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Sacubitril/Valsartan (LCZ696) in Heart Failure

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Book cover Heart Failure

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 243))

Abstract

It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin–angiotensin–aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years – until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all p < 0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ACEI:

Angiotensin-converting enzyme inhibitor

AE:

Adverse event

ANP:

Atrial natriuretic peptide

ARB:

Angiotensin receptor blocker

ARNI:

Angiotensin receptor neprilysin inhibitor

AT1 :

Angiotensin II type 1

AUC:

Area under the plasma concentration curve

bid:

Twice daily

BNP:

B-type natriuretic peptide

BP:

Blood pressure

cGMP:

Cyclic guanosine monophosphate

CI:

Confidence interval

C max :

Maximum plasma concentration

CNP:

C-type natriuretic peptide

CSF:

Cerebrospinal fluid

CV:

Cardiovascular

ED:

Emergency department

EF:

Ejection fraction

eGFR:

Estimated glomerular filtration rate

EMPHASIS-HF:

Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure

HbA1c:

Glycated hemoglobin

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HFrEF:

Heart failure with reduced ejection fraction

HR:

Hazard ratio

hsTnT:

High sensitivity troponin T

KCCQ:

Kansas City Cardiomyopathy Questionnaire

LVEF:

Left ventricular ejection fraction

MAGGIC:

Meta-analysis Global Group in Chronic Heart Failure

MedDRA:

Medical Dictionary for Regulatory Activities

MI:

Myocardial infarction

NEP:

Neprilysin

NEPI:

Neprilysin inhibitor

NNT:

Number needed to treat

NP:

Natriuretic peptide

NPR:

Natriuretic peptide receptor

NT-proBNP:

N-terminal pro B-type natriuretic peptide

NYHA:

New York Heart Association

OATP:

Organic anion transporter protein

PARADIGM-HF:

Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure

PARAMOUNT:

Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction

PP:

Pulse pressure

PRA:

Plasma renin activity

PRC:

Plasma renin concentration

RAAS:

Renin–angiotensin–aldosterone system

SNS:

Sympathetic nervous system

SOLVD:

Studies of Left Ventricular Dysfunction

T max :

Time to peak concentration

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Acknowledgments/Disclosures

Y. Khder, M. P. Lefkowitz, and V. Shi are employees of Novartis, the manufacturer of sacubitril/valsartan. The authors thank Roohi Chopra, Sreedevi Boggarapu, and Ronald B. Langdon (all of Novartis) for the writing and editorial support.

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Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Postfach, 4002, Basel, Switzerland

    Yasser Khder

  2. Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA

    Victor Shi & Martin P. Lefkowitz

  3. British Heart Foundation Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    John J. V. McMurray

Authors
  1. Yasser Khder
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  2. Victor Shi
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  3. John J. V. McMurray
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  4. Martin P. Lefkowitz
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Corresponding author

Correspondence to Yasser Khder .

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Editors and Affiliations

  1. Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover Klinik für Kardiologie und Angiologie, Hannover, Niedersachsen, Germany

    Johann Bauersachs

  2. Heart Institute, Stony Brook University , Stony Brook, New York, USA

    Javed Butler

  3. Heart and Lung Diseases, Bayer Pharma Aktiengesellschaft Heart and Lung Diseases, Wuppertal, Nordrhein-Westfalen, Germany

    Peter Sandner

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Khder, Y., Shi, V., McMurray, J.J.V., Lefkowitz, M.P. (2016). Sacubitril/Valsartan (LCZ696) in Heart Failure. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2016_77

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