Digitalis for heart failure – how was it disowned?

20th September 2026, A/Prof Chee L Khoo (in collaboration with A/Prof Masis Perk)

heart failure

It has been12 months now since we highlighted on GPVoice that digitalis is making a comeback in the management of heart failure. We pointed out the important role it has in heart failure (HF) but its use was downplayed in most of the major guidelines. This is despite increasing clinical trial data supporting this old, but well tested drug. We tracked the history of the downfall of digitalis in HF management but explored the latest data supporting its reincarnation. Since then, two things have happened: Dr Masis Perk shared his 30-year experience with digitalis from Nova Scotia, Canada with GPVoice and the DECISION trial has now published. Dr Masis is an A/Professor at Dalhousie University’s Department of Medicine in Halifax, Nova Scotia, Canada. First, let us hear from A/Prof Masis:

In the original 1997 DIG trial, digoxin was added to diuretics and angiotensin converting e zyme inhibitor (ACEi) in patients with HF in sinus rhythm (1). Much was concentrated on the lack of mortality improvement with digoxin but the 28% reduction in hospitalisation for HF was downplayed. In later subanalyses, it was thought that high serum digoxin levels which was present in 24% of patients caused an increase in mortality which may be responsible for diluting the overall mortality improvement numbers (2,3).

When low dose digitoxin was used in the DIGIT-HF trial, there was a significant 15% reduction in the combined endpoint of all-cause death and first hospital admission for heart failure (4). That was in 2025 when we discussed the renaissance of digoxin. We were waiting for the DECISION trial to report then.

DECISION is a double-blind, placebo-controlled trial whereby 1,001 patients with symptomatic chronic heart failure and a left ventricular ejection fraction of ≤ 50% were randomised to low-dose digoxin or placebo, with a target serum digoxin concentration of 0.5–0.9 ng/ml (5). The mean age of the participants was 72 ± 9 years, 28% were women and 29% had atrial fibrillation.

The primary outcome was a composite of total worsening heart failure events, defined as total hospitalizations or total urgent hospital visits for worsening heart failure and cardiovascular mortality.

The mean age was 72 years and 28% were women. The mean left ventricular ejection fraction (LVEF) was 33% and 29% of patients had atrial fibrillation. The median NT-proBNP concentration was 1,404 pg/ml, and mean estimated glomerular filtration rate (eGFR) was 56 ml/min/1.73 m2.

Low-dose digoxin was generally well tolerated and safe, and results were similar between men and women. The results of this trial indicate that in patients with heart failure and reduced or mildly reduced ejection fraction, low-dose digoxin did not significantly reduce the composite endpoint of total worsening heart failure events or cardiovascular mortality.

That was the “conclusion” drawn from the trial. A few important points were noted though. The discontinuation rate was fairly high – 24% in the digoxin and 21% in the placebo groups. When they performed an as-treated sensitivity analysis (i.e. exclude those that discontinued), there were a total of 135 primary outcome events occurred in the digoxin group (incidence rate per 100 patient-years of 10.60), compared to 212 primary-outcome events in the placebo group (incidence rate per 100 patient-years of 16.12), with a rate ratio of 0.66 (95% CI 0.47–0.92, P = 0.015).

But wait, there is more.  Sometimes, when we prescribe certain medications to patients, it is difficult to know whether it is working or not. We sometimes, tell the patient to stop the medication and if they feel worse, well, the medication may be working after all.

As part of the DECISION trial, they had planned to explore the effects of blinded withdrawal from low-dose digoxin vs withdrawal of placebo over a 6-week follow-up period. At the end of study, participants were randomised to either ongoing digoxin or placebo in a phased withdraw of the drugs. In other words, participants on digoxin were withdrawn from digoxin and the participants on placebo were withdrawn from placebo (6).

In the withdrawal phase, the incidence rate of cardiovascular death or worsening heart failure increased in patients withdrawn from low-dose digoxin but not in those withdrawn from placebo (42.8 events per 100 patient-years and 5.9 events per 100 patient-years, respectively). The RR for the change in risk in the patients withdrawn from low-dose digoxin was 7.55 (95% CI, 2.72–20.95), P < .001), whereas the change in the risk in patients withdrawn from placebo was not significant [RR = 0.89 (95% CI, 0.18–4.44, P = .036). In other words, patients withdrawn from digoxin experienced a more than seven-fold higher rate of these events driven by HF-related hospitalisations.

There are many cardiologists who still believe in a role for digoxin in patients with HF and you may very well have many a patient still on digoxin. Think carefully before withdrawing digoxin and do discuss with the cardiologist if he/she suggests stopping digoxin. Perhaps, for those patients with HF not already on digoxin, should we ask whether there is a role for adding digoxin. For those still on digoxin, we need to monitor the serum levels of digoxin on a regular basis.

References

  1. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N. Engl. J. Med. 336, 525–533 (1997).
  2. Adams, K. F. et al. Clinical benefits of low serum digoxin concentrations in heart failure. J. Am. Coll. Cardiol. 39, 946–953 (2002).
  3. Rathore, S. S., Curtis, J. P., Wang, Y., Bristow, M. R. & Krumholz, H. M. Association of serum digoxin concentration and outcomes in patients with heart failure. J. Am. Med. Assoc. 289, 871 (2003).
  4. Bavendiek, U. et al. Digitoxin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 393, 1155–1165 (2025).
  5. van Veldhuisen, D.J., Rienstra, M., Mosterd, A. et al. Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial. Nat Med 32, 2647–2653 (2026)
  6. Peter van der Meer, Dirk J van Veldhuisen, Geert H D Voordes, et al. Blinded withdrawal of randomized treatment with low-dose digoxin or placebo in heart failure: the DECISION trial, European Heart Journal, 2026;, ehag385,