Back to the future - digitalis therapy reloaded? The suitability for digitoxin treatment in a real-world, outpatient heart failure patient cohort

Introduction

Albeit cardiac glycosides have been used for more than 200 years as part of the treatment armamentarium for heart failure (HF), as a consequence of the recently published landmark trials resulting in a paradigm shift in the treatment of HF and other publications, their use has been significantly overshadowed. However, according to the recently published DIGIT-HF trial, cardiac glycoside digitoxin therapy may be a prognosis-modifying therapeutic agent for patients with HF with reduced ejection fraction (HFrEF), in addition to the conventional, modern first-line guideline-directed medical therapy (GDMT).

Aim

To assess the potential suitability for digitoxin treatment in a real-world, consecutive, outpatient HF patient cohort of a tertiary cardiac referral center, based on the main randomisation criteria (LVEF ≤ 40% with NYHA functional class [FC] III-IV or LVEF ≤ 30% with NYHA FC II, stable on GDMT, heart rate [HR] ≥ 60 min-1) of the DIGIT-HF trial.

Patients and methods: A retrospective observational study was conducted in a consecutive outpatient cohort of HF patients followed up at a HF Outpatient Clinic of a tertiary cardiac referral center between 05.01.2022 and 16.06.2025. For each patient, we considered the first event to avoid redundancy. The data of 431 patients (male: 70%, age: 58 [48-68] years, LVEF: 34 [25-48]%, HFrEF: 62%, NT-proBNP: 985 [380-2812] pg/mL, eGFR ≤ 60 mL/min/1.73m2: 42%, coronary artery disease: 34%, hypertension: 70%, atrial fibrillation: 38%, RASi: 91%, βB: 93%, MRA: 89%, SGLT2i: 63%, triple therapy [TT: RASi + βB + MRA]: 79%, quadruple therapy [QT: TT + SGLT2i]: 55%, CRT-P/CRT-D: 12%, ICD: 16%) were analysed.

Theoretical eligibility for digitoxin therapy was evaluated according to the main aforementioned inclusion and exclusion criteria of the DIGIT-HF trial. Stable GDMT was defined as the application of the optimised standard of care for HF categories recommended by the current international HF Guidelines.

Results

18% of the patient cohort had LVEF ≤ 40% and were in NYHA FC III-IV, while 30% had LVEF ≤ 30% and were in NYHA FC II. In the total cohort, 97% of the patients were non-de novo diagnosed HF patients, of whom 77% received TT/QT. 88% of the entire patient group had a HR ≥ 60 min-1. Based on these aforementioned criteria, altogether 39% of the outpatient HF cohort would have been eligible for digitoxin therapy. In the HFrEF subgroup, with the concomitant application of these parameters, digitoxin could have been applied in 62% of the HFrEF patients.

Conclusions

According to the results of the current analysis, 39% of the real-world, consecutive HF patient cohort would be theoretically eligible for digitoxin therapy with a potential application rate of 62% in the HFrEF subgroup. Hence, for a significant proportion of HF patients, digitoxin might be an almost-forgotten, although promising prognosis-modifying additional treatment possibility.