Old cardio drug pulls a surprise in DIGIT-HF trial

Adding the cardiac glycoside digitoxin to guideline-directed medical therapy (GDMT) improves clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF), as shown in the DIGIT-HF trial, which took over 10 years to complete due to funding constraints.

Cardiac glycosides, derived from the foxglove plant, have been used in cardiology for two centuries, but digoxin and digitoxin have gradually fallen out of favour in HF treatment.

In the DIGIT-HF trial presented at ESC 2025, digitoxin reduced the absolute risk of all-cause mortality and hospitalization for worsening HF by 4.6 percent vs placebo over a median follow-up of 36 months (hazard ratio [HR], 0.82). [N Engl J Med 2025;393:1155-1165]

The researchers randomly assigned 1,240 patients (mean age 66 years, 20.4 percent women) with chronic HF, left ventricular ejection fraction (LVEF) <40 percent, and NYHA functional class III symptoms (or those with LVEF <30 percent and NYHA functional class II symptoms) to receive digitoxin or placebo.

Lead investigator Dr Udo Bavendiek from Hannover Medical School, Germany said the overall benefit of digitoxin was consistent in patients taking an angiotensin receptor-neprilysin inhibitor (ARNI) or sodium-glucose cotransporter 2 (SGLT2) inhibitor at baseline, as well as in those taking triple or quadruple combinations recommended by clinical guidelines.

During his presentation, he highlighted the difficulty of getting patients already taking multiple medications for HF to add another drug. “But this was made possible in the trial.”

The researchers plan to examine the data in detail to potentially identify those who are most likely to benefit most from digitoxin. In a subgroup analysis, for instance, patients without an implantable cardioverter-defibrillator (ICD) at baseline appeared to have a greater reduction in the risk of all-cause mortality or admission for worsening HF than those with an ICD. Bavendiek said this finding came as a surprise, and they intend to investigate ICD protocols further to better understand the result.

Dr Carlos Santos-Gallego from Icahn School of Medicine at Mount Sinai, New York, New York, US said DIGIT-HF is clearly a win for digitoxin in this patient population. The 18-percent relative reduction in risk is significant, but not as “clinically relevant” as the 35 percent reduction in HF hospitalizations with SGLT2 inhibitors.

“Therefore, the four pillars of treatment—ARNI, beta-blockers, mineralocorticoid receptor antagonist [MRA], and SGLT2 inhibitors—will continue as clear first-line therapy, but digitoxin seems to be a great option for patients who remain symptomatic despite being on these four pillars,” he explained. 

Dr Michelle Kittleson from Cedars-Sinai Medical Center in Los Angeles, California, US, who was not involved in the trial, commented that DIGIT-HF was a critical study as it has been nearly three decades since the DIG trial in patients with chronic HF was published. [N Engl J Med 1997;336:525-533] However, she is not convinced that the results of DIGIT-HF should change practice given the relatively small absolute effect size. Additionally, there were almost twice as many serious adverse events with digitoxin vs placebo.

“Patients are already at risk of polypharmacy, and quadruple therapy remains difficult to put into practice in HFrEF,” she said. “Until there is a better understanding of the serious adverse events and causes of death, I would prioritize achieving target doses of ARNI, beta-blocker, MRA therapy, and SGLT2 inhibition in HFrEF before considering cardiac glycoside therapy.”

Study discussant Dr Theresa McDonagh from King’s College London, UK said registry studies suggest that only 15 percent of HFrEF patients are on digoxin. She noted that over the years, the recommendations to use digoxin have been downgraded, but she believes DIGIT-HF will warrant a rethink, with a 2a recommendation possible in future guidelines.

“I think this will change clinical use for both digoxin and digitoxin,” she said. “Digitoxin may be used more frequently, as it is a safer cardiac glycoside than digoxin,” with serum concentrations remaining stable without requiring dose adjustments.