This study could mark a form of "renaissance" for cardiac glycosides, nearly 30 years after the DIG trial with digoxin, commented Theresa McDonagh of King's College Hospital in London after the presentation of the study, during the first hotline session of the congress.
In DIG, digoxin had shown an ability to reduce the risk of hospitalisation for worsening heart failure, but it had no effect on mortality, recalled Udo Bavendiek of Hannover Medical School in Hanover, Germany, when presenting the results. He also recalled that an analysis of this study had shown favorable results with a low dose of digoxin (0.5 to 0.9 ng/ml), while a higher dose (1 ng/ml or more) had, on the contrary, a negative effect.
Due to these mixed results, cardiac glycosides, which have been used "for 200 years," as the authors recall in the NEJM, have been somewhat relegated to the background since the arrival of several classes of safer drugs with a more significant effect.
Digitoxin has the advantage over digoxin of having a more stable serum concentration, including in cases of deterioration of renal concentration (elimination being hepatic), which reduces the risk of an excessive concentration that could be deleterious. However, there was no randomized study to confirm its interest. Moreover, it was important to see what its effectiveness would be in the current context where the treatment of heart failure has evolved compared to the DIG period.
The DIGIT-HF study was therefore launched, mainly with German centers. However, it encountered inclusion difficulties, and the initial objective of 2,190 patients had to be revised downwards: finally, 1,240 patients were included, between 2015 and 2023. These patients, who had NYHA class II heart failure with an ejection fraction of less than 30% or NYHA class III-IV with an ejection fraction of less than 40%, were randomized between digitoxin and a placebo, in addition to optimal treatment.
The included patients were 70% in class III-IV. They had treatment considered optimal: 95% were on beta-blockers, 93% on renin-angiotensin system inhibitors, including 40% on angiotensin and neprilysin inhibitors, 76% were taking a mineralocorticoid antagonist, and 19% an SGLT2 inhibitor, a class that has more recently entered the therapeutic arsenal for this disease. There were also 65% with implantable defibrillators and 25% with resynchronisations.
The primary endpoint of the study was the occurrence of a first hospitalisation for worsening heart failure or death from any cause. It was reduced by 18%.
More specifically, after a median follow-up of three years, 39.5% of patients treated with digitoxin died or were hospitalised for heart failure, compared to 44.1% of patients in the placebo group.
Reevaluation of cardiac glycosides
Similar trends were observed for the two components of the primary endpoint analyzed separately, with a 14% reduction in deaths (27.2% vs. 29.5%), which, however, is not statistically significant - but Theresa McDonagh, who commented on the study, recalled that it was underpowered due to a smaller than expected number of patients - and a 15% reduction in hospitalisations for heart failure (28.1% vs. 30.4%).
The treatment showed efficacy in all subgroups, particularly in patients on angiotensin and neprilysin inhibitors or SGLT2 inhibitors, and in those who had triple or quadruple therapy of the main recommended treatments, the German researcher showed.
The proportion of patients reporting a serious adverse event was higher in the digitoxin group (4.7% vs. 2.8% with placebo), which, however, was not statistically significant. The excess came mainly from cardiac pathologies (3.4% vs. 1.8%), mainly arrhythmic.
Theresa McDonagh estimated that these favorable results should lead to an increased role for cardiac glycosides in the recommendations for the management of heart failure. If, at this stage, this only applies to digitoxin, another study, DECISION, is underway in the Netherlands evaluating digoxin in the same indication, and the results will determine whether the reevaluation applies to all members of this therapeutic class or only to digitoxin.
(NEJM)
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