Sacubitril/valsartan vs enalapril for paediatric HF a toss-up in head-to-head trial

Sacubitril/valsartan appears to be safe and beneficial in the treatment of children with heart failure (HF) attributable to systemic left ventricular systolic dysfunction (LVSD), with the drug having comparable efficacy as enalapril, according to the 52-week data from the phase 2/3 PANORAMA-HF* trial.

PANORAMA-HF included 375 paediatric HF patients (mean age 8.1 years, 52 percent female) who were randomly assigned to receive treatment with sacubitril/valsartan (n=187) or enalapril (n=188) for 52 weeks. At week 52, sacubitril/valsartan did not outperform enalapril in terms of the primary global rank endpoint (Mann-Whitney probability, 0.52, 95 percent confidence interval [CI], 0.47–0.58; Mann-Whitney odds, 0.91, 95 percent CI, 0.72–1.14; p=0.42). [Circulation 2024;doi:10.1161/CIRCULATIONAHA.123.066605]

For the endpoint, the patients were ranked from worst to best based on clinical HF events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory (PedsQL) physical functioning domain. This was created to address the lack of validated clinical efficacy endpoints in large cardiovascular outcome trials in paediatric populations, as the investigators pointed out.

When the clinical events were assessed individually, the sacubitril/valsartan and enalapril arms did not significantly differ in terms of the proportion of patients with category 1 clinical events (more severe events, such as death, the requirement of listing for an urgent heart transplant, or the requirement for mechanical circulatory or respiratory support; 10.2 percent vs 16.0 percent) or category 2 clinical events (worsening HF with or without intensive care unit or general ward hospitalization; 9.6 percent vs 4.8 percent; time to first category 1 or 2 events: adjusted hazard ratio [aHR], 1.07, 95 percent confidence interval [CI], 0.66–1.72; p=0.80).

Likewise, the proportion of patients who achieved a clinically relevant improvement in NYHA/Ross functional class was similar in the sacubitril/valsartan and enalapril arms (37.7 percent vs 34.0 percent; odds ratio, 1.1, 95 percent CI, 0.7–1.7; p=0.76), as were the proportion of patients with NYHA/Ross class I (no symptoms or limitations) from baseline to week 52 (from 13.4 percent to 48.5 percent vs from 18.1 percent to 47.5 percent) and the magnitude of the reduction in NT-proBNP levels (adjusted geometric mean ratio, 0.91, 95 percent CI, 0.69–1.20; p=0.50).

“Similar trends were observed for measures of health-related quality of life (PedsQL and PGIC scores). Improvement in PedsQL scores at week 52 exceeded the previously reported threshold for clinically meaningful improvement for both patient self-reported (4.8) and parent proxy-reported (5.5) scores in only the sacubitril/valsartan arm, suggesting a possible health-related quality of life advantage with sacubitril/valsartan vs enalapril,” the investigators noted.

In terms of safety, the sacubitril/valsartan and enalapril arms had comparable rates of adverse events (AEs; 88.8 percent vs 87.8 percent) and serious AEs (36.9 percent vs 33.0 percent). The most clinically relevant serious AE was hypotension in the sacubitril/valsartan arm (2.1 percent) and hyperkalemia in the enalapril arm (1.1 percent).

“This study suggests that sacubitril/valsartan has an acceptable safety profile in children with HF that is consistent with studies in adults,” said the investigators.

International guidelines for HF recommend sacubitril/valsartan as first-line treatment in adults with reduced ejection fraction. The preliminary 12-week findings of PANORAMA-HF, which is said to be the largest trial in paediatric HF, served as the basis for the US Food and Drug Administration approval of sacubitril/valsartan in ≥1-year-old patients with HF attributable to systemic LVSD.