Clinical Representativeness of the PARADIGM-HF Study in an Outpatient Cohort of Patients with Heart Failure, Including Chagas Disease, Treated According to Guideline-directed Medical Therapy: Prospective Study, in a Single Center in Brazil

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Rose Mary Ferreira Lisboa da Silva
Paulo Vitor Chaves Garcia
Elaine Kimie Iwayama Ikematu


Background: In the PARADIGM-HF trial there was a 20% reduction in hospitalization and cardiovascular mortality in patients with heart failure (HF) and treated according to guideline-directed medical therapy. Eligibility for the use of sacubitril/valsartan in the real world has varied between 12% and 76%. There are no studies on the national scene on this eligibility.

Aims: To investigate the clinical eligibility of the PARADIGM-HF trial in patients with HF in the outpatient clinic of a university institution, which also includes Chagas disease, and to compare the profile of the two populations.

Study Design: This is a single center, prospective, observational study.

Place and Duration of Study: Department of Internal Medicine, Faculty of Medicine, Hospital das Clínicas, Federal University of Minas Gerais, Brazil, duration 6 consecutive months.

Methods and Results: We included 136 consecutive outpatients with HF, 53 women, and mean age of 54.2 years, underwent clinical and laboratory evaluation. The main etiologies of HF were ischemic, Chagas disease and idiopathic. The means of baseline variables were 117.2 mmHg for systolic blood pressure, 78.4 bpm for heart rate, 1.8 for dyspnea functional class, 0.39 for ejection fraction (EF) and 74.2 mL/min for creatinine clearance. The exclusion criteria considered in the PARADIGM-HF trial and present in this study were systolic blood pressure less than 95 mmHg in 15.4% and creatinine clearance less than 30 mL/min in 5.1% of patients. 22.1% had mid-range EF and 55.9% had reduced EF. Comparing this cohort of patients with the population of the PARADIGM-HF trial, age, systolic blood pressure, proportion of male patients, ischemic etiology, hypertension, patients with atrial fibrillation, use of angiotensin-converting enzyme inhibitor, furosemide and beta-blocker were lower in this study (p ≤ 0.01, chi-square and Student's t tests). The proportion of diabetic patients, use of angiotensin receptor blocker, aldosterone antagonist and digoxin were similar between groups as well as proportion of patients with cardiac resynchronization therapy.

Conclusions: Up to 44% of patients in this study did not meet the main randomized trial criteria. Chagas disease was one of the main etiologies. Furthermore, systolic blood pressure, proportion of hypertensive patients was lower, which may have influenced the underutilization of some medications.

Sacubitril/valsartan, angiotensin receptor-neprilysin inhibitor, chronic heart failure, chagas disease, eligibility, guideline-directed medical therapy.

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How to Cite
Silva, R. M. F. L. da, Garcia, P. V. C., & Ikematu, E. K. I. (2020). Clinical Representativeness of the PARADIGM-HF Study in an Outpatient Cohort of Patients with Heart Failure, Including Chagas Disease, Treated According to Guideline-directed Medical Therapy: Prospective Study, in a Single Center in Brazil. Cardiology and Angiology: An International Journal, 9(3), 38-45.
Original Research Article


Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. Authors/Task Force Members; Document Reviewers. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the Special Contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975.

DOI: 10.1002/ejhf.592

Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol. 2017;14(1):30-38.

DOI: 10.1038/nrcardio.2016.163

Hasenfuss G. Pathophysiology of heart failure. In: Libby P, Bonow RO, Mann DL, Zipes DP, (Eds.). Braunwald’s Heart Disease. 11. Ed. Philadelphia: Saunders Elsevier. 2019;2040.

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibi-tion versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.

DOI: 10.1056/NEJMoa1409077

Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70(6):776-803.

DOI: 10.1016/j.jacc.2017.04.025

Rodrigues G, Tralhão A, Aguiar C, Freitas P, Ventosa A, Mendes M. Is the PARADIGM-HF cohort representative of the real-world heart failure patient population? Rev Port Cardiol. 2018;37(6): 491-496.

DOI: 10.1016/j.repc.2017.09.023

Simpson J, Benson L, Jhund PS, Dahlström U, McMurray JJV, Lund LH. "Real World" eligibility for sacubitril/valsartan in unselected heart failure patients: Data from the Swedish heart failure registry. Cardiovasc Drugs Ther. 2019;33(3):315-322.

DOI: 10.1007/s10557-019-06873-1

Kapelios CJ, Lainscak M, Savarese G, Laroche C, Seferovic P, Ruschitzka F, et al. Heart failure long-term registry investigators. Sacubitril/valsartan eligibility and outcomes in the ESC-EORP-HFA heart failure long-term registry: Bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM-HF trial. ESC Guidelines and Real World. Eur J Heart Fail. 2019;21(11):1383-1397.

DOI: 10.1002/ejhf.1532

Coordenação de Avaliação e Monitoramento de Tecnologias – Ministério da Saúde; 2019.


Ramires FJA, Martinez F, Gómez EA, Demacq C, Gimpelewicz CR, et al. 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;5(6):1069-1071.

DOI: 10.1002/ehf2.12355

Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn't. BMJ. 1996;312(7023):71-2.

DOI: 10.1136/bmj.312.7023.71

Pinto G, Tondi L, Gemma M, De Marco A, Silipigni C, Spoladore R, et al. Real-life indications to sacubitril/valsartan treatment in patients with chronic systolic heart failure. J Cardiovasc Pharmacol. 2019;73(5):301-306.

DOI: 10.1097/FJC.0000000000000665

Hsiao FC, Wang CL, Chang PC, Lu YY, Huang CY, Chu PH. Angiotensin receptor Neprilysin inhibitor for patients with heart failure and reduced ejection fraction: Real-world experience from Taiwan. J Cardiovasc Pharmacol Ther. 2020;25(2): 152-157.

DOI: 10.1177/1074248419872958

Norberg H, Bergdahl E, Lindmark K. Eligibility of sacubitril-valsartan in a real-world heart failure population: A community-based single-centre study. ESC Heart Fail. 2018;5(2):337-343.

DOI: 10.1002/ehf2.12251

Silva CP, Del Carlo CH, Oliveira Junior MT, Scipioni A, Strunz-Cassaro C, Ramirez JA, et al. Why do patients with chagasic cardiomyopathy have worse outcomes than those with non-chagasic cardiomyopathy? Arq Bras Cardiol. 2008;91(6):358-62.

DOI: 10.1590/s0066-782x2008001800006

Shen L, Ramires F, Martinez F, Bodanese LC, Echeverría LE, Gómez EA, et al. 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;10(11):e004361.


Martinez F, Perna E, Perrone SV, Liprandi AS. Chagas disease and heart failure: An expanding issue worldwide. Eur Cardiol. 2019;14(2):82-88.

DOI: 10.15420/ecr.2018.30.2

Pellicori P, Urbinati A, Shah P, MacNamara A, Kazmi S, Dierckx R, et al. Proportion of patients with chronic heart failure are eligible for sacubitril-valsartan? Eur J Heart Fail. 2017;19(6):768-778.

DOI: 10.1002/ejhf.788

Han J, Chung F, Nguyen QL, Mody FV, Jackevicius CA. Evaluation of patients with heart failure to determine eligibility for treatment with sacubitril/valsartan: Insights from a veterans administration healthcare system. Pharmacotherapy. 2019;39(11): 1053‐1059.


Nordberg Backelin C, Fu M, Ljungman C. Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting. ESC Heart Fail; 2020.

DOI: 10.1002/ehf2.12644

Epub ahead of print.

Kristensen SL, Martinez F, Jhund PS, Arango JL, Bĕlohlávek J, Boytsov S, et al. Geographic variations in the PARADIGM-HF heart failure trial. Eur Heart J. 2016;37(41):3167-3174.

DOI: 10.1093/eurheartj/ehw226

Bocchi EA, Rassi S, Veiga Guimarães G. Argentine, Chile and Brazil SHIFT investigators. Reply: Sacubitril/valsartan for Chagas' heart disease heart failure? ESC Heart Fail. 2018;5(6):1072-1073.

DOI: 10.1002/ehf2.12344

Bocchi EA, Bestetti RB, Scanavacca MI, Cunha Neto E, Issa VS. Chronic chagas heart disease management: From etiology to cardiomyopathy treatment. J Am Coll Cardiol. 2017;70(12):1510-1524.

DOI: 10.1016/j.jacc.2017.08.004

Smith GH, Shore S, Allen LA, Markham DW, Mitchell AR, Moore M, et al. Discussing out-of-pocket costs with patients: Shared decision making for sacubitril-valsartan in heart failure. J Am Heart Assoc. 2019;8(1):e010635.

DOI: 10.1161/JAHA.118.010635

Sumarsono A, Vaduganathan M, Ajufo E, Navar AM, Fonarow GC, Das SR, et al. Contemporary patterns of medicare and medicaid utilization and associated spending on sacubitril/valsartan and ivabradine in heart failure. JAMA Cardiol. 2019;5(3):336–9.

DOI: 10.1001/jamacardio.2019.4982