Secondary prevention of anthracycline cardiotoxicity in childhood cancer survivors
Mené sur 182 patients ayant survécu à un cancer pédiatrique traité par hautes doses d'anthracycline (âge médian : 24,7 ans ; durée médiane de suivi : 725 jours), cet essai de phase IIB évalue l'intérêt, pour réduire le risque d'insuffisance cardiaque, de faibles doses de carvédilol
Anthracyclines are a class of chemotherapeutic drugs widely used in the treatment of childhood cancer that are well known for their dose-dependent association with heart failure even decades after exposure. 1 Heart failure is typically preceded by an asymptomatic phase of cardiac dysfunction, during which preventive actions can be taken to halt the progression to heart failure. 2 However, solid evidence for secondary prevention in individuals who have undergone treatment for childhood cancer (ie, childhood cancer survivors) is unavailable, and questions remain over when secondary preventive actions would be beneficial—for instance, in which survivors, at what time after anthracycline exposure, and at what degree of cardiac dysfunction. 2 The only randomised controlled trial investigating secondary prevention to date in anthracycline-exposed childhood cancer survivors, the ACE Inhibitor After Anthracycline (AAA) Study, did not find a preventive effect of enalapril on the decline in echocardiographic measures of cardiac function. 3 Therefore, the results of the PREVENT-HF trial published in The Lancet Oncology have been much awaited. 4 PREVENT-HF was a randomised, double-blind, placebo-controlled, phase 2b trial that investigated the protective effect of low-dose carvedilol versus placebo on echocardiographic indices and blood biomarkers over 2 years of follow-up in childhood cancer survivors. Individuals who had completed treatment with high doses of anthracyclines (cumulative dose of ≥250 mg/m2 by age 21 years) at least 2 years previously and had preserved left ventricular function were eligible for enrolment. After a median follow-up of 725 days (IQR 378–730), the trial did not show a protective effect of carvedilol on the primary outcome of the study: left ventricular wall thickness–dimension ratio Z score (LVWT/Dz; –0·14 [95% CI –0·43 to 0·16] in the carvedilol group vs −0·45 [−0·77 to −0·13] in the placebo group; difference 0·31 [95% CI –0·10 to 0·73]; p=0·14). Of the secondary outcomes, left ventricular end-systolic wall stress was lower in the carvedilol group compared with in the placebo group; however, we believe this might have been due to a reduction in blood pressure rather than a beneficial effect on cardiac function, because all other secondary outcomes, such as left ventricular ejection fraction, left ventricular diameters, and natriuretic peptide concentrations, were not significantly different in the carvedilol group compared with the placebo group. The trial was underpowered for clinical endpoints, but in exploratory analyses a lower proportion of patients had cardiac events in the carvedilol group than in the placebo group, although there was no significant difference between the groups. In post-hoc analyses, cardiac-event free survival was found to potentially be superior in the carvedilol group compared with the placebo group in the treatment-adherent group (p=0·052).
The Lancet Oncology 2024