Sacubitril/valsartan: from the PARADIGM-HF trial results to heart failure patients in internal medicine. A narrative review


Data regarding the treatment of heart failure (HF) patients derived from randomized, controlled clinical trials, which, with rare exceptions, appear to be distant from the real world of internal medicine. Many trials have been conducted in cardiology departments: however, the characteristics of patients admitted to cardiology wards are largely different from those of patients hospitalized in internal medicine wards. Recently, the PARADIGM-HF study established the efficacy of sacubitril-valsartan – the first drug of the angiotensin II receptor neprilysin inhibitor (ARNI) class - versus enalapril in increasing survival and reducing hospitalizations in a selected population of HF patients with reduced ventricular function. Although practical guidance on the use of ARNI has been published, it is not specific to HF patients admitted to internal medicine wards. In this review, we examine all available data in order to understand if the characteristics of HF patients followed in internal medicine departments hinder or contraindicate the use of sacubitril-valsartan and what indications appear more appropriate in this setting.



PlumX Metrics


Download data is not yet available.


Swedberg K, Cleland J, Dargle H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). The task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005;26:1115-40. DOI:

Ministero della Salute. Rapporto annuale sull’attività di ricovero ospedaliero (Dati SDO 2016). Available from:

Lewis KS, Butler J, Bauersachs J, Sandner P. The three-decade long journey in heart failure drug development. Handb Exp Pharmacol 2017;243:1-14.

Brenner H, Bouvier AM, Foschi R, et al. Progress in colorectal cancer survival in Europe from the late 1980s to the early 21st century: the EUROCARE study. Int J Cancer 2012;131:1649-58. DOI:

Coleman MP, Forman D, Bryant H, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet 2011;377:127-38. DOI:

Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012;62:220-41. DOI:

Murdoch DR, Love MP, Robb SD, et al. Importance of heart failure as a cause of death: changing contribution to overall mortality and coronary heart disease mortality in Scotland 1979-1992. Eur Heart J 1998;19:1829-35. DOI:

Cleland JG, Gemmell I, Khand A, Boddy A. Is the prognosis of heart failure improving? Eur J Heart Fail 1999;1:229-41. DOI:

Wilhelmsen L, Rosengren A, Eriksson H, Lappas G. Heart failure in the general population of men-morbidity, risk factors and prognosis. J Intern Med 2001;249:253-61. DOI:

Cowie MR, Wood DA, Coats AJ, et al. Incidence and aetiology of heart failure; a population-based study. Eur Heart J 1999;20:421-28. DOI:

McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.

Liu RC. Focused treatment of heart failure with reduced ejection fraction using sacubitril/valsartan. Am J Cardiovasc Drugs 2018;18:473-82. DOI:

Sauer AJ, Cole R, Jensen BC, et al. Practical guidance on the use of sacubitril/valsartan for heart failure. Heart Fail Rev 2019;24:167-76. DOI:

Maggioni AP, Orso F, Calabria S, et al. The real-world evidence of heart failure: findings from 41,413 patients of the ARNO database. Eur J Heart Fail 2016;18:402-10. DOI:

Marangoni E, Lissoni F, Raimondi Cominesi I, Tinelli S. Epidemiologia, impatto organizzativo e costi dello scompenso cardiaco in Italia. G Ital Cardiol 2012;13:139-44.

Di Lenarda A, Scherillo M, Maggioni AP, et al. Current presentation and management of heart failure in cardiology and internal medicine hospital units: A tale of two worlds - The TEMISTOCLE study. Am Heart J 2003;146:e12:1-10. DOI:

Pérez-Belmonte LM, Zafra FJ, Pérez-Diaz JM, et al. Heart failure in internal medicine and cardiology: epidemiological and clinical characteristics. Eur J Intern Med 2013;24:e16. DOI:

Petrovic V, Ibrahim S, Palda VA. A tale of two specialties: differences between heart failure patients admitted to internal medicine and cardiology. CJGIM 2013;8:4-7.

Verdiani V, Panigada G, Fortini A, et al. The heart failure in internal medicine in Tuscany: the SMIT Study. Ital J Med 2015;9:349-55. DOI:

Ponikowsky P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; doi:10.1093/eurheartj/ehw128. DOI:

Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation. 2017;136:e137-61. DOI:

Jhund PS, McMurray JJV. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016;102:1342-47. DOI:

Jhund PS, Fu M, Bayrman E, Chen CH, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576-84. DOI:

Lewis EF, Claggett BL, McMurray JJV, et al. Health- related quality of life outcomes in PARADIGM-HF. Circ Heart Fail 2017; doi:10.1161/CIRCHEARTFAILURE.116.003430. DOI:

Chandra A, Lewis EF, Claggett BL, et al. Effects of sacubitril/valsartan on physical and social activity limitations in heart failure patients: a secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol 2018;3:498-505. DOI:

Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with decompensated heart failure: a report from the ADERE database. J Cardiac Fail 2007;13:422-30. DOI:

Ecder T. Renal and metabolic effects of valsartan. Kardiyol Derg 2014;14:S14-9. DOI:

Wong PC, Guo J, Zhang A. The renal and cardiovascular effects of natriuretic peptides. Adv Physiol Educ 2017;41:179-85. DOI:

Voors AA, Gori M, Liu LC, et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in heart failure patients and preserved ejection fraction. Eur J Heart Fail 2015;17:510-7. DOI:

Senni M, McMurray JJV, Wachter R, et al. Initatiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 2016;18:1193-202. DOI:

Damman K, Gori M, Claggett B, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. J Am Coll Cardiol HF 2018;6:489-98. DOI:

Biagi P, Gussoni G, Iori I, et al. Clinical profile and predictors of in-hospital outcome in heart failure patients. The FADOI-CONFINE Study. Int J Cardiol 2011;152:88-94. DOI:

Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in heart failure patients and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5:333-40. DOI:

Birkenfeld AL, Boschmann M, Moro C, et al. Lipid mobilization with physiological atrial natriuretic peptide concentrations in humans. J Clin Endocrinol Metab 2005;90:3622-28. DOI:

Birkenfeld AL, Budziarek P, Boschmann M, et al. Atrial natriuretic peptide induces postprandial lipid oxidation in humans. Diabetes 2008;57:3199-204. DOI:

Coué M, Badin PM, Vila IK, et al. Defective natriuretic peptide receptor signaling in skeletal muscle links obesity to type 2 diabetes. Diabetes 2015;64:4033-45. DOI:

Engeli S, Birkenfeld AL, Badin PM, et al. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J Clin Invest 2012;122:4675-9. DOI:

Gheorghiade M, Vaduganathan M, Ambrosy A, et al. Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure. Heart Fail Rev 2013;18:107-22. DOI:

Bӧhm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 2017;38:1132-43. DOI:

Vardeny O, Claggett B, Kachadourian J, et al. Incidence, predictors, and outcomes associated with hypotensive episodes among heart failure patients receiving sacubitril/valsartan or enalapril: the PARADIGM-HF Trial. Circ Heart Fail 2018;11:e004745. DOI:

Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretics use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail 2019;21:337-341. DOI:

Cermakova P, Eriksdotter M, Lund LH, et al. Heart failure and Alzheimer’s disease. J Intern Med 2015;277:406-25. DOI:

Vodovar N, Paquet C, Mebazaa A, et al. Neprilysin, cardiovascular, and Alzheimer’s desease: the therapeutic split? Eur Heart J 2015;36:902-5. DOI:

McMurray JJ, Packer M, Solomon SD. Neprilysin inhibition for heart failure. N Engl J Med 2014;371:2336-7. DOI:

Patel N, Gluck J. Is Entresto good for the brain? World J Cardiol 2017;9:594-9. DOI:

Cannon JA, McMurray JJ, Quinn TJ. “Heart and minds”: association, causation and implication of cognitive impairment in heart failure. Alzheimer Res Ther 2015;7:22. DOI:

Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness N Engl J Med 2013;369:1306-16. DOI:

Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009;302:1658-65. DOI:

Hernandez AF, Mi X, Hammill BG, et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among heart failure patients and reduced ejection fraction. JAMA 2012;308:2097-107. DOI:

Bress AP, King JB, Brixner D, et al. Pharmacotherapy treatment patterns, outcomes, and health resource utilization among heart failure patients with reduced ejection fraction at a U.S. Academic Medical Center. Pharmacotherapy 2016;36:174-86. DOI:

Ferreira JP, Rossignol P, Machu JL, et al. Mineralcorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail 2017;19:1284-93. DOI:

Patterson SJ, Reaves AB, Tolley EA, et al. Underutilization of aldosterone antagonists in heart failure. Hosp Pharm 2017;52:698-703. DOI:

Fortini A, Verdiani V, Panigada G, et al. Triple therapy at discharge from internal medicine wards in heart failure patients with reduced ejection fraction: results from an observational study. Clin Ter 2018;169:e287-91.

Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication on the randomized aldactone evaluation study. N Engl J Med 2004;351:543-51. DOI:

Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-92. DOI:

Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralcorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril. A secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol 2017;2:79-85. DOI:

Jankowska EA, Ponikowska B, Majda J, et al. Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol 2007;115:151-5. DOI:

Palazzuoli A, Ruocco G, Pellegrini M, et al. Prognostic significance of hyperuricaemia in patients with acute heart failure. Am J Cardiol 2016;117:1616-21. DOI:

Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest 2014;44:573-8. DOI:

Mogensen UM, Køber L, Jhund PS, et al. Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF. Eur J Heart Fail 2018;20:514-22. DOI:

Vardeny O, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan vs enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail 2016;18:1228-34. DOI:

Okumura N, Jhund PS, Gong J, et al. Effects of sacubitril/valsartan in the PARADIGM-HF Trial (prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure) according to background therapy. Circulation Heart Fail 9:e003212. DOI:

Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin- Neprylisin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539-48. DOI:

Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction after hemodynamic stabilization: primary results of the TRANSITION study. Eur Heart J 39;Suppl1:886. DOI:

Heart failure, angiotensin receptor neprilysin inhibitor, therapy, elderly, hospitalized patients.
  • Abstract views: 74

  • PDF: 71
  • HTML: 0
How to Cite
Verdiani, V. (2021). Sacubitril/valsartan: from the PARADIGM-HF trial results to heart failure patients in internal medicine. A narrative review. Italian Journal of Medicine, 15(1).