Angiotensin receptor/neprilysin inhibitor: a novel therapy in the treatment of heart failure

Rohini Gupta, Pavan Malhotra, Diwanshu Sharma


Recently US Food and Drug Administration (FDA) approved valsartan/sacubitril is the first angiotensin receptor/neprilysin inhibitor (ARNI) that offers a new standard of treatment to physicians for the patients of heart failure with reduced ejection fraction. Sacubitril is a prodrug which gets activated to sacubitrilat and this inhibits the enzyme neprilysin which is a membrane bound endopeptidase and which in turn is responsible for the degradation of various natriuretic peptides. The action of Valsartan which selectively blocks the angiotensin II type-1 receptor is needed in addition to sacubitril because inhibition of neprilysin is accompanied by the activation of renin-angiotensin system. The combination appears to be a suitable alternative for patients of heart failure with persistent symptoms or with recent exacerbation or hospitalization while on standard optimized treatment. The availability of this novel sacubitril/valsartan combination is an important development in the heart failure management.


Neprilysin, Sacubitril/valsartan, Heart failure, ARNI

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Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation. 2000;102(Suppl IV):14-23.

Maron BA, Rocco TP. Pharmacotherapy of congestive heart failure. Section III: modulation of cardiovascular function. In: Bruton LL, Chabner BA, Knollmann BC (editors), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition. New York: McGraw-Hill Co; 2012:754-75.

Mayo clinic staff. Diseases and conditions: heart failure, 2015. Available at

American Heart Association. Ejection fraction heart failure measurement, 2015. Available at DiagnosisofHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_ 306339_Article.jsp#.

Gheorghiade M, Filippatos G, Felker GM. Diagnosis and management of acute heart failure syndromes. In: Mann DL, Zipes DP, Libby P, Bonow RO (editors), Braunwald's heart disease: a textbook of cardiovascular medicine, 9th edition. Philadelphia: Elsevier; 2012:517-42.

Centers for disease control and prevention. Heart failure fact sheet, 2013. Available at failure.htm.

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC committee for practice guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-847.

Yancy CW, Jessup M, Bozkurt B. ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810-52.

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.

Matsas R, Fulcher IS, Kenny AJ, Turner AJ. Substance P and Leuenkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc Natl Acad Sci USA. 1983;80:3111-5.

Vanneste Y, Michel A, Dimaline R, Najdovski T, Deschodt-Lanckman M. Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site. Biochem J. 1988;254:531-7.

Lang CC, Motwani JG, Coutie WJ, Struthers AD. Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism. Clin Sci (Lond). 1992;82:619-23.

Abassi ZA, Golomb E, Agbaria R, Roller PP, Tate J, Keiser HR. Hydrolysis of iodine labelled urodilatin and ANP by recombinant neutral endopeptidase EC. Br J Pharmacol. 1994;113:204-8.

Brandt RR, Mattingly MT, Clavell AL, Barclay PL, Burnett JC. Neutral endopeptidase regulates C-type natriuretic peptide metabolism but does not potentiate its bioactivity in vivo. Hypertension. 1997;30:184-90.

Cha YM, Dzeja PP, Redfield MM, Shen WK, Terzic A. Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat. Am J Physiol Heart Circ Physiol. 2006;290:H1686-92.

Clerico A, Iervasi G. Alterations in metabolic clearance of atrial natriuretic peptides in heart failure: how do they relate to the resistance to atrial natriuretic peptides? J Card Fail. 1995;1:323-8.

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.

US Food and Drug Administration. FDA approves new drug to treat heart failure. Press release, 2015. Available at Announcements/ucm453845.htm.

US Food and Drug Administration. Diovan new indication approval letter; 2005. Available at

Product information for Entresto. Novartis Pharmaceuticals Co. East Hanover, NJ 07936, 2015. Available at

Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54-61.

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