17th Expert Committee on the Selection and Use of Essential Medicines

Geneva, March 2009

CardiacFailureinChildren

SeanBeggs
1
AngusThompson
2
RoseNash
2
AnnaTompson
2
GregoryPeterson
2

1.PaediatricDepartment,RoyalHobartHospitalandUniversityof
Tasmania
2.UMORE,SchoolofPharmacy,UniversityofTasmania

September2008
Contents

Summary_________________________________________________________________________________3
Introduction ______________________________________________________________________________5
Burdenofdiseasefromcardiacfailureinchildren ____________________________________________6
Whatmedicinesareessentialforthetreatmentofcardiacfailureinchildren?_______________ _____8
CurrentstatusoftheEMLcandguidelines ____________________________________________8
Diuretics __________________________________________________________________________9
Digoxin __________________________________________________________________________11
Angiotensinconvertingenzymeinhibitors(ACEinhibitors) ___________________________13
Angiotensinreceptorblockers(ARBs) _______________________________________________16
Aldosteroneantagonists ___________________________________________________________17
Betablockers _____________________________________________________________________18
Antiarryhtmicdrugs_______________________________________________________________19
Inotropes_________________________________________________________________________19
Othertherapies ___________________________________________________________________19
Discussion ______________________________________________________________________________19
Treatment ________________________________________________________________________19
UnansweredQuestions ____________________________________________________________27
Conclusion ______________________________________________________________________________21
Appendix1:SearchStrategy _______________________________________________________________22
References_______________________________________________________________________________35

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Summary
In children, cardiac failure is most often caused by congenital heart disease and
cardiomyopathy. These causes are significantly different from those usually responsible for
theconditioninadults,whichincludecoronaryarterydiseaseandhypertension.
Literature searches were undertaken using a variety of search engines including PubMed,
the Cochrane Library, BMJ Clinical Evidence and the National Guideline Clearinghouse to
identifyevidenceforthemanagementofcardiacfailure.Thereisalargeamountofresearch
published on the management of heart failure in adults, which has given rise to significant
changesinmanagementinthelastdecade.However,therearefarfewerstudiesinchildren
andthosewhichdoexistareoftensmall,retrospectiveanduseadiverserangeofmeasures
toassessefficacy.
As a result, the management of cardiac failure in children has largely evolved based on
clinical experience and the application of adult data, supported by the more limited
paediatric literature. Given the significant differences in aetiology of heart failure between
the adult and paediatric populations, this is not ideal. However, clinical experience in
paediatricswiththedrugswhichhavebeenproventobebeneficialinadultsprovidessome
reassurancethattheoutcomesmaybesimilarlybeneficial.
Onthisbasis,itisrecommendedthattheEMLcisexpandedtoincludeadditionaltreatment
optionsforchildrenwithcardiacfailure,namelyanACEinhibitorandabetablocker.
InthecaseofACEinhibitors,thetwosupportedbythegreatestpaediatricdataarecaptopril
andenalapril.Theformerhastheadvantageofgreaterstabilityinliquidformulationandthe
latter the advantage of requiring less frequent dosing. It should be noted that there is very
limited published data on the paediatric use of those ACE inhibitors most widely used in
adults (such as ramipril, lisinopril and perindopril) and none at all in children with heart
failure. Captopril is proposed for addition to the EMLc, as the representative of the ACE
inhibitorgroup.
In terms of betablockers, the vast majority of evidence in paediatric cardiac failure is with
carvedilol, which is supported by findings from the trials in adults, where it has been
consistently shown to improve outcomes. Carvedilol should therefore be considered the
betablockerofchoiceinchildrenwithcardiacfailureandbeconsideredforinclusiononthe
EMLc.
The EMLc already includes a number of drugs used in management of cardiac failure in
children:frusemide,digoxin,spironolactoneanddopamine.Althoughthisreviewconsiders
itappropriatetoretainthesefourdrugsintheEMLcatthecurrenttime,itshouldbenoted
thatthereisalackofrobustresearchtosupporttheuseofthesedrugsinthepaediatricheart
failurepopulation;inparticulardigoxin,whichappearstoremainwidelyusedbasedsolely
onlongstandingclinicalpractice.
Although Angiotensin Receptor Blockers (ARBs) are increasingly used in cardiac failure in
adults, especially where there is intolerance to ACE inhibitors, there is no published
evidence supporting their use in children with the condition. Consequently, it is not
consideredappropriatetoincludeanARBintheEMLcatthecurrenttime.
Whilst there is data emerging for a range of other therapy options, this is not sufficiently
robusttowarranttheirinclusionintheEMLcatthecurrenttime.
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By adding an ACE inhibitor and betablocker to the EMLc, a greater number of those
children worldwide who have cardiac failure should be able to benefit from improved
outcomes.
There is also a pressing need for improved research into the treatments used in paediatric
cardiac failure, as well as extension of product licenses where appropriate; and greater
availability and standardisation of the formulations required for effective delivery of these
treatments.
Inadditiontoworkaroundthedrugsusedtotreatheartfailure,continuedeffortstoreduce
theburdenofmalnutritionandmalariawhichmayexacerbateheartfailurethroughanaemia
andothercauses;areessentialindevelopingnations.
Introduction
ThesubcommitteeoftheExpertCommitteeontheSelectionandUseofEssentialMedicines
identified Cardiac Failure as an area where more information was required to inform their
decisionforfuturemeetings.
The aim of this review was to address the following questions that came out of the initial
meeting.
1. Whatistheburdenofdiseasefromcardiacfailureinchildrenunder12
yearsofage?
2. Whatmedicinesareessentialfortreatment?
3. ArethesealreadyontheEMLcinanappropriatedosageformand
strength?
4. Ifnot,whatneedstobeadded?
In order to address the above questions, a search and review of existing literature was
undertaken,asoutlinedinAppendix1.
Burdenofdiseasefromcardiacfailureinchildren
Cardiac failure is a clinical syndrome where the heart is unable to provide the output
required to meet the metabolic demands ofthebody; however, the causes and mechanisms
ofcardiacfailurearesignificantlydifferentbetweenadultsandchildren(1).
Inadults,cardiacfailureusuallyinvolvesfailureoftheleftventricle,withthemostcommon
causes in developed nations being coronary artery disease; hypertensioninduced cardiac
stress, arrhythmias and valvular disease. In developing nations, it has been reported that
other causes are frequently implicated, including rheumatic heart disease (20.1%) and
cardiomyopathy(16.8%)(2).
Inchildren,thecausesofcardiacfailurearesignificantlydifferentandmanycasesaredueto
congenitalmalformations,suchaslefttorightshunts.Inthesepatientsthefunctionofboth
the right and the left ventricles will be affected and these children suffer from highoutput
cardiac failure. Other significant causes of heart failure in children are cardiomyopathy (3)
andanthracyclinetoxicity,whichleadtolowoutputcardiacfailure.Indevelopingnations,
many cases are caused or exacerbated by anaemia, often secondary to malaria and
malnutrition(4).Ithasalsorecentlybeenidentifiedthatinfantsinethnicminoritygroupsin
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developedcountriesmaybeatriskofheartfailurelinkedwithhypocalcaemiaandvitaminD
deficiency(5).
There is also a much higher proportion of children with heart failure who have undergone
cardiac procedures (61.4%) compared to adults with heart failure (0.28%); this reflects the
incidence of congenital defects, frequent surgical intervention to correct this, and the
subsequent and eventual deterioration in cardiac function that is seen in many of these
children.
Accurately estimatingtheincidenceofcardiacfailureinchildrenisproblematic.Congenital
heart disease occurs in around 8 per 1000 live births; however, many of these children
receive early surgical intervention and it has been estimated that the yearly incidence of
heartfailureasaresultofcongenitaldefectsisbetween1and2per1000livebirths(6).Asa
result, cardiomyopathy contributes significantly to the number of paediatric patients who
presentwiththesymptomsofcardiacfailure.DatafromtheUnitedStates(7)andAustralia
(8) suggests the incidence of cardiomyopathy to be 1.13 per 100,000 and 1.24 per 100,000,
respectively.Nonetheless,itshouldberecognisedthatnotallpatientswithcardiomyopathy
haveheartfailure,whichissupportedbydatafromtheUK(9),whichreportstheincidence
ofheartfailureassessedatfirstpresentationtohospitaltobearound0.87per100,000.Data
from Nigeria suggests that 7.02% of emergency paediatric admissions to a tertiary centre
hospital are for cardiac failure, with over 90% of cases being from lower socioeconomic
groups (4). In general the prognosis for children with cardiomyopathy is poor, with 5year
mortality reported at around 80% (10) and many cases progress to requiring heart
transplantationwhendrugtherapyprovesinsufficient.
What medicines are essential for the treatment of cardiac failure
inchildren?
CurrentstatusoftheEMLcandguidelines
TheOctober2007cardiovascularmedicinessectionoftheWHOEssentialMedicinesListfor
Children (EMLc) contains digoxin, frusemide, spironolactone and, on the complementary
list, dopamine. Clinical practice in the management of cardiac failure in children uses a
wider range of medicines than those currently on the EMLc; consequently, the sub
committeerequestedthisreview.
Management of cardiac failure in adults is covered by a number of national guidelines (11
15). In contrast, although there are many reviews of the management of cardiac failure in
children (6, 1623), there are no national or international guidelines to steer consistent
evidencebasedpractice.
Theapproachtothemanagementofcardiacfailureinchildrenhasconsequentlydeveloped
from a combination of clinical experience, small scale studies in paediatric populations and
the application of adult trial data to the paediatric population. Given the significant
differences in the causes of cardiac failure between the adult and paediatric populations,
cautionisrequiredwhenapplyingevidenceinthiswayanditmaybemisleading(6).
Mostofthe drugs usedinpaediatriccardiacfailurearenot licensedfor useinchildrenand
are not routinely available in suitable formulations, which introduces additional
complications in terms of practical dose administration and potential bioavailability and
bioequivalence(24).
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This review seeks to summarise the evidence which is available and provide a basis on
which the committee can formulate guidance on the management of cardiac failure in
children,supportedbyanappropriateEMLc.
Diuretics

RationalforuseofDiuretics:
Diureticshavetwomaineffectswhichmaybebeneficialinheartfailure:
increasedwaterloss
increasedsodiumloss

Diuretics have been widely used in cardiac failure in both adults and children for many
years, providing rapid relief from the symptoms of fluid overload; however, the effects of
diureticsondiseaseprogressionandsurvivalhavebeenunclear.
Mostpatientswithheartfailurewhorequirediuretictherapyaretreatedwithloopdiuretics,
rather than thiazides, as they are more powerful agents (11). However, the use of loop
diuretics has been questioned on the basis of the lack of randomised clinical trials and the
potential for undesirable effects on intracellular and extracellular magnesium and calcium
ionconcentrations,andthiaminedeficiency(23,25).
A Cochrane systematic review specifically considered the risks and benefits of diuretics in
heart failure and found a limited number of studies which met their criteria. Based on 14
trials, with 525 participants, this review drew the conclusion that diuretics appeared to
reduceriskofdeathanddeteriorationofcardiacfailurecomparedtoplacebo,andimproved
exercisecapacitywhencomparedtootheractivetreatments(26).
One review of paediatric heart failure has specifically laid out a treatment pathway, which
positions diuretics, including frusemide, as a first step (alongside digoxin) (20). Consistent
withthisapproach,manyofthetrialslookingatACEinhibitorsandbetablockersincardiac
failureinchildrenhavereportedtheirusewasinadditiontostandardtherapy,whichwhere
specified,haswithoutexceptionincludeddiuretics,particularlyfrusemide
Of the available loop diuretics, frusemide is the most widely used in cardiac failure and is
alreadyincludedintheEMLc,inarangeofpresentations.Bumetanideisalsoavailableand
used in paediatrics, although there is limited published data on the use of this alternative
loopdiureticinheartfailureamongstchildren(27).
Research in adults with heart failure has suggested that torasemide, a longeracting loop
diuretic,isatleastaseffectiveasfrusemide(28).Morerecently,asmallstudyspecificallyin
childrenwithcardiacfailureconcludedthattorasemidewassafeandeffectiveinthisgroup,
with significant improvements in heart failure index measurements amongst newly
diagnosedpatients(29).
As highlighted above, the loop diuretics have been the most widely used in heart failure,
althoughinsomesituationsothertypesofdiureticshavearole.Inadultpatientswithmild
heart failure, thiazide diuretics may be effective as monotherapy. In refractory oedema,
sometimes referred to as braking, there is an apparent decrease in the urine volume
produced by standard diuretic therapy and this occurs in children and infants, as well as
adults (30). In this situation combinations of drugs with different sites of action have been
used, most commonly a thiazide (or thiazidetype) diuretic with a loop diuretic. One small
study in children with frusemideresistant oedema, reported that the combination of
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frusemide with metolazone (a thiaziderelated diuretic) produced significant improvements
inurinaryvolumeandsodiumexcretion(31)intheabsenceofchronicrenalinsufficiency.A
review of the same approach in adults reported that there were few studies, but based on
these and an additional observational study, concluded that use of low dose metolazone
(5mg) added to loop diuretics is effective and relatively safe for adult outpatients with
refractoryheartfailure(32),althoughsignificantelectrolytedisturbanceswerereported.
Hydrochlorothiazide is included on the essential medicines list for adults as an option in
both hypertension and heart failure. A review by the European Medicines Evaluation
Agency(EMEA)hasidentifiedaneedfortheindicationsforhydrochlorothiazide,including
heart failure, to be extended to all age groups, as well as the development of an age
appropriateformulation(33).Thesamereviewmakesnoreferencetometolazone.
Theroleofthosediureticswhicharealdosteroneantagonistsisdiscussedseparately,astheir
applicationinheartfailureisdifferenttothatofthethiazideandloopdiuretics.
BasedontheexistinginclusionoffrusemideintheEMLc,itswidespreaduse,availabilityin
formulations suitable for paediatric administration and the lack of any compelling data
showing specific advantages of other loop diuretics, it is considered appropriate to retain
frusemideastheloopdiureticofchoiceintheEMLc.
Theneedforanadditionaldiuretic,ofthethiazide(orthiazidetype),islessclear.Whilstthe
limited evidence supports use of metolazone, the EMEA appears to consider
hydrochlorothiazide as the preferred option. At this point in time there is insufficient
evidencetoarguefortheirinclusionontheEMLc.
Digoxin

RationalforuseofDigoxin:
Digoxinhasanumberofeffectswhichmaybebeneficialinheartfailure:
inotropiceffects
slowedheartrate,improvingbalanceofoxygensupplyanddemand
inhibitionofsympatheticnervoussystem
inhibitionofreninrelease

Cardiacglycosideshavebeenusedinthemanagementofcardiacfailureforover200years.
Whilstdigoxinandrelateddrugsarestillconsideredtohavearole in thepresenceofatrial
fibrillation, their place in the therapy of patients with cardiac failure without atrial
fibrillation has been increasingly questioned, particularly given the significant changes in
heartfailuremanagementoverthelast20years.
There is a dearth of research published evaluating the role of digoxin in children with
cardiac failure. However it is notable that many of the trials looking at other therapies in
paediatric cardiac failure have referred to standard treatment, which has almost without
exception included digoxin, indicating that it remains widely used, despite the lack of trial
evidence.
ACochranesystematicreviewsoughttoclarifytheevidenceinadultswithheartfailurewho
were in sinus rhythm and identified thirteen articles which met their criteria and reported
endpointsincludingmortality,clinicalstatusandhospitalisation.Thisreviewconcludedthat
the data shows no evidence of a difference in mortality between treatment and control
groups, but that digitalis therapy is associated with a lower rate of hospitalisation and of
clinicaldeterioration(34).
Page 7 of 31
Thereisnoequivalentsystematicreviewlookingattheroleofdigoxininpaediatriccardiac
failureandthesignificanceoftheconclusionsoftheCochranereviewforchildrenisunclear,
especiallygiventhedifferingaetiology.Thosereviewsanddiscussionswhichhavefocussed
onpaediatriccardiacfailurevaryintheirassessments,withsomesuggestinguseofdigoxin
iscontroversial(22)whilstotherspositionitasafirstlinetreatmentalongsidediuretics(20).
At a time when betablockers are being more widely used, it is important to note that a
clinically significant interaction has been documented between carvedilol and digoxin. This
can result in significant increases in digoxin levels, which necessitates a reduction in the
digoxindosetoavoidtheriskofdigoxintoxicity(35).Itwouldbeprudenttohighlightthisin
any guidance on management of heart failure where these two drugs may be given
concurrently.
DigoxininarangeofformulationsisalreadyincludedintheEMLcand,givenitsapplication
in other indications, it is considered appropriate for it to be retained. However, the specific
inclusionofdigoxinforcardiacfailurewouldappeartobebasedonlongestablishedclinical
practiceratherthanonrobustevidenceandthisshouldbenotedbythecommittee.
AngiotensinConvertingEnzymeInhibitors(ACEinhibitors)

Rationalforuseofangiotensinconvertingenzyme(ACE)inhibitors:
ACEinhibitorsreducetheeffectsthatresultfromtheactivationofthereninangiotensinaldosterone
(RAA)systemwhichoftenoccursinheartfailure.ThebeneficialeffectsofACEinhibitorsinheart
failuremaythereforeinclude:
reducedAngiotensinIImediatedvasoconstriction
reducedAngiotensinIImediatedpotentiationofsympatheticnervoussystemactivity
reducedAngiotensinIImediatedaldosteronereleaseandtherefore
o reducedsodiumandwaterretention
o reducedmyocardialfibrosis
o reducedinhibitionofnitricoxiderelease
reducedbreakdownofvasodilatorybradykinin

A number of angiotension converting enzyme inhibitors have been studied in large

randomised trials in the management of cardiac failure in adults, with generally consistent
findings of reduced symptoms, morbidity and mortality. Of those studied enalapril,
lisinoprilandramiprilhavethegreatestweightofevidenceinheartfailure.Thereisnodata
directly comparing the different ACE inhibitors on which any conclusions about the
superiorityofoneoveranothercanbedrawn.BasedonstudiesandreviewsofvariousACE
inhibitors in other conditions, such as postMI (36), hypertension (37, 38), stroke (39),
diabetes (40) and renal disease (41), and the generally favourable outcomes seen, there has
been a tendency to consider that ACE inhibitors exhibit a class effect. Consequently, other
drugs in the group such as perindopril, captopril and trandolapril are also widely used in
adults.
In children with cardiac failure, the ACE inhibitors which have been most studied are
captopril and enalapril, with more modest data for cilazapril. Whilst there is some data
supporting ramipril and lisinopril in children with hypertension (42, 43), there is no
published data on the use of these drugs in children with heart failure and no published
studiesontheuseofperindoprilinchildrenforanyindication.
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ThekeystudiesontheuseofACEInhibitorsinchildrenwithcardiacfailurearesummarised
inTable1.Itshouldbenotedthatmanyofthestudieshavebeenretrospectiveandassessed
surrogatemarkersforclinicaloutcomes.
In common with experiences in adults, a number of children treated with ACE inhibitors
experienceddeteriorationinrenalfunctionandhypotension.Inmanycasesdiscontinuation
oftheACEinhibitororreductionindosewaseffectiveinreducingtheseproblems;however,
some of the studies reported renal failure and death in a small number of cases. It should,
however, be noted that as many of the patients included in these reports were already
significantly haemodynamically compromised, the exact role of the ACE inhibitor in the
development of these adverse outcomes is unclear. Other adverse effects were reported in
one of these trials and included one case of neutropaenia and one case of cough, both of
whichresolvedondiscontinuationoftheACEinhibitor(44).
Onthebasisoftheavailabledata,arecentreviewofuseinpaediatricpracticeconcludedthat
myocardial dysfunction should be treated with ACE inhibitors, mildmoderate valvular
insufficiency is effectively treated with ACE inhibitors and large left to right shunts should
be surgically treated, unless surgery is not appropriate, when an ACE inhibitor should be
used(45).
There is currently not an ACE inhibitor included on the EMLc; based on the evidence and
current clinical opinion, this needs to be addressed. Enalapril and captopril account for the
majority of the evidence from studies in children; consequently, any ACE inhibitor to be
includedintheEMLcwouldmostrationallybeoneofthesetwo.
A recent review has concluded that the lack of definitive data comparing individual drugs
makes it inappropriate to recommend a specific ACE inhibitor for use in children (45);
however, for practical purposes the inclusion of one ACE inhibitor on the EMLc would be
desirable.IntheabsenceofcompellingclinicalreasonstoselectaspecificACEinhibitor,itis
appropriate to consider other factors which may affect the practical administration of these
drugs.Itisrecognisedthatthepreparationofenalaprilinaliquidformulationischallenging,
whereas in some countries a licensed liquid formulation of captopril is available, to
supplementthetabletformulationwhichwouldbeappropriateforolderchildren.However,
theshorterdurationofactionofcaptoprilnecessitatesmorefrequentadministration,usually
threetimesperdaycomparedtoonceortwiceperdayforenalaprilandthelatterisalready
includedintheessentialmedicineslistforadults.Therelativemeritsofthesefactorsneedsto
be carefully considered in any decision which is made regarding inclusion of an ACE
inhibitorintheEMLc.

Table1.SummaryofstudiesonACEinhibitorsinPaediatricCardiacFailureandrelatedconditions
(DCM=dilatedcardiomyopathy,LVD=leftventriculardysfunction,VSD=ventricularseptaldefect)
Study Populationtreated
withACEinhibitor
ACEInhibitorused Keyfindingsandcomments
(46) 27withDCM Captopril
(0.93.9mg/kg/day)
Significantly improved survival over first two years, trend towards this continued
thereafter.
(47) 18LVDpost
doxorubicin
Enalapril
(mean18mg/day)
Left ventricular function improved over the first six years, deteriorating between 6
and10years.
(48) 12withDCM Captopril Improvementsinhaemodynamiceffects.
(44) 63withLVD
(congenital&acquired)
Enalapril
(mean0.3mg/kg/day)
58% of patients improved, 30% had no improvement and 12% had sideeffects.
3patientsdiedwithcardiac/renalfailure.
(49) 8withCMandHF Enalapril
(0.5mg/kg/day)
Persistentclinicalimprovementafteroneyear,withdecreasedheartsizereported.
(50) 6withVSDandHF Enalapril
(0.120.43mg/kg/day)
Clinicalimprovementsinallpatients,improvementsinbodyweightandfeeding
(51) 8withVSDandHF Enalapril
(0.16mg/kg/day)
Enalaprilat
Clinicallyeffectiveandwelltoleratedinallpatients
(52) 20withlefttoright
shuntsandHF
Captopril
(0.92.5mg/kg/day)
Clinical improvement in most patients, four developed renal failure or hypotension.
Improvementsinweightgainandrespirationratereported.
(53) 20withaortic
regurgitation
Captopril
(11.5mg/kg/day)
Leftventriculardilatationandhypertrophywerereversed.
(54) 13withDCMandpost
surgical
Cilazapril
(0.04mg/kg/day)
TreatmentreducedleftventricularafterloadandincreasedLVshortening.

AngiotensinReceptorBlockers(ARBs)

RationalforuseofAngiotensinReceptorBlockers(ARBs):
Angiotensin Receptor Blockers (ARBs) reduce some of the effects that result from the activation of the renin
angiotensinaldosterone (RAA) system which often occurs in heart failure. The beneficial effects ARBs in heart
failuremaythereforeinclude:
reducedAngiotensinIImediatedvasoconstriction
reducedAngiotensinIImediatedpotentiationofsympatheticnervoussystemactivity
reducedAngiotensinIImediatedaldosteronereleaseandtherefore
o reducedsodiumandwaterretention
o reducedmyocardialfibrosis
o reducedinhibitionofnitricoxiderelease

ThreeARBshavebeenstudiedinadultswithheartfailurecandesartan,losartanandvalsartan.
Although an initial small trial with losartan was encouraging, a subsequent larger study failed to
confirm that it was as effective as an ACE inhibitor (55). Candesartan (56) and valsartan (57) have,
however,beenshowninsubsequenttrialstoprovidebeneficialoutcomesinadultswithheartfailure;
althoughtheyhavenotbeenshowntobesuperiortoACEinhibitors.Asregardstheinclusionofheart
failureasalicensedindicationforthesetwoARBs,thereisinternationalvariation.
InviewofthemoreestablishedevidencebaseforACEinhibitorsincardiacfailureandthelowercost
of the latter, some guidelines for adult heart failure recommend that ARBs are only used as an
alternativetoACEinhibitorswherepatientsareintoleranttothese,usuallyasaresultofapersistent
drycough(11).
ThereisverylittlepublisheddataontheuseofARBsinchildren.Thepharmacokineticsofirbesartan
inhypertensivechildrenhavebeenreported(58),ashastheeffectivenessoflosartaninhypertensive
children(59);however,nopublishedstudiesspecificallyontheuseofARBsinchildrenwithcardiac
failurewereidentified.ItshouldbenotedthatheartfailuredataforthesetwospecificARBsiseither
lackingorsuboptimal.
ArecentreviewhasconcludedthatasthereisnoefficacydataonARBsinchildrenwithheartfailure,
they should only be used where there is intolerance to an ACE inhibitor (21), which is in line with
generalpracticeinadults.Inlinewiththis,itisnotconsideredappropriatetomakerecommendations
toaddanARBtotheEMLcatthecurrenttimeortoincludeanARBinguidanceonmanagementof
cardiacfailureinchildren.
Aldosteroneantagonists

Rationaleforuseofaldosteroneantagonists:
Aldosteroneantagonistsreducesomeoftheeffectsthatresultfromtheactivationofthereninangiotensin
aldosterone(RAA)systemwhichoftenoccursinheartfailure.Thebeneficialeffectsofaldosteroneantagonistsin
heartfailuremaythereforeinclude:
Reducedsodiumretention
Reducedwaterretention
Reducedmyocardialfibrosis
Reducedinhibitionofnitricoxiderelease
Slowedheartrate,improvingbalanceofoxygensupplyanddemand
Reducedmyocardialapoptosisandfibrosis
Antiarrhythmiceffects

There has been renewed interest in the role of aldosterone antagonists in heart failure following
research in adults demonstrating that the addition of spironolactone at low doses (25mg per day) to
standard care was beneficial in terms of symptoms and hospital admissions (60). Use of
spironolactonehadpreviouslywanedasaconsequenceofconcernsoverpotentialcarcinogenicityand
anadverseeffectprofilewhichincludedantiandrogeniceffectswhichcouldbeproblematicformale
patients,especiallywhenthedrugwasusedatthehigherdosesrequiredinliverdisease.
Theliteraturesupportingtheroleofspironolactoneinpaediatricheartfailureishoweverlimited.One
study in heart failure reported that it enhances the effect of digoxin and thiazide diuretics (61). The
second (62), in a paediatric population with heart, lung and other pathologies, reported that
spironolactone can be added to loop and/or thiazide diuretics, although it highlighted the need for
close monitoring of potassium levels and recommended that further research is needed to look at
pharmacokineticsandthemostappropriatedosingintervalinchildren.
Eplerenone is a newer, more specific aldosterone antagonist which has been studied in the postMI
settinginadultsandhasbeenshowntoreducetheonsetofheartfailureinthissetting(63).Ithasalso
beenusedinpatientsrequiringanaldosteroneantagonistwhoareintoleranttospironolactone.There
isnopublishedevidenceontheroleofeplerenoneinthemanagementofpaediatricheartfailure.One
review commented that eplerenone is one of the few newer drugs for which paediatric dosing has
been established (64), although it should be noted that this refers to the manufacturers data on file
ratherthanpublishedstudies.
Spironolactone is already included in the EMLc and although the available evidence specifically in
paediatrics is modest, it remains appropriate for it to be retained. In the absence of any clear
advantagesforeplerenonefromadultstudiesandthelackofpublisheddataonitsuseinchildren,itis
notconsideredappropriatetoincludethisintheEMLcatthecurrenttime.
Betablockers

Rationaleforuseofbetablockers:
Betablockerscountertheactivationofthesympatheticnervoussystemwhichisoftenseeninheartfailure.The
beneficialeffectsofbetablockersinheartfailuremaythereforeinclude:
Slowedheartrate,improvingbalanceofoxygensupplyanddemand
Reducedmyocardialapoptosisandfibrosis
Antiarrhythmiceffects
SynergismwithACEinhibitors

Anumberofbetablockershavebeenstudiedinlargerandomisedtrialsinthemanagementofcardiac
failureinadults,withgenerallyconsistentfindingsofreducedsymptoms,morbidityandmortality.Of
thosestudied,bisoprolol(65,66),carvedilol(67,68),metoprolol(69)and,mostrecently,nebivolol(70)
Page 12 of 31
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have the greatest weight of evidence and are the most widely used in clinical practice in adult heart
failure.
Althoughtheadultdataforbucindololislessfavourablethanthatforotherbetablockersintermsof
outcome data (89), findings from the research with this agent may have significance for paediatrics,
given the recurrent concern about applying adult data to paediatrics where the aetiology is usually
different.Oneofthebucindololtrialsinadultsincludedpatientswithcardiomyopathy,amajorcause
of heart failure in children and the benefits of betablocker treatment were significant in this group
(90).
Onestudyinadultsdirectlycomparedcarvedilolandmetoprololandindicatedsuperioreffectsfrom
carvedilol (71), although it has been suggested that the formulation of metoprolol used in this study
mayhavecontributedtothesefindings;otherwise,thereisnodatafromwhichfirmconclusionsabout
thespecificadvantagesofonebetablockeroveranothercanbedrawn.
In children with heart failure and related conditions, carvedilol has been the most widely studied
betablocker.Table2summarisesthestudiescarriedouttodate.Beyondthesestudies,experiencehas
been gained with betablockers in children with a variety of other conditions, such as migraine.
However,fewofthesehavemuchsignificanceforthemanagementofheartfailure,withthepossible
exception of a recent evaluation of metoprolol as an antihypertensive in children (72). No published
dataontheuseofnebivololinchildrenwithheartfailurewasidentified.
Reviews have commented that children with severe CHF who are started on betablockers are
unlikely to tolerate the reduction in sympathetic drive (23), although this observation may be less
relevant to those with earlier stage disease. Concern has also been raised that whilst betablocker
therapy in adults reduces sudden cardiac death, the effect of betablockade in children does not
appeartoreducetheQTintervalinthesameway(91),thesignificanceofthisisnotyetknown.
In addition to the studies shown in Table.2, other work has assessed the systemic exposure to
carvedilol amongst paediatric heart failure patients and has indicated that higher doses relative to
bodyweightarerequiredtoprovideexposurecomparabletoadults.Itwassuggestedthatpaediatric
carvediloldosesshouldsubsequentlybe:1mg/kg/dayforadolescents,2mg/kg/dayforchildrenaged2
to11yearsand3mg/kg/dayforinfants(aged28daysto23months)(73).Itshouldbenotedthatthe
doses of carvedilol used in many of the studies summarised in Table.2 have been lower than these
recommendations,insomecasessignificantlylower.
The recently published randomised trial with carvedilol (74) has prompted significant debate and
comment. The authors and subsequent reviews have commented that these findings may have been
due to an unexpected level of improvement in the placebo arm, the low dose of carvedilol used and
the study being underpowered (7577). It has been suggested that, on this basis, the findings of this
trial may not mean there is no role for betablockers in this population (76) and that it is likely beta
blockerswillcontinuetobeusedbasedontheevidencefromadults(75).
There is currently no betablocker included on the EMLc; based on the evidence and current clinical
opinion, this needs to be addressed. Although a number of betablockers have been studied in heart
failure,thegreatestweightofevidenceiswithcarvedilolbothinadultsandpaediatrics;itistherefore
consideredappropriatetorecommendthisbetablockerisaddedtotheEMLc.
Table2.SummaryofstudiesonbetablockersinPaediatricCardiacFailureandrelatedconditions
(DCM=dilatedcardiomyopathy,LVD=leftventriculardysfunction,VSD=ventricularseptaldefect)
Study Population treated
withbetablocker
Betablockerused Keyfindingsandcomments
(78)
Retrospective
46with
cardiomyopathyor
congenitalheart
disease
Carvedilol
(mean0.46mg/kg)
Three month followup showed 67% of patients had improved NYHA class. 54%
hadsideeffects,mainlydizziness,hypotensionandheadachewhichweregenerally
tolerated. Adverse outcomes (death, transplantation and ventricularassist device)
werereportedin30%ofpatients.Improvementsweresustainedin25childrenwho
continuedtherapyfor12months.
(79)
Placebo
controlled
doubleblind
RCT
14withHFawaiting
transplant
Carvedilol
(0.2mg/kg/day)
Nine were removed from transplant list with improvements in LVEF and NHYA
class, four died and one underwent transplant. Amongst the 8 receiving placebo,
two died, two were transplanted and there was no significant improvement in
LVEF.
(80)
Openlabel
prospective
15withDCMand
congenitalheart
disease
Carvedilol
(0.7mg/kg/day)
Evaluated effect amongst those not responsive to standard therapy including
digoxin, diuretic and ACE inhibitor. In this study all patients achieved target dose
and at six month followup significant improvement in Ross Score and ejection
fractionwasreported.
(81)
Retrospective
23withDCM
congenitalheart
disease,anthracycline
inducedcardiac
damage
Carvedilol
(medianmaximum
0.9mg/kg/day
Assessed effect in children on treatment with ACE inhibitors, diuretics,
spironolactone and digoxin. This reported improvements in ejection fraction and
allowed3patientstoberemovedfromtransplantlist.Benefitsweremostsignificant
inthosewhostartedcarvedilolatanearlyage.
(82)
Retrospective
24withDCM Carvedilol
(mean0.98
mg/kg/day)
AnotherstudywhereaddedtotherapywithACEinhibitor,digoxinanddiuretic.22
patients continued for 2 years, with 15 patients (68%) had improvement in the
NYHA class; there was one death and three required transplant. Adverse effects
occurredin5patients(21%)andcarvedilolwasstoppedin2patients(8%).
(83). 20withDCMand
congenitalheart
disease
Carvedilol
(max0.8mg/kg/day)
SignificantimprovementinejectionfractionamongstthosewithDCMtreatedfor6
months, with a trend towards delay in need for transplant and death. Carvedilol
wasstoppedinthreepatientsduringthestudy.
(74).
Placebo
controlled
doubleblind
RCT
103withventricular
systolicdysfunction
Carvedilol
(max.0.4mg/kg)
Carvedilolpatientsrandomisedtooneoftwoarms,onereceiving0.2mg/kgandthe
other 0.4mg/kg. Of all those on carvedilol, 58 improved (56%), 25 worsened (24%)
and 20 were unchanged (19%), this was not significantly different to those on
placebo.
Page 15 of 31
Study Population treated
withbetablocker
Betablockerused Keyfindingsandcomments
(84). 3withdoxorubicin
cardiomyopathy
Metoprolol
(max2575mgbd)
ImprovedNYHAclassandejectionfractioninallpatientsandenabledtwoofthree
patientstoberemovedfromtransplantationwaitinglists.
(85) 15withDCM Metoprolol
(max2.3mg/kg/day)
Improvements in systolic ventricular function followed the addition of metoprolol
tolongstandingconventionaltherapywithdiuretics,digoxinandACEinhibitor.
(86) 11withDuchennes
cardiomyopathy
Metoprololand
Bisoprolol
Reported improvements in symptoms and ventricular function after 6 months
therapy,effectssustainedfor2to5years.
(87) 6withlefttoright
shunts
Propranolol
(max3mg/kg/day)
Addedtoexistingtherapywithdiureticsanddigoxin,improvementsinheartfailure
scorenoted,reducedaldosteroneandreninlevels,5of6patientsstoppeddiuretics.
(88) 10withlefttoright
shunts
Propranolol
(max2mg/kg/day)
Addedtoexistingtherapywithdiureticsanddigoxin,comparedtocontrolpatients
those receiving propranolol had improvements in heart failure scores and reduced
aldosteroneandreninlevels.
AntiarrhythmicMedication

Rationaleforuseofantiarrhythmicmedication:
Antiarrhythmicmedicationcanreducetheincidenceofcardiacarrhythmiasandmaypotentiallybeusefulin
heartfailurewhereventriculartachyarrhythmiasareamajorcauseofmortality

Arrhythmiasareamajorcauseofmortalityandmorbidityinchildrenwithcardiacfailure(92).Over
half of children with dilated cardiomyopathy who die have ventricular arrhythmias at the time of
presentation and almost twothirds of those awaiting transplantation have lifethreatening
arrhythmias(93,94).
Antiarrhythmicmedicationhasbeenusedinchildren,althoughthereisalackoftrialdatalookingat
itsroleinpaediatriccardiacfailure.Aswithmanyothertherapyoptions,therehasbeenextrapolation
from studies in adults. In addition, there are risks associated with some antiarrhythmic medications,
in that they may have negative inotropic effects or have proarrhythmic effects. Two studies showed
that Class 1c antiarrhythmic drugs increased mortality, the first in paediatrics with structural heart
disease(95)andthesecondinadultspostmyocardialinfarction(96).
Theroleofbetablockersincardiacfailurehasbeendiscussedelsewhereanditislikelythatsomeof
the benefits reported are likely to be due to antiarrhythmic properties. The specific antiarrhythmic
propertiesofsotalolhavebeenstudiedinchildren,withsomesuccess,butwithsideeffectsaffecting
2030%ofpatients(97).
Amiodarone has been studied in children and whilst some studies suggested it was well tolerated
(98),othershaveraisedconcernsthattheintravenousformulationmaybelinkedwithhypotensionor
collapse(99).
Alternative approaches to the management of rhythm problems in children with heart failure have
beenevaluatedandpaediatricelectrophysiologyhasthepotentialtoprovidebeneficialeffectswithor
withoutadjunctivedrugtherapy(92).
Given the limited role for antiarrhythmics in heart failure and lack of studies in children showing
beneficialoutcomes,theinclusionofanantiarrhythmictotheEMLcisnotconsideredappropriate.
Inotropes

Rationaleforuseofinotropes:
Insevereheartfailure,wherecardiacoutputandbloodpressurearelow,inotropicdrugswhichstimulate
cardiaccontractilityand/orproduceperipheralvascoconstrictionhavebeenusedtotryandmaintaintissue
perfusion.

Management of the acute phase of cardiac failure has seen the use of inotropic (also referred to as
inodilator)drugstomaintainperfusionofvitalorgans,andtheexistingEMLcincludesdopamineon
thesupplementarylisttofulfillthisrole.
Anumberofinotropeshavebeenusedinacutecardiacfailure;amongstthesearethecatecholamines,
dopamineanddobutamine,andthephosphodiesteraseinhibitors,milrinoneandamrinone.
Itisrecognisedthatacutecardiacfailureisoftencomplicatedbydeteriorationinrenalfunctionthatis
associatedwithworsenedoutcomesandithasbeensuggestedthatthiscardiorenalsyndromeoccurs
in children (100). The application of dopamine in acute heart failure also aims to address this
decreasedrenalfunctionandevidencesuggeststhatitiseffectiveinachievingthisinadults,although
itisconsideredthatfurtherevaluationisneeded(101).
In some situations, more than one inotrope has been given concomitantly, in an attempt to optimise
thespecificeffectsoftheindividualdrugs.However,datafromadultssuggeststhatuseofmorethan
oneinotropeinacuteheartfailureisassociatedwithincreasedmortality(102).
The appropriateness of all inotropes in acute cardiac failure is controversial, based on the lack of
robustevidenceandlackofalternativeoptions(103).Tworecentreviewshaveadvisedthatthereisa
limited role for inotropes in adults. One suggested that the use of inotropes should be restricted to
patients who, despite a high left ventricular filling pressure, remain hypotensive (103). The second,
that routine use in the acute setting is not indicated, but that there may be a role in those with
hypoperfusionorshockandinthoseawaitingtransplantorrevascularisation(104).
In common with the chronic management of cardiac failure, many of the studies in the acute phase
have been carried out in adults and the significance of their findings for children is unclear. In
children, the catecholamines have been the drugs of choice, with their pharmacokinetics permitting
titrationtoresponseanditiswithdopaminethatthereisthegreatestexperience(105).Thealternative
phosphodiesterase inhibitors produce significant pulmonary vasodilation and have little effect on
myocardial oxygen demand. Of the two available, milrinone is favoured on the basis of its shorter
halflifeandwidertherapeuticindex(105).
Children with acute cardiac failure generally fall into one of two groups, those with established
cardiomyopathy and those who were previously healthy (106). In the former group, the acute phase
maypresentwherethepatienthasbecomerefractorytoexistingtreatmentorwhenprecipitatedbyco
morbidconditionssuchasanaemiaoroverwhelminginfection.Itisinsituationssuchasthesewhere
inotropicsupporthasbeenutilised.Inthecaseofthosepatientswithexacerbations,treatmentofthe
underlyingcause,wherepossible,shoulddeterminethattheneedforinotropicsupportisshortterm.
In the case of children refractory to existing treatment, the options for long term treatment may be
limited and are likely to include consideration for cardiac transplantation. Proceeding to transplant
immediately will however often not be possible or appropriate, due to the instability of the patient,
access to a transplant unit or availability of a suitable donor. Consequently, there may be a
requirement for the use of additional supportive treatments for a period of several months. In this
situation, inotropes have been used as a so called bridgingtherapy, which has been delivered in
boththeinpatientandoutpatientsettings.
In one report, seven children with advanced chronic heart failure were given parenteral inotropic
therapy (mean 10 weeks), in the outpatient setting. Six patients were successfully bridged to
transplantation and one died. During the period of treatment, inotropes led to symptomatic
improvementsandreductionsinhospitaladmissionsandpresentationsattheemergencydepartment
(107).
Page 17 of 31
In another similar study, 21 children awaiting transplant were given inotrope therapy (dobutamine,
milrinoneordopamine)athome.Survivalat12monthswasreportedas84%,withimprovedcardiac
andrenalfunction,andreducedhospitalisations(108).
A recent study has shown that amongst paediatric patients with acute heart failure due to
cardiomyopathy or myocarditis, up to 96% will recover over a twoyear period, during which time
they will require a package of intensive support, which includes inotropes and extracorporeal
membraneoxygenation(109).
It should also be recognised that the use of nonpharmacological interventions has a significant and
increasingroleinthemanagementofacutecardiacfailureinchildren(110).
Basedontheavailableadultdataandtheabsenceofpaediatricevidence,theroutineuseofinotropes
inacutecardiacfailureinchildrencannotberecommended.Inotherscenarios,suchasuseshortterm
alongsidetreatmentofexacerbating conditionsandasabridgingtherapypendingtransplantation,it
wouldappearappropriatetoincludeaninotropeontheEMLc.Intheabsenceofcompellingevidence
forchange,itissuggestedthattheEMLcretainsdopamine,asitpossessesboththecardiacandrenal
effectsthatareusefulinthisclinicalsituation.
Othertherapies

Rationaleforuseofothermedication:
Continuedburdenofcardiacfailurewithsignificantmorbidityandmortalitydespitetheexistingtreatment
options

Anumberofothertherapiesareunderevaluationinthemanagementofcardiacfailure,manyofthese
intheacutephaseofthecondition.
Natriureticpeptides:NesiritideisarecombinantBtypenatriureticpeptideapprovedforuseinsome
nationsforthetreatmentofdecompensatedheartfailureinadults.
Three studies have evaluated the role of nesiritide in children with heart failure in an intensive care
setting andhave reported improvements in renal function and increased urine output (111113). The
authorsofthesestudiesandafurtherreview(114)haveallconcludedthatfurtherworkisneededto
assesstheroleofnesiritide.
ThestrengthoftheevidenceavailabletodatedoesnotwarranttheinclusionofnesiritideintheEMLc
fortheroutinemanagementofcardiacfailureinchildrenatthecurrenttime.
Calcium sensitisers: Levosimendan is the first of this group to be evaluated. One study in children
with severe heart failure refractory to dobutamine, showed encouraging signs in terms of ejection
fraction, reduction discontinuation of catecholamine therapy and adverse effects (115). There are a
number of other reports on beneficial effects in individual patients; however, a recent review
commentedthatfurtherexperienceanddataisrequired(64).
On this basis, levosimendan is not considered appropriate for inclusion in the EMLc for the routine
managementofcardiacfailureinchildrenatthecurrenttime.
Page 18 of 31
Endothelinreceptorantagonists:Anumberofthese,includingbosentan,tezosentan,darusentanand
sitaxsentan, have been developed and studied in a range of conditions, including pulmonary
hypertension and heart failure. Evidence of efficacy to date is variable and there are concerns about
the hepatotoxicity of bosentan. There is no data on efficacy or safety in children. Depending on
findings,theongoingworkinadultpopulationsmaygiverisetopaediatricstudiesinduecourse(64).
Rolesforendothelinreceptorantagonistsremaintobeclarifiedandthereisnoplaceforthesedrugsin
theEMLcfortheroutinemanagementofcardiacfailureinchildrenatthecurrenttime.
Discussion
Treatment
Clinical practice in the management of cardiac failure in children currently uses some or all of the
following drug treatments: diuretics, digoxin, spironolactone, ACE inhibitors, betablockers and
inotropes.
There are no national or international guidelines on the management of cardiac failure in children
and,consequently,theapproachtotreatmentisbasedonacombinationofclinicalexperienceamongst
those involved in management, application of findings from many studies in adults with cardiac
failureandthemodestdatafromstudiesinchildren.
The data from studies in children is suboptimal and when considered in isolation provides a poor
basisformakingdecisionsandwiderrecommendations.Thereareseveralreasonsforthis,including
the small size of many studies, reliance on retrospective studies, the variation in causes of cardiac
failureandagerangeamongststudyparticipants,thedosesofdrugsusedandvariationinmeasures
usedtoassessoutcomes.
There is, however, reasonable evidence that some children with cardiac failure do benefit from
treatmentwithdrugswhichhaveaprovenevidencebaseinadults,inparticularACEinhibitors and
betablockers.
UnansweredQuestions
In compiling this report there are a number of recurrent themes which require consideration when
developingtheEMLcandguidelinesonthemanagementofcardiacfailureinchildren.Thesefallinto
fourmainareas.
Paediatricpracticebasedonadultevidence
Althoughtheavailablepaediatricsliteratureprovidesgroundsforoptimismintheuseofdrug
therapy for cardiac failure, there remain questions about clinical practice in children being
drivenprimarilybystudiescarriedoutinadults,wheretheunderlyingpathologyofpaediatric
heartfailureissignificantlydifferent.
Specificdrugissues
Questionshavebeenaskedaboutthemetabolicandelectrolyticeffectsofloopdiuretics,which
may have potentially deleterious effects on the underlying pathology of heart failure.
However, given that the presentation of cardiac failure is associated with oedema, which
Page 19 of 31
invariably responds rapidly and significantly to diuretics, resolving these issues will be
challenging.
Theroleofdigoxinalsoremainssomewhatunclear,basedonthelackofrobustevidence.
Dosage
The literature provides ample evidence of a wide disparity of dosing regimens being used in
paediatricpracticeanditneedstobeconsideredthatthesemayhavehadsignificanteffectson
the outcome of some of the studies referred to. There is a need for further evaluation of the
pharmacokineticsofmanydrugsusedinheartfailureinchildrentoconfirmboththedoseand
dosingintervalthatisrequiredforoptimalclinicalbenefit.
Useofproductsoutsideoflicense
In common with many other areas of paediatric clinical practice, the management of heart
failure currently uses unlicensed drugs and licensed drugs outside of their product license.
Thereareseveralinherentproblemsassociatedwiththis.
To obtain a marketing authorisation to treat a specific condition in a specific patient
group, the manufacturer is required to submit data to the licensing authorities to
support claims of efficacy and an acceptable balance of risks and benefits.
Consequently,whenusinganunlicenseddrugoralicenseddrugoutsideofitslicense,
healthcare professionals and patients/carers are required to formulate their own
judgmentsastoappropriatenessbasedonsuboptimalinformation.
Prescribers andothersinvolved inthedelivery of unlicenseddrugsorlicenseddrugs
outsideoftheirlicensetothepatient,carrygreaterlegalresponsibilitiesshouldharmbe
caused, than would be the case if prescribing was of a licensed product within the
termsofitslicense.
Unlicensed products are not as readily available as licensed products, which can
introducebarrierstothetimelydeliveryofmedicationtopatients.
Unlicensed products are not required to conform to the same consistent standards of
manufacture as licensed products and there may be greater variation in the
bioavailabilityoftheactiveingredientbetweendifferentunlicensedformulationsthan
therewouldbebetweendifferentlicensedformulationsforthesamedrug.
Inanidealsituation,allthedrugswhicharerequiredwouldbelicensedforuseinchildrenfor
the management of cardiac failure and be available in formulations which were appropriate
for administration to children at the doses required. It has been suggested that where the
requireddrugsarenotavailableaslicensedproducts,theyshouldnotbeusedandthatgreater
pressureshouldbeexertedonmanufacturersandotherorganisationstoinvestintheresearch
necessarytoshowtheeffectiveness(orotherwise)ofthedrugsinvolved,thusestablishingthe
evidencebasenecessarytoenablelicenseapplicationstobemade.This,however,wouldcreate
a dilemma in that children would continue to present with heart failure whilst this research
was undertaken and those outside of the trials would be denied treatments which, based on
the limited data available already, may have had a significant probability of improving their
outcome.
Page 20 of 31
Thereiswithoutdoubtaneedforagreaterevidencebaseinthemanagementofcardiacfailure
in children and the development of this through research should be encouraged. In the
meantime the risks associated with the use of unlicensed and off label medications could be
reduced by the requirement for greater standardisation in their manufacture to provide
patients, carers and healthcare professionals greater confidence in their stability and
bioavailability. The development of a prescribing reference to guide the appropriate off label
use of medication in children would also assist in reducing the risks associated with this
necessary practice. The WHO should give consideration to these two areas as medium and
shorttermpriorities,toimprovethemanagementofheartfailureinchildren.
Conclusion
Thelasttwentyyearshavewitnessedasignificantadvanceintheevidenceforandavailabilityofdrug
therapies which can have a huge impact on the outcome for adult patients with heart failure. The
situationwithpaediatriccardiacfailurehasfollowedasimilarpattern,buthastendedtobebasedon
lessrobustevidence.
There is a compelling need for larger and higher quality studies on the drug treatment of cardiac
failure in children to provide a more robust evidence base from which practice can develop.
Alongside this is the need for greater availability and standardisation of products and formulations
suitableforadministrationtochildren.
In the meantime, there is sufficient experience and evidence on which to base provisional
recommendationsaffectingtheEMLc.ThesewouldbefortheadditionofanACEinhibitorandbeta
blocker to the EMLc, (refer to accompanying applications for inclusion) to be used alongside those
therapy options already included in the EMLc: frusemide, digoxin, spironolactone and dopamine,
wheretheyareclinicallyindicated.
Page 21 of 31
Appendix1: Search Strategy
SearchesPerformed
Initial:
ReviewedcurrentEMLc
SearchedWHOwebsite
ReviewedEMEAAssessmentofthepaediatricneedsCardiovascularproducts,Oct06
BritishNationalFormularyforChildren,BMA/RPSGB/RCPCH,London,2008
ThePaediatricCardiologyPharmacopeia,2004Update
PubMed:
Cardiacfailure(title)ANDChildren(anyfield);Review16found
Heartfailure(title)ANDChildren(anyfield);Review65found:lookedat2000+only
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);Review;2000200822found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);Review;200020083found
Heartfailure(title)ANDChildren(Title);2000200865found
Heartfailure(title)ANDChildren(Title)ANDepidemiology(anyfield);200520085found
Heartfailure(title)ANDpaediatricsORpediatrics(title);ANDepidemiology(anyfield);200520080found
Cardiacfailure(title)ANDChildren(Title)ANDepidemiology(anyfield);200520081found
Cardiacfailure(title)ANDpaediatricsORpediatrics(title);ANDepidemiology(anyfield);200520080found
Heartfailure(title)ANDChildren(anyfield)ANDepidemiology(anyfield);2005200821found
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDepidemiology(anyfield);2005200813
found
Cardiacfailure(title)ANDChildren(anyfield)ANDepidemiology(anyfield);200520086found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDepidemiology(anyfield);200520084
found
Heartfailure(title)ANDChildren(anyfield)ANDburden(anyfield);200520083found
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDburden(anyfield);200520081found
Cardiacfailure(title)ANDChildren(anyfield)ANDburden(anyfield);200520081found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDburden(anyfield);200520081found
Heartfailure(title)ANDChildren(anyfield)ANDmanagement(anyfield);2005200825found
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDmanagement(anyfield);2005200820
found
Cardiacfailure(title)ANDChildren(anyfield)ANDmanagement(anyfield);200520084found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDmanagement(anyfield);200520085
found
Heartfailure(title)ANDChildren(anyfield)ANDtreatment(anyfield);2005200875found
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDtreatment(anyfield);2005200858found
Cardiacfailure(title)ANDChildren(anyfield)ANDtreatment(anyfield);2005200824found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDtreatment(anyfield);2005200813
found
Cardiacfailure(title)ANDChildren(anyfield)ANDincidence(anyfield);1995200821found
Cardiacfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDincidence(anyfield);200520080found
Heartfailure(title)ANDChildren(anyfield)ANDincidence(anyfield);2005200865found
Heartfailure(title)ANDpaediatricsORpediatrics(anyfield);ANDincidence(anyfield);200520082found
Heartfailure(title)ANDchildren(anyfield)ANDdiuretic(anyfield);199520084found
Heartfailure(title)ANDpediatric(anyfield)ANDdiuretic(anyfield);199520084found
Cardiacfailure(title)ANDchildren(anyfield)ANDdiuretic(anyfield);199520080found
Cardiacfailure(title)ANDpediatric(anyfield)ANDdiuretic(anyfield);199520080found
Heartfailure(title)ANDchildren(anyfield)ANDACEinhibitor(anyfield);199520081found
Page 22 of 31
Heartfailure(title)ANDpediatric(anyfield)ANDACEinhibitor(anyfield);199520082found
Cardiacfailure(title)ANDchildren(anyfield)ANDACEinhibitor(anyfield);199520080found
Cardiacfailure(title)ANDpediatric(anyfield)ANDACEinhibitor(anyfield);199520080found
Heartfailure(title)ANDchildren(anyfield)ANDbetablocker(anyfield);199520088found
Heartfailure(title)ANDpediatric(anyfield)ANDbetablocker(anyfield);199520086found
Cardiacfailure(title)ANDchildren(anyfield)ANDbetablocker(anyfield);199520080found
Cardiacfailure(title)ANDpediatric(anyfield)ANDbetablocker(anyfield);199520080found
Heartfailure(title)ANDchildren(anyfield)ANDdigoxin(anyfield);1995200817found
Heartfailure(title)ANDpediatric(anyfield)ANDdigoxin(anyfield);1995200814found
Cardiacfailure(title)ANDchildren(anyfield)ANDdigoxin(anyfield);199520080found
Cardiacfailure(title)ANDpediatric(anyfield)ANDdigoxin(anyfield);199520080found
Heartfailure(title)ANDchildren(anyfield)ANDspironolactone(anyfield);199520082found
Heartfailure(title)ANDpediatric(anyfield)ANDspironolactone(anyfield);199520081found
Cardiacfailure(title)ANDchildren(anyfield)ANDspironolactone(anyfield);199520080found
Cardiacfailure(title)ANDpediatric(anyfield)ANDspironolactone(anyfield);199520080found
Acuteheartfailure(title)ANDchildren(anyfield);1995200823found
Acutecardiacfailure(title)ANDchildren(anyfield);199520086found
Acuteheartfailure(title)ANDpediatric(anyfield);1995200817found
Acutecardiacfailure(title)ANDpediatric(anyfield);199520084found
Heartfailure(title)ANDdopamine(anyfield);19952008127found
Heartfailure(title)ANDdobutamine(anyfield);19952008333found
Children(title)ANDdopamine(anyfield);19952008273found
Pediatric(title)ANDdopamine(anyfield);1995200855found
Children(title)ANDdobutamine(anyfield);1995200837found
Pediatric(title)ANDdobutamine(anyfield);1995200823found
Children(title)ANDmilrinone(anyfield);1995200812found
Pediatric(title)ANDmilrinone(anyfield);1995200811found
Heartfailure(title)ANDchildren(anyfield)ANDinotropic(anyfield);1995200811found
Cardiacfailure(title)ANDchildren(anyfield)ANDinotropic(anyfield);199520081found
Heartfailure(title)ANDpediatric(anyfield)ANDinotropic(anyfield);1995200812found
Cardiacfailure(title)ANDpediatric(anyfield)ANDinotropic(anyfield);199520081found
Heartfailure(title)ANDchildren(anyfield)ANDdopamine(anyfield);199520086found
Cardiacfailure(title)ANDchildren(anyfield)ANDdopamine(anyfield);199520080found
Heartfailure(title)ANDpediatric(anyfield)ANDdopamine(anyfield);199520085found
Cardiacfailure(title)ANDpediatric(anyfield)ANDdopamine(anyfield);199520081found
Heartfailure(title)ANDchildren(anyfield)ANDdobutamine(anyfield);199520083found
Cardiacfailure(title)ANDchildren(anyfield)ANDdobutamine(anyfield);199520081found
Heartfailure(title)ANDpediatric(anyfield)ANDdobutamine(anyfield);199520088found
Cardiacfailure(title)ANDpediatric(anyfield)ANDdobutamine(anyfield);199520082found
Heartfailure(title)ANDchildren(anyfield)ANDnesiritide(anyfield);199520083found
Cardiacfailure(title)ANDchildren(anyfield)ANDnesiritide(anyfield);199520080found

CochraneLibrary:
Cardiacfailure;nootherlimits25itemsfound
Heartfailure;nootherlimits64itemsfound
Childrencardiacfailure;nootherlimits4itemsfound
Childrenheartfailure;nootherlimits5itemsfound
Pediatriccardiacfailure;nootherlimits18itemsfound
Pediatricheartfailure;nootherlimits5itemsfound
Page 23 of 31

BMJClinicalEvidence
Cardiacfailure;nootherlimits100itemsfound
Heartfailure;nootherlimits153itemsfound
Childrencardiacfailure;nootherlimits7itemsfound
Childrenheartfailure;nootherlimits9itemsfound
Pediatriccardiacfailure;nootherlimits2itemsfound
Paediatriccardiacfailure;nootherlimits3itemsfound
Pediatricheartfailure;nootherlimits5itemsfound
Paediatricheartfailure;nootherlimits2itemsfound

NationalGuidelineClearinghouse
Cardiacfailure;nootherlimits313itemsfound
Heartfailure;nootherlimits418itemsfound
Childrencardiacfailure;nootherlimits126itemsfound
Childrenheartfailure;nootherlimits157itemsfound
Pediatriccardiacfailure;nootherlimits67itemsfound
Paediatriccardiacfailure;nootherlimits17itemsfound
Pediatricheartfailure;nootherlimits78itemsfound
Paediatricheartfailure;nootherlimits14itemsfound

Page 24 of 31
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