Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec 3:e2519808.
doi: 10.1001/jama.2025.19808. Online ahead of print.

Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized Clinical Trial

Renato D Lopes  1   2 , Edimar Alcides Bocchi  3 , Luis Eduardo Echeverría  4 , Caroline Demacq  5 , Pedro Gabriel Melo de Barros E Silva  2 , Lilian Mazza Barbosa  2 , Lucas Damiani  2 , Sarfaraz Sayyed  6 , Liandra A F Yoshida  2 , Remo Holanda M Furtado  2 , Carlos A Morillo  7 , Ruben Kevorkian  8 , Felix Ramires  3 , M Cecilia Bahit  9 , Antonio Magaña  10 , Adolfo Chávez-Mendoza  10 , Adegil Henrique Miguel da Silva  11 , Aguinaldo Coelho da Silva  12 , Aguinaldo F Freitas Jr  13 , Alfredo Alejandro Romano  14 , Anne Parneix  15 , Armando Segura  16 , Cesar Cassio Broilo França  17 , Cristian Edgardo Botta  18 , Edileide de Barros  19 , Eduardo Roque Perna  20 , Eleonora Montenegro  21 , Franklin Roberto Quiroz Diaz  22 , Gilson Soares Feitosa-Filho  23   24 , Graciela Viviana Severini  25 , Israel Molina  26 , Jacqueline Dos Santos Sampaio Miranda  27 , Jorgelina Sala  28 , José Francisco Kerr Saraiva  29 , Justo Carbajales  30 , Lilia Nigro Maia  31 , Luiz Carlos Santana Passos  32 , Marcus Vinicius Simões  33 , Maria da Consolação V Moreira  34 , Maria Carmo P Nunes  35 , Mauro Esteves Hernandes  36 , Miguel Hominal  37 , Raquel Saa Zarandon  38 , Ricardo Leon de la Fuente  39 , Roque Aras  40 , Silméia Garcia Zanati Bazan  41 , Telêmaco Luiz da Silva Jr  42 , Vagner Madrini  3 , Wilson Alves de Oliveira Jr  43 , Wladmir Faustino Saporito  44 , Claudio Gimpelewicz  45 , John J V McMurray  46 ; Prevention and Reduction of Adverse Outcomes in Chagasic Heart Failure Trial Evaluation (PARACHUTE-HF) Investigators
Collaborators, Affiliations

Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized Clinical Trial

Renato D Lopes et al. JAMA. .

Abstract

Importance: The efficacy and safety of guideline-recommended treatments for heart failure (HF) are uncertain in patients with Chagas disease.

Objective: To evaluate the efficacy and safety of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan in patients with HF with reduced ejection fraction due to Chagas disease.

Design, setting, and participants: From December 10, 2019, through September 13, 2023, patients with HF, confirmed diagnosis of Chagas disease, left ventricular ejection fraction of 40% or less, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 600 pg/mL or greater (or B-type natriuretic peptide [BNP] ≥150 pg/mL) or 400 pg/mL or greater (or BNP ≥100 pg/mL) if hospitalized for HF within the previous 12 months were screened at 83 sites in Argentina, Brazil, Colombia, and Mexico. Statistical analysis was conducted between May and July 2025.

Interventions: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or enalapril (target dose, 10 mg twice daily), in addition to standard therapy.

Main outcomes and measures: The primary end point was a hierarchical composite outcome tested, in order, of death from cardiovascular causes, hospitalization for HF, or relative change in NT-proBNP from baseline to 12 weeks. The primary analysis was done using a win ratio approach.

Results: Overall, 462 participants were randomized to receive sacubitril/valsartan and 460 to receive enalapril (mean [SD] age, 64.2 [10.8] years; 387 [42.0%] were female). Over a median (IQR) follow-up of 25.2 (18.4-33.2) months, cardiovascular death occurred in 110 patients (23.8% [18.3% wins in the hierarchical comparison]) in the sacubitril/valsartan group and 117 patients (25.4% [17.5% wins]) in the enalapril group. A total of 102 patients (22.1% [7.7% wins]) in the sacubitril/valsartan group and 111 (24.1% [6.9% wins]) in the enalapril group experienced a first hospitalization for HF. Patients in the sacubitril/valsartan group had a median (IQR) decrease in NT-proBNP of 30.6% (-54.3% to -0.9%) at 12 weeks, leading to 22.5% wins, while those in the enalapril group had a 5.5% (-31.9% to 37.5%) decrease (7.2% wins). The resulting stratified win ratio was 1.52 (95% CI, 1.28-1.82; P < .001) for sacubitril/valsartan compared with enalapril.

Conclusions and relevance: In patients with HF with reduced ejection fraction due to Chagas disease, there was no significant difference in clinical outcomes between sacubitril/valsartan and enalapril, but there was a greater reduction in NT-proBNP at 12 weeks in patients in the sacubitril/valsartan group.

Trial registration: ClinicalTrials.gov Identifier: NCT04023227.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lopes reported receiving grants from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis, and Novartis; and personal fees from Pfizer, Daiichi Sankyo, Novo Nordisk, Bayer, Boehringer Ingelheim, and Bristol Myers Squibb outside the submitted work. Dr Bocchi reported receiving consulting fees from Servier, AstraZeneca, and Boehringer Ingelheim; subsidized travel, hotel, and registration fees from Servier; being a member of the steering committees of Servier, Novartis, and Boehringer Ingelheim; research grant support to his institution from Janssen, Bayer/Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Cardiol Therapeutics, and Eurofarma; and honoraria from Servier, Novartis, AstraZeneca, Boehringer Ingelheim, Viatris, and Abbott. Dr Echeverría reported receiving grants from Novartis during the conduct of the study and personal fees from Novartis outside the submitted work. Dr Demacq reported being an employee of and owning stock in Novartis during the conduct of the study. Dr de Barros e Silva reported receiving grants from Novartis during the conduct of the study and Roche Diagnostics outside the submitted work. Dr Sayyed reported being an employee of Novartis Healthcare during the conduct of the study. Dr Furtado reported receiving grants from Novartis during the conduct of the study; grants from AstraZeneca, Bayer, Libbs, Aché, Brainfarma, and Pfizer; and personal fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Roche, Servier, and Viatris outside the submitted work. Dr Morillo reported receiving grants from Novartis during the conduct of the study; and personal fees from Kardium and National Institutes of Health (NIH) for serving as the data and safety monitoring board chair outside the submitted work. Dr Kevorkian reported receiving personal fees from Hospital D.F. Santojanni during the conduct of the study. Dr Ramires reported receiving speaking fees from Novartis, Bristol Myers Squibb, and Alnylam Pharmaceuticals outside the submitted work. Dr Bahit reported serving on the Novartis advisory board outside the submitted work. Dr Coelho da Silva reported receiving research support from Novartis during the conduct of the study. Dr Segura reported receiving personal fees from Institute for Social Security and Services for State Workers. Dr Perna reported receiving clinical trial fees from Novartis during the conduct of the study and speaking fees from Novartis outside the submitted work. Dr Feitosa-Filho reported receiving institutional support from Novartis during the conduct of the study. Dr Molina reported receiving personal fees from Novartis outside the submitted work. Dr Miranda reported receiving grants from Novartis during the conduct of the study. Dr Kerr Saraiva reported receiving personal fees from Novartis during the conduct of the study. Dr Santana Passos reported receiving personal fees from Novartis Pesquisador during the conduct of the study. Dr Nunes reported receiving grants from Novartis during the conduct of the study. Dr Hernandes reported receiving grants from Instituto Brasileiro de Pesquisa Clinica Thomaz de Carvalho - IBPC during the conduct of the study. Dr Luiz da Silva Jr reported receiving grants from Novartis during the conduct of the study. Dr Gimpelewicz reported being an employee of Novartis during the conduct of the study and receiving stock from Novartis outside the submitted work. Dr McMurray reported payment to his institution from Novartis during the conduct of the study; payment to his institution from British Heart Foundation, NIH/National Heart, Lung, and Blood Institute, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Roche Diagnostics; consulting fees from Alnylam Pharmaceuticals, AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, and DalCor Pharmaceuticals; lecture fees from Alkem Metabolics, AstraZeneca, Canadian Medical & Surgical, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, JB Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, Regeneron, Hilton Pharma, Imedic Pharmaceuticals, Micro Labs Ltd, and ARMGO Pharmaceuticals; and serving as the director of Global Clinical Trial Partners outside the submitted work. No other disclosures were reported.

Comment in

References

    1. Cousin E, Nascimento BR, Mosser J, et al. Global, regional, and national burden of Chagas disease, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023. SSRN . August 7, 2025. Accessed October 2, 2025. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5381800 - PubMed
    1. Ribeiro ALP, Machado Í, Cousin E, et al. ; RAISE Study Collaborators . The burden of Chagas disease in the contemporary world: the RAISE study. Glob Heart. 2024;19(1):2. doi: 10.5334/gh.1280 - DOI - PMC - PubMed
    1. Chagas disease: a neglected emergency. Lancet. 2009;373(9678):1820. doi: 10.1016/S0140-6736(09)61002-3 - DOI - PubMed
    1. Lopes RD, Gimpelewicz C, McMurray JJV. Chagas disease: still a neglected emergency? Lancet. 2020;395(10230):1113-1114. doi: 10.1016/S0140-6736(20)30171-9 - DOI - PubMed
    1. Nunes MCP, Beaton A, Acquatella H, et al. ; American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Stroke Council . Chagas cardiomyopathy: an update of current clinical knowledge and management: a scientific statement from the American Heart Association. Circulation. 2018;138(12):e169-e209. doi: 10.1161/CIR.0000000000000599 - DOI - PubMed

Associated data