Sacubitril/Valsartan, Enalapril Show Comparable Efficacy in Pediatric Heart Failure

Both sacubitril/valsartan (Entresto) and enalapril (Vasotec) were associated with improvement in clinical measures among children aged 1 month to younger than 18 years who had heart failure attributable to systemic left ventricular systolic dysfunction, according to findings published in Circulation.¹ Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, did not show superiority over enalapril, an angiotensin-converting enzyme (ACE) inhibitor.

Over the past few years, sacubitril/valsartan has made its way onto heart failure guidelines for adults,² backed by data from the PARADIGM-HF study (NCT01035255), in which it demonstrated a 21% relative reduction in hospitalizations for heart failure with reduced ejection fraction and a 26% relative decrease in mortality compared with standard ACE inhibitor therapy.³ Recent research has explored how ensuring adherence to the medication may help avert costly hospitalizations and emergency visits, potentially helping Medicaid programs save money or allowing providers in alternative payment models to reap shared savings.^4,5

PANORAMA-HF, comparing sacubitril/valsartan with enalapril, represents the largest pediatric heart failure study of its kind. | Image Credit: © Viacheslav Yakobchuk - stock.adobe.com

Comparisons of sacubitril/valsartan vs ACE inhibitors have been conducted in adult populations, but given the 2019 approval of sacubitril/valsartan in pediatric patients older than 1 year, the investigators of the PANORAMA-HF trial (NCT02678312) conducted the randomized, double-blind study to compare the benefits of sacubitril/valsartan and enalapril in children (1 month to < 18 years) with heart failure due to systemic left ventricular systolic dysfunction.¹ It represents the largest pediatric heart failure study of its kind.

The multicenter study involved patients from 30 countries and 105 sites across Europe, the Americas, Asia, and Africa. Participants, who could have been seen as inpatients or outpatients, were required to have a left ventricular ejection fraction less than or equal to 45% or fractional shortening less than or equal to 22.5% for inclusion.

The 52-week parallel-group clinical efficacy study randomized participants 1:1 to receive either sacubitril/valsartan or enalapril. The primary outcome was a global rank end point in which patients were ranked from worst to best in terms of 5 categories of clinical heart failure events: (1) death, life support, or heart transplant requirement; (2) worsening heart failure requiring therapy intensification; (3) worsening heart failure and worsening New York Heart Association (NYHA)/Ross functional class or Patient Global Impression of Severity (PGIS) score, further ranked by Pediatric Quality of Life Inventory (PedsQL) physical functioning domain; (4) unchanged measures of NYHA/Ross and PGIS, further ranked by PedsQL physical functioning domain; and (5) improved measures of NYHA/Ross and PGIS, further ranked by PedsQL physical functioning domain. Secondary outcomes included the individual measures such as change in NYHA/Ross functional class, PedsQL, PGIS, and NT-proBNP level. Safety and tolerability were also assessed.

Of the 375 eligible patients (mean [SD] age, 8.1 [5.6] years; 52% female), 187 received sacubitril/valsartan and 188 received enalapril. After 52 weeks, the proportions of patients receiving the level 4 target dose of therapy were 64.7% and 68.9%, respectively. No significant differences in the global rank end point were observed between the 2 treatment arms (Mann-Whitney odds estimate, 0.91; 95% CI, 0.72-1.14; P = .42). This lack of statistical difference between the arms was consistent across age groups and outcome categories.

Similarities between arms were also seen in time to first heart failure event, improvement in NYHA/Ross functional class, decrease from baseline in NT-proBNP levels, and change from baseline in PGIS score. Safety was also comparable between the arms, with serious adverse events reported by 36.9% of those receiving sacubitril/valsartan and 33.0% of those receiving enalapril.

However, the change from baseline in PedsQL score exceeded the clinically meaningful difference threshold in the sacubitril/valsartan arm but not the enalapril arm. The investigators noted that this improvement, seen in both patient self-reported and parent proxy-reported scores, could suggest “a possible health-related quality of life advantage of sacubitril/valsartan over enalapril.”

Limitations of the study include the lack of validated end points in pediatric heart failure and the small number of participants younger than 1 year. Despite these challenges, the authors wrote that the PANORAMA-HF findings show that “sacubitril/valsartan has demonstrated a favorable benefit/risk ratio in the treatment of [heart failure] in pediatric patients.”

References

1. Shaddy R, Burch M, Kantor PF, et al. Sacubitril/valsartan in pediatric heart failure (PANORAMA-HF): a randomized, multicenter, double-blind trial. Circulation. Published online September 25, 2024. doi:10.1161/CIRCULATIONAHA.123.066605
2. Shaw ML. Entresto is top HFrEF treatment recommendation in updated ACC guidelines. AJMC^®. January 28, 2021. Accessed September 25, 2024. https://www.ajmc.com/view/entresto-is-top-hfref-treatment-recommendation-in-updated-acc-guidelines
3. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077
4. Gabot A, Lavitas P, Bacon R, et al. Cost-benefit analysis of sacubitril/valsartan in a Medicaid population. Am J Manag Care. 2022;28(7):349-352. doi:10.37765/ajmc.2022.89181
5. Shen X, Schwartz TT, Sullivan G, et al. Sacubitril/valsartan in Medicare alternative payment models. Am J Accountable Care. 2023;11(1):5-17. doi:10.37765/ajac.2023.89339