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

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.

Timeline

Start

2021-05-06

Primary completion

2024-12-01

Completion

2024-12-01

Publications

• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• 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. 2026 Mar 17;87(10):1220-1232. doi: 10.1016/j.jacc.2025.10.053. Epub 2025 Nov 9.

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