Cardiology in the Young
cambridge.org/cty
Review Article
Cite this article: Das BB, Scholl F, Vandale B,
Chrisant M. (2018) Sacubitril/Valsartan:
potential treatment for paediatric heart
failure. Cardiology in the Young page 1 of 5.
doi: 10.1017/S1047951118001014
Received: 3 April 2018
Revised: 10 May 2018
Accepted: 11 May 2018
Key words:
Paediatric heart failure; angiotensin receptor
blocker; neprilysin inhibitor
Author for correspondence:
B. B. Das, MD, FAAP, FACC, Joe DiMaggio
Children’s Hospital Heart Institute, Memorial
Health Care, 1150 North 35 Avenue,
Hollywood, FL 33021, USA. E-mail: bdas@mhs.
net
© Cambridge University Press 2018.
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Sacubitril/Valsartan: potential treatment for
paediatric heart failure
Bibhuti B. Das, Frank Scholl, Breanna Vandale and Maryanne Chrisant
Joe DiMaggio Children’s Hospital Heart Institute, Memorial Health Care, Hollywood, FL, USA
Abstract
The Prospective comparison of angiotensin receptor antagonist Valsartan and neprilysin
inhibitor Sacubitril with angiotensin-converting enzyme inhibitor (enalapril) to determine
impact on Global Mortality and Morbidity in Heart Failure trial has demonstrated that
Sacubitril/Valsartan is superior to Enalapril in reducing the risks of both sudden cardiac death
and death from worsening heart failure. This novel combination, Sacubitril/Valsartan, is also
shown to reduce the risk of hospitalisation and progression of heart failure in adults.
However, the benefit of Sacubitril/Valsartan in paediatric heart failure patients is unknown.
In this review, we discuss the similarities and differences in pathophysiology of heart failure in
children versus adults, and the potential role of Sacubitril/Valsartan in paediatric heart failure
patients.
Paediatric heart failure represents an important cause of morbidity and mortality in child-
hood. Aetiology and pathogenesis are different between adults and children. In children, heart
failure is commonly due to structural heart disease and reversible conditions, thus lending it
amenable to definitive therapy. Despite differences with regard to the aetiology of paediatric
and adult heart failure with systolic dysfunction, there is overlap in the pathophysiology and
clinical management of the two diseases. Although the epidemiology and management of
adult heart failure have been extensively studied, the prevalence and management of paediatric
heart failure are not well characterised. This article offers an overview on the aetiology and
pathophysiology of paediatric heart failure with a specific focus on management of ambulatory
paediatric heart failure patients who remain symptomatic despite standard of care and the role
of the combined therapy with angiotensin receptor antagonist Valsartan and neprilysin
inhibitor Sacubitril.
Definition of paediatric heart failure
Heart failure describes the inability of the heart to meet the haemodynamic needs of the body.
Paediatric heart failure can represent a wide range of abnormalities in cardiac structure and
function, both congenital and acquired, and can present as systolic/diastolic dysfunction or
both. The International Society for Heart and Lung Transplantation defines paediatric heart
failure as a clinical and pathologic syndrome that results from ventricular dysfunction,
volume, or pressure overload, alone or in combination. In children, it leads to characteristic
signs and symptoms, such as poor growth, feeding difficulties, respiratory distress, exercise
intolerance, and fatigue, and is associated with circulatory, neurohormonal, and molecular
abnormalities.1
Aetiology and prevalence of paediatric heart failure
The clinical course, outcome, and aetiology of paediatric heart failure is more heterogeneous
than in the adult population. The greatest percentage of children with heart failure comes from
those born with CHD; depending upon age, 25–75% of paediatric heart failure patients have
underlying CHD.2 The other main cause of paediatric heart failure is cardiomyopathy, with an
estimated annual incidence of 1/100,000 children in the United States, Australia, United
Kingdom, and Ireland.3–5 Of the patients listed for heart transplantation, according to the
International Society of Heart and Lung Transplant paediatric registry report, idiopathic
dilated cardiomyopathy is the most common cardiomyopathic diagnosis in children (66%).6
In the current era, however, we must consider more granular diagnoses as genetic testing has
become both more prevalent and specific. Systolic dysfunction, as in dilated cardiomyopathy,
is associated with muscular dystrophies such as Duchenne’s muscular dystrophy, myotonic
dystrophy, and multiple other neuromuscular diseases. Chemotherapy (e.g. anthracycline)-
induced cardiac disease often presents as acute systolic dysfunction and may progress to true
 2 B. B. Das et al.

Figure 1. Pathophysiology of progression of heart failure. ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; NP = natriuretic peptide.

chronic dilated cardiomyopathy. In developing countries, rheu- protein kinase G, leading to vasorelaxation, natriuresis, and diur-
matic heart disease, nutritional deficiencies, and other tropical esis. Atrial natriuretic peptide and B-type natriuretic peptide also
diseases, such as Chagas disease, provide the aetiology of pae- inhibit renin secretion and aldosterone production and attenuate
diatric heart failure and cardiomyopathy .7 cardiac and vascular remodelling, apoptosis, ventricular hyper-
trophy, and fibrosis.12 Adrenomedullin has been shown to reduce
myocyte hypertrophy, fibroblast proliferation, collagen synthesis,
Pathophysiology of paediatric heart failure and potential and aldosterone secretion.13
role of Sacubitril/Valsartan Neprilysin is the key enzyme responsible for the breakdown of
neuropeptides. The neprilysin level is increased in chronic heart
In heart failure, low cardiac output leads to reduced baroreceptor
failure, and thus the clearance of these neuropeptides is acceler-
stimulation, resulting in the activation of the sympathetic nervous
ated.14 Inhibition of neprilysin enhances the effects of endogenous
system, which increases heart rate, cardiac contractility, and
natriuretic peptides – atrial natriuretic peptide, bradykinin, and
vasoconstriction to restore the blood pressure towards normal.
adrenomedullin – which exerts vasodilation, anti-hypertrophic/
The activation of the sympathetic nervous system also includes
anti-fibrotic action mitigating the detrimental effects of angio-
the release of renin, leading to production of angiotensin II, which
tensin, endothelin, and aldosterone (Fig 2).
in turn causes vasoconstriction of renal afferent arterioles, as well
The effect of inhibition of neprilysin on the level of B-type
as release of aldosterone, which causes an increase in sodium
natriuretic peptide is minimal as B-type natriuretic peptide is
reabsorption. When the renin–angiotensin–aldosterone system
cleared from the circulation mainly by neuropeptide receptors,15
activation is undeterred, vasoconstriction (increased afterload)
making this a useful biomarker to measure and track, as a
leads to a substantial increase in cardiac work and myocardial
decrease in B-type natriuretic peptide may then be attributable to
oxygen consumption. At the cellular level, the compensatory gain
improved heart failure and not a drug effect. Concomitant inhi-
in cardiac excitation–contraction coupling mediated by sympa-
bition of angiotensin synthesis or action is particularly important,
thetic stimulation ultimately becomes unsuccessful, as the sus-
because neprilysin inhibition alone is accompanied by activation
tained leak of calcium from the sarcoplasmic reticulum leads to
depletion of intracellular calcium and ultimately impaired con-
tractility.8,9 Unfortunately, the deleterious effects predominate
over the long term, leading to pathologic myocardial remodelling,
and more rapid progression of myocardial dysfunction (Fig 1).
The ability of angiotensin-converting enzyme inhibitor/angio-
tensin receptor antagonist, aldosterone antagonists, and β-blockers
to improve survival and slow the progression of heart failure is
compatible with this hypothesis.10 However, despite the use of the
above chronic heart failure medications, patients remain at risk of
worsening heart failure.11 Progression of abnormal cardiac remo-
delling with continued elevation of angiotensin II, aldosterone,
anti-diuretic hormone, and sympathetic nervous system activation
all impair the function of endogenous neuropeptides such as
natriuretic peptides, bradykinin, and adrenomedullin. Natriuretic
peptides are coupled to, and activate, guanyl cyclase A, which
increases the intracellular concentrations of the second messenger, Figure 2. Mode of action of Sacubitril and Valsartan. ANP = atrial natriuretic peptide;
cyclic guanosine monophosphate. The latter, in turn, activates BNP = B-type natriuretic peptide; NP = natriuretic peptide.

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 Cardiology in the Young
of the renin–angiotensin–aldosterone system, possibly because
angiotensin itself may be a substrate for neprilysin.16 Although
the actions of angiotensin may be attenuated by angiotensin-
converting enzyme inhibitor, simultaneous blockade of
angiotensin-converting enzyme and neprilysin can lead to serious
angioedema. This has been shown by Omapatrilat versus Enala-
pril Randomized Trial of Utility in Reducing Events trial.17
Omapatrilat is a drug that inhibits angiotensin-converting
enzyme, neprilysin, and aminopeptidase P and causes sig-
nificant angioedema. The preferred approach may be to parallel
modulation of the neuroendocrine system by the combined use of
a neprilysin inhibitor while simultaneously blocking effects of
angiotensin action by an angiotensin receptor blocker.
The major pharmacodynamics action of angiotensin-
converting enzyme inhibitor is mediated by reversible binding
to plasma angiotensin-converting enzyme, resulting in competi-
tive inhibition of the conversion of angiotensin I to angiotensin II.
Angiotensin-converting enzyme inhibitor also blunts sympathetic
stimulation and activates the parasympathetic system. The net
haemodynamic effect of angiotensin-converting enzyme inhibitor
is reduction in total peripheral resistance and blood pressure,
without change in heart rate or fluid retention. The effect of
angiotensin receptor antagonist in heart failure is similar to that
of angiotensin-converting enzyme inhibitor. Valsartan, an
angiotensin receptor blocker, which is a component of Sacubitril/
Valsartan, has been shown to improve outcomes in adults hos-
pitalised for heart failure.18 Typically, when blockade of the
renin–angiotensin–aldosterone system is desired, it is a common
clinical practice in adult heart failure patients to begin with
angiotensin-converting enzyme inhibitor and switch to an
angiotensin receptor blocker in patients who are intolerant.
Because angiotensin receptor blockers do not block the degra-
dation of kinins, angioedema and persistent cough are uncom-
mon. The combination of Valsartan and Sacubitril may be more
effective than angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker alone because of incremental bene-
fits of neprilysin inhibition in heart failure.19
The augmentation of endogenous neuropeptides could help to
broaden the benefits of renin–angiotensin system inhibitors for
patients with heart failure.20 It is possible that neprilysin inhibi-
tion may have additional benefits including improved haemody-
namics, reduced ventricular wall stress, myocardial fibrosis,
ventricular hypertrophy, and attenuation of progressive ven-
tricular remodelling.20 Further, neprilysin inhibition of sympa-
thetic drive or potentiation of vagotropic effects and the benefits
of enhanced vagal tone in heart failure are well documented,
although just coming to prominence as an effective line of
therapy.
Management of paediatric heart failure
The goal of acute heart failure management in children is to
improve haemodynamics and prevent progression. Current
management includes stabilisation with intravenous inotropes/
vasopressors, mechanical ventilation, treatment of arrhythmia,
and progression to mechanical support if needed. Should some
recovery occur, the child is often left with chronic heart failure
and the lingering diagnosis of dilated cardiomyopathy, with or
without a genetic-based or syndrome/systemic disease-based
diagnosis. The goal of clinical management of the chronic pae-
diatric heart failure is to maintain stability, prevent progression,
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3
and provide a reasonable milieu to allow somatic growth and
optimal development. Despite the lack of sufficient randomised
prospective studies, current treatment typically includes some
combination of angiotensin-converting enzyme inhibitors, β-
blockers, diuretics, aldosterone-blocking agents, and anti-coagu-
lants; digoxin is no longer typically used, and angiotensin receptor
blockers enjoy only a small audience in paediatric heart failure
management.
When deciding on a maintenance regimen for the treatment of
paediatric heart failure, the two most often relied upon factors
include efficacy shown in adult heart failure trials, and paediatric
consensus statements and guidelines.1 Although the management
of paediatric heart failure has been extrapolated from adult trials,
there are significant barriers in applying adult data to children
because of developmental factors, age variation from birth to
adolescence, differences in aetiology and disease progression, and
differences in genetic expression profile21 and β-adrenergic sig-
nalling.22 Specifically, downregulation of β1- and β2-adrenergic
receptors is identified in children, whereas β2-adrenergic receptor
expression is maintained in adults.22 There are also differences in
phosphorylation status of phospholamban22 and expression of
phosphodiesterase isoforms23 in children versus adults.23
The landmark carvedilol study, a randomised controlled trial
in paediatric heart failure published in 2007, did not meet its
composite primary end-point measure of heart failure outcomes.
This study, however, was underpowered (n = 161), and included
the full range of children – from infancy to 18 years of age – with
CHD, including single-ventricle patients with failing systemic
right ventricle, as well as patients with normal cardiac anatomy
and systolic left ventricular failure.24 The complexity of designing
an effective paediatric heart failure drug trial, as well as inter-
preting the results, is evident in this valiant effort.
Many children with severe heart failure, progressive disease,
and unremitting symptoms are listed for heart transplant, if
available; however, cardiac transplantation is a last resort, given
the limited availability of donor organs, complicated manage-
ment, and associated morbidity or mortality.25 Although wait-list
mortality is less than the transplantation rate (17 versus 63%),
and the number of children receiving heart transplant for all
diagnoses is about 600 patients yearly world-wide,26 we do not
know how many children, who are not listed for transplant and
have no access to these services, die of heart failure each year.
Regardless of the number, it is too many. Ultimately what is
needed is a readily available, affordable, easily administered, and
safe therapy that will stall the progression of heart failure inde-
finitely, concomitantly allowing reasonably normal growth and
development. It is possible that the combination of Sacubitril and
Valsartan may meet at some of these criteria.
The efficacy of Sacubitril/Valsartan, over the standard of care
angiotensin-converting enzyme inhibitor (Enalapril) for reducing
mortality and morbidity in adult heart failure with reduced left
ventricle ejection fraction, provides strong rationale that may have
clinically meaningful benefits for paediatric heart failure patients.19
Lessons learned from adult heart failure trials
The Prospective comparison of angiotensin receptor antagonist
(Valsartan) and neprilysin inhibitor (Sacubitril) with angiotensin
converting enzyme inhibitor (Enalapril) to determine impact on
Global Mortality and Morbidity in Heart Failure (PARADIGM-
HF) trial was conducted in adult patients with heart failure from
 4 B. B. Das et al.
2009 through 2014 and included 8399 patients in 47 countries. The
results of the trial have shown that the Sacubitril/Valsartan is
superior to enalapril in reducing the risks of both sudden cardiac
death and death from worsening heart failure; it is also shown to
reduce the risk of hospitalisation and progression of heart fail-
ure.19,20,27 The PARADIGM-HF trial has also demonstrated that
when patients with an estimated glomerular filtration rate <30 ml/
min were excluded, fewer patients on Sacubitril/Valsartan devel-
oped a serum creatinine level ≥ 2.5 mg/dl (n = 139, 3.3%) than did
patients on Enalapril (n = 188, 4.5%; p = 0.007).19 This suggests that
Sacubitril/Valsartan may be superior to angiotensin-converting
enzyme inhibitor or angiotensin receptor blocker on renal function.
Furthermore, because heart failure is a common, serious compli-
cation in patients with end-stage renal disease, Sacubitril/Valsartan
might delay the progression of both conditions.
The remarkable success of PARADIGM-HF trial led to a recent
ongoing clinical trial, Prospective Comparison of Sacubitril/
Valsartan with angiotensin receptor blocker Global Outcome in
heart failure with Preserved Ejection Fraction trial, which has
begun to enroll 4300 adult heart failure patients with left ventricle
ejection fraction >45% to study the superiority of Sacubitril/
Valsartan over Valsartan.28 This trial may provide a major
breakthrough for the treatment of adults with heart failure with
preserved ejection fraction, and subsequent trial in paediatrics
may be warranted in future. In a previous study, Ruilope et al29
have demonstrated the superiority of Sacubitril/Valsartan as once-
daily doses in adults with hypertension over enalapril.
The adult target dose for Sacubitril/Valsartan was 200 mg
twice daily, which is equivalent to 3.1 mg/kg twice daily for
children. The adult study demonstrated that Sacubitril/Valsartan
was well tolerated; although patients receiving Sacubitril/Valsar-
tan had more episodes of symptomatic hypotension compared
with Enalapril, there was no increased rate of discontinuation of
therapy. In addition, the incidence of renal failure was less
common than for Enalapril during the duration of treatment
(median follow-up of 27 months), and there was no increase in
the incidence of angioedema. Overall, adverse events were com-
mon in the Enalapril group compared with Sacubitril/Valsartan.
On the basis of these favourable data and outcomes obtained in
the PARADIGM-HF trial, the Food and Drug Administration
fast-tracked the Sacubitril/Valsartan for approval in 2015, and it
became the class I recommendation for use in adult heart failure
patients in 2016 by both United States and European union heart
failure guidelines – less than a year after regulatory approval. In
the European Union, the 2016 ESC Guidelines for the diagnosis
and Treatment of Acute and Chronic Heart Failure, Sacubitril/
Valsartan got a recommendation I B, which signifies class I
“strong” (is recommended) and level of evidence B “moderate
quality”; these data were derived from one single trial.30 In the
2017 ACC/AHA Focused Update on New Pharmacological
Therapy for Heart Failure: An Update of the 2013 AHA Guide-
lines for the Management of Heart Failure, Sacubitril/Valsartan
also received a class I B recommendation.31 Therefore, Sacubitril/
Valsartan is recommended as an angiotensin-converting enzyme
inhibitor replacement to further reduce the risk of heart failure
hospitalisation and death in ambulatory patients with heart failure
and reduced left ventricle systolic function who remain sympto-
matic despite optimal treatment with angiotensin-converting
enzyme inhibitor, a β-blocker, and aldosterone antagonist.
The combination therapy of neurohormonal modulation and
angiotensin inhibition may well represent a new era of hope for
children with heart failure. The current paediatric multicentre trial
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(PANORAMA-HF study, NCT00382525) will similarly examine
whether Sacubitril/Valsartan is superior to Enalapril for the treat-
ment of heart failure in children with reduced systemic left ven-
tricle systolic function. The details of the design of the trial has
been recently published, and notably the study population is quite
homogeneous, including only patients with reduced left ventricle
systolic function.32 The target N is 180 patients in each treatment
group – Enalapril versus Sacubitril/Valsartan – and, although far
from the vast populations studied in adult heart failure trials, is
expected to provide adequate power to detect a meaningful dif-
ference in an event-driven end point (primary global rank end
point). The results from this study may change the clinical practice
of our current chronic heart failure treatment in children.
Conclusion
A judicious balance between extrapolation from adult heart fail-
ure guidelines and the development of child-specific data on
treatment represents a wise approach to optimise management of
paediatric heart failure. The successful completion of the
PANAROMA-HF study will inform and facilitate paediatric
access to Sacubitril/Valsartan, a novel treatment and hope for
children with heart failure.
Acknowledgements. We are thankful to Candice Sareli, MD, Office of
Human Research, Memorial Healthcare System for her critical review of the
manuscript.
Financial Support. This research received no specific grant from any
funding agency or from commercial or not-for-profit sectors.
Conflicts of Interest. The authors have no conflicts of interest to disclose.
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