ContentslistsavailableatScienceDirect
American Journal of Preventive Cardiology
journalhomepage:www.journals.elsevier.com/the-american-journal-of-preventive-cardiology
Practice Guideline
Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective
Gerald F. Watts
a,b,∗, David R. Sullivan
c,d, David L. Hare
e,f, Karam M. Kostner
g, Ari E. Horton
h,i,j, Damon A. Bell
a,b,k,l,m, Tom Brett
n, Ronald J. Trent
o,p, Nicola K. Poplawski
q,r,
Andrew C. Martin
s,t, Shubha Srinivasan
u,v, Robert N. Justo
w,x, Clara K. Chow
y,z,aa, Jing Pang
a, and other members of the FH Australasia Network Consensus Working Group
aSchool of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
bLipid Disorders Clinic, Cardiometabolic Service, Departments of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia
cDepartment of Chemical Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
dSydney Medical School, University of Sydney, Sydney, New South Wales, Australia
eFaculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
fDepartment of Cardiology, Austin Health, Melbourne, Australia
gDepartment of Cardiology, Mater Hospital, University of Queensland, Brisbane, Australia
hMonash Heart and Monash Children’s Hospital, Monash Health, Melbourne, Victoria, Australia
iMonash Cardiovascular Research Centre, Melbourne, Victoria, Australia
jDepartment of Paediatrics, Monash University, Melbourne, Victoria, Australia
kDepartment of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia
lDepartment of Clinical Biochemistry, Clinipath Pathology, Perth, Western Australia, Australia
mSonic Genetics, Sonic Pathology, Australia
nGeneral Practice and Primary Health Care Research, School of Medicine, University of Notre Dame Australia, Fremantle, Australia
oDepartment of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
pCentral Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia
qAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
rAdelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
sDepartment General Paediatrics, Perth Children’s Hospital, Perth, Western Australia, Australia
tDivision of Paediatrics, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
uInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, Australia
vDiscipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
wDepartment of Paediatric Cardiology, Queensland Children’s Hospital, Brisbane, Queensland, Australia
xSchool of Medicine, University of Queensland, Brisbane, Queensland, Australia
yWestmead Applied Research Centre, The University of Sydney, Sydney, New South Wales, Australia
zDepartment of Cardiology, Westmead Hospital, Sydney, New South Wales, Australia
aaGeorge Institute for Global Health, Sydney, New South Wales, Australia
a r t i c le i n f o
Keywords:
Familial hypercholesterolaemia Guidance
Care Management Adults Children Prevention
a b s t r a ct
Introduction: Familialhypercholesterolaemia(FH)isacommon,heritableandpreventablecauseofpremature coronaryarterydisease,withsignificantpotentialforpositiveimpactonpublichealthandhealthcaresavings.
Newclinicalpracticerecommendationsarepresentedinanabridgedguidancetoassistpractitionersinenhancing thecareofallpatientswithFH.
Mainrecommendations: Corerecommendationsaremadeonthedetection,diagnosis,assessmentandmanage- mentofadults,childrenandadolescentswithFH.Thereisakeyroleforgeneralpractitioners(GPs)workingin collaborationwithspecialistswithexpertiseinlipidology.Adviceisgivenongeneticandcholesteroltestingand risknotificationofbiologicalrelativesundergoingcascadetestingforFH;allhealthcareprofessionalsshouldde- velopskillsingenomicmedicine.Managementisunder-pinnedbythepreceptsofriskstratification,adherenceto healthylifestyles,treatmentofnon-cholesterolriskfactors,andappropriateuseoflow-densitylipoprotein(LDL)- cholesterolloweringtherapies,includingstatins,ezetimibeandproproteinconvertasesubtilisin/kexintype9 (PCSK9)inhibitors.Recommendationsonservicedesignareprovidedinthefullguidance.
∗Correspondingauthorat:SchoolofMedicine,FacultyofHealthandMedicalSciences,UniversityofWesternAustralia,GPOBoxX2213Perth,WA6847,Australia.
E-mailaddress:[email protected](G.F.Watts).
https://doi.org/10.1016/j.ajpc.2021.100151
Received8December2020;Receivedinrevisedform15January2021;Accepted28January2021
2666-6677/© 2021TheAuthors.PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/)
PotentialimpactoncareofFH: Theserecommendationsneedtobeutilisedusingjudiciousclinicaljudgementand shareddecisionmakingwithpatientsandfamilies.Modelsofcareneedtobeadaptedtobothlocalandregional needsandresources.InAustralianewgovernmentfundedschemesforgenetictestinganduseofPCSK9inhibitors, aswellastheNationalHealthGenomicsPolicyFramework,willenableadoptionoftheserecommendations.A broadimplementationsciencestrategyis,however,requiredtoensurethattheguidancetranslatesintobenefit forallfamilieswithFH.
1. Introduction
Familialhypercholesterolaemia(FH)isacommonandseverecause ofprematurecoronaryatherosclerosisduetovariantsingenesaffect- ingtheclearanceoflow-densitylipoprotein(LDL)-cholesterol.FHisa preventablecauseofprematurediseaseanddeath,withsignificantpo- tentialforpositiveimpactonpublichealthandhealthcaresavings[1, 2].However,lessthan10%ofpeoplewithFHhavebeenidentifiedand, ofthosetreated,over80%donotattainLDL-cholesteroltargets[2].
TheFHAustralasiaNetworkConsensusGrouphasdevelopedanew guidancetoassistcliniciansinthecareofpatientswithFH,replacing earlier recommendations[3]. This synopsis provides thekeyrecom- mendationsasactionablestatements withtheirstrengthof evidence.
Thefullguidance,endorsed byseveralorganisations(seeappendix), isavailableinHeart,LungandCirculationathttps://doi.org/10.1016/
j.hlc.2020.09.943[4]. 2. Method
Asteeringcommittee,selectedfromboardmembersoftheFHAus- tralasiaRegistryNetwork[5],appointedawriting groupandinvited contributionsfromdiverseclinicalspecialtiesandhealthconsumers[4]. Theprotocolsfollowedaredetailedelsewhere[4]. Evaluationofthe publishedevidenceon thecareofFH wasbasedon theGRADEsys- tem[4,6].Thetotalityofevidence,includingexpertopinionandpatient preferences,informedtherecommendations.
3. Keyevidenced-basedrecommendations
Recommendations arepresented witha classof recommendation (CoR)andlevelofevidence(LoE).Additionalrecommendations,includ- inglipoproteinapheresisandorganisationofcare,aregiveninthefull guidance[4].
Conversionfactorsintherecommendationsare:forcholesterol,from mmol/Ltomg/dLmultiplymmol/Lby38.67;fortriglycerides,from mmol/Ltomg/dLmultiplymmol/Lby88.57.
3.1. Phenotypicdetectionofindexcases
1. Severalstrategiesshould be considered for detectingindex cases of FH, includingselective, opportunistic anduniversal screening [1,2,7–10].[CoRModerate;LoEModerate]
2. Indexcasesshouldbesoughtbyselectivescreeningofadultswith prematureatheroscleroticcardiovasculardisease(ASCVD),primar- ilycoronaryarterydisease,andafamilyhistoryofprematureASCVD and/orhypercholesterolaemia[3,7].[CoRStrong;LoEHigh]
3. Opportunisticscreening,based on aplasma LDL-cholesterollevel
>5.0mmol/L,shouldbeemployedfordetectingadults[8]. [CoR Strong;LoEModerate]
4. Universalscreening,basedonanLDL-cholesterollevel>3.5mmol/L, shouldbeconsideredbeforepuberty(preferablybetween1and2 yearsofage,coincidingwithchildhoodimmunisation)toinitially detectchildrenwithFH[1,9].[CoRModerate;LoEModerate]
5. Alertsonlaboratoryreportsonlipidprofilesshouldbeemployedto enhancecasedetection[1].[CoRStrong;LoEModerate]
6. Digitalscreeningofelectronichealthrecordsshouldbeconsidered toenablecasedetection[1].[CoRModerate;LoEModerate]
7. TheDutchLipidClinicNetwork (DLCN)criteria(Table1)should beusedtomakeaphenotypicdiagnosisofFHinadultsbutnotin childrenoradolescents[1,10,11].[CoRStrong;LoEHigh]
8. PatientswithsuspectedFHshouldbereferredtoordiscussedwitha specialistwithexpertiseinlipidologyforfurtherassessment[3,7,8].
[CoRStrong;LoELow]
3.2. Diagnosisandassessmentofadults
1. Secondarycausesofhypercholesterolaemiashouldbeexcludedbe- foremakingadiagnosisofFH(appliesalsotochildrenandadoles- cents)[3,7,10,11].[CoRStrong;LoEHigh]
2. ThediagnosisofFHshouldbemadeusingbothphenotypic(Table1) andgeneticcriteria,butwhengenetictestingisnotavailablethedi- agnosisshouldbemadephenotypically[3,7].[CoRStrong;LoEHigh]
3. Genetictesting (aMedicarerebatable itemin Australiaforindex caseswithahighphenotypicprobabilityofFHandforcloserela- tivesofgeneticallyconfirmedindexcases)shouldbeusedtoconfirm thediagnosisofFH,especiallyifcascadetestingisplanned[3,7,12].
[CoRStrong;LoEHigh];
4. Patients should be risk assessed for the presence of other ma- jor ASCVD risk factors, includingelevated lipoprotein(a)[Lp(a)]
[3,13,14].[CoRStrong;LoEModerate]
5. Cardiovascularriskpredictionequationsderivedfromthegeneral population should not be used in patients withFH [3,13]. [CoR Strong;LoEModerate]
6. Coronaryarterycalciumscore(CACS),computedtomographycoro- naryangiography(CTCA)andcarotidultrasonographymaybecon- sideredforriskstratifyingasymptomaticpatients[3,10,11,15,16].
[CoRWeak;LoEModerate]
7. AdultswithhomozygousFHshouldbereferredtoaspecialisedcen- treforlong-termcare[7,17].[CoRStrong;LoEHigh]
3.3. Diagnosisandassessmentofchildrenandadolescents
1 Childrensuspectedof havinghomozygousFHshouldbetestedas earlyaspossible,atleastby2yearsofage[7,10,17].[CoRStrong;
LoEModerate]
2 TestingofchildrenwithsuspectedheterozygousFHusing pheno- typicand/orgenotypicstrategiesshouldbeconsideredbetweenthe agesof5and10years[10,18].[CoRModerate;LoEModerate]
3 AprobablephenotypicdiagnosisofFHshouldbeconsideredinthose with[10,18,19]:
a LDL-cholesterolof>5.0mmol/L,withaparentalhistoryofhy- percholesterolaemiaorprematureASCVD;
b LDL-cholesterolof4.0to5.0mmol/L,withaparentalhistoryof hypercholesterolaemiaorprematureASCVD;or
c LDL-cholesterol of >3.5 mmol/L, with a parent carrying a pathogenicorlikelypathogenicgenevariant.[CoRModerate;LoE Moderate]
4 ChildrenandadolescentswithheterozygousFHshouldbereviewed byapaediatricianwithexpertiseinlipidology[7,10,18,20,21].[CoR Strong;LoELow]
5 Genetic testing should be offered to diagnose children after a pathogenicorlikelypathogenicgenevarianthasbeenidentifiedin aparentorfirst-degreerelative[1,3,19].[CoRStrong;LoEModerate]
6 Childrenshouldberiskstratifiedaccordingtoage,otherASCVDrisk factors,familyhistoryof prematureASCVD andthelevelofboth
Table1
TheDutchLipidClinicNetworkcriteriaformakingthephenotypicdiagnosisoffamilialhypercholesterolaemiainadultindexcases[1–3].Foronlineuse, pleaseaccesstheFHAustralasiaNetworkcalculatorathttps://www.athero.org.au/fh/calculator/.ThesecriteriashouldnotbeusedtodiagnoseFHin childrenoradolescents[10].
Criteria ∗ Score
Section 1: Family history
First degree relative with known premature coronary and/or vascular disease (men aged < 55 years, women aged < 60 years) OR First degree relative with known LDL-cholesterol above the 95th percentile for age and gender
1 First degree relative with tendinous xanthomata and/or arcus cornealis
OR Children aged < 18 years with LDL-cholesterol above the 95th percentile for age and gender
2 Section 2: Personal history
Patients with premature coronary artery disease (men aged < 55 years, women aged < 60 years) 2 Patients with premature cerebral or peripheral vascular disease (men aged < 55 years, women aged < 60 years) 1 Section 3: Physical examination
Tendinous xanthomata 6
Arcus cornealis before 45 years of age 4
Section 3: Biochemical results: to convert cholesterol to mg/dL multiply mmol/L below by 38.67 LDL-cholesterol (mmol/L) †
LDL-cholesterol ≥ 8.5 8
LDL-cholesterol 6.5–8.4 5
LDL-cholesterol 5.0–6.4 3
LDL-cholesterol 4.0–4.9 1
Diagnosis Total Score
Definite FH > 8
Probable FH 6–8
Possible FH 3–5
Unlikely FH < 3
∗Notethatonlythehighestscoreineachsectionischosentoadduptothetotalscore,toamaximumof18.
†Ifpre-treatmentLDL-cholesterolisnotavailable,usetheFHAustralasiaNetwork’sonlinecalculator(https://www.athero.org.au/fh/calculator/)to derivetheLDL-cholesterolbyadjustingvalueforcholesterol-loweringmedication.
LDL-cholesterolandLp(a)at diagnosis[7,10,18,21].[CoR Strong;
LoEModerate]
7 InchildrenandadolescentswithheterozygousFH,measurementof carotidintima-medialthicknessusingcarotidultrasonographymay beconsideredtoassessASCVDrisk[1,10,22].[CoRWeak;LoEMod- erate]
8 ChildrenandadolescentswithhomozygousFHshouldbe referred ondiagnosistoaspecialistpaediatriccentrefor planningof care [7,10,17,21,23].[CoRStrong;LoEHigh]
3.4. Genetictesting
1. Diagnosticgenetictestingandcounsellingshouldbeofferedtoall adultindexcaseswithaprobable/definitephenotypicdiagnosisof FH(Table1)[1,3,12].[CoRStrong;LoEModerate]
2. Diagnosticgenetictestinginanadultindexcasemaybeconsidered whenthereislimitedinformationtoestablishanaccuratepheno- typicdiagnosisofFH[1,3,12,24].[CoRWeak;LoEModerate]
3. Diagnostic genetic testing of children, as potential index cases, shouldbeconsideredwhenparents,orfirst-degreerelatives,areun- knownordeceased,oraspartofuniversalscreening[1,3,9].[CoR Moderate;LoEModerate]
4. GenetictestingforFHshouldbecarriedoutinanaccreditedlabo- ratoryusingstandardisedmethodstodetectpathogenicandlikely pathogenicgenevariantscausingFH[1,3,12,24].[CoRStrong;LoE High]
5. Variantsdetectedbygenetictestingshouldbeclassifiedaccording totheAmericanCollegeofMedicalGeneticandGenomicstandards andguidelines,oracomparableclassification[24–26].[CoRStrong;
LoEHigh]
6. Ifapathogenic,orlikelypathogenic,genevariantisnotdetected,FH shouldnotbeexcluded,particularlywithahighlyprobableclinical phenotypeofFH[3,10,24].[CoRStrong;LoEHigh]
7. DiagnosticgenetictestingofindexcaseswithsuspectedFHshould berequestedbyaspecialist(arequirementoftheMedicareBenefits
ScheduleinAustralia)withappropriateskillsinthecareofpatients andfamilieswithFH[3,24,27,28].[CoRStrong;LoELow]
8. Allhealthcareprofessionalsinvolvedinconsentingfamiliesforge- netictestingshouldreceiveeducationingenomicmedicineandhave basicskillsingeneticcounselling[1,3,24,28,29].[CoRStrong;LoE Low]
3.5. Cascadetestingandrisknotificationoffamilies
1. Cascadetesting(testingofconsentingbiologicalrelativesofanin- dividualwithFH)shouldbe carriedout usingbothaphenotypic andgenotypicstrategy(Fig.1),butifgenetictestingisnotavailable aphenotypicstrategyshouldbeused[1–3,7,12].[CoRStrong;LoE High]
2. Genetictestingis morecost-effectivethanphenotypictesting and shouldbeemployedtoscreenfamilymembersafterapathogenic, orlikelypathogenic,genevarianthasbeenidentifiedinthefamily [1,12,30].[CoRStrong;LoEHigh]
3. Whengenetictesting isnot feasible,thediagnosis ofFH inclose relativesshouldbemadeusingage-andgender-specificplasmaLDL- cholesterollevels(Table2)[1–3,31].[CoRStrong;LoEHigh]
4. Risknotificationofrelativesshouldbe consistentwithlocallegis- lationandinstitutionalguidelines;risknotificationmaybeindirect (letterprovidedfornotifiertogivetorelatives)ordirect(lettersent torelatives)[1–3,7].[CoRStrong;LoELow]
5. Pre-andpost-testgeneticcounsellingshouldbe offeredtoatrisk familymembersundergoingcascadetesting [1–3,12,19,24].[CoR Strong;LoEHigh]
6. Cascadetestingandrisk notificationshouldbe co-ordinatedbya well-resourcedcentre,particularlyifemployinggenetictesting[1–
3,12,19].[CoRStrong;LoEHigh]
7. GeneticcascadetestingmaybeundertakenbyaGP(asspecifiedby theMedicareBenefitsScheduleinAustralia)withskillsinthecareof FH,guidedbyanappropriatespecialist[1–3,8,27,28].[CoRWeak;
LoELow]
Fig.1. Schemeforcascadetestingofbiolog- icalrelativesofanindexcasewithconfirmed familialhypercholesterolaemia.Adaptedfrom Wattsetal.2011[3].
ˆConsistentwithrelevantlocallegislationand institutionalguidelines
∗Accordingtoage-andgender-specificplasma LDL-cholesterol concentrations published by Starretal.[31].
Table2
Age-dependentLDL-cholesterolconcentrationsandthresholds(mmol/L;toconverttomg/dLmultiplymmol/Lby38.67)tomakeadiagnosisofFHduring cascadetestingin(a)maleand(b)femalefirst-degreerelativesofanindexcase.AdaptedfromStarretal.[31].
8. Geneticcascadetestingshouldinitiallybeprioritisedforfirst-degree relativesofavariantcarrierandsequentiallyextendedasadditional carriersareidentified;iffirst-degreerelativesdeclinetesting,test- ingshouldbeextendedtosecond-degreefollowedbythird-degree relatives(alsoappliestophenotypictestingalone)(Fig.1)[1–3,12].
[CoRStrong;LoEHigh]
9. Universalscreeningofchildrenshouldbecoupledwithchild-parent (reverse)cascadetesting[1,9,20].[CoRStrong;LoEModerate]
10. Allhealthcareprofessionalsinvolvedincascadetestingandriskno- tificationoffamiliesshouldreceiveeducationingenomicmedicine andhavebasicskillsingeneticcounselling[3,12,24,28,29].[CoR Strong;LoELow]
3.6. Managementofadults
1. AlladultpatientswithFHshouldbecounselledonlifestylemodifica- tionsandnon-cholesterolriskfactorsshouldbemanagedaccording toexpertrecommendations[1,7,11,32,33].[CoRStrong;LoEModer- ate]
2. Careshouldemployshareddecisionmakingandaddresspatients’
valuesandhealthliteracy[1,7,34].[CoRStrong;LoEModerate]
3. Therapyshouldinitiallyaimforatleasta50%reductioninLDL- cholesterol[1,11,13,35–37].[CoRStrong;LoEModerate]
4. Thefollowingtherapeutictargetsshouldbeconsidered[1,11,13,36–
38]:
a LDL-cholesterol<2.5mmol/L(absenceofASCVDorothermajor ASCVDriskfactors);
bLDL-cholesterol<1.8mmol/L(imagingevidenceofASCVDalone orothermajorASCVDriskfactors);or
cLDL-cholesterol<1.4mmol/L(presenceofclinicalASCVD).[CoR Moderate;LoEModerate]
5. Maximallytolerated high potencystatins (eg. atorvastatin or ro- suvastatin) with or without ezetimibe, and a heart-healthy diet, shouldinitiallybe employedtoachievetheabovetargets(Fig.2) [1,2,36,39].[CoRStrong;LoEHigh]
6. Aproproteinconvertasesubtilisin/kexintype9(PCSK9)inhibitor should be employed iftheaboveLDL-cholesteroltargets arenot achieved with maximally tolerated statins, ezetimibe and diet (Fig.2)[1,2,11,36,40,41].[CoRStrong;LoEHigh]
7. Patientswithstatinintoleranceshouldbemanagedaccordingtoes- tablishedguidelinesandtreatedwithnon-statins,includingezetim- ibeandPCSK9inhibitors[1,3,36,42].[CoRStrong;LoEHigh]
8. InFHpatientswithclinicalASCVD(ordiabetes)onmaximallytol- eratedstatinsandezetimibeandelevatedtriglyceridelevels(1.5–
5.6 mmol/L), use of high-dose omega-3 fatty acids (especially 4g/dayofpureeicosapentaenoicacidethylester)shouldbecon- sideredtofurtherreduce ASCVDrisk[1,43]. [CoRModerate;LoE Moderate]
9. PatientswithFHshouldcontinuecholesterol-loweringdrugthera- piesduringacuteillness,suchasrespiratoryinfections,unlessspecif- icallycontra-indicated[4,44,45].[CoRStrong;LoELow]
10. Plasmahepaticaminotransferases,creatinekinase,glucoseandcre- atinineshouldbemeasuredbeforestartinganddosetitratingstatin therapy.Hepaticaminotransferasesshouldbemonitoredregularly andcreatinekinaseifmusculoskeletalsymptomsarereported;glu- coseshouldbemonitoredifthereisariskofdiabetes(thesesafety checksalsoapplytochildrenandadolescents)[1,3,4,7].[CoRStrong;
LoEModerate]
11. All womenof child-bearing age with FH should be offered pre- pregnancycounselling,withindividualisedadviceoncontraception, beforestartingastatinandthisshouldbereinforcedannually(ap- pliesalsotoadolescentgirls)[1,3,7].[CoRStrong;LoEModerate]
12. Statinsandothersystemicallyabsorbedcholesterolloweringdrugs shouldbediscontinued3monthsbeforeconception,aswellasdur- ingpregnancyandbreastfeeding[1,3,7].[CoRStrong;LoEModerate]
Fig. 2. Sequenceoftherapyforadultswithfamilialhypercholesterolaemia (FH].MostpatientswithheterozygousFHcanbewellcontrolledwithatwo- orthree-drugcombination;statinintolerantpatientsmaybetreatedwitheze- timibeandaPCSK9inhibitor.Complextherapyregimenswillusuallyapplyto patientswithhomozygousFH[17,36,38],whichmayincludechildrenandado- lescents.LDL-cholesteroltargetsarebasedonprimaryorsecondaryprevention settings[1,4];patientsshouldbeonatleast3monthsoftherapyandabovethe targetsbeforeproceedingtonextstep.∗Fortargets,seeManagementofAdults intext.AdaptedfromPangetal.2020[2].
13. InwomenwithhomozygousFHandclinicalASCVD,useofstatins andezetimibemaybeconsideredafterthefirsttrimester[1,5,36].
[CoRWeak;LoEModerate]
14. AlthoughCACSmaybeusefulforinitialriskstratificationofasymp- tomaticpatientspriortocommencingastatin,itshouldnotbeused tomonitortheefficacyoftherapy[1,15,16,46].[CoRStrong; LoE Moderate]
15. In asymptomatic patients with heterozygous FH, carotid ultra- sonographyandCTCAmaybeusedformonitoringtheefficacyof cholesterol-loweringtherapy[1,15,22].[CoRWeak;LoEModerate]
16. In adults with homozygous FH, carotid ultrasonography, CTCA, echocardiographyandexercise stresstesting should be employed (asclinicallyindicated)toassessprogressionofASCVDandathero- matous involvementof theaorticvalve, withtheaimof guiding overallmanagement(alsoappliestochildrenwithhomozygousFH) [7,15,38].[CoRStrong;LoEModerate]
3.7. Managementofchildrenandadolescents
1. AllpatientsandfamilieswithFHshouldbecounselledonlifestyle modifications,andadvicetopreventorcorrectnon-cholesterolrisk factors (especially smoking) [1,7,10,18,21,33]. [CoR Strong; LoE Moderate]
2. Managementshouldbebasedonshareddecisionmakingwithpar- entsandoffspring,withbarrierstotreatmentadherenceaddressed [1,7,10,34].[CoRStrong;LoEModerate]
3. Initiationofstatintreatmentshouldbeconsideredatage8to10 yearsirrespectiveofgender;LDL-cholesteroltargetsinchildrenand adolescentsneednotbeasintensiveasinadults[1,7,10,18,22].[CoR Moderate;LoEModerate]
4. Earlierinitiationoftreatmentwithstatinsshouldbeconsideredin patientswithaparticularlyadversefamilyhistoryofASCVDorother majorASCVDriskfactors[1,7,10,18,22].[CoRModerate;LoEMod- erate]
5. InchildrenwithFH,aged8to10yearsonasuitablediet,anLDL- cholesteroltreatmenttarget<4.0mmol/Lora30–40%reduction inLDL-cholesterolmaybeconsidered[1,10,18,21].[CoRWeak;LoE Low]
6. InchildrenwithFHolderthan10yearsonasuitablediet,anLDL- cholesteroltreatmenttarget<3.5mmol/Lor a50%reductionin LDL-cholesterolmaybeconsidered[1,10,18,21,22].[CoRWeak;LoE Low]
7. Statintherapywithorwithoutezetimibe,andaheart-healthydiet withorwithoutplantsterol(orstanol)supplementation,shouldbe employedtoachievetheabovetargets[1,3,7,10,18,21].[CoRStrong;
LoEHigh]
8. Statinslicencedforuseinthisagegroup(pravastatin,fluvastatin, simvastatinInAustralia)shouldbeemployed;ezetimibeisalsoli- censedfrom theageof 10 yearsandshouldbe usedaccordingly [2–4].[CoRStrong;LoEHigh]
9. Theuseofatorvastatinandrosuvastatinshouldbeconsideredinhet- erozygousFHaccordingtoclinicalindicationsandshareddecision making[1–4].[CoRModerate,LoEHigh]
10. Theuse of maximaldosesof highpotency statins andezetimibe shouldbeconsideredinhomozygousFHchildrenasearlyaspossi- ble,preferablybytheageof2years[1,4,10,21,47].[CoRModerate;
LoEModerate]
11. Although statins and ezetimibe can be safely used in children, weight,growth,physicalandsexualdevelopment,andwell-being shouldbemonitored[1,3,4,10,18,21,48].[CoRStrong;LoEHigh]
12. SharedcarebetweenapaediatricianandaGPshouldbeconsidered formanaginglowercomplexitypatients[3,4,7,8,10].[CoRModer- ate;LoELow]
13. Managementshouldfocusonthenuclearortheimmediatefamily, withatleastanannualreviewofchildren;non-adherenceshouldbe addressed[3,7,10,21].[CoRStrong;LoELow]
14. Transitionof adolescents toyoungadult services should be con- sidered in advance,with support offered toenable ongoingself- managementandsharedcareintoadulthood[3,4,18,48].[CoRMod- erate;LoELow]
15. Inchildrenandadolescentswith heterozygous FH,carotid ultra- sonographymaybeemployedtomonitortherapy[1,10,22,49].[CoR Weak;LoEModerate]
16. Inpatientswithhomozygous FH,treatmentshouldcommence as soonaspossibleafterdiagnosis:theLDL-cholesteroltargetshouldbe similartoadults,whichmayrequireadditionofaPCSK9inhibitor toastatinandezetimibe,aswellastheuseoflipoproteinapheresis (Fig.2)[1,7,10,17,18,23,38].[CoRStrong;LoEModerate]
4. Conclusion
Thisguidanceisalignedwitharecentinternationalcalltoaction onFH[50].Therecommendationsneedincorporationintohealthcare pathwaysthatmeet theneeds ofthepopulation[1, 2].InAustralia, governmentfundedschemes thatsupportappropriategenetictesting anduseof PCSK9monoclonalantibodieswillcontributesignificantly toenhancingthecareofpatientswithFH[2].Thecriticalbarrierthat needstobeovercomeistranslatingourguidanceintohealthpolicyand high-qualitycare.Implementationresearchandpractice[51,52]must
beembracedasanationalhealthprioritytoincreasetheimpactofthe guidanceonimprovingthecareofallpeoplewithoratriskofFH.This challengeandrecommendationappliesgloballytoallcountriesaiming toclosemajorgapsinthecareofFH[51].
DeclarationofCompetingInterest
Theauthorsdeclarethefollowingfinancialinterests/personalrela- tionshipswhichmaybeconsideredaspotentialcompetinginterests
Disclosures
GFWhasreceivedhonorariaforadvisoryboardsandresearchgrants from Amgen, Arrowhead, Gemphire, Kowa, Novartis, Pfizer, Sanofi andRegeneron.DRShasreceivedgrantsfromRegeneron,Amgen,As- traZeneca, Amarin, Espirion, andNovartis, aswell as personal fees fromAmgenandSanofi.DLHhasreceivedconsultingfees,educational grants,researchgrantsoradvisoryboardhonorariafromAmgen,Astra- Zeneca,Boehringer-Ingelheim,Menarini,MSD,Novartis,Pfizer,Sanofi- Regeneron,ServierandVifor.DABhasreceivedhonorariafromAmgen, NestleandSanofi.TBhasreceivedgrantsandhonorariafromAmgen andSanofi.CKChasparticipatedeitherasaparticipantorspeakerined- ucationalmeetingssponsoredbypharmaceuticalcompaniesthatmake lipid-loweringtherapies.KMK,RJT,ACM,SS,RNJ,NKP,AEHandJP havenodisclosures.
Funding
No funding from the pharmaceutical industry or other industry groupswasobtainedtosupportthedevelopmentofthis guidanceon FH.JPwassupportedbyaWAHTNEarlyCareerFellowshipandthe AustralianGovernment’sMedicalResearchFutureFund.
Appendix
AlltablesandfiguresarereprintedbykindpermissionofHeart,Lung
&Circulation[2,4].
Endorsements
The full guidance [4] has been endorsed by the Australian AtherosclerosisSociety,CardiacSocietyofAustraliaandNewZealand, National HeartFoundation (Australia),AustralianCardiovascular Al- liance,HumanGeneticsSocietyofAustralasia,EuropeanAtherosclero- sisSociety,InternationalAtherosclerosisSociety,FHFoundation,Heart UK,Asian-PacificSocietyofAtherosclerosisandVascularDisease,Na- tionalLipidAssociation(US)andtheAmericanSocietyofPreventive Cardiology.
FHAustralasiaNetworkConsensusWorkingGroup
SteeringCommittee:GeraldFWatts(Chair),DavidRSullivan,David LHare,KaramMKostner,AriEHortonandJingPang.
WritingCommittee:GeraldFWatts(Chair),DavidRSullivan,David L Hare, KaramM Kostner,Ari EHorton, DamonA Bell,TomBrett, RonaldJTrent,NicolaKPoplawski,Andrew CMartin,Shubha Srini- vasan,RobertNJusto,ClaraKChowandJingPang.
Contributors:
ZanfinaAdemi(SchoolofPublicHealthandPreventiveMedicine, MonashUniversity,Melbourne,Australia)
JustinJArdill(SAHeart,Adelaide,SouthAustralia,Australia) Wendy Barnett(Lipid DisordersClinic, Cardiometabolic Services, DepartmentofCardiology,RoyalPerthHospital,Perth,WesternAus- tralia,Australia)
TimothyRBates(SchoolofMedicine,FacultyofHealthandMedi- calSciences,UniversityofWesternAustralia,Perth,WesternAustralia, Australia;StJohnofGodHospitalMidland,Perth,WesternAustralia, Australia;CurtinMedicalSchool,FacultyofHealthSciences,CurtinUni- versity,Perth,WesternAustralia,Australia)
LawrenceJBeilin(SchoolofMedicine,FacultyofHealthandMedi- calSciences,UniversityofWesternAustralia,Perth,WesternAustralia, Australia)
WarrickBishop(DepartmentofCardiology,CalvaryCardiacCentre, CalvaryHealthCare,Tasmania,Australia)
JAndrewBlack(MenziesInstituteforMedicalResearch,University ofTasmania,Hobart,Tasmania,Australia;DepartmentofCardiology, RoyalHobartHospital,Hobart,Tasmania,Australia)
AlexBrown(AboriginalHealthEquity,SouthAustralianHealthand MedicalResearchInstitute,Adelaide,SouthAustralia,Australia;Faculty ofHealthandMedicalSciences,UniversityofAdelaide,SouthAustralia, Australia)
JohnRBurnett(SchoolofMedicine,FacultyofHealthandMedical Sciences,UniversityofWesternAustralia,Perth,WesternAustralia,Aus- tralia;LipidDisordersClinic,CardiometabolicServices,Departmentof Cardiology,RoyalPerthHospital,Perth,WesternAustralia,Australia;
Departmentof Clinical Biochemistry, PathWestLaboratory Medicine WA,RoyalPerthHospitalandFionaStanleyHospitalNetwork,Perth, WesternAustralia,Australia)
Christina A Bursill (Vascular Research Centre, South Australian HealthandMedicalResearchCentre,Adelaide,SouthAustralia,Aus- tralia;FacultyofHealthandMedicalResearch,UniversityofAdelaide, Adelaide,SouthAustralia,Australia)
AlisonColley(ClinicalGeneticsServices,LiverpoolHospital,Liver- pool,NewSouthWales,Australia)
PeterMClifton(DepartmentofEndocrinology,RoyalAdelaideHos- pital,Adelaide,SouthAustralia,Australia)
Elif I Ekinci (Department of Endocrinology, Austin Health, Mel- bourne,Victoria,Australia;DepartmentofMedicine,AustinHealth,Uni- versityofMelbourne,Melbourne,Victoria,Australia)
GemmaAFigtree(KollingInstitute,RoyalNorthShoreHospital,Syd- ney,NewSouthWales,Australia;FacultyofMedicineandHealth,Uni- versityofSydney,Sydney,NewSouthWales,Australia;TheGeorgeIn- stituteforGlobalHealth,Sydney,NewSouthWales,Australia)
BrettHForge(West GippslandHospital,Warragul,Victoria,Aus- tralia)
JacquieGarton-Smith(HealthNetworks,DepartmentofHeathWest- ern Australia, Perth, Western Australia, Australia; Clinical Services, RoyalPerthHospital,Perth,WesternAustralia,Australia;WAPrimary HealthAlliance,Perth,WesternAustralia,Australia)
DorothyFGraham(SchoolofMedicine,FacultyofHealthandMed- icalSciences,UniversityofWesternAustralia,Perth,WesternAustralia, Australia;Departmentof MaternalandFetalMedicine, KingEdward MemorialHospital,Subiaco,WesternAustralia,Australia)
IanHamilton-Craig(Schoolof Medicine,Flinders University,Ade- laide,SouthAustralia,Australia)
ChristianRHamilton-Craig(CardiologyProgram,ThePrinceCharles Hospital,Brisbane,Queensland,Australia;FacultyofMedicine,Univer- sityofQueensland,Brisbane,Queensland,Australia;SchoolofMedicine, GriffithUniversity,SunshineCoast,Queensland,Australia)
ClareHeal(SchoolofMedicineandDentistry,JamesCookUniver- sity,Mackay,Queensland,Australia)
CharlotteM Hespe(GeneralPractice andPrimary CareResearch, SchoolofMedicine,TheUniversityofNotreDame,Sydney,NewSouth Wales,Australia)
AmandaJHooper(SchoolofMedicine,FacultyofHealthandMedi- calSciences,UniversityofWesternAustralia,Perth,WesternAustralia, Australia;Departmentof Clinical Biochemistry,PathWestLaboratory MedicineWA,RoyalPerthHospitalandFionaStanleyHospitalNetwork, Perth,WesternAustralia,Australia)
LaurenceGHowes(CardiacServices,GoldCoastUniversityHospital, Southport,Queensland,Australia)
JodieIngles(AgnesGingesCentreforMolecularCardiologyatCen- tenaryInstitute,TheUniversityofSydney,Sydney,NewSouthWales, Australia;Facultyof MedicineandHealth,TheUniversityofSydney,
Sydney,NewSouthWales,Australia;DepartmentofCardiology,Royal PrinceAlfredHospital,Sydney,NewSouthWales,Australia)
EdwardDJanus(WesternHealthChronicDiseaseAlliance,Western Health,Melbourne,Victoria,Australia;DepartmentofMedicine,West- ernHealth,Melbourne,Victoria,Australia)
Nadarajah Kangaharan(Department of Cardiology, RoyalDarwin Hospital, Darwin, Northern Territory, Australia; Menzies School of HealthResearch,Darwin,NorthernTerritory,Australia;NorthernTer- ritoryMedicalSchool,FlindersUniversity,Adelaide,SouthAustralia, Australia)
AnthonyCKeech(NHMRCClinicalTrialsCentre,UniversityofSyd- ney, Sydney,NewSouthWales,Australia;DepartmentofCardiology, Royal Prince AlfredHospital, Camperdown,New South Wales, Aus- tralia)
AndrewBKirke(RuralClinicalSchoolofWesternAustralia,Univer- sityofWesternAustralia,Bunbury,WesternAustralia,Australia)
LeonardKritharides(DepartmentofCardiology,ConcordHospital, Sydney,Australia;TheANZACResearchInstitute,UniversityofSydney, Sydney,Australia)
CampbellVKyle(DepartmentofBiochemistry,LabPlus,Auckland CityHospital,Auckland,NewZealand)
PaulLacaze(PublicHealthGenomics,SchoolofPublicHealthand Preventive Medicine, Monash University, Melbourne, Victoria, Aus- tralia)
StephenCH Li(CorePathologyandClinicalChemistry,Pathology West, NSW Health Pathology, Sydney, New South Wales, Australia;
Lipid Clinic,WestmeadHospital,Westmead, NewSouth Wales,Aus- tralia)
Stjepana Maticevic (Departmentof General Medicine,SirCharles GairdnerHospital,Perth,WesternAustralia,Australia)
BrendanMMcQuillan (SchoolofMedicine,Facultyof Healthand MedicalSciences,UniversityofWesternAustralia,Perth,WesternAus- tralia, Australia;Departmentof CardiovascularMedicine,SirCharles GairdnerHospital,Perth,WesternAustralia,Australia)
Sam Mirzaee (Monash Cardiovascular Research Centre, Monash- Heart,Melbourne,Victoria,Australia)
TrevorAMori(SchoolofMedicine,FacultyofHealthandMedical Sciences,UniversityofWesternAustralia,Perth,WesternAustralia,Aus- tralia)
AllisonCMorton(Genesiscare,SouthWestHealthCampus,Bunbury, WesternAustralia,Australia)
DavidMColquhoun(SchoolofMedicine,UniversityofQueensland, Brisbane,Queensland,Australia;WesleyMedicalCentre,WesleyHospi- talandGreenslopesPrivateHospital,Brisbane,Queensland,Australia)
Joanna C Moullin (Faculty ofHealth Sciences,Curtin University, Perth,WesternAustralia,Australia)
PaulJNestel(BakerHeart&DiabetesInstitute,Melbourne,Victoria, Australia;DepartmentofCardiology,TheAlfredHospital,Melbourne, Victoria,Australia)
KristenJNowak(OfficeofPopulationHealthGenomics,Publicand AboriginalHealthDivision,DepartmentofHealth,GovernmentofWest- ernAustralia,Perth,WesternAustralia,Australia)
RichardCO’Brien(AustinClinicalSchool,UniversityofMelbourne, Melbourne, Victoria, Australia; Departmentof Endocrinology,Austin Health,Melbourne,Victoria,Australia)
NicholasPachter(GeneticServicesofWestern Australia,King Ed- wardMemorialHospital,Perth,WesternAustralia,Australia;Schoolof Medicine,FacultyofHealthandMedicalSciences,UniversityofWest- ernAustralia,Perth,WesternAustralia,Australia;SchoolofMedicine, FacultyofHealthSciences,CurtinUniversity,Perth,WesternAustralia, Australia)
MichaelMPage(SchoolofMedicine,FacultyofMedicineandHealth Sciences,UniversityofWesternAustralia,Perth,WesternAustralia,Aus- tralia;DepartmentofClinicalBiochemistry,WesternDiagnosticPathol- ogy,Perth,WesternAustralia,Australia)
PeterJPsaltis(VascularResearchCentre,SouthAustralianHealth andMedicalResearch Institute, Adelaide,South Australia, Australia;
AdelaideMedicalSchool,UniversityofAdelaide,Adelaide,SouthAus- tralia,Australia)
Jan Radford (Launceston Clinical School, Tasmanian School of Medicine,UniversityofTasmania,Tasmania,Australia)
Nicola J Reid (Lipid Disorders Service, Cardiology Department, ChristchurchHospital,Christchurch,NewZealand)
ElizabethNRobertson(DepartmentofCardiology,RoyalPrinceAl- fred Hospital,Camperdown,New South Wales,Australia; Facultyof MedicineandHealth,CharlesPerkinsCentre,UniversityofSydney,Syd- ney,NewSouthWales,Australia)
JacquelineDMRyan(PerthLipidClinic,Perth,WesternAustralia, Australia)
MitchellNSarkies(CentreforHealthcareResilienceandImplemen- tation Science, Australian Institute of Health Innovation,Faculty of Medicine,HealthandHumanSciences,MacquarieUniversity,Sydney, NewSouthWales,Australia;HealthEconomicsandDataAnalyticsDis- cipline,SchoolofPublicHealth,FacultyofHealthSciences,CurtinUni- versity,Perth,WesternAustralia,Australia)
CarlJSchultz(SchoolofMedicine,FacultyofHealthandMedical Sciences,UniversityofWesternAustralia,Perth,WesternAustralia,Aus- tralia;DepartmentofCardiology,RoyalPerthHospital,Perth,Western Australia,Australia)
Russell S Scott (Internal Medicine, Christchurch Hospital, Christchurch,Canterbury,NewZealand)
ChristopherSemsarian(Agnes GingesCentreforMolecularCardi- ologyatCentenaryInstitute,TheUniversityofSydney,Sydney,New SouthWales,Australia;FacultyofMedicineandHealth,TheUniversity ofSydney,Sydney,NewSouthWales,Australia;DepartmentofCardiol- ogy,RoyalPrinceAlfredHospital,Sydney,NewSouthWales,Australia) LeonASimons(UniversityofNewSouthWalesandStVincent’sHos- pital,Sydney,NewSouthWales,Australia)
CatherineSpinks(DepartmentofChemicalPathology,RoyalPrince AlfredHospital,Camperdown,NewSouthWales,Australia)
Andrew M Tonkin (Department of Epidemiology andPreventive Medicine,MonashUniversity,Melbourne,Victoria,Australia)
FrankvanBockxmeer (Schoolof Medicine,FacultyofHealthand MedicalSciences,UniversityofWesternAustralia,Perth,WesternAus- tralia,Australia)
KathrynEWaddell-Smith(DepartmentofCardiovascularMedicine, FlindersMedicalCentre,Adelaide,SouthAustralia,Australia)
NatalieCWard(SchoolofMedicine,FacultyofHealthandMedi- calSciences,UniversityofWesternAustralia,Perth,WesternAustralia, Australia;CurtinHealthInnovationResearchInstitute,CurtinUniver- sity,Perth,WesternAustralia,Australia)
HarveyDWhite(GreenLaneCardiovascularServices,AucklandCity HospitalandAucklandUniversity,Auckland,NewZealand)
AndrewMWilson(DepartmentofCardiology,St.Vincent’sHospi- tal,Melbourne,Victoria,Australia;FacultyofMedicine,Dentistryand Health Sciences,Universityof Melbourne, Melbourne, Victoria, Aus- tralia)
IngridWinship(DepartmentofMedicine(RoyalMelbourneHospi- tal),Universityof Melbourne GenomicMedicine,Melbourne Health, Melbourne,Victoria,Australia)
AnnMarieWoodward(LipidDisordersClinic,CardiometabolicSer- vices,DepartmentofCardiology,RoyalPerthHospital,Perth,Western Australia,Australia)
Stephen JNicholls (Departmentof Medicine, Monash University, Melbourne,Victoria,Australia)
Healthconsumercontributors:
PeterBrett(FHAustralasiaSupportGroup,Melbourne,Victoria,Aus- tralia)
LukeElias(FHAustralasiaSupportGroup,Sydney,NewSouthWales, Australia)
WynandMalan(FHAustralasiaSupportGroup,Perth,WesternAus- tralia, Australia; Schoolof Health Sciences,CurtinUniversity, Perth, WesternAustralia,Australia)
JohnIrvin(FHAustralasiaSupportGroup,Perth,WesternAustralia, Australia)
KirstenLambert(FHAustralasiaSupportGroup,Perth,WesternAus- tralia, Australia;Schoolof Education,Edith CowanUniversity,Joon- dalup,WesternAustralia,Australia)
AnnettePedrotti(FHAustralasiaSupportGroup,Perth,WesternAus- tralia,Australia)
References
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