THE ROLE OF NEPRILISYN INHIBITOR IN

HEART FAILURE MANAGEMENT

Yudi Her Oktaviono

Department of Cardiology and Vascular Medicine
DR. Soetomo Teaching Hospital
Faculty of Medicine-Airlangga University,
Surabaya, Indonesia

1
 Heart failure definition

• ESC 2016: HF is a clinical syndrome

characterized by typical symptoms that
may be accompanied by signs caused
by a structural and/or functional cardiac
abnormality, resulting in a reduced
cardiac output and/ or elevated
intracardiac pressures at rest or during
Left
stress 1 atrium

• ACCF/AHA 2013: HF is a complex Right

atrium
clinical syndrome that results from any Left
structural or functional impairment of ventricle

ventricular filling or ejection of blood2 Right

ventricle

ESC:
2 European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation
1. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200; 2. Yancy et al. JACC 2013;62:e147–239
2
 The pathophysiology of chronic HF

Damage to cardiac myocytes and extracellular matrix leads to

changes in the size, shape and function of the heart (remodeling)
and cardiac wall stress

These changes lead to systemic neurohormonal imbalance

This may lead to fibrosis, apoptosis, hypertension, hypertrophy,

cellular and molecular alterations, myotoxicity

Remodeling and progressive Hemodynamic alterations,

worsening of LV function salt and water retention

Morbidity and mortality HF symptoms

arrhythmias, pump failure dyspnea, edema, fatigue

LV=left
3 ventricular
McMurray. N Engl J Med 2010;362:228–38; Francis et al. Ann Intern Med 1984;101:370–7; Krum, Abraham. Lancet 2009;373:941–55
3
 HFrEF and HFpEF
Heart failure definition

Systolic dysfunction Diastolic dysfunction

HFrEF HFmEF HFpEF

LVEF≤ 40% LVEF 40-49% LVEF ≥ 50%

Echocardiography is a useful method for evaluating left ventricular ejection fraction

HFpEF: heart failure with preserved ejection fraction, HFmEF : heart failure with mid-range ejection frection
Ponikowski
4 et al. Eur Heart J 2016; 37(27): 2129-2200; McMurray et al. Eur Heart J 2012;33:1787–847;
Dickstein et al. Eur Heart J 2008;29:2388–442
4
 Patterns of ventricular remodeling are
different for HFrEF and HFpEF

Left ventricle
normal

HFrEF HFpEF
Volume Pressure
HFrEF – a condition of HFpEF – a condition of
overload overload
volume overload pressure overload
• characterized by Increased Increased • characterized by
diastolic pressure systolic pressure
eccentric hypertrophy concentric hypertrophic
growth
• results in thinning of the Increased Increased
LV walls, decreased diastolic wall stress systolic wall stress • results in normal sized
systolic function and − LV cavity with thickened
Series addition of new Parallel addition
enlarged LV volume sarcomeres of new myofibrils − walls and preserved
systolic function
Chamber Wall
enlargement thickening

Eccentric Concentric
hypertrophy hypertrophy
Left ventricle Left ventricle
volume pressure
overload overload

LV=left ventricular; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction
Adapted from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008;
Figure
5 reproduced with permission from Grossman W, et al. In: Perspectives in Cardiovascular Research; Myocardial Hypertrophy
and Failure. Vol 7. Edited by Alpert NR. New York: Raven Press; 1993:1–15. Copyright © 1993 Wolters Kluwer Health
5
Decline in systolic function leads to activation of three
major neurohormonal systems
Sympathetic
nervous system
Epinephrine α 1, β1, β2
Norepinephrine receptors

Vasoconstriction
RAAS activity
Natriuretic peptide Vasopressin
system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs

Vasodilation
Blood pressure Renin-angiotensin-
Sympathetic tone aldosterone system
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone
Fibrosis Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

Levin et al. N Engl J Med 1998;339:321–8. Nathisuw an & Talbert.

Ang=angiotensin; AT1R=angiotensin II type 1 receptor; Pharmacotherapy 2002;22:27–42 . Kemp & Conte. Cardiovascular
6 HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide Pathology 2012;365–71 . Schrier & Abraham. N Engl J Med
receptors; RAAS=renin-angiotensin-aldosterone system 1999;341:577–85. Volpe et al., Clin Science, 2016: 130:57-77
Sympathetic (or adrenergic) nervous system

 SNS exerts its effects mainly via

release of
• Norepinephrine by cardiac
nerve terminals
• Epinephrine
by adrenal glands
 Elevated SNS activation in HF
causes enhanced GRK2
mediated cardiac b1AR and
b 2AR desensitisation and b1AR
downregulation leading to
progressive depletion of
adrenergic and inotropic
reserves of the heart

AC=adeny late cy clase; Ach=acety lcholine; Aldo=aldosterone; AR=adrenergic receptor;

ATP=adenosine triphosphate; cAMP=cy clic adenosine monophosphate; Epi=epinephrine;
Gi/o=inhibitory /other G protein; Gs= stimulatory G protein; GRK2=G protein–coupled receptor kinase
7 2; MR=mineralocorticoid receptor; NE=norepinephrine; NET=norepinephrine transporter; PKA=protein
kinase A Lymperopoulos et al.., Circ Res 2013;113:739–53.
RAAS: Initially compensatory and subsequently
pathological in HF
Angiotensinogen
Renin
Ang I
ACEIs ACE Direct renin
RAAS suppression is an effective Ang II inhibitors*
strategy in treating HF
ARBs
AT1 receptor

Signalling
cascade

Biological actions

MRAs

Hypertrophy Vasoconstriction Aldosterone Na +/H2O ADH Norepinephrine release

Fibrosis hypertrophy secretion retention Secretion Sympathetic tone

Cardiac remodeling Blood Blood volume Heart rate

Myocyte necrosis Pressure Contractility

ACE=angiotensin-conv erting enzy me; ACEI=angiotensin-conv erting-enzy me inhibitor; Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier and Abraham. N
ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; MRA=mineralocorticoid Engl J Med 1999;341:577–85; Brewster et al. Am J Med Sci 2003;326:15–24;
8 Schmieder. Am J Hy pertens 2005;18:720–30; McMurray et al. Eur Heart J
receptor antagonist; RAAS=renin-angiotensin-aldosterone sy stem 2012;33:1787–847 Francis et al. Ann Intern Med 1984;101:370–7;
Von Lueder et al. Circ Heart Fail 2013;6:594–605.
Natriuretic peptides have potential beneficial
actions in HF
Release of ANP and BNP from heart and CNP in vasculature1,2

 Sympathetic outflow2
 Vasopressin2 ANP/BNP2
 Salt appetite and water intake 2
CNP
(endothelium)3

Relaxation;  arterial stiffness 4

 Hypertrophy2, 4
 Fibroblast proliferation4,

 Na+/H2O loss2 Vasodilation2,3,4

 Aldosterone2  Systemic vascular resistance4
 Renin2  Pulmonary artery pressure4
 Pulmonary capillary wedge pressure 4
 Right atrial pressure5

ANP=atrial natriuretic peptide; 1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Levin et al. N Engl J Med 1998;339;321–8;
9 BNP=B-type natriuretic peptide; 3. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 4. Langenickel and Dole. Drug Discov Today:
CNP=C-type natriuretic peptide; HF=heart failure 5. Marcus et al., Circulation 1996; 94: 3184-89.
 Natriuretic peptides have potential for
protection of the heart, vessels and kidneys

NPs are released in response to cardiac wall stress and act in the brain,
adrenal gland, kidney, vasculature and heart

Sympatho-inhibitory

Inhibition of
RAAS

ANP Lusitropic
Enhanced endothelial function Attenuation of cardiac remodeling
Endothelin inhibition BNP (LVH) and fibrosis
Vasodilation
Aldosterone suppression

Antiproliferative effect:
reverse vascular remodeling Renin inhibition
(arterial stiffness) Improved renal hemodynamics
Increased natriuresis and diuresis
Attenuation of renal fibrosis

ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; LVH=left ventricular hypertrophy; NPs=natriuretic peptides;
RAAS=renin-angiotensin-aldosterone system
Figure
10 reproduced with permission from Boerrigter G, Burnett JC Jr. Expert Opin Investig Drugs 2004;13(6):643–52. Copyright © 2004.
Informa Healthcare; Rubattu et al. Am J Hypertens 2008;21:733–41; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52
10
 Natriuretic peptides inhibit the activity of the RAAS and
counterbalance the sympathetic nervous system

ANP and BNP inhibit the RAAS ANP interacts with baroreflex control
via actions in the kidneys of the circulation to inhibit the
and the adrenal glands 1 activity of the SNS2

ANP/BNP ANP

Modulation of
arterial and
cardiopulmonary
baroreceptors

Inhibition of renin Inhibition of aldosterone

secretion secretion Decrease in SNS outflow

Decrease in BP Decrease in BP

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; BP=blood pressure; NPs=natriuretic peptides;
RAAS=renin-angiotensin-aldosterone
11 system; SNS=sympathetic nervous system
1. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; 2. Rubattu et al. Am J Hypertens 2008;21:733–41
11
 The natriuretic peptide system: NPs are formed by
cleavage of precursor molecules1−6
proBNP
Pre-proBNP
 Wall stress as a result of volume (aa1-aa108)
expansion or pressure overload
induces the synthesis of
precursors of NPs2
 Heart acts as an endocrine organ Cleavage
releasing NPs in response to
mechanical stretch countering some
effects of the RAAS2
 NP system consists mainly of NT-proBNP BNP1–32
three peptides1,6 (aa1-aa76) (aa77-aa108)
• ANP: Produced primarily in atrial
myocardium
DPP-4 Meprin A?
• BNP: Produced primarily in the
ventricular myocardium
• CNP: Predominates in brain, kidney,
vascular endothelial cells and
plasma
BNP3–32 BNP7–32

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide; DPP-4=dipeptidyl peptidase-4; NT-
12 proBNP=N-terminal pro-BNP; NP=natriuretic peptide;;RAAS= renin-
angiotensin-aldosterone system
1. Volpe et al., Clin Science, 2016: 130:57-77 2. Daniels and Maisel. J Am
Coll Cardiol 2007;50:2357–68;. 3. Melanson and Lew androwski. Am J Clin
Pathol 2005;124:S122–8; 4. Ichiki and Burnett. Circulation 2010;122:229–
32; 5. Ruskoaho. Endocrine Rev 2003;24:341–56; 6. Levin et al. N Engl J
Med 1998;339;321–8.
 Discovery of NPs: Factors involved in homeostatic
balance of electrolyte and body fluid1,2

 In addition to natriuretic effects,3 natriuretic peptides have

other potential actions in HF: ANP
H 2N

19811
Vasodilation3–5 Sympathetic outflow3
HOOC-

Diuresis3 Vasopressin3 Discovered in rat atria1

Aldosterone3 Systemic vascular resistance5,3 BNP

Renin3 Pulmonary artery pressure5
H 2N

19882
Fibroblast proliferation5–7 Pulmonary capillary wedge pressure5
Hypertrophy3,8–10
HOOC-

Right atrial pressure11 Discovered in the porcine brain,2 and

subsequently found to be expressed in atrial and
Arterial stiffness5 ventricular tissue3,12

 Release of NPs is thought to be a compensatory physiological CNP

mechanism that opposes the effects of the RAAS and SNS in H 2N

199014
patients with HF5 HOOC-

 Scientists hypothesized that HF is an ‘NP-deficient’ state, 12

Discovered in the central nervous system 14
although subsequent efforts to increase NP levels via exogenous and also expressed in vascular endothelial cells 12

application were unsuccessful13

ANP=atrial natriuretic peptide; BNP=B-type
natriuretic peptide; CNP=C-type natriuretic
peptide; HF=heart failure; NP=natriuretic
13
peptide; RAAS=renin-angiotensin-aldosterone
system; SNS=sympathetic nervous system
1. de Bold et al. Life Sci 1981;28:89–94; 2. Maekawa et al. Bioch Biophys Res Commum1988;157:410–16; 3. Levin et al. N Engl J Med
1998;339;321–8; 4. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 5. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–
9; 6. D'Souza et al. Pharmacol Ther 2004;101:113–29; 7. Cao and Gardner. Hypertension 1995;25:227–34; 8. Gardner et al. Hypertension
2007;49:419–26; 9. Tokudome et al. Circulation 2008;117;2329–39; 10. Horio et al. Hypertension 2000;35:19–24; 11. Marcus et al., Circulation
1996; 94: 3184-89. 12. Mangiafico et al. Eur Heart J. 2013;34:886–93c; 13. O’Connor et al. N Engl J Med 2011;365:32–43; 14. Sudoh et al.
Biochem Biophys Res Commun 1990;168:863–70
 Preclinical studies indicate natriuretic peptides mediate potent cardiac
antihypertrophic and antifibrotic effects beyond the control of BP and blood
volume

Preclinical evidence

Effects on cardiac remodeling ANP BNP CNP

  
1 1 1
Inhibition of cardiac fibroblast proliferation

Inhibition of hypertrophy
4 in cardiac myocytes and 2 3
 
fibroblasts

Inhibition of macrophage infiltration, collagen synthesis,


4

and pro-inflammatory chemotactic factors

5
Relaxation of coronary arteries 
6 5 7
Reduction of infarct size   

1. Cao & Gardner. Hypertension 1995;25:227–34 2. Horio et al. Hypertension

ANP=atrial natriuretic peptide; BP=blood pressure; BNP=B- 2000;35:19–24 3. Del Ry, Peptides, 2013,40:93-98. 4. Fujita et al. Heart
type natriuretic peptide; CNP=C-type natriuretic peptide; Vessels 2013;28:646–57; 5. Hobbs et al. Circulation 2004;110:1231–5 6.
14 Zhang et al. Vasc Endovascular Surg 2008;42:263–7; 7. Kousholt. Dan Med J
BP=blood pressure 2012;59:B4469
 Effects of the natriuretic peptide system: NPs mediate a
wide range of physiological effects via NP receptors

Cardiomyocytes 1 Endothelial cells 1

ANP and BNP

CNP
NPR-A NPR-B NPR-C

GTP GTP Receptor

cGMP cGMP
Internalization recycling

 Vasodilation1,2
 Antihypertrophy1,2  Vasodilation1,2 Degradation
 Antiproliferation2  Antihypertrophy1,2 of NPs7
 Vascular regeneration3  Antiproliferation2
 Myocardial relaxation4,5  Vascular regeneration1
 Diuresis, natriuresis 1,2  Venodilation1 Natriuretic peptide
 Antiapoptosis 6  Antifibrosis1 degradation and clearance
 Anti-aldosterone1,2
 Renin secretion inhibition7
 Reduced sympathetic tone8
 Lipolysis 7

1. Mangiaf ico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hy pertension

2007;49:419–26; 3. Y amahara et al., PNAS, 2003, 100:3404-09. 4. Y amamoto et
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type al. ,AJP, 1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6.
15 natriuretic peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016:
triphosphate; NPR=neprilysin receptor 130:57-77. 8. Lev in et al. N Engl J Med 1998;339;321–8.
 Natriuretic peptides are cleared via NPR-C and degraded
by the protease, neprilysin

Cardiomyocytes 1 Endothelial cells 1 ANP

BNP
ANP and BNP CNP Inactive
cleavage
CNP
products
NPR-A NPR-B NPR-C
NEP
Neprilysin

Receptor
GTP GTP recycling
cGMP cGMP
Endocytosis
 Vasodilation1,2  Vasodilation1,2
 Antihypertrophy 1,2  Antihypertrophy 1,2
 Antiproliferation2  Antiproliferation2 Inactivation
 Vascular regeneration3  Vascular regeneration1 of NPs7
 Myocardial relaxation4,5  Venodilation1
 Diuresis, natriuresis 1,2  Antifibrosis 1
 Antiapoptosis 6
Natriuretic peptide
 Anti-aldosterone1,2 degradation and clearance
 Renin secretion inhibition7
 Reduced sympathetic tone8
 Lipolysis 7

Natriuretic peptide signaling and effects

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-
16 type natriuretic peptide; cGMP=cyclic guanosine monophosphate;
GTP=guanosine triphosphate; NPR=neprilysin receptor
1. Mangiaf ico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension
2007;49:419–26; 3. Y amahara et al., PNAS, 2003, 100:3404-09. 4. Y amamoto et al.
,AJP, 1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6.
Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016:
130:57-77. 8. Levin et al. N Engl J Med 1998;339;321–8;.
 Neprilysin inhibition must be accompanied by
simultaneous RAAS blockade
Angiotensinogen
Neprilysin
 Neprilysin metabolizes Ang I and Ang II 1,2 Renin inhibitor
 Inhibition of neprilysin alone is insufficient as it associated Ang I Neprilysin Ang-(1–7)
with an increase in Ang II levels, counteracting the potential
benefits of neprilysin inhibition2 ACE Neprilysin
inhibitor
 Neprilysin inhibition must be accompanied by simultaneous Inactive
Ang II Neprilysin
RAAS blockade (e.g. AT1 receptor blockade)2 fragments

AT1 receptor

Signaling
cascade

Biological actions

Hypertrophy Vasoconstriction Na+/H2O retention Norepinephrine release

Fibrosis Hypertrophy Aldosterone release ↑ Sympathetic tone

1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;

17 ACE=angiotensin converting enzyme; Ang=angiotensin;
AT1=angiotensin 1; RAAS=renin-angiotensin-aldosterone system 2. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.
 Metabolism of vasoactive peptides by neprilysin: Many
substrates are metabolized with differing levels of affinity

ANP, BNP, CNP Implications for neprilysin

inhibition
Ang II
 Neprilysin substrates can have
Ang I opposing biological actions 1,2
 Overall effect is dependent upon the
Adrenomedullin NEP net effect on neprilysin metabolism of
individual substrates 1
Substance P
Inactive
 Benefits in enhancing NP system may
Bradykinin fragments be offset by increased Ang II 1,2
or metabolites
Endothelin  Needs to be complemented by
simultaneous RAAS suppression1,2

*Not an exhaustive list of all neprilysin substrates; the most

relevant substrates for cardiovascular physiology are listed

Ang=angiotensin; ANP=atrial natriuretic peptide;

BNP=B-type natriuretic peptide; CNP=C-type
18 natriuretic peptide; RAAS=renin-angiotensin- 1.Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9; 2.
aldosterone system; NEP=neprilysin; NP=natriuretic Mangiafico et al., Eur. Heart J. 2013 34: 886-93;.
peptide
 Effects of the natriuretic peptide system: cardiovascular and
renal effects of NP system counteract the action of RAAS

Inactive
NP ANP ANP/CNP/
fragments
ANP/BNP/CNP BNP CNP BNP Ang II

Neprilysin NPR-A NPR-B NPR-C AT1 receptor

GTP GTP
Receptor
Signalling
recycling
cascades
Internalization
cGMP
Gene expression; ↑ protein
synthesis; ↑ cell proliferation
Inactive peptides

Vasodilation Vasoconstriction
 Cardiac fibrosis/hypertrophy  Cardiac fibrosis/hypertrophy
 Natriuresis/diuresis  Sodium/water retention

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;

CNP=C-type natriuretic peptide; Ang=angiotensin; Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension
19 AT1=angiotensin type 1; NP=natriuretic peptide; 2007;49:419–26; Von Lueder et al. Circ Heart Fail 2013;6:594–605;
NPR=neprilysin receptor Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82–97..
 Sacubitril/valsartan: Neprilysin inhibition combined with RAAS
blockade is an alternative to an ACEI or ARB in patients with
HFrEF1
β-blockers
SNS
Epinephrine α 1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
Heart rate
NP system HF SYMPTOMS &
PROGRESSION Contractility
NPRs NPs

Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone
Natriuresis/diuresis
RAAS (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Sacubitril/valsartan Hypertrophy
Fibrosis

ACEI=angiotensin-conv erting enzy me inhibitor; Ang=angiotensin; ARB=angiotensin

receptor blocker; AT1R=angiotensin II ty pe 1 receptor; HF=heart f ailure;
HFrEF=heart f ailure with reduced ejection f raction; MRA=mineralocorticoid receptor
20 antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors;
RAAS=renin-angiotensin-aldosterone sy stem; SNS=sy mpathetic nerv ous system
1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Minguet et al., Exp.
Opin.Pharamacother, 2015, 16:435-46;,
Figure ref erences: Lev in et al. N Engl J Med 1998;339:321–8
 Landmark trials in patients with HFrEF

CHARM-Alternative 3 (2003)
SOLVD-T 1 (1991) 2,028 patients SHIFT 5 (2010) PARADIGM-HF7 (2014)
2,569 patients Candesartan (ARB) vs 6,558 patients 8,442 patients
Sacubitril/valsartan (ARNI) vs
Ecnalapril (ACEI) vs placebo: placebo: Isvabradine (If inhibitor) vs enalapril:
• 16%  all-cause mortality • 23%  CV mortality or HF placebo: • 20%  CV mortality or HF
hospitalization • 18%  CV death or HF hospitalization
hospitalization
CIBIS-II8 (1999)
2,647 patients
Bisoprolol (BB) vs placebo:
• 34%  all-cause mortality

1990s 2000s 2010s

CHARM-Added4 (2003) EMPHASIS-HF6 (2011)

MERIT-HF2 (1999) 2,548 patients 2,737 patients
3991 patients Candesartan (ARB) vs Eplerenone (MRA) vs
Metorprolol vs placebo: placebo: placebo:
• 34%  all-cause mortality • 15%  CV mortality or HF • 37%  CV mortality or HF
hospitalization hospitalization

ACEI=angiotensin-conv erting enzy me inhibitor; ARB=angiotensin receptor
blocker; ARNI=angiotensin receptor neprily sin inhibitor; BB=beta blocker;
CV=cardiov ascular; HF=heart f ailure; HFrEF=heart f ailure with reduced
21 ejection f raction; MRA=mineralocorticoid receptor antagonist. See notes f or
def initions of study names
1. SOLVD Inv estigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study
group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4.
McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–
85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med
2014;371:993–1004 8 CIBIS-II Inv estigators. Lancet 1999;353:9–13
 Mortality in HFrEF remains high despite several therapies
that improve survival
 Survival rates in chronic HF have improved with the use of therapeutic interventions that target
the renin-angiotensin and sympathetic signalling
 However, significant mortality remains, ~50% of patients die within 5 years of diagnosis1-3

ACEIs* ARBs* b -Blockers* MRAs*

vs Placebo
+ ACEI/ARB vs. + ACEI/ARB + b-block ers vs.
vs Placebo ACEI/ARB alone ACEI/ARB + b-block ers
Reduction in relative risk of
all-cause mortality

16% 17%
(4.5% ARR; (3.0% ARR;
mean follow up
of 41.4 months)
median follow up
of 33.7 months)
24%
(7.6% ARR; mean
SOLVD 4,5
CHARM- 34% follow up of 24
months)
Alternative6 (3.8% ARR;
mean follow up EMPHASIS-
of 1.3 years) HF1,8
MERIT-HF7

*On top of standard therapy at the time of study, except in CHARM-Alternative w here patients w ere intolerant to ACEI.
Patient populations varied betw een trials and as such relative risk reductions cannot be directly compared

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor
blocker; HF=heart failure; ARR=absolute risk reduction; HFrEF=heart
22 failure with reduced ejection fraction; LVEF=left ventricular ejection fraction;
MRA=mineralocorticoid receptor antagonist
1. Go et al. Circulation 2014;129:e28-e292; 2. Y ancy et al. Circulation
2013;128:e240–327; 3. Lev y et al. N Engl J Med 2002;347:1397–402; 4. McMurray
et al. Eur Heart J 2012;33:1787–847; 5. SOLVD Inv estigators. N Engl J Med
1991;325:293–302; 6. Granger et al. Lancet 2003;362:772–66; 7. MERIT-HF study
group. Lancet 1999;353: 2001-7; 8. Pitt et al. N Engl J Med 1999;341:709-17
 Combination of ACEI, b-blockers and MRA was
considered the cornerstone of therapy for HFrEF1

ACEI +BB + MRA 0.44 (0.26, 0.66)

ACEI + ARB +BB 0.52 (0.31, 0.80)

ACEI +MRA 0.57 (0.35, 0.91)

ARB + BB 0.47 (0.23, 0.86)

ACEI + ARB 0.83 (0.51, 1.24)

ACEI + BB 0.57 (0.41, 0.72)

BB 0.57 (0.33, 0.94)

ARB 0.88 (0.61, 1.26)

ACEI 0.83 (0.66, 1.01)

0 0,5 1 1,5

HR (95% credible interval) for treatment vs. placebo*

*HR<1 favors treatment

Results are based on random-effects network meta-analysis using Bayesian models2

Studies included: 57 RCTs, Phase II/III (Jan 1987- April 2015) assessing guideline-recommended drug classes for HFrEF
Patient population: Patients (aged ≥18 years) with chronic HFrEF (LVEF <45%) and NYHA class II–IV of varying etiology presenting in the
outpatient department were included

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin

receptor blocker; BB=beta blocker; HR=hazard ratio; HFrEF=heart
23 failure w ith reduced ejection fraction; LVEF=left ventricle ejection 1. McMurray et al. Eur Heart J 2012;33:1787–847;.2. Burnett H et al.
fraction; MRA=mineralocorticoid receptor antagonist; ; NYHA=New Circ Heart Fail. 2017;10:e003529
York Heart Association; RCT=randomized controlled trial
 PARADIGM-HF: sacubitril/valsartan (ARNI) significantly
reduced the risk of CV death or HF hospitalization
compared with an ACEI
PARADIGM-HF
Intervention Sacubitril/valsartan 200
mg bid vs. enalapril 10
mg bid* Enalapril

Cumulative probability
No. of patients 8442 Sacubitril/valsartan

Average age (years) 63.8

Female (%) 21.7

LVEF ≤35% (NYHA II)

Primary endpoint Composite of CV death

or first HF hospitalization
20% relative risk reduction
Median follow-up 27 p<0.001
(months)

*On top of standard therapy for HF with an ACEI (enalapril) as an active

comparator. Days since randomization
More details on the PARADIGH-HF and its sub-analyses can be found in
Chapter 3.

CV=cardiovascular; bid=twice daily; HF=heart failure; HFrEF=heart failure with reduced

ejection fraction; LVEF=left ventricular ejection fraction; NYHA=New York Heart
24 Association; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine
Impact on Global Mortality and morbidity in Heart Failure McMurray et al.,N. Eng. J Med. 2014, 371:993-1004
 Substitution of an ACEI with ARNI resulted in further
reduction in all cause mortality in patients with HFrEF

b -Blockers* MRAs* ARNIs†

ACEIs* ARBs* ARNI + b-block ers + MRA vs.
vs Placebo + ACEI/ARB vs. + ACEI/ARB + b-block ers vs.
vs Placebo
ACEI/ARB alone ACEI/ARB + b-block ers ACEI/ARB + b-block ers + MRA
Reduction in relative risk of
all-cause mortality

16% 17% 16%

(2.8% ARR;
(4.5% ARR; (3.0% ARR; median follow up
mean follow up
of 41.4 months)
median follow up
of 33.7 months)
24% of 27 months)
(7.6% ARR; mean
SOLVD1,2 PARADIGM
CHARM- 34% follow up of 21
months) -HF6
Alternative3 (3.8% ARR;
mean follow up EMPHASIS-
of 1 year) HF1,5
MERIT-HF4

*On top of standard therapy at the time of study, except in CHARM-Alternative w here patients were intolerant to ACEI:
†On top of standard therapy and as a replacement for ACE!s (enalapril)
Patient populations varied betw een trials and as such relative risk reductions cannot be directly compared

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor
blocker; HF=heart failure; ARR=absolute risk reduction; HFrEF=heart failure
25 with reduced ejection fraction; LVEF=left ventricular ejection fraction;
MRA=mineralocorticoid receptor antagonist
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD
Investigators. N Engl J Med 1991;325:293–302; 3. Granger et al. Lancet
2003;362:772–66; 4. MERIT-HF study group. Lancet 1999;353: 2001-7 5.
Pitt et al. N Engl J Med 1999;341:709-17; 6. McMurray et al.,N. Eng. J
Med. 2014, 371:993-1004
 Combination therapy with ARNI, b-blockers and MRA is
associated with greatest reduction in all-cause mortality
ARNI +BB + MRA 0.37 (0.19, 0.65)

ACEI +BB + MRA 0.44 (0.26, 0.66)

ACEI + ARB +BB 0.52 (0.31, 0.80)

ACEI +MRA 0.57 (0.35, 0.91)

ARB + BB 0.47 (0.23, 0.86)

ACEI + ARB 0.83 (0.51, 1.24)

ACEI + BB 0.57 (0.41, 0.72)

BB 0.57 (0.33, 0.94)

ARB 0.88 (0.61, 1.26)

ACEI 0.83 (0.66, 1.01)

0 0,5 1 1,5

HR (95% credible interval) for treatment vs. placebo*

*HR<1 favors treatment

Results are based on random-effects network meta-analysis using Bayesian models

Studies included: 57 RCTs, Phase II/III (Jan 1987- April 2015) assessing guideline-recommended drug classes for HFrEF
Patient population: Patients (aged ≥18 years) with chronic HFrEF (LVEF <45%) and NYHA class II–IV of varying etiology presenting in the
outpatient department were included

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker;

ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; HR=hazard ratio;
26 HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor
antagonist; NYHA=New York Heart Association; RCT=randomized controlled trial Burnett H et al. Circ Heart Fail. 2017;10:e003529
 Therapeutic algorithm for a patient with
symptomatic HFrEF
Class I recommendation

Class IIa recommendation

aSy mptomatic ¼ NYHA Class II-IV. bHFrEF ¼ LVEF ,40%. cIf ACE inhibitor not tolerated/contra-indicated, use ARB. dIf MR antagonist not tolerated/contra-indicated, use ARB. eWith a hospital admission for HF within the last 6 months or with
elev ated natriuretic peptides (BNP . 250 pg/ml or NTproBNP . 500 pg/ml in men and 750 pg/ml in women). f With an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization
within recent 12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL). gIn doses equivalent to enalapril 10 mg b.i.d. hWith a hospital admissionfor HF within the previous year. iCRT is recommended if QRS ≥ 130 msec and
LBBB (in sinus rhythm). jCRT should/may be considered if QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision).

ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin-receptor blocker;

CRT=cardiac resynchronisation therapy; HR-heart rate; H-ISDN=hydrazine and isosorbide
dinitrate; HFrEF=heart failure with reduced ejection fraction; LVAD=left ventricular assist
27 dev ice; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association;
VF/VT=v entricular fibrillation/ventricular tachycardia Ponikow ski et al., Eur Heart J, 2016; 37:2129-200
 Summary

• HF is a complex clinical syndrome that results from any structural or

functional impairment of ventricular filling or ejection of blood
• The most common cause of HF is coronary artery disease
• The most frequently reported signs and symptoms of HF are dyspnea,
edema and cough
• HF has a complex pathophysiology involving activation of two key
neurohormonal systems:
• Renin–angiotensin–aldosterone system
• Sympathetic nervous system

• Natriuretic peptides counteract the detrimental effects of RAAS and SNS

activation.
• Multiple pharmacological agent are useful in improving mortality and
morbidity.
• Among them, ARNI was superior to ACEi in reducing the risks of death and
28
of hospitalization for heart failure
28
 HFrEF: Evolution of Natriuretic Peptide
Based Treatment

31
 Exogenous application of NPs as a therapeutic approach
was ineffective in patients with HF

 Nesiritide is a recombinant BNP with vasodilatory properties

 Clinical efforts to enhance NP levels via exogenous application had modest beneficial effects
compared with placebo in addition to standard care, in patients with AHF1

p=0.007
Patients (%)
68.2

Death or rehospitalization for HF

70 66.1 0 2 4 6 8 10 12
moderately better dyspnea (%)

p=0.03
Patients with markedly or

60
50 44.5 42.1 Nesiritide
9.4
40 (n=3,423)

30 p=0.31
Placebo
20 10.1
(n=3,413)
10
0
Nesiritide Placebo Nesiritide Placebo Percentage point difference (95% Cl): –0.7 (–2.1 to 0.7)
(n=3,416) (n=3,444) (n=3,371) (n=3,398)
6 Hours 24 Hours

 Physicians hypothesized that the lack of efficacy with exogenous application of NPs may be due, in
part, to the high turnover of NPs in cardiac disorders2

32 1. O’Connor et al. N Engl J Med 2011;365:32–43;

AHF=acute heart failure; NP=natriuretic peptide 2. Minguet et al. Expert Opin Pharmacother 2015;16:435–46
 NEP inhibition elevates NP levels in patients with HF

Candoxatril is an orally active inhibitor of neprilysin

Single oral doses of candoxatril increase ANP and BNP levels in seven patients with chronic HF1#
Before treatment After treatment

50 100 * *
*
Plasma BNP (pmol/L)

Plasma ANP (pmol/L)

*
40 * 80
*
30 60

20 40

10 20

0 0
0 mg 10 mg 50 mg 200 mg 0 mg 10 mg 50 mg 200 mg
Dose of candoxatril Dose of candoxatril
#Seven patients (mean age 65) with chronic HF NYHA II–III were given candoxatril 10, 50, 200 mg or placebo as a single dose in a four-way crossover study.
Values as mean and SEM; *p<0 05 vs 0 mg (placebo) (ANOVA);

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; HF=heart failure;

33 NP=natriuretic peptide; NYHA=New York Heart Association; SEM=standard
error of mean 1. Lang et al. Lancet 1991;338:255
 NEP inhibitor monotherapy showed promise, but failed to
demonstrate efficacy in patients with chronic HF1

 Candoxatril was shown to have the following hemodynamic effects compared with
placebo in patients with chronic HF1-3

Systemic or
Left and right Arterial pulmonary
Heart rate Cardiac index
atrial pressures pressures vascular
(no change) (no change after
(reduced) (no change) resistance exercise)
(no change)

 Another neprilysin inhibitor, ecadotril, led to numerically more deaths, as well as no evidence of
clinical efficacy compared with placebo in patients with HF 2
 Consequently, the development of both candoxatril and ecadotril for HF was discontinued 2

Westheim et al. J Am Coll Cardiol 1999;34:1794–801;

2. Cleland and Sw edberg. Lancet 1998; 351:1657–83
34 3. McDow ell and Nicholls, Cardiovasscular drug reviews, 2000; 18:
HF=heart failure; NEP=neprilysin 259-70
 Rationale for lack of efficacy with NEP inhibitor
monotherapy in patients with chronic HF1

 Subsequent studies provided possible Metabolism of natriuretic and other

explanations for the lack of clinical efficacy vasoactive peptides* by NEP 5,6
with neprilysin inhibition monotherapy,
including:
Natriuretic peptides
 lack of effect on renal hemodynamics2
 induction of systemic vasoconstrictor rather than Angiotensin II
vasodilator effects3 (potentially due to increase in Angiotensin I
levels of the potent vasconstrictor ET-1)4
Adrenomedullin NEP
Substance P
 Further, neprilysin degrades multiple
substrates5,6 (figure), which may affect Bradykinin
efficacy due to: Endothelin Inactive
 opposing biological actions of neprilysin fragments
or metabolites
substrates7
 increased Ang II levels offsetting beneficial effects *Not an exhaustive list of all NEP substrates; the most relevant
substrates for cardiovascular physiology are listed
of enhancing the NP system7

1. Westheim et al. J Am Coll Cardiol 1999;34:1794–801; 2. Kimmelstiel et al. Cardiology

1996;87:46–53; 3. Kentsch et al. Eur J Clin Pharmacol 1996;51:269–72;
4. McDowell et al. Br J Clin Pharmacol 1997;43:329–32; 5. Ando et al. Hy pertension
35 Ang=angiotensin; ET=endothelin; HF=heart failure; NEP neprilysin; 1995;26:1160–6; 6. Von Lueder et al. Pharmacol Ther 2014;144: 41–9;
NP=natriuretic peptide; 7. Langenickel and Dole. Drug Discov Today :Ther Strateg 2012;9:e131–9.
 Neprilysin degrades other substrates, including Ang II and
vasoactive peptides relevant for cardiovascular physiology
Ang II
Ang I
ANP Adrenomedullin
BNP Bradykinin
CNP ET-1
ANP Substance P
ANP BNP
BNP CNP CNP Inactive Ang II
cleavage
products
NPR-A NPR-B NPR-C
AT1 receptor
Neprilysin

GTP GTP
Receptor
Endocytosis recycling Signaling
cascades

cGMP
Inactivation
of NPs1,2,5
Vasodilation Vasoconstriction
 Cardiac fibrosis/hypertrophy  Cardiac fibrosis/hypertrophy
 Natriuresis/diuresis  Sodium/water retention

ANP=atrial natriuretic peptide; Ang= angiotensin;

AT1=angiotensin ty pe 1; BNP=B-ty pe natriuretic Guo et al. Cell Res 2001;11:165–80; Mehta and Griendling. Am J Phy siol Cell Phy siol 2007;292:C82–97;
36 peptide; CNP=C-ty pe natriuretic peptide; ET1= Mangiaf ico et al. Eur Heart J 2013;34:886–93; Langenickel and Dole. Drug Discov Today : Ther Strateg
endothelin !; NPR=neprily sin receptor 2012;9:e131–9; Lev in et al. N Engl J Med 1998;339;321–8.; Volpe et al., Clin Science 130, 57-77.
 Evolution of pharmacologic approaches in HF: Co-inhibition of
neprilysin and RAAS as a new therapeutic strategy1

SNS β-blockers

Epinephrine α 1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS &
PROGRESSION
Heart rate
Contractility
NPRs NPs

Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone
Natriuresis/diuresis
RAAS (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Neprilysin inhibitors enhance NPs and Aldosterone
other vasoactive peptides Dual inhibition of Hypertrophy
Fibrosis
neprilysin and RAAS: a
complementary
therapeutic strategy?

Ang=angiotensin; AT1R=angiotensin type-1 receptor; HF=heart

failure; NP=natriuretic peptide; NPR=natriureitc peptide receptor; 1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73;
37 RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic
nervous system Figure references: Levin et al. N Engl J Med 1998;339:321–8;.
 Preliminary clinical evidence with dual NEP and ACE
inhibition showed promise in patients with chronic HF

 The potential clinical benefits with NEP inhibitors can only be leveraged if NEP substrates with opposing
actions to NPs are also inhibited (e.g. Ang II and ET-1)
 In the IMPRESS study, the efficacy and safety profile of the dual neprilysin-ACE inhibitor omapatrilat was
compared with the ACEI lisinopril in 573 patients with HFrEF over 24 weeks*
• Omapatrilat showed a trend towards reducing death or admission for HF and improved NYHA class in patients who had NYHA
class III and IV as compared to Lisinopril

Death, admission for heart failure, or

Death or admission for heart failure discontinuation of treatment
0.15 0.15

Proportion with event

Proportion with event

p=0.052 p=0.035
Lisinopril Lisinopril
0.10 0.10
Omapatrilat Omapatrilat

0.05 0.05

0 0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
Time from randomization (days) Time from randomization (days)
*A randomized, double-blind, parallel trial in patients with chronic HF NYHA class II–IV, LVEF ≤40%, and receiving an ACEI. Omapatrilat 40 mg (n=289) or lisinopril
20 mg (n=284)

ACEI=angiotensin converting enzyme inhibitor; IMPRESS=Inhibition of MetaloProtease by

38 omapatrilat in a Randomized Exercise and Symptoms Study; HFrEF; heart failure w ith
reduce ejection fraction; LVEF=left ventricular ejection fraction 1. Rouleau et al. Lancet 2000;356:615–20
 OVERTURE study showed trends towards efficacy with dual
neprilysin-ACEI but raised significant safety concerns

 In the OVERTURE study, the dual  Development of omapatrilat was

neprilysin-ACE inhibitor omapatrilat discontinued due to:
was compared with the ACEI enalapril
in 5,770 patients with HFrEF for a • Lack of efficacy (see figure)
mean of 14.5 months* attributed to sub-optimal neprilysin and
ACE inhibition over 24 hours due to the
Time to death or HF hospitalization once-daily dosing regimen
1.0
• Safety concern
Event-free survival (%)

0.8 p=0.187 unacceptable risk of angioedema (24

patients [0.8%] vs 14 patients [0.5%] for
0.6 omapatrilat and enalapril, respectively).
This was attributed to simultaneous
0.4 neprilysin and ACE inhibition leading to
Omapatrilat
elevated bradykinin levels, which are
0.2 Enalapril
associated with cough and angioedema
0
0 3 6 9 12 15 18 21 24
Months

*A randomized, double-blind, parallel trial in patients with chronic HF NYHA class II–IV. Omapatrilat 40 mg (n=2,886) or enalapril 10 mg b.i.d. (n=2,884)

ACE=angiotensin converting enzyme; ACEI=ACE inhibitor; b.i.d= tw ice a day;

HF=heart failure; HFrEF=heart failure w ith reduced ejection fraction;
39 OVERTURE=Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing
Events; NEP=neprilysin; RCT=randomized clinical trial Packer et al.Circulation 2002;106:920–6
 Co-inhibition of neprilysin and AT1-receptor as an alternative to ACE
inhibition in HF patients: better efficacy with lower angioedema risk?

• Bradykinin is a substrate of both neprilysin and ACE along with other vasopeptidases
(APP, DPP-4)
• Simultaneous inhibition of ACE and neprilysin results in elevated levels of bradykinin
leading to higher risk of cough and angioedema1,2
• A selective neprilysin inhibitor coupled with an ARB can enhance beneficial effects of NP
system while inhibiting RAAS with minimal effect on bradykinin degradation1

Bradykinin breakdown

Omapatrilat inhibits Active Inactive

ACE, APP and NEP2 bradykinin bradykinin

ACE APP NEP DPP-4

Selective NEP and Active Inactive

ARB inhibition bradykinin bradykinin

ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker;

APP=aminopeptidase P; DPP-4=dipeptidyl peptidase; HF=heart failure;
40 NEP=neprilysin; NP=natriuretic peptide system; RAAS=renin angiotensin 1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. Gu et al. J Clin
aldosterone system Pharmacol 2010;50: 401–14;
 The emergence of sacubitril/valsartan: Neprilysin inhibition
combined with AT1 blockade as a therapeutic strategy in HF

Stand-alone  Tested enhancing the effects of NPs by reducing their breakdown through
neprilysin neprilysin inhibition1-3
inhibition
• e.g. candoxatril4, thiorphan5
 Ultimately not developed for clinical use in HF3

Omapatrilat  Omapatrilat developed to both inhibit neprilysin and suppress the RAAS, via
(Neprilysin and ACE inhibition6,7
ACE inhibition)
 Demonstrated a trend towards reduced morbidity and mortality in HFrEF7
 Development was halted due to increased frequency of angioedema1-3,7

Sacubitril/valsartan  Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor

(Neprilysin
(ARNI)
inhibition and AT 1  Alternative approach to simultaneously suppressing the RAAS via AT1 receptor
receptor blockade) blockade and enhancing NP system 1,2
 PARADIGM-HF is the first study to test the effect of sacubitril/valsartan on
morbidity and mortality in patients with HFrEF3,8

ACE=angiotensin-conv erting enzy me; ARNI=angiotensin receptor neprily sin
inhibitor; AT1=angiotensin II ty pe 1; HF=heart f ailure; HFrEF=heart f ailure with
reduced ejection f raction; NP=natriuretic peptide; PARADIGM-HF=Prospectiv e
41 comparison of ARNI with ACEI to Determine Impact on Global Mortality and
morbidity in Heart Failure; RAAS=renin-angiotensin-aldosterone sy stem
1. Volpe et al., Clin Science 2016, 130:57-77; 2. Minguet et al., Exp. Opin.
Pharamacother, 2015, 16:435-46 3. McMurray et al. Eur J Heart Fail.
2013;15:1062–73; 4. Northridge et al. Am Heart J. 1999;138:114957; 5.
Eberlin et al. Front Pharmacol. 2012;3:93; 6. Rouleau et al. Lancet
2000;356:615–20 7. Packer et al. Circulation 2002;106:920–6; 8. McMurray et
al. Eur J Heart Fail. 2014;16:817–25
 Sacubitril/valsartan is the first agent (ARNI) to demonstrate a significant
clinical benefit with NP system enhancement with AT1 blockade in chronic
HFrEF
1990s 2009 2014
NEP inhibitors Sacubitril/valsartan Sacubitril/valsartan (ARNI)
NEP inhibition alone fails to (ARNI) PARADIGM-HF study
demonstrate efficacy in patients Phase III PARADIGM-HF sacubitril/valsartan was
with chronic HF, mainly due to (HFrEF) and superior to enalapril in
1981 the ‘promiscuity’ of NEP Phase II PARAMOUNT reducing the risks of death
Discovery towards other substrates such (HFpEF) studies and HF hospitalization in
of ANP1 as Ang II3 initiated5-7 patients with HFrEF 7

20091980s2010 1990s 2012

2011 2013
2000s 2014 2015
2010s

1988 2002 2012

NEP identified as Omapatrilat (NEPi+ACEI) Sacubitril/valsartan (ARNI)
the primary Combined NEP and ACE inhibition PARAMOUNT study
enzyme with omapatrilat indicates trends NEP inhibition and AT 1R blockade
responsible for towards efficacy in chronic HF, but with sacubitril/valsartan significantly
degrading ANP2 raises significant safety reduced NT-proBNP levels compared
concerns3,4 with valsartan in patients with HFpEF6

ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting enzyme inhibitor;
Ang=angiotensin; ANP=atrial natriuretic peptide; ARNI=angiotensin receptor neprilysin
inhibitor; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFpEF=heart failure with
42 preserv ed ejection fraction; HFrEF=heart failure with reduced ejection fraction;
NEP=neprily sin;
1. de Bold et al. Lif e Sci 1981;28:89–94; 2. Sonnenberg et al. Peptides
1988;9:173–80; 3. . Langenickel and Dole. Drug Discov Today 2012, 9: e131-
139; 4. Packer et al. Circulation 2002;106:920–6; 5. McMurray et al. Eur J
Heart Fail 2013;15:1062–73; 6. Solomon et al. Lancet 2012;380:1387–95; 7.
McMurray et al. N Engl J Med 2014;371:993–1004
43
44
45