Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial
Robert E. Shaddy, Michael Burch, Paul F. Kantor, Susan Solar‐Yohay, Tania Garito, Sijia Zhang, Michele Kocun, Chad Mao, Antoinette Cilliers, Xu Wang, Charles E. Canter, Joseph W. Rossano, Gonzalo Wallis, Jondavid Menteer, Linda Daou, Jacek Kusa, Kürşad Tokel, Daniel Dilber, Zhuoming Xu, Tingting Xiao, Nancy Halnon, Kevin P. Daly, M.J. Bock, Warren A. Zuckerman, Tajinder P. Singh, Manisha Chakrabarti, Aviva Levitas, Michele Senni, Giorgia Grutter, Gi Beom Kim, Jinyoung Song, Hye Won Lee, Ching Kit Chen, Joan Sánchez-de-Toledo, Yuk M. Law, Suthep Wanitkun, Yanqin Cui, Rui Anjos, Timur Meşe, Damien Bonnet, Laszlo Ablonczy, Neeraj Aggarwal, Gabriella Agnoletti, Mohammed AlHabdan, Pascal Amedro, Rebecca Ameduri, Giuseppe Alberto Annoni, Alfred Asante-Korang, Nasser Audi, Jean Ballweg, Felix Berger, Maria Bosaleh, Gerald Boyle, Biagio Castaldi, Milan Chag, Vaclav Chaloupecky, Ghassan Chehab, Jennifer Conway, Ingo Daehnert, Stefano Di Bernardo, Sven Dittrich, Eser Dogan, Andrea Donti, Kritvikrom Durongpisitkul, Silvia Favilli, Brian Feingold, Luis Garcia-Guereta, Nuria Gil-Villanueva, Lauren Glass, Elena Gomez-Guzman, Matthias Gorenflo, Ferran Gran, Yoichiro Hirata, Keiichi Hirono, Kenji Hoshino, Kai-Sheng Hsieh, Mohammad Hussain, Ryo Inuzuka, Mikiko Ishido, Aamir Jeewa, Jonathan Johnson, Eero Jokinen, Jo Won Jung, Anna Kaneva-Nencheva, Beth Kaufman, Lazaros Kochilas, Shine Kumar, Ashwin Lal, Irina Viktorovna Leontyeva, I-Chun Lin, Irene Lytrivi, Ivan Malcic, Antonio Marinho da Silva, Constancio Medrano Lopez, Ornella Milanesi, Shelley Deanne Miyamoto, Hideki Motomura, Irena Odri Komazec, Hiroshi Ono, Giuseppe Pacileo
Abstract
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: =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.