Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease
Renato D. Lópes, Edimar Alcides Bocchi, Luis Eduardo Echeverría, Caroline Demacq, Pedro Gabriel Melo de Barros e Silva, Lilian Mazza Barbosa, Lucas Petri Damiani, Sarfaraz Sayyed, Liandra A. F. Yoshida, Remo H.M. Furtado, Carlos A. Morillo, Rubén Kevorkián, Félix José Alvarez Ramires, M. Cecilia Bahit, Antonio Magaña, Adolfo Chávez‐Mendoza, Adegil Henrique Miguel da Silva, Aguinaldo Coelho da Silva, Aguinaldo Figueiredo Freitas, Alfredo Alejandro Romano, Anne Parneix, Armando Segura, César Cássio Broilo França, Cristian Botta, Edileide de Barros, Eduardo Perna, Eleonora Montenegro, Franklin Roberto Quiroz Diaz, Gilson Soares Feitosa-Filho, Graciela Viviana Severini, Israel Molina, Jacqueline Miranda, Jorgelina Sala, José Ferreira Saraiva, Justo Carbajales, Lília Nigro Maia, Luiz Carlos Santana Passos, Marcus Vinı́cius Simões, Maria da Consolação Vieira Moreira, Maria Carmo Pereira Nunes, Mauro Esteves Hernandes, Miguel Hominal, Raquel Saa Zarandon, Ricardo León de la Fuente, Roque Aras, Silméia Garcia Zanati Bazan, Telêmaco Luiz da Silva, Vagner Madrini, Wilson Alves de Oliveira, Wladmir Faustino Saporito, Claudio Gimpelewicz, John J.V. McMurray, Prevention and Reduction of Adverse Outcomes in Chagasic Heart Failure Trial Evaluation (PARACHUTE-HF) Investigators, Lívia Figueira Avezum Oliveira, Weimar Kunz Sebba Barroso de Souza, Pedro Vellosa Schwartzmann, Adalberto Menezes Lorga Filho, Dilma Souza, Alberto Gomes Taques Fonseca, Juliana Ascenção de Souza, Ricardo Mourilhe Rocha, Murillo de Oliveira Antunes, Flavio de Souza Brito, Claudia da Silva Fragata, Walter Oliveira, Estevao Lanna Figueiredo, Eduardo Abib, Raphael Barreto Silva, Carlos Eduardo Batista de Lima, Ricardo Pereira Silva, Creuza Macedo Goes Rocha, Marcelo Demaman Andres, Aloisio Rocha, Luciano Freitas Fernandes, Cezar Mesas, Márcia Maria Noya Rabelo, José Albuquerque de Figueiredo Neto, Gilmar Reis, Donaldy Gustavo da Silva Sampaio, Juan Antonio Muntaner, Oscar Romano Montaña, Claudio Andres Pereyra Sueldo, Lilia Luz Lobo Marquez, Miguel Visser, Diego Felipe Martinez, Hugo Armando Luquez, Gustavo Adolfo Paterlini, Pablo Guzman, Matias Nicolas Lugo, María Jazmín Fernandez Moutin, Norberto Bornancini, Daniela García Brasca, Manuel John de Francisco Liévano Triana, Juan Diego Higuera Cobos, Guillermo Orlando Trout Guardiola, Alejandro Olaya Sánchez, Enrique Alexander Berríos Bárcenas, Gustavo Francisco Mendez Machado, Hilda Peralta Rosado, Alexandre Kajita
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.