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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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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