<\/a> comparing digoxin to placebo \u2014 both in combination with standard therapy \u2014 in 6800 patients with heart failure. People with reduced left ventricular ejection fraction (HFrEF) who used the drug were less likely to require hospitalization, but the primary endpoint of all-cause mortality did not differ between the two groups.<\/p>\n \u201cDigoxin\/digitoxin received a class 1 recommendation in earlier heart failure guidelines, but this has since been downgraded to a weaker class 2b,\u201d in light of therapeutic advances, Gregg Fonarow, MD<\/a>, told Medscape Medical News.<\/p>\n Can New Study Findings Resurrect an Old Drug?<\/strong><\/p>\n Heart failure medications have evolved substantially in the quarter-century since the DIG trial, said Fonarow, who directs the Ahmanson-UCLA Cardiomyopathy Center and is the co-director of UCLA\u2019s Preventative Cardiology Program. Two new trials are reexamining digitoxin and digoxin to see if they offer any benefit over and above the \u201cfantastic 4<\/a>\u201d of heart failure pharmacotherapy: Angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors.<\/p>\n At this year\u2019s Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2025<\/a> in Belgrade, Serbia, investigators reported early data from the DIGIT-HF<\/a> trial, which is comparing digitoxin or placebo in combination with guideline-directed therapy in 1212 patients with symptomatic HFrEF.<\/p>\n \u201cWe started DIGIT-HF to demonstrate whether digitoxin at low serum concentrations improves outcomes on top of a modern guideline-directed medical therapy and to show that the use of digitoxin is safe,\u201d lead investigator Udo Bavendiek, MD, told Medscape Medical News. \u201cThe latter is of particular importance because cardiac glycosides are needed for effective frequency control in patients with atrial fibrillation and HFrEF when beta-blocker treatment alone is not enough for effective rate control.\u201d<\/p>\n Results should arrive later this year, but Bavendiek, of Hannover Medical School in Hannover, Germany, said the study population is more complex relative to the subjects in pivotal trials of other contemporary therapies for heart failure.<\/p>\n DIGIT-HF patients had a \u201cpronounced HF symptomatic burden,\u201d Bavendiek and his co-authors wrote in the European Journal of Heart Failure<\/a>, but also were receiving \u201csuperior implementation of contemporary HF treatment,\u201d including guideline-directed medications: 40% were receiving ARNI, 70% MRA, 64% had a cardioverter-defibrillator, and 25% had received cardiac resynchronization therapy.<\/p>\n If digitoxin shows a benefit in this severely ill population already on optimized therapy, this finding would be of great interest, Bavendiek told Medscape Medical News. So far, use of digitoxin appears safe in this population, with no new safety signals observed. The investigators opted for digitoxin because its hepatic excretion is preferred in patients with impaired kidney function, as opposed to digoxin, which is excreted via the kidneys.<\/p>\n Another ongoing trial with the potential to inform the use of glycosides is the DECISION<\/a> study of more than 1000 patients with symptomatic heart failure and a left ventricular ejection fraction below 50%. Unlike DIGIT-HF, the DECISION trial uses low-dose digoxin, said lead investigator Dirk Jan van Veldhuisen, MD<\/a>, of University Medical Center Groningen in Groningen, the Netherlands. This decision was based on sub-analyses of the DIG trial suggesting serum concentrations of digoxin > 1.2 ng\/mL were associated with increased mortality, while more favorable outcomes were seen with lower concentrations. In DECISION, the target serum concentration is 0.5-0.9\u2009ng\/mL The DECISION investigators also enrolled more women to develop a better understanding of the use of digoxin in this population.<\/p>\n