UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Use of angiotensin receptor-neprilysin inhibitor in heart failure with reduced ejection fraction

Author
Mark H Drazner, MD, MSc
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC

INTRODUCTION

Blockade of the renin-angiotensin-aldosterone system is a key component of treatment of patients with heart failure with reduced ejection fraction (HFrEF, also known as systolic HF or HF due to systolic dysfunction) [1-3]. Augmentation of beneficial counter-regulatory systems such as natriuretic peptides is an additional strategy to treat HF [4]. Inhibition of neprilysin raises levels of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. The combination of neprilysin inhibitor plus angiotensin II receptor blocker (ARB) therapy is used as an alternative to angiotensin converting enzyme (ACE) inhibitor (or single agent ARB) therapy.  

This topic will discuss the clinical evidence on and use of the combination of ARB and neprilysin inhibitor (known as angiotensin receptor-neprilysin inhibitor or ARNI) therapy in HFrEF. The role of ACE inhibitors in HFrEF and an overview of pharmacologic treatment of HFrEF are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and "ACE inhibitors in heart failure with reduced ejection fraction: Therapeutic use" and "Overview of the therapy of heart failure with reduced ejection fraction".)

MECHANISM OF ACTION

Detrimental neurohormonal activation involving the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system is a key target for heart failure (HF) therapy. Augmentation of beneficial counter-regulatory systems such as natriuretic peptides is an additional strategy to treat HF [4]. Inhibition of neprilysin (a neutral endopeptidase) raises levels of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin and may thus have beneficial hemodynamic effects in patients with HF. This approach differs from the administration of nesiritide (B-type natriuretic peptide) in the setting of acute HF, which did not improve clinical outcomes in the ASCEND-HF trial, as discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and "Nesiritide in the treatment of acute decompensated heart failure", section on 'Clinical trials'.)

Importantly, neprilysin, in addition to degrading counter-regulatory vasoactive peptides thought to be favorable in the setting of heart failure (ie, natriuretic peptides), also degrades the deleterious neurohormone angiotensin II. Ecadotril, a pure neprilysin inhibitor, was found not to be beneficial in HF patients [5].  

Strategies were then undertaken to inhibit both neprilysin and the RAAS system. Ompatrilat was a compound that inhibited neprilysin, angiotensin converting enzyme (ACE), and aminopeptidase P. The commercial development of this compound was halted due to an unacceptably high rate of angioedema [], attributed to an increase in bradykinin levels, which occurred since neprilysin, ACE, and aminopeptidase P each degrade bradykinin [6]. This is an important outcome to remember for it emphasizes the need to avoid concomitant neprilysin inhibition and ACE inhibition when treating patients with HF.  

           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Apr 27, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 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:e240.
  2. Ponikowski P, Voors AA, Anker SD, 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.
  3. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An 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 2016; 68:1476.
  4. McMurray JJ, Packer M, Desai AS, 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.
  5. Cleland JG, Swedberg K. Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. The International Ecadotril Multi-centre Dose-ranging Study Investigators. Lancet 1998; 351:1657.
  6. Fryer RM, Segreti J, Banfor PN, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol 2008; 153:947.
  7. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf (Accessed on July 22, 2015).
  8. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371:993.
  9. Packer M, McMurray JJ, Desai AS, 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.
  10. Desai AS, Claggett BL, Packer M, et al. Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. J Am Coll Cardiol 2016; 68:241.
  11. Moe GW, Ezekowitz JA, O'Meara E, et al. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol 2015; 31:3.
  12. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An 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. Circulation 2016; 134:e282.
  13. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585.
  14. Feldman AM, Haller JA, DeKosky ST. Valsartan/Sacubitril for Heart Failure: Reconciling Disparities Between Preclinical and Clinical Investigations. JAMA 2016; 315:25.
  15. Cannon JA, Shen L, Jhund PS, et al. Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. Eur J Heart Fail 2017; 19:129.