Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC (PARACHUTE-HF)

A Multicenter, Prospective, Randomized, Open-label, Blinded-endpoint, Phase 4 Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With Chronic Chagas' Cardiomyopathy. The Study is Also Know as Prevention And Reduction of Adverse Outcomes in Chagasic Heart failUre Trial Evaluation (PARACHUTE-HF).

The purpose of this study was to evaluate the effect of sacubitril/valsartan 200 mg BID compared with enalapril 10 mg BID, in addition to conventional heart failure (HF) treatment, in improving a hierarchical composite of cardiovascular (CV) events (i.e. CV death or the occurrence of first HF hospitalization) and causing a greater reduction in n terminal prohormone of brain natriuretic peptide (NT-proBNP, at Week 12 from Baseline) in participants with HF with reduced ejection fraction (HFrEF) caused by chronic Chagas' cardiomyopathy (CCC).

Study Overview

• Status: Completed
• Conditions: Heart Failure; Chagas Disease
• Intervention / Treatment: Drug: Sacubitril/valsartan; Drug: Enalapril

Detailed Description

This was a multinational, multicenter, parallel-group, prospective, randomized, open-label, with blinded-endpoint adjudication, active-controlled study. The target projected sample size was approximately 900 participants (450 in each arm). It was estimated that approximately 1800 participants would be screened at sites in Latin America, including Argentina, Brazil, Colombia, and Mexico.

Participants who met the eligibility requirements were randomly assigned in a 1:1 ratio to receive sacubitril/valsartan (target dose of 200 mg twice daily) or enalapril (target dose of 10 mg twice daily), in addition to their usual therapy, stratified by country, using a central, concealed, web-based, automated randomization system. Both groups entered a titration period of 3 to 6 weeks, aiming to achieve the target dose of sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. The study follow-up succeeded the titration period and was to last until a total number of 302 events was reached and all randomized participants had a minimum follow-up of 12 weeks.

• Study Type: Interventional
• Enrollment (Actual): 922
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1155 AHD
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400CDS
    • Novartis Investigative Site
  • Córdoba, Argentina, 5000
    • Novartis Investigative Site
  • Córdoba, Argentina, X5003DCE
    • Novartis Investigative Site
  • Córdoba, Argentina, X5004BAL
    • Novartis Investigative Site
  • Córdoba, Argentina, X5006CBI
    • Novartis Investigative Site
  • Formosa, Argentina, P3600
    • Novartis Investigative Site
  • Formosa, Argentina, P3634XAR
    • Novartis Investigative Site
  • Mendoza, Argentina, M5500CHC
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FWO
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000EOZ
    • Novartis Investigative Site
  • Santiago del Estero, Argentina, G4200AQK
    • Novartis Investigative Site
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1221ADC
      • Novartis Investigative Site
    • CABA, Buenos Aires, Argentina, C1425BEI
      • Novartis Investigative Site
    • Ramos Mejía, Buenos Aires, Argentina, B1704ETD
      • Novartis Investigative Site
    • San Martín, Buenos Aires, Argentina, 1604
      • Novartis Investigative Site
    • Temperley, Buenos Aires, Argentina, 1834
      • Novartis Investigative Site
  • Córdoba Province
    • Villa María, Córdoba Province, Argentina, X5900JKA
      • Novartis Investigative Site
  • Salta Province
    • Salta, Salta Province, Argentina, A4406BPF
      • Novartis Investigative Site
  • San Miguel de Tucuman
    • San Miguel de Tucumán, San Miguel de Tucuman, Argentina, T4000ICL
      • Novartis Investigative Site
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, 2000
      • Novartis Investigative Site
    • Rosario, Santa Fe Province, Argentina, S2000DIF
      • Novartis Investigative Site
  • Tucumán Province
    • San Miguel Tucuman, Tucumán Province, Argentina, T4000IFL
      • Novartis Investigative Site
    • San Miguel Tucuman, Tucumán Province, Argentina, T4000JCU
      • Novartis Investigative Site
• Brazil
  • São Paulo, Brazil, 05403-000
    • Novartis Investigative Site
  • São Paulo, Brazil, 15015-210
    • Novartis Investigative Site
  • Ceará
    • Fortaleza, Ceará, Brazil, 60430 370
      • Novartis Investigative Site
    • Fortaleza, Ceará, Brazil, 60125-025
      • Novartis Investigative Site
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 41253-190
      • Novartis Investigative Site
    • Salvador, Estado de Bahia, Brazil, 40050-410
      • Novartis Investigative Site
    • Salvador, Estado de Bahia, Brazil, 40110060
      • Novartis Investigative Site
    • Salvador, Estado de Bahia, Brazil, 40323-010
      • Novartis Investigative Site
  • Federal District
    • Brasila, Federal District, Brazil, 70673623
      • Novartis Investigative Site
    • Brasília, Federal District, Brazil, 70390-700
      • Novartis Investigative Site
    • Brasília, Federal District, Brazil, 70673-416
      • Novartis Investigative Site
  • Goiás
    • Goiânia, Goiás, Brazil, 74605-020
      • Novartis Investigative Site
    • Goiânia, Goiás, Brazil, 74223-060
      • Novartis Investigative Site
    • Goiânia, Goiás, Brazil, 74223-130
      • Novartis Investigative Site
  • Maranhão
    • São Luís, Maranhão, Brazil, 65020-070
      • Novartis Investigative Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-270
      • Novartis Investigative Site
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • Novartis Investigative Site
    • Belo Horizonte, Minas Gerais, Brazil, 30140 062
      • Novartis Investigative Site
    • Montes Claros, Minas Gerais, Brazil, 39401-001
      • Novartis Investigative Site
    • Passos, Minas Gerais, Brazil, 37904-020
      • Novartis Investigative Site
    • Uberaba, Minas Gerais, Brazil, 38025-440
      • Novartis Investigative Site
    • Uberlândia, Minas Gerais, Brazil, 38400 500
      • Novartis Investigative Site
    • Uberlândia, Minas Gerais, Brazil, 38400-328
      • Novartis Investigative Site
  • Paraná
    • Londrina, Paraná, Brazil, 86038-440
      • Novartis Investigative Site
  • Pará
    • Belém, Pará, Brazil, 66087-660
      • Novartis Investigative Site
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50100-060
      • Novartis Investigative Site
  • Piauí
    • Teresina, Piauí, Brazil, 64001-380
      • Novartis Investigative Site
  • Rio Grande do Sul
    • Ijuí, Rio Grande do Sul, Brazil, 98700-000
      • Novartis Investigative Site
  • Rio de Janeiro
    • Rio de Janeiro, Rio de Janeiro, Brazil, 20551-030
      • Novartis Investigative Site
    • Rio de Janeiro, Rio de Janeiro, Brazil, 22240-006
      • Novartis Investigative Site
  • São Paulo
    • Botucatu, São Paulo, Brazil, 3880-1001
      • Novartis Investigative Site
    • Bragança Paulista, São Paulo, Brazil, 13183-091
      • Novartis Investigative Site
    • Campinas, São Paulo, Brazil, 13060 080
      • Novartis Investigative Site
    • Campinas, São Paulo, Brazil, 13020-431
      • Novartis Investigative Site
    • Campinas, São Paulo, Brazil, 13060-904
      • Novartis Investigative Site
    • Indaiatuba, São Paulo, Brazil, 13330-570
      • Novartis Investigative Site
    • Marília, São Paulo, Brazil, 17515-000
      • Novartis Investigative Site
    • Ribeirão Preto, São Paulo, Brazil, 14048-900
      • Novartis Investigative Site
    • Ribeirão Preto, São Paulo, Brazil, 14010-190
      • Novartis Investigative Site
    • Santo André, São Paulo, Brazil, 09080-001
      • Novartis Investigative Site
    • Sao Jose Rio Preto, São Paulo, Brazil, 15090-000
      • Novartis Investigative Site
    • São Paulo, São Paulo, Brazil, 05403-000
      • Novartis Investigative Site
    • São Paulo, São Paulo, Brazil, 04012 909
      • Novartis Investigative Site
    • Tatuí, São Paulo, Brazil, 18270-170
      • Novartis Investigative Site
    • Votuporanga, São Paulo, Brazil, 15500 003
      • Novartis Investigative Site
• Colombia
  • Bogota DC, Colombia, 110111
    • Novartis Investigative Site
  • Florida Blanca, Colombia, 681001
    • Novartis Investigative Site
  • Floridablanca, Colombia, 681004
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 110121
      • Novartis Investigative Site
  • Magdalena Department
    • Santa Marta, Magdalena Department, Colombia, 30360
      • Novartis Investigative Site
  • Santander Department
    • San Gil, Santander Department, Colombia, 684031
      • Novartis Investigative Site
• Mexico
  • Ciudad de, Mexico, 14080
    • Novartis Investigative Site
  • Oaxaca City, Mexico, 68000
    • Novartis Investigative Site
  • Xalapa, Mexico, 91193
    • Novartis Investigative Site
  • Yucatán
    • Mérida, Yucatán, Mexico, 97000
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Male or female ≥ 18 years of age

• Diagnosis of NYHA Class II-IV HFrEF established by:

  1. LVEF ≤ 40% within 12 months prior to Visit 1 made by any local measurement using echocardiography, multiple gated acquisition scan (MUGA), computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or ventricular angiography, provided no subsequent measurement above 40% AND
  2. NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at Visit 1 OR
  3. NT-proBNP ≥ 400 pg/mL (or BNP ≥ 100 pg/mL) at Visit 1 and a hospitalization for HF within the last 12 months
• Chagas' disease diagnosis confirmed by at least two different serological tests for anti-Trypanosoma cruzi based on different principles or with different antigenic preparations, such as: enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence [IFI], indirect hemagglutination [IHA], western blot (WB), chemiluminescent immunoassay (CLIA). If documented history is not available, the tests may be performed during the screening

Key Exclusion Criteria:

• Patients with history of suspected or proven angioedema or unable to tolerate ACEIs, ARBs or ARNI (e.g., due to cough, hypotension, renal dysfunction, hyperkalemia)
• Use of sacubitril/valsartan in the past 3 months

• Patients requiring continuous intravenous inotropic therapy or with indication of advanced support intervention for HF:

  1. already on list for a heart transplantation
  2. with current indication of left ventricular assist device, or cardiac resynchronization therapy (CRT)
• Systemic systolic blood pressure lower than 95 mmHg or symptomatic hypotension
• Serum potassium > 5.2 mmol/L
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 of body surface area
• Severe gastrointestinal form of chronic Chagas' disease (demonstrated megaesophagus and/or important megacolon, e.g.: with compromised oral intake or surgical indication).
• Clinical conditions or systemic diseases limiting proper patient participation
• Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

• Presence of other cardiac conditions:

  1. Previous cardiac surgery
  2. Heart failure where, in the Investigator's judgement, there is a possible alternative primary etiology e.g., due to coronary artery disease, valve disease, congenital heart disease or other causes.
  3. Untreated arrhythmia or serious conduction disease e.g., bradyarrhythmias, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, etc.
  4. Primary uncorrected valvar pathology like moderate to severe aortic stenosis, mitral stenosis and primary mitral regurgitation
  5. Planned organ transplantation (or in listing for transplantation), planned cardiac or other major surgery (including ventricular assist device implantation)
• History of malignancy of any organ system within the past 5 years.
• Current confirmed COVID19 infection
• Past COVID19 infection with persistent symptom burden suspected due to COVID19 (persistent symptoms may include, but are not limited to, continued cough, breathing difficulty, muscle/joint aches, and gastrointestinal symptoms from the time of COVID19 infection onward)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/valsartan; Participants received 3 to 6 weeks of titrated dosing with sacubitril/valsartan to achieve the target dose of 200 mg twice daily.	Drug: Sacubitril/valsartan; Participants randomized to sacubitril/valsartan who were previously treated with angiotensin-converting enzyme inhibitors (ACEIs) had a 36-hour washout prior to receiving oral treatment with 50, 100, or 200 mg, film-coated tablets.; Other Names: LCZ696; Entresto; Vymada
Active Comparator: Enalapril; Participants received 3 to 6 weeks of titrated dosing with enalapril to achieve the target dose of 10 mg twice daily.	Drug: Enalapril; Oral treatment with 5 or 10 mg tablets.; Other Names: Renitec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical Composite Endpoint Composed of Time to Cardiovascular (CV) Death, Time to First Heart Failure (HF) Hospitalization, and Relative Change in NT-proBNP From Baseline to Week 12	The primary efficacy endpoint was analyzed using the win ratio approach comparing every participant in the sacubitril/valsartan arm to every participant in the enalapril arm to determine a winner. A winner in the pair-wise comparison had a delayed time to the occurrence of CV death; if time to the occurrence of CV death was censored, a winner had a delayed time to the occurrence of first HF hospitalization event; if the times to both CV events were censored, a winner had a more favorable (less increase or more decrease) change in NT-proBNP between Baseline and Week 12. The estimated win ratio was defined as the total number of winners in the sacubitril/valsartan arm divided by the total number of winners in the enalapril arm. A win ratio >1 represents a favorable outcome for the study drug being assessed.	Total follow-up time up to approximately 36 months
Percentage of Participants Who Died From Cardiovascular Causes		Total follow up time up to approximately 36 months
Percentage of Participants With First Hospitalization for Worsening Heart Failure		Total follow up time up to approximately 36 months
Change From Baseline to Week 12 in NT-proBNP Levels	Geometric mean factor change was derived from a linear regression model of log(NT-proBNP), adjusted for country and baseline value.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With First Hospitalization Due to Heart Failure or Death From Cardiovascular Causes		From the date of randomization to the first occurrence (total follow up time up to approximately 36 months)
Percentage of Participants Who Died From Any Cause		From date of randomization until the date of death from any cause assessed up to the end of the study, up to approximately 36 months
Number of Participants Who Had Sudden Death or Resuscitated Sudden Cardiac Arrest		From date of randomization until the date of the sudden death or resuscitated sudden cardiac arrest assessed up to the end of the study, up to approximately 36 months
Number of Participants Who Had Visits to an Emergency Room Due to Heart Failure (HF) Where Intravenous Therapy Was Required		From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
Number of Days Alive and Out of the Hospital	The duration of hospital-free survival within 1 year from randomization was summarized.	From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
Number of Hospitalizations Due to Heart Failure (HF) or Death Due to Cardiovascular (CV) Causes (Recurrent Events)		From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Ventricular Fibrillation or Sustained Ventricular Tachycardia	The number of ventricular fibrillation or sustained ventricular tachycardia needing specific pharmacological, electrical or other treatment was determined.	From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
Number of Anti-tachycardia Pacing or Shock Therapies		From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Bocchi EA, Echeverria LE, Demacq C, de Barros E Silva PGM, Mazza Barbosa L, Chiang LM, Damiani L, Morillo CA, Kevorkian R, Ramires F, Bahit MC, Ferrari A, Chavez-Mendoza A, Magana-Serrano JA, McMurray JJV, Gimpelewicz C, Lopes RD; PARACHUTE-HF Investigators. Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial. JACC Heart Fail. 2024 Aug;12(8):1473-1486. doi: 10.1016/j.jchf.2024.05.021.
• Lopes RD, Bocchi EA, Echeverria LE, Demacq C, de Barros E Silva PGM, Barbosa LM, Damiani L, Sayyed S, Yoshida LAF, Furtado RHM, Morillo CA, Kevorkian R, Ramires F, Bahit MC, Magana A, Chavez-Mendoza A, Miguel da Silva AH, Coelho da Silva A, Freitas AF Jr, Romano AA, Parneix A, Segura A, Franca CCB, Botta CE, de Barros E, Perna ER, Montenegro E, Quiroz Diaz FR, Feitosa-Filho GS, Severini GV, Molina I, Miranda JDSS, Sala J, Kerr Saraiva JF, Carbajales J, Maia LN, Santana Passos LC, Simoes MV, Moreira MDCV, Nunes MCP, Hernandes ME, Hominal M, Zarandon RS, Leon de la Fuente R, Aras R, Bazan SGZ, Luiz da Silva T Jr, Madrini V, de Oliveira WA Jr, Saporito WF, Gimpelewicz C, McMurray JJV; Prevention and Reduction of Adverse Outcomes in Chagasic Heart Failure Trial Evaluation (PARACHUTE-HF) Investigators. Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized Clinical Trial. JAMA. 2026 Jan 6;335(1):49-59. doi: 10.1001/jama.2025.19808.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Actual): March 16, 2025
• Study Completion (Actual): March 31, 2025

Study Registration Dates

• First Submitted: July 10, 2019
• First Submitted That Met QC Criteria: July 16, 2019
• First Posted (Actual): July 17, 2019

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: heart failure; enalapril; ACEI; ARB; Chagas' disease; angiotensin receptor-neprilysin inhibitor; ARNI; sacubitril/valsartan
• Additional Relevant MeSH Terms: Vector Borne Diseases; Cardiovascular Diseases; Heart Diseases; Infections; Protozoan Infections; Parasitic Diseases; Euglenozoa Infections; Trypanosomiasis; Heart Failure; Chagas Disease; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Dipeptides; Enalapril; sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696B3302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No