Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial
Authors: Shaddy Robert , Burch Michael , Kantor Paul F. , Solar-Yohay Susan , Garito Tania , Zhang Sijia , Kocun Michele , Mao Chad , Cilliers Antoinette , Wang Xu , Canter Charles , Rossano Joseph , Wallis Gonzalo , Menteer Jondavid , Daou Linda , Kusa Jacek , Tokel Kursat , Dilber Daniel , Xu Zhuoming , Xiao Tingting , Halnon Nancy , Daly Kevin P. , Bock Matthew J. , Zuckerman Warren , Singh Tajinder P. , Chakrabarti Manisha , Levitas Aviva , Senni Michele , Grutter Giorgia , Kim Gi Beom , Song Jinyoung , Lee Hyoung Doo , Chen Ching Kit , Sanchez-de-Toledo Joan , Law Yuk , Wanitkun Suthep , Cui Yanqin , Anjos Rui , Mese Timur , Bonnet Damien , Ablonczy Laszlo , Aggarwal Neeraj , Agnoletti Gabriella , AlHabdan Mohammed , Amedro Pascal , Ameduri Rebecca , Alberto Annoni Giuseppe , Asante-Korang Alfred , Audi Nasser , Ballweg Jean , Berger Felix , Bosaleh Maria , Boyle Gerald , Castaldi Biagio , Chag Milan , Chaloupecky Vaclav , Chehab Ghassan , Conway Jennifer , Daehnert Ingo , Di Bernardo Stefano , Dittrich Sven , Dogan Eser , Donti Andrea , Durongpisitkul Kritvikrom , Favilli Silvia , Feingold Brian , Garcia-Guereta Luis , Gil-Villanueva Nuria , Glass Lauren , Gomez-Guzman Elena , Gorenflo Matthias , Gran Ferran , Hirata Yoichiro , Hirono Keiichi , Hoshino Kenji , Hsieh Kai-Sheng , Hussain Mohammad , Inuzuka Ryo , Ishido Mikiko , Jeewa Aamir , Johnson Jonathan , Jokinen Eero , Won Jung Jo , Kaneva-Nencheva Anna , Kaufman Beth , Kochilas Lazaros , Kumar Shine , Lal Ashwin , Viktorovna Leontyeva Irina , Lin I-Chun , Lytrivi Irene , Malcic Ivan , Marinho da Silva Antonio , Medrano Lopez Constancio , Milanesi Ornella , Deanne Miyamoto Shelley , Motomura Hideki , Odri Komazec Irena , Ono Hiroshi , Pacileo Giuseppe , Mark Payne Ronald , Ramakrishnan Sivasubramanian , Riggi Chiara , Rusconi Paolo , Sabiniewicz Robert , Salaymeh Khaled , Schumacher Kurt , Schweigmann Ulrich , Seguela Pierre-Emmanuelle , Shih Renata , Singh Rakesh , Yurievna Sitnikova Maria , Spicer Robert , Stiller Brigitte , Sugiyama Hisashi , Sundararaghavan Sreekanthan , Takeda Atsuhito , Thambo Jean-Benoît , Trigo Pereira Conceicao , Ulger Tutar Zulal , Vaughn Gabrielle , Velez Hernan , Vignati Gabriele , Wang Jieh-Neng , Wang Jou-Kou , Yasuda Kazushi , Ziolkowska Lidia , Zuhlke Liesl 
Published: September 2024

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.