Pharmacological Therapy

The Mechanism of Action of LCZ696

Juan Tamargo Menendez

Department of Pharmacology, School of Medicine, University Complutense, Madrid, Spain

Abstract
Heart failure (HF) represents a growing financial burden on healthcare systems and despite therapeutic advances, mortality remains
high. Current treatments focus on blocking neurohormonal pathways, such as the renin-angiotensin aldosterone system (RAAS). Recent
research has focused on the natriuretic peptide system, which confers beneficial effects in HF, whereas activation of the RAAS and of the
sympathetic nervous system has detrimental effects. LCZ696 (sacubutril/valsartan), a first-in-class angiotensin II AT1 receptor neprilysin
inhibitor, has a unique mode of action that targets both pathways. Clinical studies to date indicate that LCZ696 is effective and safe in mild
to moderate arterial hypertension and in HF patients with preserved ejection fraction, and has been shown to be superior to enalapril in
patients with moderate to severe HF due to reduced left ventricular ejection fraction.

Keywords
Angiotensin receptor, neprilysin inhibitor heart failure, natriuretic peptides, LCZ696, neprilysin, renin-angiotensin-aldosterone system

Disclosure: The author has no conlicts of interest to declare.

Acknowledgement(s): This work was supported by grants from the Instituto de Salud Carlos III (PI11/01030 and Red de Investigación Cardiovascular-RIC, RD12/0042/0011)
and Fundación BBVA. Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Novartis Pharma AG.
Received: 27 January 2016 Accepted: 3 February 2016 Citation: Cardiac Failure Review, 2016;2(1):40–6 DOI: 10.15420/cfr.2016:1:1
Correspondence: Juan Tamargo Menendez, Department of Pharmacology, School of Medicine, University Complutense, 28040 Madrid, Spain. E: jtamargo@med.ucm.es

Chronic heart failure (HF) is a complex and progressive clinical II and aldosterone. The RAAS regulates vascular tone and blood
syndrome resulting from any abnormality of cardiac structure or pressure (BP) by means of vasoconstriction and renal sodium and
function. The American College of Cardiology Foundation/American water retention.6 Abnormalities in cardiac function in HF activate the
Heart Association guideline defines HF as ‘a complex clinical syndrome RAAS and sympathetic nervous system in order to maintain perfusion of
that results from any structural or functional impairment of ventricular vital organs.7 However, prolonged activation of these systems increases
filling or ejection of blood’.1 The European Society of Cardiology systemic vascular resistance and causes sodium and water retention,
definition is ‘an abnormality of cardiac structure or function leading myocardial hypertrophy, fibrosis and apoptosis, which accelerates the
to failure of the heart to deliver oxygen at a rate commensurate with progression of HF and promotes end-organ damage.6,8–10
the requirements of the metabolising tissues, despite normal filling
pressures (or only at the expense of increased filling pressures).2 The blockade of beta-adrenergic receptors leads to symptomatic
improvement and reduced morbidity and mortality in patients
HF prevalence and the number of HF-related hospitalisations are with HFrEF.9–13 In addition, the central role of the RAAS system in
increasing, and the prognosis remains poor, with a 5-year mortality worse HF has led to the therapeutic use of RAAS inhibitors,2,8 including
than many cancers.3,4 There has been significant progress in HF therapy, angiotensin-converting enzyme (ACE) inhibitors,14 angiotensin receptor
but mostly in HF with reduced ejection fraction (HFrEF), while for patients blockers (ARBs) in patients who cannot tolerate ACE inhibitors15 and
with preserved ejection fraction (HFpEF), no therapy has improved clinical mineralocorticoid receptor antagonists in the treatment of chronic
outcomes.2,5 Despite such advances, however, morbidity and mortality HF.16,17 ARBs competitively inhibit the binding of angiotensin II to its AT1
of HFrEF still remains high. It is evident, therefore, that substantial unmet receptors located on blood vessels and other tissues, and improve
needs exist in HF therapy. This article aims to review the mechanism symptoms, haemodynamics and outcomes in chronic HF.1,2 These
of action and clinical development of sacubitril/valsartan (LCZ696), a beneficial effects are attributed to the inhibition of the deleterious
first-in-class angiotensin receptor neprilysin inhibitor that has recently effects of AT1 receptor stimulation, i.e., vasoconstriction, Na+ and
received regulatory approval in the US and Europe. water retention, aldosterone and vasopressin release, stimulation of
sympathetic tone, inflammation, fibrosis and cell growth (see Figure 1).
The Role of the Renin-Angiotensin-Aldosterone
System in Heart Failure However, ACE inhibitors, ARBs, aldosterone receptor antagonists and
Neurohumoral activation, in particular, of the renin-angiotensin- combinations of drugs in these classes are limited in their ability to
aldosterone system (RAAS) and the sympathetic nervous system, fully inhibit the activity of the RAAS.6,18 Furthermore, ACE inhibitors and
plays a major role in the development and progression of HF.1,2 The ARBs induce a reactive rise in plasma renin activity that may eventually
RAAS is an essential component in the regulation of cardiovascular surpass their RAAS-inhibitory effect, and plasma aldosterone levels
homeostasis that exerts its actions through the hormones angiotensin remain elevated in a subset of patients despite therapy, a phenomenon

40 © RADCLIFFE CARDIOLOGY 2016

 LCZ696

known as aldosterone escape or aldosterone breakthrough.19 In Figure 1: The Role of the Natriuretic Peptides in Heart Failure
addition, ARBs do not enhance bradykinin-mediated vasodilation and
are considered less effective than ACE inhibitors.2 Heart failure

For the past 25 years, an add-on therapy approach to chronic HF Natriuretic peptides Renin angiotensin
system LCZ696 system
has been used, beginning with diuretics, then adding ACE inhibitors
(or ARBs) and beta blockers, followed by mineralocorticoid receptor
ANP, BNP, CNP Sacubitril (AHU377) Angiotensinogen
antagonists.13,20,21 Ivabradine, which reduces heart rate, is also approved as
Ang I
an add-on therapy in HF.22 Nevertheless, morbidity and mortality remain Inactive
Neprilysin LBQ657
products
high and there is, therefore, a need for new therapeutic targets in HF. Ang II

Adrenomedullin
VALSARTAN AT1R
Role of Natriuretic Peptides in Heart Failure Bradykinin
Angiotensin II
Substance P
While the activation of the RAAS and sympathetic nervous system is Vasoconstriction Endothelin-1 Vasoconstriction
↓Blood pressure β amiloid peptide ↑Blood pressure
detrimental in HF, other counter-regulatory pathways are activated ↓Sympathetic tone
↓Aldosterone levels
↑Sympathetic tone
↑Aldosterone levels
in HF, including the natriuretic peptide (NP) system (see Figure 2). ↓Hypertrophy/fibroses
↓Inflammation
↑Hypertrophy/fibroses
↑Inflammation
Diuresis/natriuresis ↓Cardiac output
The NP system consists of atrial (ANP),23 B-type (BNP)24 and C-type Na+/water retention
Endothelial dysfunction
(CNP) NPs; these hormones regulate BP and fluid homeostasis.25–27 ANP
The natriuretic peptide (NP) system comprises three homologous peptides: atrial (ANP),
is synthesised and secreted in atria, BNP is secreted from the ventricles brain (BNP) and C-type (CNP), and two biologically active receptors. ANP and BNP bind to the
natriuretic receptor-A (NPR-A) and CNP specifically binds to the NPR-B. NPR-A and NRP-B are
in response to mechanical stretch and increased intracardiac volume/ coupled to particulate forms of guanylyl cyclase (GC-A and GC-B) and catalyse the synthesis
pressure and CNP mostly originates from endothelial and renal cells of cyclic guanosine (cGMP), which modulates the activity of cGMP-dependent protein kinase
G (PKG) to exert its multiple cardiac, vascular and renal actions. The NP-cGMP-PKG signalling
and is secreted in response to endothelium-dependent agonists and pathway is terminated by phosphodiesterases (PDEs) that hydrolyse cGMP to guanosine
pro-inflammatory cytokines.25,26,28 NPs activate three transmembrane monophosphate (GMP). NPs are removed from the circulation and inactived by the
clearance receptor (NPR-C) and degraded by several peptidases, including neprilysin (neutral
receptors: natriuretic peptide receptor (NPR)-A, NPR-B and NPR-C.27 endopeptidase) (NEP). In addition, the NPR-C mediates non-cGMP regulated biological
actions. DAG: = diacilglicerol; GTP = guanosine triphosphate; IP3 = inositol 1,4,5-trifosfato;
The binding of NPs to type A (NPR-A) and type B (NPR-B) receptors LTCC = L-type calcium channel; PLC = phospholypase C; RAAS = renin-angiotensin-
activates guanylate cyclase, increasing levels of the second messenger aldosterone system; UROD = urodilatin.

cyclic guanosine monophosphate (cGMP) and its effector molecule

protein kinase G. This induces natriuresis, diuresis, vasodilation Figure 2: Mechanism of Action of LCZ696 on
Natriuretic Peptides
and inhibition of the RAAS system and the sympathetic nervous
system, as well as antifibrotic, antiproliferative and antithrombotic
NEP 24.11 Degradation
effects (see Figure 2).25,26,28
ANP
BNP ANP, BNP
UROD CNP CNP, UROD
A growing body of evidence suggests that hypertension and HF may
be consequences of a dysregulated NP system and that patients Ca2+
LTCC NPR-A NPR-B NPR-C
with HF and hypertension may have a deficiency of biologically
active NPs.28,29 NPR-C clears NP from the circulation through receptor- AC
P α1 β γ PLC
mediated internalisation and degradation. Urodilatin, a renally ATP
synthesised isoform of ANP, stimulates NPR-A located in the glomeruli GC GC GC GC
AC cAMP DAG +IP3
and collecting ducts and promote Na+ excretion.30
Inactive non-cGMP
GTP cGMP GTP products mediated
effects
Another key component of the NP system is neprilysin (neutral
PKG PDE
endopeptidase 24.11), which catalyses the degradation of ANP, BNP
and CNP as well as the degradation of bradykinin, adrenomedullin,
Arteriolar and venous vasodilation, natriuresis, inhibition of the RAAS
endothelin-1, substance P and angiotensin II (see Figure 1).31 Neprilysin and sympathetic tone, inhibition of platelet aggregation, antifibrotic,
antihypertrophic, anit-inflammatory and lusitropic effects.
is a potentially useful therapeutic target in HF.6,28 Inhibition of neprilysin
ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; CNP = C-type natriuretic
increases the levels of NP, causing vasodilation and a reduction in
peptide; cGMP = cyclic guanosine monophospate; DAG = diacilglicerol; GC = guanylyl
extracellular fluid volume. Neprilysin does not hydrolyse N-terminal cyclase-A; GMP = guanosine monophosphate; GTP = guanosine triphosphate; IP3 = inositol
1,4,5-trifosfato; LTCC = L-type calcium channel; NEP = neprilysin (neutral endopeptidase);
prohormone of brain NP (NT-proBNP), therefore the latter is a useful NPR = natriuretic peptide receptor; PDE = phosphodiesterase; PKG = protein kinase G;
cardiac biomarker to assess therapeutic effect and prognosis in PLC = phospholypase C; RAAS = renin-angiotensin-aldosterone system; UROD = urodilatin.

patients treated with neprilysin inhibitors.32

normotensives, an effect prevented by enalapril, and does not reduce
Clinical Development of Vasopeptidase Inhibitors BP in hypertensive subjects, probably because its vasodilatory effect
Augmentation of NPs by direct administration of these peptides is may be offset by an increased activity of the RAAS and sympathetic
difficult because oral delivery is ineffective and parenteral delivery nervous system and/or by downregulation of NP receptors.41,42 In
problematic. While nesiritide has been shown to produce a modest addition, since neprilysin acts on numerous physiological targets, the
improvement in dyspnoea, it does not favourably affect clinical effect of candoxatril was broader than anticipated.41
outcomes, decongestion or renal function33–35 and safety concerns
have been raised.36,37 Blockade of NP breakdown by neprilysin inhibitors Neprilysin inhibition results in activation of the RAAS, therefore, in order
has, therefore, been investigated.38 Oral neprilysin inhibitors, such as to be clinically beneficial, neprilysin inhibition requires concomitant
candoxatril, produced clinical benefit in patients with chronic HF.39,40 inhibition of the RAAS.43 Vasopeptidase inhibitors are dual inhibitors
However, candoxatril has no effect on, or increases, systolic BP (SBP) in of ACE and neprilysin and, therefore, emerged as a new therapeutic

C A R D I A C FA I L U R E R E V I E W 41
Pharmacological Therapy

Table 1: Summary of Clinical Trials of LCZ696

Authors/Trial Clinical Setting Trial Treatment Primary Endpoint Primary Outcomes

Name Description
PARADIGM-HF57 HFrEF: class II–IV, LVEF Phase III LCZ696 (200 mg twice Composite of CV death or HF LCZ696 significantly reduced CV
≤40 % (changed to ≤35 %), R, DB, PG, ACS daily) or enalapril hospitalisation or hospitalisation (20 %; p<0.001),
plasma BNP ≥150 pg/ml n=8,442 (10 mg twice daily) CV death (20 %) and all-cause
(N-terminal pro-BNP Follow-up 27 mortality (16 %) versus enalapril
≥600 pg/ml) months
TITRATION60 HFrEF (NYHA class II–IV, Phase I LCZ696: from 50 to Proportion of patients Treatment was successful in
LVEF ≤35 %, on beta R, DB, PA 200 mg twice daily in a experiencing pre-specified 78 % and 84 % of patients in the
blockers) n=498 3-week (condensed) adverse events* and laboratory condensed and conservative
versus 6-week outcomes including SBP <95 regimens, respectively. The
(conservative) regimen mmHg and a doubling of serum target dose was achieved and
creatinine from baseline maintained for 12 weeks in 76 %
of patients
PARAMOUNT61 HFpEF (LVEF ≥45 %, Phase II LCZ696 (200 mg twice daily) Change in NT-proBNP from At 12 weeks, NT-proBNP was
NT-proBNP >400 pg/ml) DB, R, PG versus valsartan (160 mg baseline to 12 weeks significantly reduced in the
n=301 twice daily) for 36 weeks LCZ696 group versus valsartan
PARAGON-HF63 HFpEF (NYHA class II–IV, Phase III LCZ696 (50, 100 and 200 Composite endpoint of CV Ongoing
LVEF >45 %) R, DB, ACS mg) versus valsartan (40, 80 death and total (first and
n=4,300 and 160 mg) for up to recurrent) HF hospitalisations
57 months
UK HARP-III Proteinuric CKD (eGFR Phase III LCZ696 (200, 400 mg once Difference in change in Ongoing
(ISRCTN11958993)73 ≥20 <45 ml/min/1.73m2; R daily) versus irbesartan measured eGFR from baseline
or eGFR ≥45 <60 ml/ n=360 (150, 300 mg once daily) to 6 months
min/1.73m2 and urine
ACR ≥20 mg/mmol)
Ruilope et al64 Mild–moderate Phase III LCZ696 (100, 200, 400 mg Mean difference across the Significant reduction of SBP/
hypertension R, DB, PC, ACS once daily); valsartan three single-dose pairwise DBP with LCZ696 200 mg and
n=1,215 (80, 160, 320 mg once comparisons of LCZ696 versus 400 mg versus valsartan 160
daily); AHU377 (200 mg valsartan in mean sitting DBP and 320 mg Significant reduction
once daily) versus placebo at 8 weeks in ambulatory BP with LCZ696
versus valsartan
Kario et al65 Mild–moderate Phase III LCZ696 (100, 200 or 400 mg Mean difference across the Significant reductions in SBP/
hypertension (Asian R, DB, PC once daily) versus placebo 3 single-dose pairwise DBP, and pulse pressure with
population) n=362 for 8 weeks comparisons of LCZ696 versus LCZ696 versus placebo
placebo in DBP
*Symptomatic hypotension, hyperkalaemia, renal dysfunction, angioedema. ACR = albumin:creatinine ratio; ACS = active-controlled study; BP = blood pressure; CI = confidence interval;
CKD = chronic kidney disease; CV = cardiovascular; DB = double-blind; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure
with preserved ejection fraction; HR = hazard ratio; LA = left atria; LV = left ventricle; LVEF = left ventricular ejection fraction; N-terminal pro-BNP = N-terminal prohormone of brain natriuretic
peptide; NYHA = New York Heart Association; PC = placebo-controlled; PA = parallel assignment; PG = parallel group; R = randomised; SBP/DBP = systolic/diastolic blood pressure.

option in HF and hypertension, but their pharmacological profile is of two molecular moieties (in a 1:1 molar ratio) in a single crystalline
complex.44 Omapatrilat was more effective than either lisinopril or complex comprising valsartan (an ARB) and sacubitril (AHU377).52 After
amlodipine in reducing BP,44 but in patients with chronic HF it was not ingestion, LCZ696 undergoes rapid dissociation into valsartan and
more effective than enalapril in reducing the combined risk of death sacubitril, a prodrug that is subsequently de-ethylated by esterases to
or hospitalisation for HF requiring intravenous treatment.45 However, LBQ657, a neprilysisn inhibitor.
omapatrilat was discontinued due to the risk of angioedema, possibly
due to excessive inhibition of bradykinin degradation (presumably via In healthy volunteers, LCZ696 causes dose-dependent increases in
neprilysin, ACE and aminopeptidase P).46,47 ANP, plasma and urinary cGMP, renin concentration and activity and
angiotensin II levels, as a result of neprilysin inhibition and AT1 receptor
Mechanism of Action of LCZ696 blockade (see Figure 1).52 After LCZ696 administration, levels of cGMP
Following the disappointing outcomes of combined ACE/neprilysin significantly increased at 4 and 12 hours and returned to baseline levels
inhibition, the combination of neprilysin and an ARB was investigated. at 24 hours; all RAAS biomarkers reached a maximum after 4 hours and
ARBs have a lesser effect on bradykinin48 and have been associated remained elevated at 24 hours.52 Thus, the pharmacodynamic effects of
with lower risk of angioedema compared with ACE inhibitors, not valsartan and LBQ657 are similar. In HF patients, levels of urinary cGMP,
significantly different from placebo.49,50 Therefore, RAAS blockade at the plasma BNP and renin concentration and activity were higher during
AT1 receptor appears to be a preferable strategy to ACE inhibition.51 treatment with LCZ696 than with enalapril, while circulating levels of
LCZ696 (Entresto™, Novartis) is a first-in-class angiotensin II receptor- markers of myocardial wall stress (N-terminal pro-BNP) and myocardial
neprilysin inhibitor (ARNI) whose multimodal mode of action involves injury (troponin T) were lower during treatment with LCZ696 than with
neprilysin inhibition and AT1 receptor blockade. LCZ696 is composed enalapril.53,54 After 21 days of LCZ696 administration (100 mg titrated to

42 C A R D I A C FA I L U R E R E V I E W
 LCZ696

200 mg daily) a significant lowering of plasma NT-proBNP, aldosterone Figure 3: Kaplan-Meier Curve for Primary Study Endpoint
and endothelin-1 levels was observed.55 of PARADIGM-HF (Composite of Death from Cardiovascular
Causes or First Hospitalisation for Heart Failure)

Nevertheless, the precise mechanism by which LCZ696 reduces Primary endpoint

cardiovascular mortality in HF patients is uncertain.56 The observed 1.0
Hazard ratio, 0.80
benefit is likely to be related to the incremental benefits of neprilysin (95 % confidence interval, 0.73–0.87)
inhibition, which may counteract the detrimental effects of RAAS and p<0.001
0.6

Cumulative probability
sympathetic nervous system activation. Other possible mechanisms
0.5
might include: a haemodynamic improvement related to NP-mediated
reduction in ventricular wall stress; an improvement in ventricular 0.4
Enalapril
function; modification of the basis for fatal ventricular arrhythmias 0.3
via decreased myocardial fibrosis and hypertrophy, attenuation 0.2 LCZ696
of ventricular remodelling or direct anti-arrhythmic properties;
0.1
sympatholytic or vagotonic effects of hormones potentiated by
neprilysin inhibition; and anti-atherosclerotic or anti-thrombotic 0.0
0 180 360 540 720 900 1,080 1,260
effects of enhanced NP expression leading to an improvement Days since randomisation
in regional myocardial perfusion.56 Further understanding of the Number at risk
LCZ696 4,187 3,922 3,663 3,018 2,257 1,544 896 249
mechanisms of action of LCZ696 would provide a deeper insight into
Enalapril 4,212 3,883 3,579 2,922 2,123 1,488 853 236
the pathophysiology of HF and should be a priority in the future. The natriuretic peptide (NP) system comprises three homologous peptides: atrial (ANP),
brain (BNP) and C-type (CNP), and two biologically active receptors. ANP and BNP bind
to the natriuretic receptor-A (NPR-A) and CNP specifically binds to the NPR-B. NPR-A and
Pharmacokinetic Properties of LCZ696 NRP-B are coupled to particulate forms of guanylyl cyclase (GC-A and GC-B) and catalyse
Valsartan and LBQ657 have similar pharmacokinetic profiles, with rapid the synthesis of cyclic guanosine (cGMP), which modulates the activity of cGMP-dependent
protein kinase G (PKG) to exert its multiple cardiac, vascular and renal actions. The NP-cGMP-
absorption, reaching maximum plasma concentrations within 1.5–4.5 PKG signalling pathway is terminated by phosphodiesterases (PDEs) that hydrolyse cGMP to
guanosine monophosphate (GMP). NPs are removed from the circulation and inactived by the
hours, and a half-life of 8.9–16.6 and 9.9–11.1 hours, respectively, clearance receptor (NPR-C) and degraded by several peptidases, including neprilysin (neutral
indicating that both agents exhibit comparable pharmacokinetic endopeptidase) (NEP). In addition, the NPR-C mediates non-cGMP regulated biological actions.
DAG: = diacilglicerol; GTP = guanosine triphosphate; IP3 = inositol 1,4,5-trifosfato; LTCC = L-type
properties and that LCZ696 was suitable for once- or twice-daily calcium channel; PLC = phospholypase C; RAAS = renin-angiotensin-aldosterone system;
dosing.52 Sacubitril (AHU377) reaches peak plasma levels within 0.5–1.1 UROD = urodilatin. From McMurray et al., Angiotensin-neprilysin inhibition versus enalapril in
heart failure. N Engl J Med 2014;371(11): 993–1004. Copyright © (2014) Massachusetts Medical
hours and presents a half-life of 1.1–3.6 hours owing to its rapid Society. Reprinted with permission from Massachusetts Medical Society.
conversion into the active metabolite LBQ657, which explains the
rapid onset of activity of LCZ696. LCZ696 achieves 90 % inhibition of The trial was terminated early after a median follow up of 27 months
neprilysin.52 Importantly, LCZ696 does not inhibit aminopeptidase A, due to evidence of an overwhelming benefit with LCZ696. The primary
unlike omapatrilat, thus minimising the risk of angiodema.52 In healthy endpoint, a composite of death from cardiovascular causes or
volunteers, LCZ696 400 mg and valsartan 320 mg provide similar hospitalisation for HF, occurred in 21.8 % of the LCZ696 group and 26.5
exposure to valsartan. % of the enalapril group (hazard ratio [HR] in the LCZ696 group, 0.80; 95
% confidence interval [CI], 0.73–0.87; p<0.001) (see Figure 3). During the
Clinical Development of LCZ696 trial, the numbers of patients who would need to have been treated to
Heart Failure prevent one primary event and one cardiovascular death were 21 and
The main clinical trials investigating the efficacy and safety of 32, respectively. Death from any cause was reported in 17 % of patients
LCZ696 are summarised in Table 1. The pivotal clinical trial in the receiving LCZ696 and 19.8 % receiving enalapril (HR 0.84; 95 % CI
development of LCZ696 was the Prospective comparison of ARNI 0.76–0.93; p<0.001); of these 13.3 % and 16.5 %, respectively, died from
with ACEI to Determine Impact on. Global Mortality and morbidity in cardiovascular causes (HR 0.80; 95 % CI 0.71–0.89; p<0.001).57 Using
Heart Failure (PARADIGM-HF) study, which recruited patients (n=8,442) actuarial estimates from the PARADIGM-HF trial, and assuming that the
with chronic HF (New York Heart Association [NYHA] class II–IV) and protective effects of LCZ696 are sustained during long-term use, it has
reduced left ventricular ejection fraction (LVEF; ≤40 % to ≤35 %).57 The been estimated that treatment with LCZ696 could result in 1 to 2 years
trial began with a single-blind run-in period to test drug tolerability. of increased life expectancy in patients with HF.58 LCZ696 also reduced
Patients received enalapril 10 mg twice daily for 2 weeks, then 100 the risk of hospitalisation for HF by 21 % compared with enalapril
mg LCZ696 twice daily for 1–2 weeks and then 200 mg twice daily for (p<0.001) and decreased HF symptoms (p=0.001).57 Interestingly, these
2–4 weeks. Two brief (one day) washout periods were also included benefits were also observed in 2,907 patients with diabetes. In a
to minimise the potential risk of angioedema due to overlapping ACE sub-analysis of PARADIGM-HF, the benefit of LCZ696 compared with
and neprilysin inhibition. During the run-in period, 12 % of patients enalapril was consistent, regardless of glycaemia status.59
withdrew due to an adverse event. Following the run-in period,
patients underwent double-blind 1:1 randomisation to LCZ696 200 mg In addition, two recent analyses have focused on the effect of LCZ696
twice daily or enalapril 10 mg twice daily. Exclusion criteria included on the risk of clinical deterioration. A subanalysis of PARADIGM-HF
symptomatic hypotension (SBP <100 mmHg) (at screening or 95 mmHg focused on pre-specified measures of non-fatal clinical deterioration.53
at randomisation), an estimated glomerular filtration rate (eGFR) Compared with enalapril, fewer patients in the LCZ696 group required
<30 ml/min/1.73 m2 at screening or at randomisation or a decrease treatment intensification for HF (520 versus 604; HR 0.84; 95 % CI
in the eGFR >25 % (which was amended to 35 %) between screening 0.74–0.94; p=0.003) or an emergency department visit for worsening
and randomisation, a serum K+ level >5.2 mmol/L at screening HF (HR 0.66; 95 % CI 0.52–0.85; p=0.001). Patients receiving LCZ696
(or >5.4 mmol/L at randomisation) or a history of angioedema or had 23 % fewer hospitalisations for worsening HF (851 versus 1,079;
unacceptable side effects during ACE inhibitor or ARB therapy. 95 % CI 0.67–0.85; p<0.001) and 18 % fewer stays in intensive care

C A R D I A C FA I L U R E R E V I E W 43
Pharmacological Therapy

(768 versus 879; p=0.005), and were 31 % less likely to receive HFpEF. Treatment with LCZ696 for 36 weeks resulted in lower serum
intravenous positive inotropic agents (p<0.001) and 22 % less likely to creatinine, higher eGFR and an increase in urinary albumin to creatinine
have cardiac transplantation or implantation of a cardiac device for ratio compared with valsartan.62
HF (p=0.07). The reduction in hospitalisation was noted within the first
30 days after randomisation. Worsening symptoms were consistently Although the PARAMOUNT study was not powered to detect clinical
more commonly reported in the enalapril group.53 outcomes, it was a hypothesis-generating trial that provided the basis
for the ongoing phase III Prospective comparison of Angiotensin
Another analysis focused on the mode of death in the PARADIGM- Receptor neprilysin inhibitors with Angiotensin converting enzyme
HF trial. The majority of deaths were cardiovascular (80.9 %), and inhibitors to Determine Impact on Global Mortality and morbidity in
treatment with LCZ696 significantly reduced the risk of cardiovascular Heart Failure (PARAGON-HF) trial, which aims to enrol 4,300 patients.
death (HR 0.80; 95 % CI 0.72–0.89; p<0.001). This reduced risk was Enrolment criteria are symptomatic HFpEF, NYHA class II–IV, LVEF
primarily due to a reduction in both sudden cardiac death (HR 0.80; ≥45 % requiring treatment with diuretics for HF ≥30 days prior to study
95 % CI 0.68–0.94; p=0.008) and death due to worsening HF (HR 0.79; entry, structural heart disease (left atrial enlargement or left ventricular
95 % CI 0.64–0.98; p=0.034). The treatment effect on sudden cardiac hypertrophy) documented by echocardiogram, a HF hospitalisation
death was not affected by the presence or absence of an implantable within 9 months prior to study entry and/or an elevated NT-proBNP.63
cardioverter-defibrillator.56 Of note, LCZ696 reduced cardiovascular The primary endpoint is a composite of cardiovascular death and total
death to a similar extent as its reduction of HF hospitalisation, while HF hospitalisations. The treatment arm with the lower rate of events
the results of many pivotal studies of RAAS in HF found a more will be deemed to have the most successful response.
pronounced reduction in hospitalisations for worsening HF than
cardiovascular death.56 Arterial Hypertension
LCZ696 has also shown efficacy in clinical studies of hypertension. In
The Safety and Tolerability of Initiating LCZ696 in Heart Failure a multinational study with sites in 18 countries, patients (n=1,328) with
Patients (TITRATION) study demonstrated the safety and efficacy of mild-to-moderate hypertension were randomised to 8 weeks’ treatment
up-titrating LCZ696 from 50 mg twice daily to a target dose of 200 mg with LCZ696 (100, 200 or 400 mg daily), valsartan (80, 160 or 320 mg
twice daily in a 3- (condensed) versus 6-week (conservative) regimen daily), sacubitril (200 mg daily) or placebo.64 The reduction in mean resting
in patients with HFrEF (EF ≤35 %) on beta-blockers. The study enrolled SBP and diastolic BP (DBP) was significantly greater for 200 mg LCZ696
a broader range of patients than PARADIGM-HF, including inpatients versus 160 mg valsartan (-11/-6.1 versus -5.7/-3.2 mmHg; p<0.001) and
and patients naïve to ACE inhibitors or ARBs.60 The study involved an for 400 mg LCZ696 versus 320 mg valsartan (-12.5/-6.9 versus -6.4/4.1
open-label run-in period in which LCZ696 was tested for tolerability mmHg; p<0.005).64 Response rates were also significantly higher in
and safety at a 50 mg twice daily for 5 days. Patients were then patients on 200 mg LCZ696 versus 160 mg valsartan (91/163, 56 %;
randomised to up-titration of LCZ696 to 200 mg during the next 3 p=0.0095), and on 400 mg LCZ696 versus 320 mg valsartan (103/163,
(condensed) or 6 weeks (conservative) regimen. Primary endpoints 63 %; p=0.026). No differences were found between 100 mg LCZ696
included the proportion of patients experiencing pre-specified adverse and 80 mg valsartan. In a multicentre study carried out in Japan, China,
events (symptomatic hypotension, hyperkalaemia, renal dysfunction, South Korea, Taiwan and Thailand, patients aged ≥18 years (n=389) with
angioedema) and outcomes including SBP <95 mmHg and a doubling hypertension were randomised to LCZ696 (100, 200 or 400 mg once
of serum creatinine from baseline. In the primary endpoint of daily once daily) or placebo (n=92) for 8 weeks. Reductions in SBP, DBP
tolerability, there were no differences between groups. Treatment (p<0.0001) and pulse pressure (p<0.001) were significantly greater with
was successful in 78 % and 84 % of patients in the condensed and all doses of LCZ696 than with placebo. The reductions are greater than
conservative regimens, respectively (p=0.07). The target dose was those observed in white European populations, as this Asian population
achieved and maintained for 12 weeks in 76 % of patients. The has a higher salt intake and increased salt sensitivity. There were also
study also suggested that patients on ACE inhibitors or ARBs should significant reductions in 24-hour, daytime and nighttime ambulatory SBP,
probably be moved less quickly to up-titration of LCZ696. DBP and pulse pressure for all doses of LCZ696 compared with placebo
(p<0.0001).65 Although the mechanism is uncertain, this effect can be
There is a lack of effective treatments for patients with HFpEF, therefore related to its vascular effects and/or to reduced effective circulating
LCZ696 was evaluated in this treatment setting. Prospective comparison volume. In the PARAMOUNT trial the reduction from baseline in mean
of ARNI with ARB on Management Of heart failUre with preserved ejectioN SBP/DBP was -9.3/-4.9 mmHg with LCZ699 (200 mg twice daily) and
fraction (PARAMOUNT) was a phase II study in patients with NYHA class -2.9/-2.1 mmHg with valsartan (160 mg twice daily).61 In the PARADIGM-
II–III HF and LVEF ≥45 %. Participants (n=301) were randomised to HF trial where 71 % of patients had hypertension, LCZ696 therapy
LCZ696 (titrated to 200 mg twice daily) or valsartan (titrated to 160 mg resulted in a significant reduction in SBP compared with enalapril (mean
twice daily). The primary endpoint was change in NT-proBNP, a marker difference -2.7 mmHg; p<0.001) over a period of 3 years. The role of the
of left ventricular wall stress.61 At 12 weeks, NT-proBNP was significantly reduction in SBP on the decreased rate of death and HF hospitalisation
reduced in the LCZ696 group compared with the valsartan group (from observed in this trial is uncertain.
783 pg/ml to 605 pg/ml in the LCZ696 group versus from 862 pg/ml to
835 pg/ml in the valsartan group; ratio LCZ696:valsartan, 0.77; 95 % CI Safety Profile of LCZ696
0.64–0.92; p=0.005). In addition, after 36 weeks more patients in the In clinical studies of hypertension, LCZ696 was well-tolerated and no
LCZ696 group showed improvements in NYHA functional class and cases of angioedema or deaths were reported. The most common
reduced left atrial size compared with valsartan, consistent with reverse adverse events were headache and pruritus,64 nasopharyngitis and
left atrial remodelling. LCZ696 was well tolerated with adverse effects upper respiratory tract infection.64,65 Hypotension or syncope occurred
similar to those of valsartan. A recently reported analysis from this study in five patients (one each in the placebo, 400 mg LCZ696 and 200 mg
investigated the effects of LCZ696 on renal function in patients with AHU377 groups; two in the 200 mg LCZ696 group).64 Adverse events

44 C A R D I A C FA I L U R E R E V I E W
 LCZ696

resulting in treatment discontinuation occurred in 1–2 % of patients Although clinical trials to date have demonstrated the tolerability
on LCZ696, with the highest occurrence in the AHU377 and placebo of LCZ696, it can be argued that the similar rates of adverse events
groups.64 However, patients with diabetes and renal disease (eGFR among LCZ696 and standard therapy may have been the result of
>30 ml/min/1.73 m2) were excluded from these trials. patient selection bias. Thus, data from on-going clinical trails and
clinical practice are needed to evaluate its long-term efficacy.
In the PARADIGM-HF study, 12 % of patients did not complete the
run-in period because of adverse events, most frequently cough, Clinical use of LCZ696
hyperkalaemia, renal dysfunction or hypotension. Across the study LCZ696 has been approved by the European Medicines Agency72 and
period, LCZ696 was discontinued in 746 patients (17.8 %) and enalapril US Food and Drug Administration73 to reduce the risk of cardiovascular
in 833 patients (19.8 %). During the double-blind phase, the LCZ696 death and hospitalisation in adult patients with symptomatic chronic
group had higher rates of hypotension (p<0.001) and non-serious HFrEF. It is usually administered in conjunction with other HF therapies,
angioedema (p=0.31), but significantly lower rates of serum creatinine in place of an ACE inhibitor or an ARB. If switching from an ACE inhibitor,
≥2.5 mg/dl, serum potassium ≥6 mmol/L and cough than the enalapril a washout period of 36 hours is important. The recommended starting
group, and a lower overall incidence of adverse events. Fewer dose is 49/51 mg (sacubitril/valsartan) twice daily. This may be increased
patients in the LCZ696 group than in the enalapril group stopped after 2–4 weeks to the target maintenance dose of 97/103 mg (sacubitril/
drug medication because of an adverse event (10.7 % versus 12.3 %; valsartan) twice daily as tolerated by the patient. The starting dose
p=0.03) or renal impairment (0.7 % versus 1.4 %; p=0.002).57 In the should be reduced to 24/26 mg (sacubitril/valsartan) twice daily for
PARAMOUNT trial the number of patients with hypotension, renal patients not currently taking an ACE inhibitor or an ARB, or previously
dysfunction or hyperkalemia did not differ between groups.61 taking a low dose of these agents, i.e. patients with severe renal
impairment (eGFR <30 ml/min/1.73 m2) and patients with moderate
However, questions remain regarding the safety of LCZ696. Although hepatic impairment (Child-Pugh B).
it is better tolerated than valsartan in clinical studies, it showed a
higher incidence of hypotension, an important consideration in elderly Conclusion
patients, although this rarely resulted in discontinuation of treatment, While drugs targeting the RAAS represent the cornerstone of HF
and the number of discontinuations due to hypotension were balanced treatment, there is a need for novel therapeutic approaches. LCZ696
across both groups. In addition, the question of angioedema in daily is an effective and safe alternative to ACE inhibitors and may change
clinical practice remains unanswered. Angioedema is more common in future first-line approaches to HF therapy because of its significant
patients of African origin,66,67 but these were under-represented in the improvement in survival and reduced rates of rehospitalisation.
PARADIGM-HF (5 %). There is also a need for studies in ACE inhibitor- Additionally, LCZ696 has been found more effective than valsartan
naïve patients, where benefits were less pronounced in PARADIGM-HF, in hypertensive patients, although comparative studies with other
although it should be noted that all patients had an enalapril run-in antihypertensive drugs are needed and its effects on cardiovascular
phase so were not truly naïve. outcomes are unknown. Ongoing clinical trials will define its future role
in the treatment of HF and other cardiovascular diseases, where ACE
A recent review paper discussing preclinical models and human inhibitors or ARBs are currently first-line therapies.
genetic analyses suggested that neprilysin inhibitors may lead to
an accumulation of amyloid beta-peptide in the brain and may thus For LCZ696 to displace ACE inhibitors and ARBs in daily clinical practice,
accelerate Alzheimer’s disease progression in at-risk patients.68 more information on real-life use of LCZ696 is required, including
This is a hypothetical concern and not based on any human safety and efficacy in patient groups not included in PARADIGM-HF, i.e.
studies: a Chinese study found no association between two NEP patients with acute decompensated HF and more advanced symptoms
gene polymorphisms and Alzheimer’s disease in elderly people.69 (NYHA IV only represented 0.8 % of the study population); elderly and
Furthermore, a 2-week LCZ696 administration in human healthy black patients; patients with resistant hypertension, nephropathy and
volunteers did not modify Abeta1−40 and Abeta1−42 levels in the proteinuric renal disease; patients receiving high doses (≥10 mg twice
cerebrospinal fluid70 and no cognition-related adverse events related daily); or treated with ARBs. There is some preliminary evidence of
to treatment have been reported in any of the randomised clinical LCZ696 in hypertensive patients with diabetes; furthermore, the benefit
trials to date, probably because multiple (20) proteins are involved of LCZ696 in the PARADIGM-HF trial was reported in 2,907 patients
in the clearance of amyloid beta-peptides. There is therefore no with diabetes. It will also be important to determine which patients
conclusive evidence for an association between NEP and Alzheimer’s will benefit most, for example ACE inhibitor/ARB naïve patients, who
disease in humans. Cognition-related adverse effects were observed are commonly encountered in the clinic. For the first time in 30 years,
in the PARADIGM-HF trial, as expected in a study population physicians must make a careful therapeutic decision: instead of adding
including elderly patients, but the incidence was balanced in both to a drug regimen, they have the option to replace ACE inhibitors or
treatment arms.71 Serial cognition testing will be performed in ARBs with LCZ696. This decision should be made with the knowledge
PARAGON-HF.63 In addition, a dedicated study investigating cognition that the agent provides proven benefits in terms of reduced mortality
and PET imaging is planned. and fewer re-hospitalisations. n

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