Angiotensin Receptor-Neprilysin Inhibition in Chagas Cardiomyopathy With Reduced Ejection Fraction: ANSWER-HF.

NCT04853758 | Recruiting Phase 3

• 1 other identifier: 33360220500000068
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Chagas disease is considered by the World Health Organization (WHO) as one of the most neglected tropical diseases in the world, having relevance in many Latin America countries. In addition, it already affects North America, Europe, Asia and Oceania. Some studies suggest that chagasic heart failure has a worse prognosis, with up to 50% shorter survival than other etiologies. The PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study showed 20% reduction in mortality comparing sacubitril/valsartan with the standard treatment with ACE (angiotensin converting enzyme) inhibitors. In the scenario of chagasic cardiomyopathy, a post hoc analysis of PARADGIM-HF was reported on 113 patients. Reduced risk of cardiovascular death or hospitalization for HF was noted in the group treated with sacubitril/valsartan. Attention was drawn the study's limitations that included the small number of patients and reduced statistical power. Therefore, the benefit of this new class remains uncertain in heart failure due to Chagas cardiomyopathy. The ANSWER-HF Trial will be a clinical, randomized, single-center, prospective, double-blind, controlled study. It will include 200 consecutive participants with Chagas cardiomyopathy and left ventricular ejection fraction less than 40% randomized independently. The objective of this study is to evaluate the benefit of sacubitril/valsartan compared with enalapril in patients with heart failure due to Chagas cardiomyopathy, with reduced ejection fraction. The primary endpoint of the study is the change of left ventricular ejection fraction determined by transthoracic echocardiography. Secondary endpoints include: assessment of ventricular arrhythmias; evaluation of functional class; assessment of functional capacity; assessment of ventricular remodeling; and evaluation of biomarkers. The patients will be followed for 6 months after treatment start. All patients will be undergone to Doppler Echocardiography, 24-hour Holter, 6-minute walk test, Biochemical and hematological exams and Biomarkers at the baseline and after 6 months.

Conditions

Chagas Cardiomyopathy

Keywords

Heart Failure; Chagas Disease; Chagas Cardiomyopathy; Sacubitril/Valsartan

Outcome Measures

Primary Outcomes (2)

• Change of left ventricular ejection fraction (LVEF)

  The primary endpoint of the study will be studied by transthoracic echocardiography. The LVEF will be evaluated using Simpson method.

  6 months

• Win Ratio Analysis

  Hierarchical composite analysis composed of: 1. Time to cardiovascular death; 2. Time to first heart failure hospitalization; 3. Relative change in NT-proBNP from baseline to final visit; 4. Relative change in left ventricular ejection fraction from baseline to final visit

  6 meses

Secondary Outcomes (18)

• Number of premature ventricular beats

  6 months

• Percentage of premature ventricular beats.

  6 months

• Ventricular arrhythmias density

  6 months

• Sustained ventricular tachycardia rates

  6 months

• New York Heart Association functional class

  6 months

Study Arms (2)

Sacubitril/Valsartan

ACTIVE COMPARATOR

100 consecutive participants randomized independently at the Heart Institute - School of Medicine of the University of São Paulo (InCor),will receive sacubitril/valsartan.

Drug: Sacubitril / Valsartan Oral Tablet [Entresto]

Enalapril

ACTIVE COMPARATOR

100 consecutive participants randomized independently at the Heart Institute - School of Medicine of the University of São Paulo (InCor),will receive enalapril.

Drug: Enalapril

Interventions

Sacubitril / Valsartan Oral Tablet [Entresto] DRUG

100 consecutive participants randomized independently at the Heart Institute - School of Medicine of the University of São Paulo (InCor),will receive sacubitril/valsartan for 6 months.

Also known as: Angiotensin receptor-neprilisin inhibitor (ARNI)

Sacubitril/Valsartan

Enalapril DRUG

100 consecutive participants randomized independently at the Heart Institute - School of Medicine of the University of São Paulo (InCor),will receive enalapril for 6 months.

Also known as: Angiotensin converting enzyme inhibitors (ACE inhibitors)

Enalapril

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Positive serology for Chagas;
• Age \> 18 years old;
• New York Heart Association (NYHA) heart failure and functional class II, III or IV;
• Left ventricular ejection fraction \<40% at least in the last 3 months;
• Patients using a beta-blocker with stable dose (last 4 weeks) and optimized;
• Patients using ACEI or ARB with a stable dose (last 4 weeks) and optimized.

You may not qualify if:

• Participants who do not agree to participate in the study
• Participants who do not want to receive sacubitril/ valsartan medication;
• Patients with symptomatic hypotension;
• Patients with systolic blood pressure (SBP) lower than 95 mmHg on randomization;
• Patients with creatinine clearance (ClCr) less than 30 mL/min;
• Patients with serum potassium \> 5.2 mmol/L;
• Patients with a history of angioedema or who experienced severe side effects with ACE inhibitors.

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• InCor Heart Institute: collaborator

Study Sites (1)

Heart Institute (Incor) University of Sao Paulo

São Paulo, 05403000, Brazil

RECRUITING

Related Publications (11)

• Hotez PJ, Fenwick A, Savioli L, Molyneux DH. Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 2009 May 2;373(9674):1570-5. doi: 10.1016/S0140-6736(09)60233-6. No abstract available.

  PMID: 19410718 RESULT

• Bocchi EA, Rassi S, Guimaraes GV; Argentina, Chile, and Brazil SHIFT Investigators. Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial. ESC Heart Fail. 2018 Jun;5(3):249-256. doi: 10.1002/ehf2.12240. Epub 2017 Dec 20.

  PMID: 29266804 RESULT

• Ianni BM, Arteaga E, Frimm CC, Pereira Barretto AC, Mady C. Chagas' heart disease: evolutive evaluation of electrocardiographic and echocardiographic parameters in patients with the indeterminate form. Arq Bras Cardiol. 2001 Jul;77(1):59-62. doi: 10.1590/s0066-782x2001000700006.

  PMID: 11500748 RESULT

• Araujo FG, Chiari E, Dias JC. Demonstration of Trypanosoma cruzi antigen in serum from patients with Chagas' disease. Lancet. 1981 Jan 31;1(8214):246-9. doi: 10.1016/s0140-6736(81)92088-2.

  PMID: 6109902 RESULT

• Carod-Artal FJ, Gascon J. Chagas disease and stroke. Lancet Neurol. 2010 May;9(5):533-42. doi: 10.1016/S1474-4422(10)70042-9.

  PMID: 20398860 RESULT

• Barretto AC, Higuchi ML, da Luz PL, Lopes EA, Bellotti G, Mady C, Stolf N, Arteaga-Fernandez E, Pileggi F. [Comparison of histologic changes in Chagas' cardiomyopathy and dilated cardiomyopathy]. Arq Bras Cardiol. 1989 Feb;52(2):79-83. Portuguese.

  PMID: 2596992 RESULT

• Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy. Circulation. 1994 Dec;90(6):3098-102. doi: 10.1161/01.cir.90.6.3098.

  PMID: 7994859 RESULT

• Shen L, Ramires F, Martinez F, Bodanese LC, Echeverria LE, Gomez EA, Abraham WT, Dickstein K, Kober L, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, Jhund PS, Gimpelewicz CR, McMurray JJV; PARADIGM-HF and ATMOSPHERE Investigators and Committees. Contemporary Characteristics and Outcomes in Chagasic Heart Failure Compared With Other Nonischemic and Ischemic Cardiomyopathy. Circ Heart Fail. 2017 Nov;10(11):e004361. doi: 10.1161/CIRCHEARTFAILURE.117.004361.

  PMID: 29141857 RESULT

• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.

  PMID: 25176015 RESULT

• Ramires FJA, Martinez F, Gomez EA, Demacq C, Gimpelewicz CR, Rouleau JL, Solomon SD, Swedberg K, Zile MR, Packer M, McMurray JJV. Post hoc analyses of SHIFT and PARADIGM-HF highlight the importance of chronic Chagas' cardiomyopathy Comment on: "Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial" by Bocchi et al. ESC Heart Fail. 2018 Dec;5(6):1069-1071. doi: 10.1002/ehf2.12355. Epub 2018 Oct 9. No abstract available.

  PMID: 30298996 RESULT

• Madrini V Jr, Souza PVR, Fernandes F, Ianni BM, Martins AS, Luzuriaga GJ, Fonseca KCB, Ribeiro ODN, da Cruz AB, Oliveira R, Antunes TL, Pessoa FG, Damiani LP, Quaglio LS, Correia VM, Antunes MO, Mady C, Guimaraes PO, Tavares CAM, Biselli B, Gruppi CJ, Mathias W Jr, Bihan DCSL, Bocchi EA, Lopes RD, Alvarez Ramires FJ; ANSWER-HF Investigators. Sacubitril-Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: Primary Results of ANSWER-HF Randomized Trial. J Am Coll Cardiol. 2025 Nov 9:S0735-1097(25)10064-8. doi: 10.1016/j.jacc.2025.10.053. Online ahead of print.

  PMID: 41396086 DERIVED

Related Links

• Sustaining the drive to overcome the global impact of neglected tropical diseases. Second WHO report on neglected tropical diseases

MeSH Terms

Conditions

Chagas Cardiomyopathy; Heart Failure; Chagas Disease

Interventions

sacubitril; Valsartan; sacubitril and valsartan sodium hydrate drug combination; Enalapril; Angiotensin-Converting Enzyme Inhibitors

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Dipeptides; Oligopeptides; Peptides; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Felix José JA Ramires, MD,PhD

  Instituto do Coração - INCORHCFMUSP

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Felix José A Ramires, MD, PhD

CONTACT

551126615057; felix.ramires@incor.usp.br

Vagner Madrini Junior, MD

CONTACT

1126615057; vagner.madrini@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomization will be carried out by the Heart Institute - School of Medicine of the University of São Paulo (InCor), using a RedCap platform, with blinded randomization being performed 1:1 for each arm of the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The ANSWER-HF will be a clinical, randomized, single-center, prospective, double-blind, controlled study. It will include 200 consecutive participants. This study will evaluate the benefit of sacubitril/valsartan compared with enalapril in patients with HF due to Chagas cardiomyopathy, with reduced ejection fraction(EF). Inclusion criteria are a positive serology for Chagas; age \> 18 years old; NYHA HF and functional class II, III or IV; LVEF \<40% at least in the last 3 months; patients using a beta-blocker with stable dose (1 month) and optimized; and using ACEI or ARB with a stable dose (1 month) and optimized. Exclusion criteria are participants who do not agree to participate in the study or do not want to receive sacubitril/ valsartan; with symptomatic hypotension; with SBP lower than 95 mmHg on randomization; with ClCr less than 30 mL/min; potassium \> 5.2 mmol/L; and with a history of angioedema or who experienced severe side effects with ACE inhibitors.

Study Record Dates

• First Submitted: April 6, 2021
• First Posted: April 21, 2021
• Study Start: May 6, 2021
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: April 4, 2024

Record last verified: 2024-04

Locations

BR (1)