• VEERENDRA UPPARA Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research-Autonomous, Anantapur, Andhra Pradesh, India.
  • SAISEKHAR KODIVANDLA Department of Pharmacy Practice, Resident Intern, Raghavendra Institute of Pharmaceutical Education and Research- Autonomous, Anantapur, Andhra Pradesh, India.
  • ASHIK ALI SHAIK Department of Pharmacy Practice, Resident Intern, Raghavendra Institute of Pharmaceutical Education and Research- Autonomous, Anantapur, Andhra Pradesh, India.


Heart failure (HF) is a major global public health problem irrespective of its causes. It generates an enormous clinical, societal, and economic, health loss burden with an increase in its prevalence reaching an epidemic proportion. The morbidity and mortality associated with heart failure are increasing the health-related burdens worldwide, especially in low- and middle-income countries. This review highlights the trends in HF burden, the clinical spectrum of HF, and the importance of neurohormonal pathways and the evolution of angiotensin receptor neprilysin inhibition in HF with updated clinical practice guidelines.

Keywords: Heart failure, Sacubitril/valsartan, Neprilysin, Angiotensin receptor blockers


1. Lippi G, Sanchis-Gomar F. Global epidemiology and future trends of heart failure. AME Med J 2020;5:15.
2. Guha K, McDonagh T. Heart failure epidemiology: European perspective. Curr Cardiol Rev 2013;9:123-7.
3. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372:1333-41.
4. Conard N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal trends and patterns in heart failure incidence: A population-based study of 4 million individuals. Lancet 2018;391:572-80.
5. Cleland JG, van Veldhuisen DJ, Ponikowski P. The year in cardiology 2018: Heart failure. Eur Heart J 2019;40:651-61.
6. Ferreira JP, Kraus S, Mitchell S, Perel P, Piñeiro D, Chioncel O, et al. World heart federation roadmap for heart failure. Glob Heart 2019;14:197-214.
7. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: A report from the American heart association. Circulation 2019;139:e56-528.
8. Weiwei C, Runlin G, Lisheng L, Manlu Z, Wen W, Yongjun W, et al. Outline of the report on cardiovascular diseases in China, 2014. Eur Heart J Suppl 2016;18:F2-11.
9. Huffman MD, Prabhakaran D. Heart failure: Epidemiology and prevention in India. Natl Med J India 2010;23:283-8.
10. Gupta R, Joshi P, Mohan V, Reddy KS, Yusuf S. Epidemiology and causation of coronary heart disease and stroke in India. Heart 2008;94:16-26.
11. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 2000;342:145-53.
12. Fox KM, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8.
13. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2010 update: A report from the American heart association. Circulation 2010;121:e46-215.
14. Harikrishnan S, Sanjay G, Anees T, Viswanathan S, Vijayaraghavan G, Bahuleyan CG, et al. Clinical presentation, management, in-hospital and 90-day outcomes of heart failure patients in Trivandrum, Kerala, India: The Trivandrum heart failure registry. Eur J Heart Fail 2015;17:794-800.
15. Grigaliunas G, Lycholip E, Burneikait? G, Grigali?nien? A, Kaklauskait? G, Ma?i?nas R, et al. Heart failure awareness: A cross-sectional study on misconceptions and educational opportunities. Semin Cardiovasc Med 2018;24:9-15.
16. Callender T, Woodward M, Roth G, Farzadfar F, Lemarie JC, Gicquel S, et al. Heart failure care in low-and middle-income countries: A systematic review and meta-analysis. PLoS Med 2014;11:e1001699.
17. Lainscak M, Letonja M, Kovacic D, Hodoscek LM, Marolt A, Bartolic CM, et al. General public awareness of heart failure: Results of questionnaire survey during heart failure awareness day 2011. Arch Med Sci 2014;10:355-60.
18. Störk S, Kavoliuniene A, Vinereanu D, Ludwig R, Seferovic P, Dickstein K, et al. What does the lay public know about heart failure? Findings from the heart failure awareness day initiative. Eur J Heart Fail 2010;12:1076-84.
19. Remme WJ, McMurray JJ, Hobbs FD, Cohen-Solal A, Lopez-Sendon J, Boccanelli A, et al. Awareness and perception of heart failure among European cardiologists, internists, geriatricians, and primary care physicians. Eur Heart J 2008;29:1739-52.
20. Remme WJ, McMurray JJ, Rauch B, Zannad F, Keukelaar K, Cohen-Solal A, et al. Public awareness of heart failure in Europe: First results from SHAPE. Eur Heart J 2005;26:2413-21.
21. Lam CS, Teng TK, Tay WT, Anand I, Zhang S, Shimizu W, et al. Regional and ethnic differences among patients with heart failure in Asia: The Asian sudden cardiac death in heart failure registry. Eur Heart J 2016;37:3141-53.
22. Dokainish H, Teo K, Zhu J, Roy A, Al Habib KF, El Sayed A, et al. Global mortality variations in patients with heart failure: Results from the international congestive heart failure (INTER-CHF) prospective cohort study. Lancet Glob Health 2017;5:e665-72.
23. Dewan P, Jhund PS, Shen L, Petrie MC, Abraham WT, Ali MA, et al. Heart failure with reduced ejection fraction: Comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe, and the Americas. Eur J Heart Fail 2019;21:577-87.
24. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347:305-13.
25. Reddy KS, Prabhakaran D, Shah P, Shah B. Differences in body mass index and waist: Hip ratios in North Indian rural and urban populations. Obes Rev 2002;3:197-202.
26. Rodgers A, Ezzati M, Hoorn SV, Lopez AD, Lin RB, Murray CJ, Comparative Risk Assessment Collaborating Group. Distribution of major health risks: Findings from the global burden of disease study. PLoS Med 2004;1:e27.
27. Thakur JS, Negi PC, Ahluwalia SK, Vaidya NK. Epidemiological survey of rheumatic heart disease among school children in the Shimla hills of Northern India: Prevalence and risk factors. J Epidemiol Community Health 1996;50:62-7.
28. Manyemba J, Mayosi BM. Penicillin for secondary prevention of rheumatic fever. Cochrane Database Syst Rev 2002;3:CD002227.
29. Ali MK, Narayan KM, Mohan V. Innovative research for equitable diabetes care in India. Diabetes Res Clin Pract 2009;86:155-67.
30. Gerber Y, Weston SA, Redfield MM, Chamberlain AM, Manemann SM, Jiang R, et al. A contemporary appraisal of the heart failure epidemic in Olmsted county, Minnesota, 2000 to 2010. JAMA Intern Med 2015;175:996-1004.
31. Greenberg B. Angiotensin receptor-neprilysin inhibitor (ARNI) in heart failure. Int J Heart Fail 2020;2:73-90.
32. Ahmed M, Morrissey H, Ball PA. Mental ill-health and heart failure comorbidity. Int J Curr Pharm Res 2019;11:11-7.
33. Deora S, Goswami KC. Angiotensin receptor neprilysin inhibitor for all with heart failure with reduced ejection fraction. In: Ganguly K, Roy D, editors. Cardiology Society of India. Ch. 86. New Delhi: Evangel Publishing; 2020. p. 655-6.
34. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 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 Heart J 2016;37:2129-200.
35. Reed BN, Street SE, Jensen BC. Time and technology will tell: The pathophysiological basis of neurohormonal modulation in heart failure. Heart Fail Clin 2104;10:543-57.
36. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:2007-18.
37. Serneri GG, Boddi M, Cecioni I, Vanni S, Coppo M, Papa ML, et al. Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res 2001;88:961-8.
38. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987;59:59A-65.
39. Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens 1991;9:17-22.
40. Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: Evidence for an aldosterone-induced vasculopathy. Clin Sci 2002;103:425-31.
41. Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: Implications for therapy. Eur J Heart Fail 2017;19:167-76.
42. Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment. Clin Sci (Lond) 2016;130:57-77.
43. Hata N, Seino Y, Tsutamoto T, Hiramitsu S, Kaneko N, Yoshikawa T, et al. Effects of carperitide on the long-term prognosis of patients with acute decompensated chronic heart failure: The PROTECT multicenter randomized controlled study. Circ J 2008;72:1787-93.
44. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43.
45. Clarkson PB, Wheeldon NM, Macleod C, Coutie W, MacDonald TM. Brain natriuretic peptide: Effect on left ventricular filling patterns in healthy subjects. Clin Sci (Lond) 1995;88:159-64.
46. Colucci WS, Elkayam U, Horton DP, Abraham WT, Bourge RC, Johnson AD, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246-53.
47. Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA 2013;310:2533-43.
48. Abraham WT, Cheng ML, Smoluk G, Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) Study Group. Clinical and hemodynamic effects of nesiritide (B-type natriuretic peptide) in patients with decompensated heart failure receiving beta-blockers. Congest Heart Fail 2005;11:59-64.
49. Keating GM, Goa KL. Nesiritide: A review of its use in acute decompensated heart failure. Drugs 2003;63:47-70.
50. Colucci WS. Nesiritide for the treatment of decompensated heart failure. J Card Fail 2001;7:92-100.
51. Riter HG, Redfield MM, Burnett JC, Chen HH. Nonhypotensive low-dose nesiritide has differential renal effects compared with standard-dose nesiritide in patients with acute decompensated heart failure and renal dysfunction. J Am Coll Cardiol 2006;47:2334-5.
52. Owan TE, Chen HH, Frantz RP, Karon BL, Miller WL, Rodeheffer RJ, et al. The effects of nesiritide on renal function and diuretic responsiveness in acutely decompensated heart failure patients with renal dysfunction. J Card Fail 2008;14:267-75.
53. Mitrovic V, Seferovic P, Simeunovic D, Ristic AD, Miric M, Moiseyev VS, et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J 2006;27:2823-32.
54. Packer M, O’Connor C, McMurray JJ, Wittes J, Abraham WT, Anker SD, et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med 2017;376:1956-64.
55. Potter LR. Natriuretic peptide metabolism, clearance, and degradation. FEBS J 2011;278:1808-17.
56. Kerr MA, Kenny AJ. The purification and specificity of a neutral endopeptidase from the rabbit kidney brush border. Biochem J 1974;137:477-88.
57. Bayes-Genis A, Barallat J, Richards AM. A test in context: Neprilysin: Function, inhibition, and biomarker. J Am Coll Cardiol 2016;68:639-53.
58. McKinnie SM, Fischer C, Tran KM, Wang W, Mosquera F, Oudit GY, et al. The metalloprotease neprilysin degrades and inactivates apelin peptides. ChemBioChem 2016;17:1495-8.
59. Newby DE, McDonagh T, Currie PF, Northridge DB, Boon NA, Dargie HJ. Candoxatril improves exercise capacity in patients with chronic heart failure receiving angiotensin-converting enzyme inhibition. Eur Heart J 1998;19:1808-13.
60. Northridge DB, Currie PF, Newby DE, McMurray JJ, Ford M, Boon NA, et al. Placebo-controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure. Eur J Heart Fail 1999;1:67-72.
61. Northridge DB, Newby DE, Rooney E, Norrie J, Dargie HJ. Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure. Am Heart J 1999;138:1149-57.
62. Westheim AS, Bostrøm P, Christensen CC, Parikka H, Rykke EO, Toivonen L. Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild stable chronic heart failure. J Am Coll Cardiol 1999;34:1794-801.
63. Bevan EG, Connell JM, Doyle J, Carmichael HA, Lorimer AR,McInnes GT. Candoxatril, a neutral endopeptidase inhibitor: Efficacy and tolerability in essential hypertension. J Hypertens 1992;10:607-13.
64. Ferro CJ, Spratt JC, Haynes WG, Webb DJ. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation 1998;97:2323-30.
65. Dalzell JR, Seed A, Berry C, Whelan CJ, Petrie MC, Padmanabhan N, et al. Effects of neutral endopeptidase (neprilysin) inhibition on the response to other vasoactive peptides in small human resistance arteries: Studies with thiorphan and omapatrilat. Cardiovasc Ther 2014;32:13-8.
66. Packer M, Califf RM, Konstam MA, Krum H, McMurry JJ, Rouleau JL, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: Omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE). Circulation 2002;106:920-6.
67. Sheth T, Parker T, Block A, Hall C, Adam A, Pfeffer MA, et al, IMPRESS Investigators. Comparison of the effects of omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure. Am J Cardiol 2002;90:496-500.
68. Nathisuwan S, Talbert RL. A review of vasopeptidase inhibitors: A new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy 2002;22:27-42.
69. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomized trial. Lancet 2000;356:615-20.
70. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat, and enalapril in patients with hypertension: The omapatrilat cardiovascular treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-11.
71. Feng L, Karpinski PH, Sutton P, Liu Y, Hook DF, Hu B, et al. LCZ696: A dual-acting sodium supramolecular complex. Tetrahedron Lett 2012;53:275-6.
72. Bloch MJ, Basile JN. Combination angiotensin receptor blocker-neutral endopeptidase inhibitor provides additive blood pressure reduction over angiotensin receptor blocker alone. J Clin Hypertens (Greenwich) 2010;12:809-12.
73. Hubers SA, Brown NJ. Combined angiotensin receptor antagonism and neprilysin inhibition. Circulation 2016;133:1115-24.
74. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail 2014;2:663-70.
75. Chrysant SG. Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: Sacubitril/valsartan. J Am Soc Hypertens 2017;11:461-8.
76. Segura J, Salazar J, Ruilope LM. Dual neurohormonal intervention in CV disease: Angiotensin receptor and neprilysin inhibition. Expert Opin Investig Drugs 2013;22:915-25.
77. Gu J, Noe A, Chandra P, Al-Fayoumi S, Saylan ML, Sarangapani R, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50:401-14.
78. Kobalava Z, Kotovskaya Y, Averkov O, Pavlikova E, Moiseev V, Albrecht D, et al. Pharmacodynamic and pharmacokinetic profiles of sacubitril/valsartan (LCZ696) in patients with heart failure and reduced ejection fraction. Cardiovasc Ther 2016;34:191-8.
79. Ayalasomayajula S, Langenickel TH, Pal P, Boggarapu S, Sunkara G. Clinical pharmacokinetics of sacubitril/valsartan (LCZ696): A novel angiotensin receptor-neprilysin inhibitor. Clin Pharmacokinet 2017;56:1461-78.
80. Ayalasomayajula S, Langenickel TH, Chandra P, Wolfson ED, Albrecht D, Zhou W, et al. Effect of food on the oral bioavailability of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects. Int J Clin Pharmacol Ther 2016;54:1012-18.
81. Minguet J, Sutton G, Ferrero C, Gomez T, Bramlage P. LCZ696: A new paradigm for the treatment of heart failure? Expert Opin Pharmacother 2015;16:435-46.
82. Prasad PP, Yeh CM, Gurrieri P, Glazer R, McLeod J. Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol 2002;40:801-7.
83. Fala L. Entresto (sacubitril/valsartan): First-in-class angiotensin receptor neprilysin inhibitor FDA approved for patients with heart failure. Am Health Drug Benefits 2015;8:330-4.
84. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: Rationale for and design of the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062-73.
85. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: Mortality bang for your buck. J Clin Pharm Ther 2016;41:119-27.
86. Bruhn C. Angiotensin-receptor- and neprilysin-inhibition: A new option against heart failure. Med Monatsschr Pharm 2016;39:4-8.
87. King JB, Shah RU, Bress AP, Nelson RE, Bellows BK. Cost-effectiveness of sacubitril-valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2016;4:392-402.
88. Ollendorf DA, Sandhu AT, Chapman R, Heidenreich PA, Russo E, Shore KK, et al. CardioMEMSTM HF system (St. Jude Medical Inc.) and Sacubitril/Valsartan (Entresto ™, Novartis AG) for Management of Congestive Heart Failure: Effectiveness, Value, and Value-based Price Benchmarks: Final Report. Institute for Clinical and Economic Review; 2015. Available from: https://www.collections.nlm.nih.gov/catalog/ nlm:nlmuid-101672986-pdf.
89. Gaziano TA, Fonarow GC, Claggett B, Chan WW, Voinet CD, Turner SJ, et al. Cost-effectiveness analyses of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol 2016;1:666-72.
90. Ademi Z, Pfeil AM, Hancock E, Trueman D, Haroun RH, Deschaseaux C, et al. Cost-effectiveness of sacubitril/valsartan in chronic heart failure patients with reduced ejection fraction. Swiss Med Wkly 2017;147:w14533.
91. Liang L, Wu DB, Aziz MI, Wong R, Sim D, Leong KT, et al. cost-effectiveness of sacubitril/valsartan versus enalapril in patients with heart failure and reduced ejection fraction. J Med Econ 2018;21:174-81.
92. 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;70:776-803.
21 Views | 56 Downloads
How to Cite
UPPARA, V., S. KODIVANDLA, and A. ALI SHAIK. “A REVIEW ON GLOBAL TRENDS IN HEART FAILURE AND EVOLUTION OF ANGIOTENSIN–NEPRILYSIN INHIBITOR”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 13, no. 12, Dec. 2020, pp. 32-37, doi:10.22159/ajpcr.2020.v13i12.39503.
Review Article(s)