www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
PERSPECTIVES
IN
CARDIOLOGY
Standardization
of
laboratory
lipid
profile
assessment:
A
call
for
action
with
a
special
focus
on
the
2016
ESC/EAS
dyslipidemia
guidelines
---
Executive
summary
A
consensus
endorsed
by
the
Cardiovascular
Risk
and
Prevention
Group
of
the
Portuguese
Internal
Medicine
Society,
the
Portuguese
Atherosclerosis
Society,
the
Portuguese
Society
of
Cardiology,
the
Portuguese
Society
of
Laboratory
Medicine,
and
the
Portuguese
Association
of
Clinical
Chemistry
Pedro
Marques
da
Silva
a,∗,
João
Sequeira
Duarte
b,
Pedro
von
Hafe
c,
Victor
Gil
d,
Jorge
Nunes
de
Oliveira
e,
Germano
de
Sousa
faNúcleodeInvestigac¸ãoArterial,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,EPE,Lisboa,Portugal bServic¸odeEndocrinologia,HospitaldeEgasMoniz,CentroHospitalardeLisboaOcidental,EPE,Lisboa,Portugal cServic¸odeMedicinaInterna,CentroHospitalarSãoJoão,Porto,Portugal
dUnidadeCardiovascular,HospitalLusíadasLisboa,Lisboa,Portugal
eLaboratóriodeAnálisesClínicasProf.DoutorJoaquimJ.NunesdeOliveira,PóvoadoVarzim,Portugal fGrupoGermanodeSousa,CentrodeMedicinaLaboratorial,PoloTecnológicodeLisboa,Lisboa,Portugal
Received2April2017;accepted24July2017 Availableonline21April2018
KEYWORDS Dyslipidemia; Cardiovascularrisk; Laboratory procedures; Laboratoryreports; Harmonization; Standardization
Abstract Evenwithimprovementsinlifestyleinterventions,bettercontrolofcardiovascular (CV)riskfactors,andimprovementsinCVoutcomes,cardiovasculardisease(CVD)remainsthe leadingcauseofmorbidityandmortalityinPortugalandEurope.Atherogenicdyslipidemias, particularlyhypercholesterolemia,haveacrucialcausalroleinthedevelopmentof atheroscle-roticCVD.Theclinicalapproachtoapatientwithdyslipidemiarequiresanaccuratediagnosis, basedonharmonizedandstandardizedlipidandlipoproteinlaboratoryassessments.Resultsand reportsofthesetests,togetherwithassessmentoftotalCVriskandtherespectivetherapeutic targets, willhelp ensure that clinical guidelines and good clinical practices are followed,
∗Correspondingauthor.
E-mailaddress:pmarques.silva@sapo.pt(P.M.daSilva).
https://doi.org/10.1016/j.repc.2017.07.013
0870-2551/©2018SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.Allrightsreserved.
increasingthereliabilityofscreeningforlipiddisorders,producingmoreaccuratediagnosesand CVriskstratification,andimprovingCVprevention.Tothisend,thisconsensusaimstoprovide clinicianswithpracticalguidancefortheharmonizationandstandardizationoflaboratorylipid tests,focusingonthemostrecentdyslipidemiamanagementguidelines.
©2018SociedadePortuguesade Cardiologia.Publishedby ElsevierEspa˜na,S.L.U.Allrights reserved. PALAVRAS-CHAVE Dislipidemia; Riscocardiovascular; Procedimentos laboratoriais; Relatórios laboratoriais; Harmonizac¸ão; Padronizac¸ão
Padronizac¸ãodaavaliac¸ãolaboratorialdoperfillipídico:umapeloàac¸ãocomfoco especialnasrecomendac¸õeseuropeiasdedislipidemiadaESC/EASde2016---sumário executivo
UmconsensoendossadopeloGrupodePrevenc¸ãoeRiscoCardiovascular
daSociedadePortuguesadeMedicinaInterna,SociedadePortuguesadeCardiologia, SociedadePortuguesadeMedicinaLaboratorialeAssociac¸ãoPortuguesadeAnalistas Clínicos
Resumo Apesardamelhorintervenc¸ãonosestilos devida,domelhorcontrolo dosfatores deriscocardiovascular(CV)edamelhoriadosresultadosCV,adoenc¸acardiovascular(DCV) continua a ser a principal causa de morbilidade e mortalidade em Portugal e na Europa. A dislipidemia aterogénica,nomeadamente ahipercolesterolemia, tem um papel causal no desenvolvimentodeDCVaterosclerótica.Aabordagemclínicadeumdoentecomdislipidemia preceituaumdiagnósticoatento,sustentadoemprocedimentoslaboratoriaisharmonizadose padronizados.OsresultadoserelatóriosdostestesdelipídiosseajuntaremoriscoCVtotale osrespetivosalvosterapêuticosgarantemqueasdiretrizesclínicaseasboaspráticasclínicas estãoaserseguidaserespeitadas,oqueaumentaaseguranc¸anorastreioenodiagnósticodas alterac¸õeslipídicasedaestratificac¸ãoderiscoemelhoraaprevenc¸ãoCV.Nessesentido,este consensotem comoobjetivofornecer aosclínicos orientac¸õespráticaspara aharmonizac¸ão e padronizac¸ãodos testes laboratoriaislipídicos, comfoco nasdiretrizes mais recentes da abordagemdasdislipidemias.
©2018SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Todosos direitosreservados.
Cardiovasculardisease(CVD)remainsoneoftheleading causesofmorbidityandmortalityworldwide.1,2InPortugal,
diseases of the circulatory system accounted for 29.5% of deaths recorded in 2013, witha mortality of 54.6 per 100000forcerebrovasculardiseaseandof32.9per100000 forischemicheartdisease.3
Atherogenic dyslipidemias, particularly hypercholes-terolemia,playanunquestionableroleinthedevelopment of atherosclerotic CVD. Accurate and timely diagnosis of dyslipidemia is of crucial importance. For this diagnosis, itisessentialtoobtainanaccuratelaboratoryassessment of the patient’s lipid profile. This information, combined with thorough clinical history collection and physical examination, can be used to determine the patient’s CV risk,akeytoolintherapeuticmanagement.4Theintensity
of risk-reduction therapy should generally be adjusted to the patient’s absolute risk for a CVD event. Appro-priate screening, prevention, diagnosis, monitoring and treatment, combined with an accurate and standardized laboratory diagnosis, areessential to themanagement of dyslipidemiasandCVDpreventioninclinicalpractice.
In Portugal, a need has been identified to harmo-nize various aspects of laboratory lipid measurements. A
meeting with specialists in clinical pathology, laboratory medicine, clinical analysis, cardiology, internal medicine and endocrinology was held with the purpose of prepar-ingnationwiderecommendationsforlipidprofileassessment andreportinginadultpatients,basedonthelatest guide-lines for CVD prevention and treatment. The recommen-dationspresentedhereinreflectthedebateandconsensus reached by this expert panel. This proposal reflects the mostrecentEuropeanguidelinesonCVDprevention5andthe
managementofdyslipidemias.4Theyshouldserveasa
foun-dationforstandardizinglipidassessmentstrategies,aswell aslaboratorylipidassessmentreports,inallnationalclinical analysis laboratories. These recommendations aredivided intofourmaintopics:CVDpreventionandtreatment guide-lines; dyslipidemiascreening; lipidbiomarker assessment; andreportingoflaboratorylipidassessments.
Cardiovascular
disease
prevention
and
treatment
guidelines
There arevariousnationalandinternational guidelineson the prevention and treatment of CVD. This expert panel recommends adopting the recommendations of the
Euro-pean Atherosclerosis Society (EAS) and European Society of Cardiology (ESC)for the managementofdyslipidemias4
andforCVDpreventioninclinicalpractice,5andfollowing
thethreespecificstandardsofgoodclinicalpractice(GCP) publishedbythePortugueseDirectorate-GeneralofHealth (DGS) on this matter,6---8 specifically in terms of CVD risk
stratification andtargetlipidvalues.TheseGCPstandards fromtheDGSshouldbesourcesofguidanceandinstruments ofclinicaldecisionsupportintheNationalHealthServiceto promotethedevelopmentofexcellenceinhealthcareand itsevaluationinthehospitalnetwork,healthcenters,family healthunitsandcontinuouscare.
Weadvocateappropriatescreening,diagnosis, monitor-ingandtreatmentofdyslipidemias,asacrucialpartofCVD preventionin clinicalpractice.Forassessment oftotalCV risk,wesupporttheSCOREriskchartfordeterminationof 10-year risk of a firstfatal atherosclerotic CVevent (e.g. myocardialinfarction,strokeorotherocclusivearterial dis-ease,includingsuddencardiacdeath),inapparentlyhealthy peoplewithnorecognizedCVD.Individualswithahistoryof aCVevent,type1or2diabetes,veryhighlevelsof individ-ualriskfactors(e.g.familialhypercholesterolemiaorblood pressure≥180/110mmHg),orchronickidneydisease,have veryhighorhightotalCVriskandnofurtherriskestimation isrequired.
The SCORE data indicate that total risk for CV events is about three times higher than the risk of fatal CVD in men,andfourtimeshigherinwomen,butsomewhatlessin theelderly. Inolderpatients thelikelihoodofa firstfatal CVeventis naturallyhigher.Inolder people(>60yearsof age),theSCOREriskthresholdshouldnotbeappliedstrictly, becausetheirage-specificriskisnormallyaroundthese lev-els,evenwhenotherCVriskfactorlevelsarenormal.
Young people with high levels of risk factors deserve particularconsideration.Lifetimeriskisprobablythebest approachtoevaluatetheimpactofriskfactorsinthis popu-lation,buttherearestillinsufficientepidemiologicalcohort data to supportits application. In young people, an esti-mateoftheirrelativerisk---ratherthantheirabsoluterisk, whichispresumablylow---ortheuseof‘CVriskage’may behelpful.4
Recommendations
for
the
screening
of
dyslipidemia
Screening for dyslipidemia is indicated in all adults (men aged ≥40 years and women aged ≥50 years or post-menopausal),particularlyinthepresenceofotherclassicCV riskfactors;inpatientswithclinicalCVD(secondary preven-tion)or withclinical conditions associatedwithincreased CV risk (primary prevention), especially in patients with obesity,metabolic syndromeand/or diabetes; and in HIV-infected patients (Table 1, adapted from9). It is also
recommended toscreen offspring of patients with severe dyslipidemiaandfamilymembers ofpatients with prema-tureCVD.
TherationaleofCVDriskassessmentistoconvince indi-viduals without treatable risk factors and low CV risk to maintainahealthylifestyle,torecommendindividualswith treatable CV risk factors or unhealthy behaviors to mod-ifytheirattitudesandtotreatandmanagemodifiablerisk
Table1 Whotoscreenfordyslipidemiainadultsatrisk. Allpatientswiththeseconditions
regardlessofage:
Menaged≥40 yearsofageand womenaged≥50 years(or postmenopausal) •ClinicalevidenceofCVD
•Abdominalaorticaneurysm •Diabetes
•Hypertension
•Currentcigarettesmoking •Stigmataofdyslipidemiaa •FamilyhistoryofprematureCVDb •Familyhistoryofdyslipidemia •CKD
•Obesity(BMI≥30kg/m2) •IBDandotherinflammatory disorders
•HIVinfection •Erectiledysfunction •COPD
•Hypertensivediseaseordiabetes inpregnancy
aArcuscorneae,xanthelasmaorxanthoma.
b Menaged <55yearsand womenaged <65yearsina
first-degreerelative.
BMI:bodymassindex;COPD:chronicobstructivepulmonary dis-ease;CVD:cardiovasculardisease;CKD:chronickidneydisease; HIV:humanimmunodeficiencyvirus;IBD:inflammatorybowel disease.
factors,andtoidentifysubjectswhowilllikelyderivemost benefit from pharmacotherapy and concomitant lifestyle interventions.
WerecommendthatCVriskreductionshouldbe individu-alizedandtreatmentgoalsshouldbeidentified.Low-density lipoproteincholesterol(LDL-C)istheprimarytreatment tar-get,buttotalcholesterol(TC)canbeacceptedifotherlipid parametersarenotavailable.Non-high-densitylipoprotein cholesterol(non-HDL-C)and/orapolipoproteinB(ApoB)can beusedassecondarytreatmenttargets.Westronglysuggest thatlipidtreatmentgoals taketotalCVriskinto consider-ation.LDL-Ctreatmenttargetsshouldbe:
• Forlow-andmoderate-riskindividuals:<115mg/dl(<3.0 mmol/l)
• For high-risk patients: <100 mg/dl (<2.6 mmol/l), or a reductionofatleast50%ifbaselineLDL-Cisbetween100 and200mg/dl(2.6-5.2mmol/l).
• Forveryhigh-riskpatients:<70mg/dl(<1.8mmol/l)ora decreaseofatleast50%ifbaselineLDL-Cisbetween70 and135mg/dl(1.8-3.5mmol/l).
Thediagnosisofdyslipidemiashouldalwaysbeconfirmed bysubsequentlaboratoryassessmentoflipidprofile,carried outinaminimumof fourweeks,priortothebeginningof anypharmacologicaltherapy(inlinewiththeDGS’sstandard no.019/2011).6
The frequency of testing depends on the person’s CV riskprofile.After4-12weeksfromthestart ofdrug treat-ment a second fasting lipid panel should be performed. Subsequently,assessmentsshouldbeperformedeverythree months untilthe lipid goals are achieved,and thereafter
every12months,asclinicallyindicated.However,when LDL-C loweringtherapy is adapted (e.g. any intensificationof lifestyleinterventions,titrationofstatintherapy,oradding ofnon-statintherapies),werecommendanewlipidpanel, again4-12weeksaftertreatmentadjustment,followedby resumptionoftheaboveregimen.
Recommendations
for
lipid
biomarker
assessment
We recommend that a baseline lipid assessment should include estimation of TC, triglycerides (TG), high-density lipoproteincholesterol(HDL-C),LDL-C(calculatedwiththe Friedewaldformula,based onfasting plasmaTC,TG, and HDL-C values, or determined directly), and non-HDL-C. Fastingandnon-fastinglipidlevelshavesimilarprediction strength and shouldbe regarded ascomplementary. Non-fasting lipid levels can be applied in screening and risk estimation; however, in general, a 12-hour fasting period isstillconsideredoptimalwhenlipoproteinmeasurements areusedinCVriskscreeningandestimationandfor charac-terizingdyslipidemiasbeforetreatment.
We are aware of the significant limitations of the Friedewald formula.10,11 Its estimates are not valid when
TG >400 mg/dl (>4.5 mmol/l), in patients with type III hyperlipoproteinemia (dyslipidemia with accumulation of cholesterol-rich remnants) or chylomicronemia, or in nonfastingspecimens.Recently,novelLDL-Cestimation for-mulassuchas(non-HDL-C)-(TG/adjustable factormg/dl) have been proposed,12 in which an adjustable factor was
establishedasthestrata-specificmedianTG:verylow den-sitylipoproteincholesterol(VLDL-C)ratio.Althoughthisnew methodappearstoprovideabetterestimateofLDL-C (par-ticularlyinpatientswithLDL-C≤70mg/dlinthepresence
Table2 IndicationsforLp(a)screening. •PrematureCVD
•Familialhypercholesterolemia
•FamilyhistoryofprematureCVDand/orelevatedLp(a) •RecurrentCVDdespiteoptimallipid-loweringtherapy •≥5%10-yearriskoffatalCVDaccordingtoSCORE •HemodialysisandCKDa
•Intermediate(3-5%)10-yearriskoffatalCVD accordingtoSCOREa
a PossibleindicationsforLp(a)determination,butnotclearly
statedinthecurrentinternationalguidelines.
CVD:cardiovasculardisease;CKD:chronickidneydisease;Lp(a): lipoprotein(a);SCORE:SystematicCOronaryRiskEvaluation.
of high TG levels),it needs tobemore widely validated, andtheformulaselectedineachlaboratorydetermination shouldbeclearlystated.
If available, and in particular clinical circumstances, ApoB and lipoprotein(a) (Lp(a)) can also be estimated. Non-HDL-Cis an umbrellatermfor allplasma atherogenic lipoproteins (VLDL, VLDL remnants, intermediate-density lipoproteins,LDL,and Lp(a)).Itis calculatedasTCminus HDL-C,andisassociatedwithApoBlevels.ApowerfulCVrisk predictor,non-HDL-Cissimpletocomputeanddoesnotneed fasting conditions.13 This is the reason for including
non-HDL-C,unlikeApoB,inthestandardlipidprofileassessment. MeasurementofLp(a)isnotcurrentlyrecommended,and shouldonlybeperformedinspecificpatients4,14,15(Table2).
CV riskis significantwhen Lp(a)>50mg/dl. Inpatients at risk withhighLp(a)levelsthe treatmentof modifiableCV risk factorsshould beintensified,particularlyLDL-C (with intensivelipid-loweringtherapy).TheeffectonCVDevents oftargetingLp(a)hasnotbeenestablishedandLp(a)should notbealipidtargetinCVprevention.
Recommendations
for
the
reporting
of
laboratory
lipid
assessments
Theexpert panelrecommendsincludingthemethodsused for lipid biomarker quantification, aswell asthe specific equipmentemployedtothatendandtheassociated varia-tioncoefficients,inalllaboratorylipidreports.
We strongly emphasize the importance of lipid test reports includingspecific informationontargetLDL-C val-ues, according tothedifferentCV risk levels(<70 mg/dl, <100mg/dland<115mg/dl),inlinewiththeDGS’sstandard no. 005/2013.8 This should be accompanied by a
suppor-ting statement,suchas‘‘CVrisktobedeterminedbythe attendingphysician’’(Figure1).Wealsopropose that lab-oratoryreports shouldflagnonstandard lipidvaluesbased ondesirableconcentrationcut-points,definedbyguidelines andconsensusstatements.4,5,9,16
Final
word
Atherosclerotic CVD is preventable. We and our scientific societieswishtopromotethebesthealthcareforindividuals ofbothsexesandallageswhoareatCVrisk.Weareaware thateffectiveCVpreventionisfrequentlyoverlookedinour dailypractice.CVpreventionisinfactanethicalobligation. ItisimportanttorecognizeCVrisk,tostresstheimportance oflaboratoryreports,andtoidentifyclinicalsituationsthat warrantjudiciousintervention.
Funding
No external funding was used in the preparation of this manuscript.
Conflicts
of
interest
PMShasreceivedlecturehonorariaorconsultingfeesfrom Bayer, Jaba Recordati, Merck Sharp and Dohme Portugal, Kowa Pharmaceuticals, Novartis, Daiichi Sankyo, Amgen, Sanofi-Regeneron,andTecnimede.JSDhasreceivedlecture honorariaorconsultingfeesfromNovo-Nordisk,MerckSharp and Dohme Portugal, Sanofi-Regeneron, Novartis Oncol-ogy,Boehringer-Ingleheim,andTecnimede.VGhasreceived honorariafromAstraZeneca,MerckSharpDohmePortugal, Bial,JabaRecordati,andAmgen.Theothermembershave noconflictsofinteresttodeclare.
Acknowledgment
The consensus panel wishes to express its gratitude to Anabela Farrica and Diogo Ribeiro of Eurotrials, Scien-tificConsultants,S.A., whoseassistance wasinvaluable in preparingthefirstdraftofthisdocument.
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