Randomized Controlled Trial

. 2024 Nov 26;150(22):1756-1766.

doi: 10.1161/CIRCULATIONAHA.123.066605. Epub 2024 Sep 25.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial

Robert Shaddy¹, Michael Burch², Paul F Kantor¹, Susan Solar-Yohay³, Tania Garito⁴, Sijia Zhang⁵, Michele Kocun³, Chad Mao⁶, Antoinette Cilliers⁷, Xu Wang⁸, Charles Canter⁹, Joseph Rossano¹⁰, Gonzalo Wallis¹¹, Jondavid Menteer¹, Linda Daou¹², Jacek Kusa¹³, Kursat Tokel¹⁴, Daniel Dilber¹⁵, Zhuoming Xu¹⁶, Tingting Xiao¹⁷, Nancy Halnon¹⁸, Kevin P Daly¹⁹, Matthew J Bock²⁰, Warren Zuckerman²¹, Tajinder P Singh¹⁹, Manisha Chakrabarti²², Aviva Levitas²³, Michele Senni²⁴, Giorgia Grutter²⁵, Gi Beom Kim²⁶, Jinyoung Song²⁷, Hyoung Doo Lee²⁸, Ching Kit Chen²⁹, Joan Sanchez-de-Toledo³⁰, Yuk Law³¹, Suthep Wanitkun³², Yanqin Cui³³, Rui Anjos³⁴, Timur Mese³⁵, Damien Bonnet³⁶; PANORAMA-HF Investigators

Collaborators, Affiliations

Collaborators

PANORAMA-HF Investigators:
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, Ronald Mark Payne, Sivasubramanian Ramakrishnan, Chiara Riggi, Paolo Rusconi, Robert Sabiniewicz, Khaled Salaymeh, Kurt Schumacher, Ulrich Schweigmann, Pierre-Emmanuelle Seguela, Renata Shih, Rakesh Singh, Maria Yurievna Sitnikova, Robert Spicer, Brigitte Stiller, Hisashi Sugiyama, Sreekanthan Sundararaghavan, Atsuhito Takeda, Jean-Benoît Thambo, Conceicao Trigo Pereira, Zulal Ulger Tutar, Gabrielle Vaughn, Hernan Velez, Gabriele Vignati, Jieh-Neng Wang, Jou-Kou Wang, Kazushi Yasuda, Lidia Ziolkowska, Liesl Zuhlke

Affiliations

¹ Children'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.).
² Great Ormond Street Hospital for Children, London, UK (M.B.).
³ Novartis Pharmaceuticals Corporation, East Hanover, NJ (S.S.-Y., M.K.).
⁴ Novartis Pharma AG, Basel, Switzerland (T.G.).
⁵ Novartis, Shanghai, China (S.Z.).
⁶ Children's Healthcare of Atlanta and Emory University, GA (C.M.).
⁷ Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa (A.C.).
⁸ National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (X.W.).
⁹ Washington University School of Medicine, St. Louis, MO (C.C.).
¹⁰ Children's Hospital of Philadelphia, PA (J.R.).
¹¹ Levine Children's Hospital, Charlotte, NC (G.W.).
¹² Hotel Dieu de France Hospital, Beirut, Lebanon (L.D.).
¹³ Regional Specialist Hospital in Wroclaw, Poland (J.K.).
¹⁴ Baskent University Medical Faculty, Ankara, Turkey (K.T.).
¹⁵ University Hospital Centre, Zagreb, Croatia (D.D.).
¹⁶ Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, China (Z.X.).
¹⁷ Children's Hospital of Shanghai, China (T.X.).
¹⁸ Mattel Children's Hospital and David Geffen School of Medicine, UCLA, Los Angeles, CA (N.H.).
¹⁹ Boston Children's Hospital and Harvard Medical School, MA (K.P.D., T.P.S.).
²⁰ Pediatrics, Division of Cardiology, Loma Linda University Children's Hospital, CA (M.J.B.).
²¹ Columbia University Medical Center, Morgan Stanley Children's Hospital of New York, New York (W.Z.).
²² Department of Congenital & Pediatric Cardiology, Indraprastha Apollo Hospitals, New Delhi, India (M.C.).
²³ Division of Pediatric Cardiology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.L.).
²⁴ University of Milan-Bicocca, A.S.S.T. Papa Giovanni XXIII, Bergamo, Italy (M.S.).
²⁵ Bambino Gesù Children Hospital, IRCSS, Rome, Italy (G.G.).
²⁶ Seoul National University College of Medicine, Seoul National University Children's Hospital, Korea (G.B.K.).
²⁷ Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J.S.).
²⁸ Pusan National University Yangsan Hospital Yangsan-si, Gyeongsangnam-Do, Korea (H.D.L.).
²⁹ Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (C.K.C.).
³⁰ Hospital Sant Joan de Deu Esplugues de Llobregat, Spain (J.S.-d.-T.).
³¹ Seattle Children's Hospital, WA (Y.L.).
³² Ramathibodi Hospital Mahidol University, Bangkok, Thailand (S.W.).
³³ Guangzhou Women and Children's Medical Center Guangzhou, Guangdong, China (Y.C.).
³⁴ Centro Hospitalar Lisboa Ocidental EPE Hospital de Santa Cruz Carnaxide, Lisboa, Portugal (R.A.).
³⁵ University of Health Sciences Turkey Dr. Behcet Uz Childrens Hospital-Konak/Izmir, Turkey (T.M.).
³⁶ M3C-Necker, Congenital and Paediatric Cardiology Department, Hospital Necker-Enfants Malades, University of Paris Cité, France (D.B.).

PMID: 39319469
PMCID: PMC11593999
DOI: 10.1161/CIRCULATIONAHA.123.066605

Randomized Controlled Trial

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial

Robert Shaddy et al. Circulation. 2024.

. 2024 Nov 26;150(22):1756-1766.

doi: 10.1161/CIRCULATIONAHA.123.066605. Epub 2024 Sep 25.

Authors

Collaborators

PANORAMA-HF Investigators:
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, Ronald Mark Payne, Sivasubramanian Ramakrishnan, Chiara Riggi, Paolo Rusconi, Robert Sabiniewicz, Khaled Salaymeh, Kurt Schumacher, Ulrich Schweigmann, Pierre-Emmanuelle Seguela, Renata Shih, Rakesh Singh, Maria Yurievna Sitnikova, Robert Spicer, Brigitte Stiller, Hisashi Sugiyama, Sreekanthan Sundararaghavan, Atsuhito Takeda, Jean-Benoît Thambo, Conceicao Trigo Pereira, Zulal Ulger Tutar, Gabrielle Vaughn, Hernan Velez, Gabriele Vignati, Jieh-Neng Wang, Jou-Kou Wang, Kazushi Yasuda, Lidia Ziolkowska, Liesl Zuhlke

Affiliations

¹ Children'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.).
² Great Ormond Street Hospital for Children, London, UK (M.B.).
³ Novartis Pharmaceuticals Corporation, East Hanover, NJ (S.S.-Y., M.K.).
⁴ Novartis Pharma AG, Basel, Switzerland (T.G.).
⁵ Novartis, Shanghai, China (S.Z.).
⁶ Children's Healthcare of Atlanta and Emory University, GA (C.M.).
⁷ Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa (A.C.).
⁸ National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (X.W.).
⁹ Washington University School of Medicine, St. Louis, MO (C.C.).
¹⁰ Children's Hospital of Philadelphia, PA (J.R.).
¹¹ Levine Children's Hospital, Charlotte, NC (G.W.).
¹² Hotel Dieu de France Hospital, Beirut, Lebanon (L.D.).
¹³ Regional Specialist Hospital in Wroclaw, Poland (J.K.).
¹⁴ Baskent University Medical Faculty, Ankara, Turkey (K.T.).
¹⁵ University Hospital Centre, Zagreb, Croatia (D.D.).
¹⁶ Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, China (Z.X.).
¹⁷ Children's Hospital of Shanghai, China (T.X.).
¹⁸ Mattel Children's Hospital and David Geffen School of Medicine, UCLA, Los Angeles, CA (N.H.).
¹⁹ Boston Children's Hospital and Harvard Medical School, MA (K.P.D., T.P.S.).
²⁰ Pediatrics, Division of Cardiology, Loma Linda University Children's Hospital, CA (M.J.B.).
²¹ Columbia University Medical Center, Morgan Stanley Children's Hospital of New York, New York (W.Z.).
²² Department of Congenital & Pediatric Cardiology, Indraprastha Apollo Hospitals, New Delhi, India (M.C.).
²³ Division of Pediatric Cardiology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel (A.L.).
²⁴ University of Milan-Bicocca, A.S.S.T. Papa Giovanni XXIII, Bergamo, Italy (M.S.).
²⁵ Bambino Gesù Children Hospital, IRCSS, Rome, Italy (G.G.).
²⁶ Seoul National University College of Medicine, Seoul National University Children's Hospital, Korea (G.B.K.).
²⁷ Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J.S.).
²⁸ Pusan National University Yangsan Hospital Yangsan-si, Gyeongsangnam-Do, Korea (H.D.L.).
²⁹ Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (C.K.C.).
³⁰ Hospital Sant Joan de Deu Esplugues de Llobregat, Spain (J.S.-d.-T.).
³¹ Seattle Children's Hospital, WA (Y.L.).
³² Ramathibodi Hospital Mahidol University, Bangkok, Thailand (S.W.).
³³ Guangzhou Women and Children's Medical Center Guangzhou, Guangdong, China (Y.C.).
³⁴ Centro Hospitalar Lisboa Ocidental EPE Hospital de Santa Cruz Carnaxide, Lisboa, Portugal (R.A.).
³⁵ University of Health Sciences Turkey Dr. Behcet Uz Childrens Hospital-Konak/Izmir, Turkey (T.M.).
³⁶ M3C-Necker, Congenital and Paediatric Cardiology Department, Hospital Necker-Enfants Malades, University of Paris Cité, France (D.B.).

PMID: 39319469
PMCID: PMC11593999
DOI: 10.1161/CIRCULATIONAHA.123.066605

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: 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.

Keywords: enalapril; heart failure; valsartan; ventricular dysfunction, left.

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Conflict of interest statement

Dr Shaddy is a consultant for Novartis, American Regent Inc., CRI Biotech, and Rocket Pharmaceuticals. S. Solar-Yohay is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Garito is an employee of Novartis Pharma AG, Basel, Switzerland, and owns its shares. Dr Zhang is an employee of Novartis, Shanghai, China. M. Kocun is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Canter holds a Data and Safety Monitoring Board chairman position at the Mayo Research Foundation and has participated on an advisory board for CareDx. Dr Rossano reports receiving consulting fees from Bayer, Enzyvant, Merck, AskBio, American Regent, and Bristol Myers Squibb. Dr Halnon reports receiving consulting fees from Novartis and grants or contracts to her institution from Novartis. Dr Daly reports grants or contracts for the TEAMMATE multicenter trial of post–heart transplant immunosuppression (different patient population; Novartis holds the nonexclusive rights to one of the drugs that was studied [everolimus] but Novartis did not provide any support for the TEAMMATE study) and for American Heart Association/Enduring Hearts (ancillary studies to the TEAMMATE study in heart transplant recipients [different drug and patient population]); consulting fees from AstraZeneca (consultation regarding a different pediatric heart failure drug and possible study in children); payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from CareDx (pediatric research board related to the use of Allosure Heart in transplant recipients); leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid in ISHLT program committee 2021–2023 (developed ISHLT scientific sessions program) and AST trainee and young faculty community of practice chair (developed content for fellows and young faculty as part of the AST). Dr Singh is co-chair of the end point adjudication committee at Novartis for PANORAMA-HF. Dr Senni reports receiving consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Bayer, Merck, MSD, Abbott, AstraZeneca, Boehringer, Vifor, and Novo Nordisk. Dr Anjos reports an unpaid position as a board member of the pediatric cardiology section of the Portuguese Medical Association. Dr Bonnet reports consulting fees from Novartis paid to his institution for being the steering committee member for the current study and participating in an advisory board for the current study. The other authors declare no competing interests.

Figures

**Figure 1.**
**New York Heart Association/Ross classification status at baseline and week 52 (overall).** *Odds ratio, 1.08 [95% CI, 0.7–1.7]; nominal 2-sided P=0.76. NYHA indicates New York Heart Association.

**Figure 2.**
**Geometric mean line plots for NT-proBNP levels (overall and by age groups).** Error bars represent 95% CIs. *Significant difference in the NT-proBNP (N-terminal pro–B-type natriuretic peptide) geometric mean data points between 2 treatment arms.

See this image and copyright information in PMC

References

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1. Peng DM, Zhang Y, Rosenthal DN, Palmon M, Chen S, Kaufman BD, Maeda K, Hollander SA, McDonald N, Smoot LB, et al. . Impact of heart transplantation on the functional status of US children with end-stage heart failure. Circulation. 2017;135:939–950. doi: 10.1161/CIRCULATIONAHA.115.016520 - PubMed
1. Ahmed H, VanderPluym C. Medical management of pediatric heart failure. Cardiovasc Diagn Ther. 2021;11:323–335. doi: 10.21037/cdt-20-358 - PMC - PubMed
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Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial

Collaborators

Affiliations

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Substances

Associated data

LinkOut - more resources

Full Text Sources

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Research Materials

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