Cardiovascular Risk Assessment: A Systematic Review of Guidelines.

Transcription

1 Cardiovascular Risk Assessment: A Systematic Review of Guidelines. Khanji, MY; Bicalho, VVS; van Waardhuizen, CN; Ferket, BS; Petersen, SE; Hunink, MGM 2016 American College of Physicians This is a pre-copyedited, author-produced PDF of an article accepted for publication in Annals of Internal Medicine following peer review. The version of record is available For additional information about this publication click this link. Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact scholarlycommunications@qmul.ac.uk

2 1 TitlePage CardiovascularRiskAssessment: ASystematicReviewofGuidelines MohammedY.Khanji *, MBBCh,ViníciusV.S.Bicalho MD,ClaudiaN.vanWaardhuizen MSc, BartS.Ferket PhD,SteffenE.Petersen * DPHIL,M.G.MyriamHunink, PhD Authors MohammedY.Khanji,MBBCh; E:m.khanji@qmul.ac.uk ViníciusV.S.Bicalho,MD; E:vsbicalho@gmail.com ClaudiaN.vanWaardhuizen,MSc; E:c.vanwaardhuizen@erasmusmc.nl BartS.Ferket,PhD; E:bart.ferket@mountsinai.org SteffenE.Petersen,DPHIL; E:s.e.petersen@qmul.ac.uk M.G.MyriamHunink,PhD (correspondingauthor) E:m.hunink@erasmusmc.nl *CentreforAdvancedCardiovascularImaging,NIHRCardiovascularBiomedicalResearchUnitat Barts,WilliamHarveyResearchInstitute,QueenMaryUniversityofLondon,London,United Kingdom. DepartmentofCardiology,MorristonHospital,Swansea,UnitedKingdom SchoolofMedicine,UniversidadeFederaldeJuizdeFora,Brazil. DepartmentofClinicalEpidemiologyandRadiology,ErasmusMC,Rotterdam,TheNetherlands. InstituteforHealthcareDeliveryScience,DepartmentofPopulationHealthScienceandPolicy, IcahnSchoolofMedicineatMountSinai,NewYork,NY,USA. CenterforHealthDecisionSciences,HarvardT.H.ChanSchoolofPublicHealth,Boston,MA,USA.

3 Abstractwordcount:274words 25 Manuscripttextwordcount:3716words Correspondingauthor: 28 M.G.MyriamHunink,MD,PhD 29 RoomNa ErasmusMC 31 POBox2040,3000CA,Rotterdam,TheNetherlands 32 Tel: /Fax:

4 Abstract 50 Background: 51 Anumberofguidelinesexistforprimarypreventioncardiovascularscreeningandriskassessment 52 fortheapparentlyhealthypopulation. 53 Purpose: 54 Tosystematicallyreviewcurrentprimarypreventionguidelinesonadultcardiovascularrisk 55 assessmentandhighlightthesimilaritiesanddifferencesinordertoaidclinician sdecisionn 56 making. 57 Datasources: 58 PublicationsinMEDLINEandCINAHLbetweenMay3,2009andJune30,2016wereidentified.In 59 additiononjune30,2016wesearchedthegninninternationalguidelinelibrary,national 60 GuidelinesClearingnhouse,NationalLibraryforHealth,CanadianMedicalAssociationInfoBaseand 61 websitesoforganizationsresponsibleforguidelinesdevelopment. 62 Studyselection: 63 TworeviewersscreenedtitlesandabstractstoidentifyguidelinesfromWesterncountries 64 containingrecommendationsforcardiovascularriskassessmentforhealthyadults. 65 Dataextraction: 66 TworeviewersindependentlyassessedrigorofguidelinedevelopmentusingAGREEIIandone 67 extractedtherecommendations. 68 Datasynthesis: 69 Ofthe21guidelines,17showedconsiderablerigorofguidelinedevelopment.Therigorously 70 developedrecommendationsaddressassessmentoftotalcardiovascularrisk(5guidelines), 71 dysglycemia(7),dyslipidemia(2),andhypertension(3).allrecommendations,withtheexception 72 ofone,advocatescreeningandthemajorityincludepredictionmodelsintegratingmultiple, 73 relativelysimpleriskfactorseitherfordecidingonfurtherscreeningortoguidesubsequent 74

5 management.thereisnoconsensusonthestrategyforscreening,recommendedtarget 75 population,screeningtestsortreatmentthresholds. 76 Limitations: 77 OnlyguidelinesdevelopedbyWesternnationalorinternationalmedicalorganizationsare 78 included. 79 Conclusion: 80 Considerablediscrepanciesinrecommendationsstillexistincardiovascularscreeningguidelines 81 withnoconsensusonoptimumscreeningstrategiesortreatmentthreshold Primaryfundingsource: 84 AspartofaBartsCharitylargeprojectgrant.Thecharityhadnoinputinthepreparationorediting 85 ofthemanuscript

6 Introduction Manynationalandinternationalbodieshighlightprimarypreventionofcardiovasculardisease (CVD),throughriskfactorreduction,asapotentialsolutiontoreducefutureburden(1).The optimaltargetgroupandinterventionthatmaximizebenefit,however,remainunclear. CardiovascularscreeningthroughhealthchecksarenowwidelyimplementedinmanyWestern countriestosystematicallydetecthighnriskindividualswhomayrequireaggressiveriskreduction throughpharmacotherapyand/orlifestyleinterventions.guidelinesadvocateuseofscreening withtheaimofmakingtheapparentlyhealthypopulationhealthierandreducingriskfactorsfor futurecvd.theinstituteofmedicine(iom)definesclinicalpracticeguidelinesas systematically developedstatementstoassistpractitionersandpatientdecisionsabouttheappropriatehealth careforspecificclinicalcircumstances (2).However,todateaninternationallyagreedguideline forcardiovascularhealthchecksdoesnotexist. PrimarycarephysiciansmaintainacentralroleinthepreventionofCVDbutstillfind implementationofpreventionstrategieschallengingandmanagementofthosewithincreased CVDriskremainssuboptimal(3).Timeconstraints,lackofperceivedusefulness,inadequate knowledge,andinconsistencyinpublishedrecommendationshavebeencitedascommonreasons fornotusingcvdpreventionguidelinesorglobalcvdriskassessmenttools(4).concernsexist regardingpooruptakeoftheprogrambythoseinvitedwithonlyabout50%attendingfora NationalHealthServicehealthcheck,muchlowerthanthe75%governmenttarget(5). Additionally,therearedoubtsraisedconcerningthemorbidityandmortalitybenefitsfromsuch programsposedbyacochranereviewandasubsequentdanishrandomizedcontrolledtrial(6,7).

7 Ferketetalperformedasystematicreviewin2010,identifyingdifferencesamongstguidelines 124 thatwouldleadtovariationsinallocationofresourcesforpreventionbetweendifferentwestern 125 healthcaresystems(8).sincethattime,thereviewedguidelineswererevisedandreplacedand 126 newevidencehasalsobecomeavailableonstatinandbloodpressureloweringtherapyinlowrisk 127 individuals(9,10).thissystematicreviewrevisitsthecvdriskassessmentguidelinesandthe 128 selectionofappropriatescreeninginterventionsbasedoncurrentlyavailableevidence

8 Methods Weconductedanupdatedsystematicreview,usingourprevioussearchstrategy(8),ofguidelines containingrecommendationsforcvdriskassessmentintheapparentlyhealthyadultpopulation notalreadyreceivingtreatmentforhighnriskcardiovascularconditionssuchasdiabetes, hypertensionandhypercholesterolemia. Datasourceandsearches Asystematicliteraturesearchwasperformedtoidentifyappropriateguidelinesfollowingthe methodsofourpreviouspublication(8).wesearchedforpublishedguidelinesusingmedlineand CINAHLbetweenMay3,2009andJune30,2016(seeAppendixforsearchstrategy).We supplementedthissearchbyusingthefollowing4guidelinesspecificdatabases;thenational GuidelineClearinghouse(US),NationalLibraryforHealthonGuidelinesFinder(UnitedKingdom), CanadianMedicalAssociationInfoBase(Canada),andGnInNInternationalGuidelineLibrary ( organizations,includingwebsitesaffiliatedwithalltheguidelinesincludedinourprevious publication,tofindadditionalorupdatedguidelinesthatwererelevant(seeappendixtable1). OursearchwasrestrictedtonationalguidelinesfromtheUnitedStates,Canada,theUnited Kingdom,AustraliaandNewZealandandtointernationalguidelineswritteninEnglish. Studyselection References that met the Institute of Medicine definition of a guideline were included. Guidelines were excluded if they (1) did not contain recommendations involving the healthy adult population, (2) were entirely focused on early detection of CVD, (3) were not produced on behalf of a professional organization, or (4) were not applicable to Western countries. In addition, only

9 guidelines produced or updated as of May 2009 were eligible for inclusion to avoid overlap with our previous systematic review and to ensure that only current guidelines were included. Dataextractionandqualityassessment Titlesandabstractswereassessedby2independentreviewers(MKandVB).Articleswereonly excludedifbothreviewersagreedtheywereineligible.discrepanciesbetweenthereviewerswere resolvedbyconsensusfollowingdiscussion.bothreviewersperformedthefinalselectionforfull dataextraction. Weusedthelatest23nitemAppraisalofGuidelinesforResearchandEvaluation(AGREE)II instrumenttodeterminetherigorofdevelopmentforeachguideline(11).therigorof developmentdomainconsidersthereportingof(1)methodstosearchforevidence,(2)criteriafor selectionofevidence,(3)strengthsandlimitationsofthebodyofevidence,(4)methodsfor formulatingtherecommendations,(5)healthbenefits,sideeffects,andrisks,(6)explicitlink betweenrecommendationsandtheevidence,(7)proceduresforexternalexpertpeerreview,and the(8)updatingprocess.eachitemisratedona7npointlikertscale.conformingtothe instructionsoftheagreeiitool,2reviewers(mkandcv)independentlyratedthe8items.both reviewersassessedbackgroundinformationontheguidelinedevelopmentprocessfrom developers websites.averagerigorscoreswereobtainedbyexpressingthesumoftheindividual scoresasapercentageofthemaximumpossiblescoreandreproducibilityofthe2reviewers scoreswasgood,withaninterclasscorrelationof0.75.werankedtheguidelinesaccordingto theirscores.editorialindependencefromthefundingbody,externalfundinganddisclosureof relationshipswithindustrybyindividualguidelinegroupmemberswerealsoassessed. Datasynthesisandanalysis

10 Onereviewer(MK)extractedalltherelevantrecommendationsfromtheguidelinesthathadan 199 AGREEIIscoreabove50%.Generallifestyleadvicewasnotincluded.Arecommendationmatrix 200 wasproducedgroupedbytheconditionsbeingdetectedbyscreening.eachmatrixwasdivided 201 into(1)amethodssection,(2)targetgroupanddeliveryofscreening,(3)recommendedscreening 202 test,and(4)thresholdsforthefollowup.consistentwithourpreviousformat,thestrengthof 203 recommendationwasclassifiedas for, consider, notfornotagainst, insufficientevidence 204 and against.iffeasiblecardiovascularriskfactorswereclassifiedintomajor,underlyingand 205 emergingriskfactorsaccordingtotheworldheartandstrokeforumscientificstatement(12) Fundingsources 208 TheworkwasprimarilyfundedaspartofaBartsCharitylargeprojectgrant.Thisworkalsoforms 209 partoftheresearchareascontributingtothetranslationalresearchportfolioofthecardiovascular 210 BiomedicalResearchUnitatBarts,whichissupportedandfundedbytheNationalInstitutefor 211 HealthResearch(SEPandMK).TheBartsCharityandtheNationalInstituteforHealthResearch 212 hadnoroleinthedesignofthestudy;thecollection,analysis,interpretationofthedata;orthe 213 decisiontoapprovepublicationofthefinishedmanuscript

11 Results Oursearchretrieved3553titles,ofwhich180wereidentifiedaspotentiallyeligible.Onthebasis 226 oftheabstracts133wereexcludedandonreviewofthefullreportsafurther26wereexcluded. 227 GuidelinessuchastheUnitedStatesPreventativeServiceTaskForce(USPSTF)guidelineson 228 aspirinusewereexcludedastheydidnotincluderecommendationsonthescreeningofhealthy 229 adultpopulation(13).finally21guidelinesoncardiovascularriskassessmentwereincluded 230 (AppendixFigure1).Table1summarizestheselectedguidelines,alongwithrigorscoreand 231 conflictsofinterest ofthe21guidelineshadarigorscoregreaterthanorequalto50%.Guidelineswere 234 categorizedaccordingtothemainpurposeofthescreening.theseincluded5guidelinesontotal 235 cardiovascularscreening(table2),7guidelinesfordysglycemiascreening(appendixtable2),2 236 guidelinesfordyslipidemiascreening(appendixtable3)and3guidelinesforhypertension 237 screening(appendixtable4) Areasofagreement 240 Recommendationsfrom16ofthe17guidelinessupportedCVDriskassessment,eitherasthe 241 primaryapproach(fiveguidelines)orasasecondarystep(elevenguidelines).ingeneraltherewas 242 consensusonhowscreeningtestsshouldbeadministeredinthegeneralpopulation.aselective 243 screeningsystembasedonknowledgeofpriorpatientcharacteristics(recordbasedscreening)or 244 duringnonnpreventivepatientvisits(casefindingoropportunisticscreening)wasadvocatedin ofthe17guidelines.twoguidelinesdidnotexplicitlyspecifyascreeningmethod(centrefor 246 DiseaseControl(CDC)/AmericanHeartAssociation(AHA)andUSPSTFhypertension)

12 Mostguidelinesrecommendedintegratingage,sex,smoking,bloodpressureandlipidlevelsinto CVDriskassessmentbyusingpredictionmodels.Howevertherewasnoconsensusonwhich predictionmodeltouse.allsevendysglycemiaguidelinesrecommendedselectingindividualsat highnriskoftype2diabetesmellitusthroughformalshortnterm(10nyear)orinformaldiabetesrisk algorithmsbasedonantecedentriskfactorsalongwiththeoftenusedthresholdof40years. Diabetesriskalgorithmswerealsousedtodecideonwhetherfurtherformaldiabetesscreening withbloodtestingwasrequired.themostcommonlymentionedriskassessmenttoolfordiabetes wasthefinlanddiabetesriskassessmentquestionnaireoramodifiedversiontailoredtothe countryimplementingit. ThemajorityofguidelinesagreedontheneedtoconsiderethnicityasariskfactorforCVDrisk andcitingspecifichighnriskethnicgroups.theunitedkingdom(nationalinstituteforhealthand ClinicalExcellence(NICE))andtheAmerican(AmericanCollegeofCardiology(ACC)/AHA) guidelinesuseethnicityinglobalcvdriskscoringalgorithms.theunitedkingdomnbasedcvdrisk score(qrisk2)calculatoradvocatedbyniceincludesmultipleethnicgroups.inthedysglycemia guidelinestheunitedkingdom,australianandcanadiandiabetesriskassessmentquestionnaires allincorporateethnicityinthepredictionoftype2diabetesonset Thereisgeneralconsensusonthelimitedroleofnovelbiomarkers(e.g.Creactiveprotein,Apo lipoproteinandprothrombinmarkers)andmarkersofsubclinicalatherosclerosis(e.g.ankle brachialindex(abi),coronaryarterycalciumscoreandcarotidultrasound).theeuropeansociety ofcardiology(esc)andacc/ahaarethetwomainguidelinesthatconsidertheuseofthese markersinlimitedsituations.theacc/ahasuggeststhatinselectedindividualswhoarenotin oneofthefourstatinbenefitgroups,andforwhomadecisiontoinitiatestatintherapyis

13 otherwiseunclear,additionalfactorsmaybeconsideredtoinformtreatmentdecisionnmaking. 273 TheseadditionalfactorsincludehighnsensitivityCnreactiveprotein>2mg/L,coronaryartery 274 calciumscore 300Agatstonunitsor 75percentileforage,sex,andethnicityandanklenbrachial 275 index<0.9.theescstatesthatroutineuseofnovelbiomarkersisnotrecommendedfor 276 refinementofcvdriskstratification.carotidatheromausingultrasound,measurementof 277 coronaryarterycalcificationandtheanklebrachialindexmaybeconsideredasariskmodifierin 278 CVDriskassessmentbutisonlyusefulinindividualsnearthresholdsforriskcategorization Thresholdsforinitiatingtreatmentarepredominantlybasedon5nor10nyearabsoluteriskforCVD 281 orbasedoncombiningageandadditionalcvdriskfactors.therewereoftenexceptionsmadefor 282 thosewithextremelevelsofasingleriskfactororthoseconsideredinahighnriskcategory(kidney 283 disease,diabetesmellitus) Aconservativeapproachtoaspirinuseinprimarypreventionistaken.Ofthe8guidelinesthat 286 makerecommendationsonaspirinuse,3donotrecommendroutineuseinprimaryprevention,3 287 ofthedysglycemiaguidelinesrecommendconsideringaspirintherapybutonlyinthepresenceof 288 additionalfactorsputtingpatientsinahighnriskcategoryandonly2guidelinesbasedthe 289 recommendationofaspirinuseonagealone.thecdc/ahaguideline,whichistheonlyguideline 290 inthisreviewthatisgenderspecific,makesrecommendationsforwomenonly,suggestsaspirin 291 useinwomenover65yearsandthecanadianhypertensioneducationprogramrecommendsits 292 useinhypertensivepatientsover55years,bothwiththecaveatthataspirinuseshouldbeguided 293 byindividualfactors.thelatestuspstfguidelineonaspirinuseinprimaryprevention,incontrast, 294 recommendsaspirinforalladultsaged50to59yearswitha10nyearcardiovasculardiseaseriskof %ormore,whoarenotatincreasedriskofbleeding,havealifeexpectancyofover10years 296 (13). 297

14 Therewasageneralconsensusontheimportanceofaddressinglifestylefactorsinalltarget groupsindependentofpharmacotherapy.recommendationsonwhoshouldreceiveintensive lifestylecounselingdifferedbetweentheguidelineswithnoconsensusbasedonglobalriskscores. Thedysglycemiaguidelinesdo,however,advocatethatallthoseathighriskfordeveloping diabetes(impairedfastingglucoseorimpairedglucosetolerance)shouldreceiveintensivelifestyle interventiontopreventtheonsetofdiabetes. Therewerenofirmstatementsregardingscreeningintervals.However,thetotalCVDrisk guidelinesadvocated5nyearlyscreeninginlowriskindividuals.recommendeddysglycemia screeningintervalsinthosewithoutevidenceofdiabeteswas3n5years.onedyslipidemia guidelinerecommended5nyearlyintervalsforadultslessthan45yearsand1n2yearlyforthose older.forthoseidentifiedashavingimpairedfastingglucoseorimpairedglucosetolerance,there wasageneralconsensusthatsubsequentannualmonitoringbeundertaken. Areasofdisagreement Therewasnoconsensusonthetargetpopulationforscreeningbetweentherecommendations. TheAmericanguidelinesfortotalcardiovascularrisk(ACC/AHA,CDC/AHA),dyslipidemia (AmericanAssociationofClinicalEndocrinologists)anddysglycemia(AmericanDiabetes Association)combinedwiththeCanadiandysglycemia(CanadianTaskForceonPreventiveHealth Care)andhypertension(CanadianHypertensionEducationProgramandCanadianTaskForceon PreventiveHealthCare)guidelinesadvocatescreeningatayoungerage(20years).TheEuropean, UnitedKingdomandAustralianguidelinesadvocateanoldertargetpopulationofover40nyear olds.

15 Althoughguidelinesmostlyagreeontheuseofriskpredictionmodelsaspartoftherisk assessmentprocessoringuidingtherapythereisnoconsensusonwhichmodeltouseparticularly withregardstototalcvdrisk.all5totalcvdriskguidelinesusedifferentriskscoresincludingthe QRISK2(NICE),SystematicCoronaryRiskEstimation(SCORE,ESC),5nyearFramingham(National VascularDiseasePreventionAlliance),PooledCohortEquation(ACC/AHA),10nyearFraminghamor Reynolds(CDC/AHA).Theseriskmodelsdifferedintheendpoints,andtheriskfactorsthey considerintheirdevelopment. Guidelinesontotalcardiovascularriskdifferregardingwhentoinitiatestatintreatment.There wasnoconsensusregardingcvdriskthresholdalthoughdirectcomparisonischallengingasall5 guidelinesuseddifferentriskpredictionmodels.themorerecentamerican(acc/aha)andunited Kingdom(NICE)recommendationsontotalcardiovascularriskhaveloweredtheirthresholdfor initiationofstatins.however,thesetwoupdatedguidelineshavealsochangedthecvdrisk equationsthattheynowutilizewhichmakesdirectcomparisontoolderthresholdsdifficultdueto differentdatasetsorendpointsthatareusedindevelopingthealgorithms.theniceguideline nowadvocatestheuseoftheqrisk2algorithmandtheacc/ahanowadvocatesthepooled CohortEquationpredictinggeneralCVDwhereaspreviouslytheybothusedtheFraminghamrisk score.the2016escguidelinehasmaintainedthesamestatinthresholdsasrecommendedinthe 2012version.Statinrecommendationsweremadein3outofthe7dysglycemiaguidelineswith onlyoneusingageover40nyearsasasoledecidingfactorinthosediagnosedwithdiabetes. Therecommendationsoninitiatingantihypertensivemedicationvariedbetweenguidelineswith noconsensusonwhatglobalriskthresholdorbloodpressureleveltouse.mostoftheguidelines

16 did,however,agreeontheimportanceofconsideringantihypertensivemedicationsindiabetic 346 patientsbutagainvariedonthebloodpressurethresholdusedtoguidethis Therewasnoconsensusontheuseoflifetimeorrelativeriskinyoungadultstoovercomethe 349 problemofusinga5to10nyeartimehorizonforpredictions.theacc/ahaadvocatetheuseof 350 lifetimerisktoguideintensivelifestyleinterventionintheyoung.theescrecommendstheuseof 351 relativeriskchartsforinformingyoungindividualsofriskwhereastheniceguidelinegenerally 352 advisesagainstusinglifetimerisktools Withregardtosubclinicalatherosclerosisscreeningteststherewasnoagreementbetweenthe 355 guidelinesregardingwhichteststouse.only2totalcvdriskguidelines(acc/ahaandesc) 356 suggestedutilizingimagingtests(coronaryarterycalciumscoringandcarotidultrasoundfor 357 atheromadetection)butthiswasonlyinselectindividualstoguidemanagementdecisions.the 358 Australianguideline(NationalVascularDiseasePreventionAlliance)wastheonlytotalCVD 359 guidelinetorecommendassessingleftventricularhypertrophyintheprimaryriskassessment

17 Discussion Weidentified21guidelines,ofwhich17wererigorouslydeveloped,oncardiovascularscreening interventionsthatcouldbeperformedwithinacardiovascularhealthcheckprogram.theaimof thissystematicreviewwasnottoprovideacomprehensiveintegrationoftheguidelinesbutrather asummaryofrigorouslydevelopednationalandinternationalguidelinesavailabletophysiciansin theformofaquickreference,whichallowseasycomparison.therewasageneralconsensuswith regardtoundertakingcvdriskscreeninganduseofpredictionmodelsforriskstratificationand guidingtreatment.theyalsoagreedontheuseofrelativelysimpleriskmarkersincludingage, gender,ethnicityandsmokinghistory.novelbiomarkersormarkersofsubclinicalatherosclerosis aregenerallynotrecommendedexceptinveryselectsubgroupofindividuals.aconservative approachtoaspirininitiationinprimarypreventionwasadvocatedandtherewasageneral agreementonintervalsforrepeatscreening.guidelinesdifferwithrespecttoselectionofthe idealtargetpopulation,whichriskpredictionmodeltouseandwhichthresholdstoutilizeto initiatestatinorantihypertensivetreatment. Weperformedabroadsearchutilizingmajormedicalpublicationrepositories,guidelinelibrary websitesandmanuallysearchingindividualguidelinedevelopmentgroupwebsites.incontrastto ourpreviouspaper,thisreviewonlysummarizesrecommendationsfromguidelines.otherreports suchaspositionandscientificstatementsarenotintheremitoftheagreeiiinstrument,and wereexcluded.alltheguidelinesincludedinthisreviewwerepublishedinthelast7yearsand representthemostrecentrecommendations.noneofthecurrent21guidelineswereincludedin ourpreviousreview.

18 Guidelinesgenerallyrecommendthatdecisionsonmanagementbebasedonglobalcardiovascular 395 riskthatconsidersmultipleriskfactors.however,theydifferregardsriskthresholdstoutilize.this 396 ispartlybecausetheriskmodelsadvocatedintheguidelinesvaryovertheuseofdatasets, 397 predictorsusedandtheirendpoints.thescoremodel(esc)usesonlyhardendpointsofcvd 398 mortalitywhereastheframingham(cdc/aha,nationalvasculardiseasepreventionalliance) 399 utilizesthebroadestendpointsconsistingofcoronarydeath,myocardialinfarction,coronary 400 insufficiency,angina,ischemicstroke,hemorrhagicstroke,transientischemicattack,peripheral 401 arterydisease,andheartfailure.furthermore,theriskthresholdforinitiatingastatinusedbythe 402 ACC/AHAof7.5%isbasedonthenewerPooledCohortEquationwhichusesthe10nyearnonnfatal 403 myocardialinfarction,coronaryheartdiseasedeath,orstrokeendpoints(18).thisvariabilitycan 404 leadtodifferentgroupsreceivingtreatment,makescomparisonbetweendifferenthealthcare 405 systemschallengingandcouldalsoleadtoinequalityofhealthcare.theaha/accguidelinesfor 406 example,wouldrecommendstatinsfornearlyallmenandtwonthirdsofwomenovertheageof nyears,exceedingtheproportionsthatwouldbeeligiblebasedonotherguidelinessuchasthe 408 ESC,whentestedinaEuropeancohort(38).Standardizationofvariousriskscoringsystems,with 409 validationandcalibration,mayhelpimproveclinicaloutcomesinindividualsatriskofdeveloping 410 CVD(39).Riskscoringsystemswouldneedtobedeveloped/updatedfordifferentcountriesdueto 411 country/regionspecificdifferencesineventratesandmortality Therearemanychallengesfacedbyprogramsthatattempttoprovidepopulationnbased 414 interventionsthatdeterminetheoverallimpactachieved.thediversityinguidelinesoncvdmay 415 partlyreflecttheuncertaintyonbenefitofscreening.althoughthereisevidencetosupportthe 416 effectivenessofparticularinterventionstoappropriateindividualsthedifficultiesinscreening 417 programsincludetheachievementofhighenoughuptakeratestoinvitations,theabilitytodeliver 418 effectiveinterventionsandpatientadherencetorecommendations. 419

19 Mostguidelinesrecommendedaselectivescreeningstrategywithsomenewerguidelines advocatingalowerthresholdforinitiatingtreatmentsuchasstatintherapy,citingrecentmetan analysisandthereducedcostsofstatinsduetopatentexpiry,asthemainreasonsforthisshift(9). Thresholdsutilizedfordecidinghighriskareoftenarbitraryandatbestdecidedonby mathematicalmodeling.studiesthatshowmodestbenefithavemainlybeenbasedon improvementsinsurrogatemarkersratherthancvdevents,withinherentlimitations(40) AMEDLINEsearchidentifiedfourprevioussystematicreviewsrelevanttoourstudy,published betweenjanuary1,2009andjune30,2016(seeappendixforsearchstrategy).twowerefromour groupincludingtheprevious(nowoutdated)versionofthisreviewandanotherfocusedon guidelinesofscreeningforperipheralvasculardiseaseonly(8,41).theremainingtwopublications werelimitedtoguidelinesonprimarycvdpreventionintheelderly(searchesuptodecember 2013)(42)orthediagnosis,assessmentandmanagementofhypertension(searchesupto September2011). Thissystematicreviewrepresentscontemporaryguidelineswithabroadinclusionofconditions eligibleforcardiovascularriskassessmentinapparentlyhealthyadultsalongwithanassessment oftheguidelinesrigorofdevelopment.comparedtoourpreviouspublicationfrom6yearsago, thetargetpopulations,riskpredictionmodelsanditsconsequencesarestillareasofdisagreement acrossguidelines(8).overthelast6yearstherehasbeenatrendtowardsadvocatingalower thresholdforinitiatingintensivelifestylemodificationandstatintherapy.riskpredictionmodels havebeenupdatedwithamoveawayfromtheframinghamriskscore,whichpreviously predominated.thereisamoreconservativeapproachtoaspirin,withmostguidelinesgenerally advocatingagainstitsuseinprimaryprevention.theuseoftestsforassessmentofsubclinical

20 atherosclerosishasbeenfurtherrestricted Theoptimalstrategyforsystematicscreeningfortheapparentlyhealthyremainstobeanswered. Someadvocatecontinuingwiththecurrentstrategyofscreeningwiththeaimoftryingtomoldit intoasystemthateventuallyshowsbenefitwhereasothersareaskingfortheprogramstobe halteduntilsuchatimethattheevidenceofbenefitjustifiestheresourcesinvestedinscreening (43,44).Recentpublicationsaddressingsomeofthesegapsandfutureresearchinidentifyingthe mosteffectivestrategieswillhelpshapefutureguidelinerecommendations(45n47) Therearesomelimitationsthatcouldbiasourfindingsandlimitgeneralizability.Onlyguidelines developedbywesternnationalorinternationalmedicalorganizationswerereviewed.we controlledforselectionbiasbyhavingacomprehensivesearchstrategy,aspreviouslygenerated withalibrarianandthearticleswereselectedandappraisedbytwoindependentresearchers. However,researcherswerenotblindedtotheorganizationnamesorcountriesoforigin.Finally, weconsideredtheguidelinedevelopmentprocessbutdidnotassesstheclinicalvalidityofthe recommendationorreviewrecommendationsforspecificlifestyleinterventionsasitwasbeyond thescopeofthisreview

21 Conclusion Considerablediscrepanciesinrecommendationsstillexistincardiovascularscreeningguidelines 469 withnoconsensusonoptimumscreeningstrategiesortreatmentthreshold.physiciansshould 470 assessthestrengthoftherecommendationsandthelevelofevidencetodecidewhichofthe 471 discrepantrecommendationstheymayimplement Endofmanuscripttext

22 Acknowledgements ProfessorHuninkreceivesroyaltiesforthetextbook:DecisionMakinginHealthandMedicine: IntegratingevidenceandvaluesnMyriamHuninkwithCambridgeUniversityPress.Theother authorshavenopotentialconflictsofinteresttodeclare. GrantSupport LargeprojectgrantfromtheBartsCharityfortheHeartAttackPreventionProgramForYou (HAPPY)LondonStudyGrantreferencenumber437/1412. Addressforreprintrequest M.G.MyriamHunink,MD,PhD RoomNa2818 ErasmusMC POBox2040,3000CA,Rotterdam,TheNetherlands Tel: /Fax: addressesforauthors MohammedY.Khanji,MBBCh; ViníciusV.S.Bicalho,MD; ClaudiaN.vanWaardhuizen,MSc; BartS.Ferket,PhD; SteffenE.Petersen,DPHIL; M.G.MyriamHunink,PhD (correspondingauthor)

23 ReproducibleResearchStatement 517 StudyProtocol:Notavailable 518 StatisticalCode:Notapplicable 519 DataSet:Seetablesandappendices.Otherinformation(e.g.listofexcludedarticlesavailableon 520 requestfromauthors)

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29 Table 1. Characteristics of 21 Guidelines Guideline by Medical Condition, year Organization Responsible for Guideline Development Total Cardiovascular risk Country Applied AGREE2 Rigor score, % Conflicts of Interest NICE (14), 2014 National Institute for Health and Clinical UK 86 EI,SCI* Excellence ESC (15), 2012 European Society of Cardiology Europe 86 SCI * NVDPA (16), 2012 National Vascular Disease Prevention Alliance Australia 85 EI,SCI ACC/AHA (17-19), American College of Cardiology United States 83 SCI * 2013 CDC (20), 2011 Centres for Disease Control and Prevention United States 65 EI,SCI * BCS (21), 2014 British Cardiovascular Society UK 45 SCI * NZGG (22), 2012 New Zealand Guidelines Group New Zealand 20 EI,SCI Dyslipidemia ESC (23), 2011 European Society of Cardiology Europe 72 SCI * ACCE (24), 2012 American Association of Clinical United States 64 SCI * Endocrinologists CCS (25), 2013 Canadian Cardiovascular society Canada 42 EI,SCI * Dysglycemia ADS/DAGDC (26), 2009 Australian Diabetes Society Australia 87 SCI CDA (27), 2013 Canadian Diabetes Association Canada 83 EI,FIP,SCI * ADA (28), 2014 American Diabetes Association United States 68 SCI * USPSTF (29), 2015 U.S. Preventative Services Task Force United States 76 EI, SCI NICE (30), 2012 National Institute for Health and Clinical UK 73 Excellence CTFPHC (31), 2012 Canadian Task Force on Preventive Health Canada 68 EI,SCI * Care ESC (32), 2013 European Society of Cardiology Europe 66 SCI * IDF (33), 2012 International Diabetes Federation International 47 FIP, SCI Hypertension CHS (34,35), 2015 Canadian Hypertension Society Canada 90 EI,SCI * USPSTF (36),2015 U.S. Preventative Services Task Force United States 79 EI, SCI CTFPHC (37), 2013 Canadian Task Force on Preventive Health Care Abbreviations: AGREE2, Appraisal of Guidelines Research and Evaluation II; EI, editorial; independence declared; FIP, funding by industrial partner reported; SCI, statement about conflicts of interest of group members present; UK, United Kingdom *Relationship with industry is reported by any group member; A group member is reported recused when a relevant area is under discussion; Conflicts of interest only available on request; Conflicts of interest only reported to the group Canada 78 SCI

30 Table 2. Recommendations for Screening in Total CVD Risk in 5 Guidelines ESC NICE NVDPA ACC/ AHA CDC/ AHA Country Europe UK Australia USA USA Year AGREE 2 Score 86% 86% 85% 83% 65% Method to evaluate Systematic review Systematic Systematic Systematic Systematic evidence Methods to formulate recommendations Consideration of costs Formal consensus Review of CEA studies Target Group Men > 40 y, Women >50 y or post menopausal Strategy Strength of recommendation Major risk factors prediction model Opportunistic screening/ case finding review Formal consensus Systematic review of published literature/ Performed CEA Aged (NHS Health Check) Opportunistic screening/ case finding/ record based review Formal consensus Review of CEA studies All adults aged >45 y or Aboriginal Torres Strait Islanders >35y Opportunistic screening/ case finding review Formal consensus Not performed Aged 21 and above Opportunistic screening/ case finding review Formal consensus and voting Review of CEA studies Women 20 y For For For For Not for and not against SCORE, general QRISK2, Framingham, ASCVD mortality CHD/stroke/TIA CHD/stroke at 10 y events at 10 y events at 5 y Pooled Cohort Equations, CHD/stroke events at 10 y if age y or lifetime (30 y) risk for y with 10 y risk 7.5% Age Sex Blood pressure TC level LDL-C level HDL-C level TC:HDL-C ratio Smoking Glucose levels 2 2 Underlying risk factors Overweight/obesity Physical inactivity Atherogenic diet Socioeconomic factors Family history of premature CVD Genetic/racial factors Diabetes Antihypertensives Emerging risk factors TG levels Renal function NR Framingham/ Reynolds Risk Score, CHD/stroke at 10 y

31 Table 2. Recommendations for Screening in Total CVD Risk in 5 Guidelines (continued). ESC NICE NVDPA ACC/ AHA CDC/ AHA Heart rate 2 Apo/lipoprotein levels 4 Glucose therapy for insulin resistance Prothrombotic markers 4 C-reactive protein level 4 3 Subclinical atherosclerosis 1 (LVH) 3 (ABI, CAC score) Thresholds Aspirin Statins Antihypertensives Intensive Lifestyle Counseling 4 (ABI, CAC score, carotid US for plaque) Not recommended in primary prevention 10 y CVD mortality 10% and LDL-C level 70 mg/dl; 10 y risk 5%-10% and LDL-C level 100 mg/dl; consider if 10 y risk <5% and LCL-C >115mg/dL; DM2 or DM1 and age >40 y 10 y CVD mortality 10% and BP 140/90 mmhg; consider if 10 y risk 5-10% and BP 140/90 mmhg; DM1 or DM2 and BP 140/85 mmhg; over 60 y and systolic BP >150mmHg or more than 80 y and systolic BP >160mmHg; BP 180/110 mmhg 10 y CVD mortality >1% or LDL-C >100mg/dL Not applicable 10 y CHD/stroke/TIA risk 10%; DM2 and 10 y CVD risk 10% (according to UKPDS tool); DM1; CKD with egfr <60 Not recommended in primary prevention 5 y CHD/stroke risk 15%; persistent BP 160/100 mmhg; TC >7.5mmol/L; 5 y CHD/stroke risk 10%-15% and family history of premature CVD NR 5 y FRS 15%; FRS 10-15% and BP persistently 160/100/ FHx CVD, high risk ethnicity; consider if FRS <10% but BP persistently 160/100 mmhg 10 y CHD/stroke/TIA risk 10% 5 y CHD/stroke risk 10%. Not applicable y with 10 y CHD/stroke risk 7.5% and LDL-C mg/dl; y with DM and LDL-C mg/dL; LDL-C level 190 mg/dl Useful in women 65 depending on risk benefit; reasonable in DM 10 y risk >20%; DM NR BP 140/90 mmhg; >130/85 in CKD and DM 10 y CHD/ stroke risk 7.5% and LDL-C mg/dl; DM1 or DM2; LDL-C level 190 mg/dl NR

32 Table 2. Recommendations for Screening in Total CVD Risk in 5 Guidelines (continued). ESC NICE NVDPA ACC/ AHA CDC/ AHA High-risk Monitoring NR NR Monitor risk NR NR profile according to clinical context if 5 y CHD/stroke risk 15%. Monitor risk profile every 6-12 months if 5 y CHD/stroke risk 10-15% Screening Intervals NR Further risk assessment on an on going basis. 5 yearly as per NSF Further risk assessment every 2 y if 5 y CHD/stroke risk <10% Further risk assessment every 4-6 y if 10 y CHD/stroke risk <7.5% NR Abbreviations: ABI, ankle brachial index; ASCVD, atherosclerotic cardiovascular disease; CEA, costeffectiveness analysis; CAC, coronary artery calcium; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cardiovascular disease; DM - diabetes mellitus; FHx, family history; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LVH, left ventricular hypertrophy; NHS, National Health Service; NR, not reported; NSF, National Service Framework; SCORE, Systematic Coronary Risk Evaluation; TC, total cholesterol; TG, triglyceride; TIA, transient ischemic attack; UK, United Kingdom; US, ultrasound; y, years; 1, Formal screening test (included in the prediction model); 2, Additional screening test 3, In selected individuals who are not in 1 of the 4 main statin benefit groups, and for who a decision to initiate statin therapy is otherwise unclear, additional factors may be considered to inform treatment decision-making. These factors include; 1. Primary LDL C 160 mg/dl or other evidence of genetic hyperlipidemias, 2. First degree relative with premature ASCVD, 3. Highsensitivity C-reactive protein >2 mg/l, 4. CAC score 300 Agatston units or 75 percentile for age, sex, and ethnicity, 5. Ankle-brachial index <0.9, or 6. Elevated lifetime risk of ASCVD. 4, Novel biomarkers have only limited additional value when added to CVD risk assessment with the SCORE algorithm in come limited cases.

33 Appendix Table 1: Website searches of guideline development organizations, including websites affiliated with all the guidelines included in our previous publication Organization Responsible for Country Website Searched Guideline Development American Academy of Family United States Physicians (AAFP) American Association of Clinical United States Endocrinologists American College of Cardiology United States American College of Physicians United States American College for United States Preventive Medicine American Diabetes Association United States (ADA) American Geriatrics Society United States (AGS) American Heart Association United States (AHA) American Medical Association United States (AMA) American Stroke Association United States Australian Diabetes Society Australia (ADS) Australian Medical Association Australia (AMA) British Cardiac Society (BCS) United Kingdom British Hypertension Society United Kingdom (BHS) Canadian Diabetes Association Canada Canadian Hypertension Society Canada (CHS) Canadian Task Force on Canada Preventive Health Care (CTFPHC) Cardiac Society of Australia and Australia New Zealand (CSANZ) Centers for Disease Control and United States Prevention (CDC)/ AHA Department of Health (DOH) United Kingdom European Society of Cardiology Europe International Diabetes International Federation (IDF) International Society of International Hypertension National Health and Medical Australia Research Council (NHMRC) National Heart Foundation Australia National Heart Lung and Blood United States Institute National Institute for Health United Kingdom and Clinical Excellence (NICE) New Zealand Guidelines Group New Zealand Royal College of General Practitioners (RCGP) United Kingdom