Enalapril vs Sacubitril/Valsartan in Pediatric Heart Failure

Source: Shaddy R, Burch M, Kantor PF, et al. Sacubitril/valsartan in pediatric heart failure (PANORAMA-HF): a randomized, multicenter, double-blind trial. Circulation. 2024;150(22);1756-1766; doi: 10.1161/CIRCULATIONAHA.123.066605.Investigators from multiple institutions conducted a randomized trial to compare the effectiveness of sacubritil/valsartan or enalapril for treatment of children with heart failure (HF) attributable to systemic left ventricular dysfunction (LVSD). Participants were patients ≥1 month to <18 years old with biventricular physiology and HF with left ventricular ejection fraction ≤45%, or fractional shortening ≤22.5%, who were enrolled at 105 sites across the world. Study children were randomized to receive sacubritil/valsartan or enalapril and followed for 52 weeks. The primary outcome was a composite of 5 categories of outcomes: Category 1 was death, listing for transplant, requirement for mechanical ventilation/respiratory support; category 2 was worsening HF; and categories 3–5 included changes from baseline to 52 weeks in New York Heart Association (NYHA)/Ross classification, Patient Global Impression of Severity (PGIS) score, and Pediatric Quality of Life Inventory (PedsQL) score. An independent committee ranked study patients by these categories, and the rankings between groups were compared using Mann-Whitney tests. Secondary outcomes were individual items in the composite score and were compared between groups with a variety of statistical tests.A total of 375 children were enrolled, with 187 randomized to sacubritil/valseartan and 188 to enalapril. The mean age of study patients was 8.1 ± 5.6 years. Baseline left ventricular ejection fractions were 32.8 ± 7.4% and 31.8 ± 7.9%, respectively, for children in the sacubritil/valsartan and enalapril treatment groups. There were 19 (10.2%) children in the sacubritil/valsartan group and 30 (16.0%) in the enalapril with a category 1 event; 18 (9.6%) and 9 (4.8%), respectively, had worsening HF. Overall, there was no significant difference of rankings of the composite outcomes between patients in the two groups (P = 0.42). Patients in both groups tended to have improvement from baseline to 52 weeks in NYHA/Ross classification, PGIS score, and PedsQL score, with no significant differences between those in the sacubritil/valsartan and enalapril groups.The authors conclude that there was no significant difference in outcomes among children with HF attributable to LVSD who were treated with sacubritil/valsartan or enalapril.Dr Philip has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.HF in children can occur as a consequence of congenital heart disease as well as cardiomyopathy. (See AAP Grand Rounds. 2024;51[4]:47.)1 The heterogeneity and lower prevalence of pediatric HF1 has necessitated extrapolation of adult HF treatment strategies to the pediatric population. Drugs such as beta blockers, furosemide, spironolactone, and enalapril are used routinely in pediatric HF. However, there are no large, randomized trials in pediatrics that have shown improved clinical HF outcomes in symptomatic systolic HF, including the Carvedilol trial.2 Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that has been proven to be more beneficial than enalapril in adult chronic HF.3 However, the benefits of ARNIs compared with enalapril have not been studied in children.In this randomized double-blind trial comparing sacubitril/valsartan and enalapril in children ≥1 month to <18 years of age with LVSD, there was no significant difference in primary outcomes, including the time to their first event (death/listing of urgent transplant, need for mechanical or respiratory support, worsening HF). Though there were improvements in NYHA/Ross functional class and PGIS and PedsQL scores, there was no significant difference between the 2 treatment arms. There was a significant drop in N-terminal pro b-type natriuretic peptide levels as early as 4 weeks, with similar reduction between treatment arms at 12 and 52 weeks. Halving the NT pro-BNP was associated with a 52% decrease in risk of an event.While the current researchers tried to alleviate the common limitations of heterogeneity in pediatrics by selecting a more homogenous group of LVSD, it is unclear why they were not able to replicate the results of the adult study.3 This may be innate to the fact that children are not “small adults” and may have different event rates compared to adults. The results of the current well-designed study underscore the fallacy of applying adult treatment strategies to pediatric patients. The most encouraging message from the results of this study was that both treatment arms showed benefit in pediatric HF.Sacubitril/valsartan and enalapril appear to be equally effective in achieving clinical improvements over 52 weeks in pediatric HF with LVSD.