29th September 2025, A/Prof Chee L Khoo
Digitalis is one of the oldest drugs in cardiovascular (CV) medicine and has generally been used in patients with heart failure (HF) and in those with atrial fibrillation (AF) or in both (1,2). In fact, up until 25 years ago, digitalis in the form of digoxin was used in around two thirds of patients with moderate to severe heart failure. It’s role in HF have been in decline ever since. Part of the reason is the availability of great heart failure drugs the last few years. Well, a new study has just published and the role of digitalis in HF might be coming back. It might eventually become the fifth pillar in our management of HF.
Why did digoxin lost favour in the last 25 years? It came down to just one landmark trial. The Digitalis Investigation Group (DIG) trial back in 1997, showed that digoxin − when added to diuretics and angiotensin-converting enzyme inhibitors − did not reduce all-cause mortality, its primary endpoint (3). Based on DIG, the 2001 European Society of Cardiology (ESC) HF Guidelines only recommended digoxin ‘to improve the clinical status of patients with persisting HF symptoms … despite ACE inhibitor and diuretic treatment’ (4). In a 2015 meta-analysis of the role of digoxin use in HF in patients in sinus rhythm, it was concluded that “there is a limited role for digoxin in the management of patients with normal sinus rhythm and congestive heart failure”. In the 2021 ESC HF guidelines, digoxin only received a class IIb recommendation for patients with sinus rhythm (5).
Interestingly, when you looked at the DIG results closely, while digoxin did not improve overall mortality, digoxin was associated with a 28% reduction of hospitalisation for worsening HF (p < 0.001), one of the secondary endpoints.
There is another reason why DIG study results did not tell the whole story. Now, digitalis has positive inotropic effect, caused by inhibition of Na/K ATPase (or sodium pump) and a negative chronotropic effect on the atrio-ventricular node. Well, since it has positive inotropic effects, the more the better, isn’t it? Digoxin back then, was often given in the maximally tolerated dose, and in 2001 it was written that the ‘usual dose of oral digoxin is 0.25–0.375 mg daily’ (4). In a number of post hoc retrospective analyses of the DIG trial, the benefits of digoxin on mortality and heart failure especially in women and in men with reduced eFGR is dependent on serum concentration of digoxin. Higher, but not lower, serum concentrations were associated with increased risk (6). Thus, if we keep an eye on the serum digoxin levels, we could have the benefits and not the harms.
Well, that’s exactly what the Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure (DIGIT-HF) trial aimed to do (7). Between May 2015 and September 2023, 1240 patients with heart failure with reduced ejection fraction (≤ 40%) with at least a New York Heart Association (NYHA) functional class II heart failure symptoms were randomised to either digitoxin or placebo. digitoxin dosage were adjusted to keep the digitoxin concentration between a target range 10.5 to 23.6 nmol/L.
What is digitoxin? We know digitalis as digoxin but digoxin is not the only digitalis glycoside. Digitoxin is a more potent and longer acting version of digoxin. Unlike digoxin, which is eliminated from the body via the kidneys, digitoxin is eliminated via the liver, and so can be used in patients with poor or erratic kidney function.
The primary outcome of the trial was composite of death from any cause or hospital admission for worsening heart failure. Secondary outcomes included death from any cause, death from cardiovascular causes, death from non-cardiovascular causes, death from heart failure, sudden death from cardiac causes, hospitalisation due to cardiovascular causes, hospitalisation due to non-cardiovascular causes, hospitalisation due to any cause, and a composite of death from cardiovascular causes or first hospitalisation for heart failure. Safety outcomes, naturally, focused on adverse events related to digitoxin toxicity.
At baseline, the majority of the patients had NYHA class III or IV heart failure. The mean left ventricular ejection fraction was 29%, and 27.2% of the patients had atrial fibrillation. At least 93% of the patients were receiving treatment with a beta-blocker and an inhibitor of the renin-angiotensin system, including the 39.5% of patients who were taking an angiotensin receptor–neprilysin inhibitor; 76.2% of the patients were taking a mineralocorticoid receptor antagonist, and 19.3% were taking a sodium–glucose cotransporter 2 inhibitor. Remember, this trial started before the ARNI and SGLT2i were part of the guideline-directed-medical-therapy (GDMT).
Over a median follow-up of 36 months, there was an 18% reduction in the primary outcome in the digitoxin group compared with the placebo group (p = 0.03). There was a 14% reduction in death from any cause in the digitoxin group compared with the placebo group. There was a15% reduction in first hospital admission for worsening heart failure in the digitoxin group and 182 (30.4%) compared with the placebo group. At least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 (2.8%) in the placebo group. Adverse events led to discontinuation of digitoxin or placebo in 56 patients (9.1%) and 61 patients (10.2%), respectively.
In other words, patients on digitoxin benefited from improvement in mortality and hospitalisation for heart failure. Digitoxin appeared to have an effect on each component of this composite outcome in the trial. Low serum digitoxin concentrations may have been associated with fewer deaths than placebo. This finding is consistent with the observed effects of low serum digoxin concentrations on mortality in the DIG trial, whereas high serum digoxin concentrations (>1.0 ng per milliliter) seemed to be harmful.
The improvement in mortality from digitoxin was fairly comparable with those achieved in the PARADIGM-HF (8) and DAPA-HF trials with ARNI and dapagliflozin respectively.
This trial utilised digitoxin which is not what we are used to in Australia. A trial of digoxin — DECISION (Digoxin Evaluation in Chronic Heart Failure: Investigational Study in Outpatients in the Netherlands) has just completed and final results of DECISION are expected at the end of 2025/beginning of 2026.
References:
- Gheorghiade M, Van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation 2006;113:2556–2564
- Bavendiek U, Davilla LA, Koch A, Bauersachs J. Assumption versus evidence: the case of digoxin in atrial fibrillation and heart failure. Eur Heart J 2017;38:2095–2099.
- Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–533.
- Remme WJ, Swedberg K. On behalf of the task force for the diagnosis and treatment of chronic heart failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560
- McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2121 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–3726
- Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcome in patients with heart failure. JAMA 2003;289:871–878.
- Bavendiek U, Großhennig A, Schwab J, et al. Digitoxin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2025 Aug 29
- McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004
- McMurray JJV, DeMets DL, Inzucchi SE, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019 May;21(5):665-675