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Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial
Robert Shaddy1, Michael Burch2, Paul F Kantor1
1Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles (R.S., P.F.K., J.M.).
Insights
Sacubitril/valsartan did not prove superior to enalapril in treating pediatric heart failure (HF) with reduced left ventricular systolic dysfunction (LVSD). Both treatments demonstrated clinically meaningful improvements over 52 weeks in children.
Area of Science:
- Pediatric Cardiology
- Pharmacology
- Clinical Trials
Background:
- Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is approved for heart failure (HF) with reduced left ventricular ejection fraction.
- Limited direct comparative data exists between ARNIs and angiotensin-converting enzyme inhibitors (ACEIs) in pediatric HF populations.
- The PANORAMA-HF trial addresses this gap by comparing sacubitril/valsartan with enalapril in children with HF due to left ventricular systolic dysfunction (LVSD).
Purpose of the Study:
- To evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of sacubitril/valsartan compared to enalapril in pediatric patients with HF.
- To determine if sacubitril/valsartan is superior to enalapril in treating children with HF attributable to systemic LVSD.
- To assess clinical outcomes and safety profiles of both treatment regimens over a 52-week follow-up period.
Main Methods:
- A randomized, double-blind trial involving 375 children (1 month to <18 years) with HF and LVSD.
- Participants were randomized to receive either sacubitril/valsartan or enalapril for 52 weeks.
- The primary efficacy endpoint was a global rank composite, considering clinical events, functional class (NYHA/Ross), and quality of life.
Main Results:
- No significant difference was found between sacubitril/valsartan and enalapril regarding the primary global rank endpoint (P=0.42).
- Both treatment groups showed clinically meaningful reductions in NYHA/Ross class, Patient Global Impression of Severity (PGIS), and NT-proBNP levels.
- Adverse event rates were similar between the groups (88.8% for sacubitril/valsartan vs. 87.8% for enalapril), with an acceptable safety profile for sacubitril/valsartan.
Conclusions:
- Sacubitril/valsartan did not demonstrate superiority over enalapril in the treatment of pediatric HF with LVSD based on the primary composite endpoint.
- Both sacubitril/valsartan and enalapril provided clinically meaningful benefits for pediatric patients with HF over 52 weeks.
- The safety profile of sacubitril/valsartan was deemed acceptable in this pediatric population.
Background:
Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD).
Methods:
Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical 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 physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point.
Results:
A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (N=187) or enalapril (N=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children.
Conclusions:
In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.
