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 http://annals.org/aim/article/2552073/cardiovascular-risk-assessment-systematic-reviewguidelines For additional information about this publication click this link. http://qmro.qmul.ac.uk/xmlui/handle/123456789/15064 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
1 TitlePage 2 3 4 5 6 7 8 9 10 11 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 12 13 M.G.MyriamHunink,PhD (correspondingauthor) E:m.hunink@erasmusmc.nl 14 15 16 17 18 19 20 21 22 23 24 *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.
Abstractwordcount:274words 25 Manuscripttextwordcount:3716words 26 27 Correspondingauthor: 28 M.G.MyriamHunink,MD,PhD 29 RoomNa2818 30 ErasmusMC 31 POBox2040,3000CA,Rotterdam,TheNetherlands 32 Tel:0031107043489/Fax:0031107044657 33 Email:m.hunink@erasmusmc.nl 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
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
management.thereisnoconsensusonthestrategyforscreening,recommendedtarget 75 population,screeningtestsortreatmentthresholds. 76 Limitations: 77 OnlyguidelinesdevelopedbyWesternnationalorinternationalmedicalorganizationsare 78 included. 79 Conclusion: 80 Considerablediscrepanciesinrecommendationsstillexistincardiovascularscreeningguidelines 81 withnoconsensusonoptimumscreeningstrategiesortreatmentthreshold. 82 83 Primaryfundingsource: 84 AspartofaBartsCharitylargeprojectgrant.Thecharityhadnoinputinthepreparationorediting 85 ofthemanuscript. 86 87 88 89 90 91 92 93 94 95 96 97 98 99
100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 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).
Ferketetalperformedasystematicreviewin2010,identifyingdifferencesamongstguidelines 124 thatwouldleadtovariationsinallocationofresourcesforpreventionbetweendifferentwestern 125 healthcaresystems(8).sincethattime,thereviewedguidelineswererevisedandreplacedand 126 newevidencehasalsobecomeavailableonstatinandbloodpressureloweringtherapyinlowrisk 127 individuals(9,10).thissystematicreviewrevisitsthecvdriskassessmentguidelinesandthe 128 selectionofappropriatescreeninginterventionsbasedoncurrentlyavailableevidence. 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148
149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 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 (www.gninn.net).wealsocarriedoutasearchofanumberofwebsitesofguidelinesdevelopment 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
174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 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
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). 206 207 Fundingsources 208 TheworkwasprimarilyfundedaspartofaBartsCharitylargeprojectgrant.Thisworkalsoforms 209 partoftheresearchareascontributingtothetranslationalresearchportfolioofthecardiovascular 210 BiomedicalResearchUnitatBarts,whichissupportedandfundedbytheNationalInstitutefor 211 HealthResearch(SEPandMK).TheBartsCharityandtheNationalInstituteforHealthResearch 212 hadnoroleinthedesignofthestudy;thecollection,analysis,interpretationofthedata;orthe 213 decisiontoapprovepublicationofthefinishedmanuscript. 214 215 216 217 218 219 220 221 222 223
Results 224 225 Oursearchretrieved3553titles,ofwhich180wereidentifiedaspotentiallyeligible.Onthebasis 226 oftheabstracts133wereexcludedandonreviewofthefullreportsafurther26wereexcluded. 227 GuidelinessuchastheUnitedStatesPreventativeServiceTaskForce(USPSTF)guidelineson 228 aspirinusewereexcludedastheydidnotincluderecommendationsonthescreeningofhealthy 229 adultpopulation(13).finally21guidelinesoncardiovascularriskassessmentwereincluded 230 (AppendixFigure1).Table1summarizestheselectedguidelines,alongwithrigorscoreand 231 conflictsofinterest 232 233 17ofthe21guidelineshadarigorscoregreaterthanorequalto50%.Guidelineswere 234 categorizedaccordingtothemainpurposeofthescreening.theseincluded5guidelinesontotal 235 cardiovascularscreening(table2),7guidelinesfordysglycemiascreening(appendixtable2),2 236 guidelinesfordyslipidemiascreening(appendixtable3)and3guidelinesforhypertension 237 screening(appendixtable4). 238 239 Areasofagreement 240 Recommendationsfrom16ofthe17guidelinessupportedCVDriskassessment,eitherasthe 241 primaryapproach(fiveguidelines)orasasecondarystep(elevenguidelines).ingeneraltherewas 242 consensusonhowscreeningtestsshouldbeadministeredinthegeneralpopulation.aselective 243 screeningsystembasedonknowledgeofpriorpatientcharacteristics(recordbasedscreening)or 244 duringnonnpreventivepatientvisits(casefindingoropportunisticscreening)wasadvocatedin14 245 ofthe17guidelines.twoguidelinesdidnotexplicitlyspecifyascreeningmethod(centrefor 246 DiseaseControl(CDC)/AmericanHeartAssociation(AHA)andUSPSTFhypertension). 247 248
249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 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. 266 267 268 269 270 271 272 Thereisgeneralconsensusonthelimitedroleofnovelbiomarkers(e.g.Creactiveprotein,Apo lipoproteinandprothrombinmarkers)andmarkersofsubclinicalatherosclerosis(e.g.ankle brachialindex(abi),coronaryarterycalciumscoreandcarotidultrasound).theeuropeansociety ofcardiology(esc)andacc/ahaarethetwomainguidelinesthatconsidertheuseofthese markersinlimitedsituations.theacc/ahasuggeststhatinselectedindividualswhoarenotin oneofthefourstatinbenefitgroups,andforwhomadecisiontoinitiatestatintherapyis
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. 279 280 Thresholdsforinitiatingtreatmentarepredominantlybasedon5nor10nyearabsoluteriskforCVD 281 orbasedoncombiningageandadditionalcvdriskfactors.therewereoftenexceptionsmadefor 282 thosewithextremelevelsofasingleriskfactororthoseconsideredinahighnriskcategory(kidney 283 disease,diabetesmellitus). 284 285 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 295 10%ormore,whoarenotatincreasedriskofbleeding,havealifeexpectancyofover10years 296 (13). 297
298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 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.
322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 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
did,however,agreeontheimportanceofconsideringantihypertensivemedicationsindiabetic 346 patientsbutagainvariedonthebloodpressurethresholdusedtoguidethis. 347 348 Therewasnoconsensusontheuseoflifetimeorrelativeriskinyoungadultstoovercomethe 349 problemofusinga5to10nyeartimehorizonforpredictions.theacc/ahaadvocatetheuseof 350 lifetimerisktoguideintensivelifestyleinterventionintheyoung.theescrecommendstheuseof 351 relativeriskchartsforinformingyoungindividualsofriskwhereastheniceguidelinegenerally 352 advisesagainstusinglifetimerisktools. 353 354 Withregardtosubclinicalatherosclerosisscreeningteststherewasnoagreementbetweenthe 355 guidelinesregardingwhichteststouse.only2totalcvdriskguidelines(acc/ahaandesc) 356 suggestedutilizingimagingtests(coronaryarterycalciumscoringandcarotidultrasoundfor 357 atheromadetection)butthiswasonlyinselectindividualstoguidemanagementdecisions.the 358 Australianguideline(NationalVascularDiseasePreventionAlliance)wastheonlytotalCVD 359 guidelinetorecommendassessingleftventricularhypertrophyintheprimaryriskassessment. 360 361 362 363 364 365 366 367 368 369 370
371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 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.
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 407 55nyears,exceedingtheproportionsthatwouldbeeligiblebasedonotherguidelinessuchasthe 408 ESC,whentestedinaEuropeancohort(38).Standardizationofvariousriskscoringsystems,with 409 validationandcalibration,mayhelpimproveclinicaloutcomesinindividualsatriskofdeveloping 410 CVD(39).Riskscoringsystemswouldneedtobedeveloped/updatedfordifferentcountriesdueto 411 country/regionspecificdifferencesineventratesandmortality. 412 413 Therearemanychallengesfacedbyprogramsthatattempttoprovidepopulationnbased 414 interventionsthatdeterminetheoverallimpactachieved.thediversityinguidelinesoncvdmay 415 partlyreflecttheuncertaintyonbenefitofscreening.althoughthereisevidencetosupportthe 416 effectivenessofparticularinterventionstoappropriateindividualsthedifficultiesinscreening 417 programsincludetheachievementofhighenoughuptakeratestoinvitations,theabilitytodeliver 418 effectiveinterventionsandpatientadherencetorecommendations. 419
420 421 422 423 424 425 Mostguidelinesrecommendedaselectivescreeningstrategywithsomenewerguidelines advocatingalowerthresholdforinitiatingtreatmentsuchasstatintherapy,citingrecentmetan analysisandthereducedcostsofstatinsduetopatentexpiry,asthemainreasonsforthisshift(9). Thresholdsutilizedfordecidinghighriskareoftenarbitraryandatbestdecidedonby mathematicalmodeling.studiesthatshowmodestbenefithavemainlybeenbasedon improvementsinsurrogatemarkersratherthancvdevents,withinherentlimitations(40). 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 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
444 445 atherosclerosishasbeenfurtherrestricted. 446 447 448 449 450 451 Theoptimalstrategyforsystematicscreeningfortheapparentlyhealthyremainstobeanswered. Someadvocatecontinuingwiththecurrentstrategyofscreeningwiththeaimoftryingtomoldit intoasystemthateventuallyshowsbenefitwhereasothersareaskingfortheprogramstobe halteduntilsuchatimethattheevidenceofbenefitjustifiestheresourcesinvestedinscreening (43,44).Recentpublicationsaddressingsomeofthesegapsandfutureresearchinidentifyingthe mosteffectivestrategieswillhelpshapefutureguidelinerecommendations(45n47). 452 453 454 455 456 457 458 459 460 Therearesomelimitationsthatcouldbiasourfindingsandlimitgeneralizability.Onlyguidelines developedbywesternnationalorinternationalmedicalorganizationswerereviewed.we controlledforselectionbiasbyhavingacomprehensivesearchstrategy,aspreviouslygenerated withalibrarianandthearticleswereselectedandappraisedbytwoindependentresearchers. However,researcherswerenotblindedtotheorganizationnamesorcountriesoforigin.Finally, weconsideredtheguidelinedevelopmentprocessbutdidnotassesstheclinicalvalidityofthe recommendationorreviewrecommendationsforspecificlifestyleinterventionsasitwasbeyond thescopeofthisreview. 461 462 463 464 465 466
Conclusion 467 468 Considerablediscrepanciesinrecommendationsstillexistincardiovascularscreeningguidelines 469 withnoconsensusonoptimumscreeningstrategiesortreatmentthreshold.physiciansshould 470 assessthestrengthoftherecommendationsandthelevelofevidencetodecidewhichofthe 471 discrepantrecommendationstheymayimplement. 472 473 Endofmanuscripttext 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491
492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 Acknowledgements ProfessorHuninkreceivesroyaltiesforthetextbook:DecisionMakinginHealthandMedicine: IntegratingevidenceandvaluesnMyriamHuninkwithCambridgeUniversityPress.Theother authorshavenopotentialconflictsofinteresttodeclare. GrantSupport LargeprojectgrantfromtheBartsCharityfortheHeartAttackPreventionProgramForYou (HAPPY)LondonStudyGrantreferencenumber437/1412. Addressforreprintrequest M.G.MyriamHunink,MD,PhD RoomNa2818 ErasmusMC POBox2040,3000CA,Rotterdam,TheNetherlands Tel:0031107043489/Fax:0031107044657 Email:m.hunink@erasmusmc.nl Emailaddressesforauthors 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 515 516 M.G.MyriamHunink,PhD (correspondingauthor) E:m.hunink@erasmusmc.nl
ReproducibleResearchStatement 517 StudyProtocol:Notavailable 518 StatisticalCode:Notapplicable 519 DataSet:Seetablesandappendices.Otherinformation(e.g.listofexcludedarticlesavailableon 520 requestfromauthors) 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546
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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
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 2016 2014 2012 2013 2011 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 40-74 (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 40-79 y or lifetime (30 y) risk for 20-59 y with 10 y risk 7.5% Age 1 1 1 1 1 Sex 1 1 1 1 1 Blood pressure 1 1 1 1 1 TC level 1 1 1 1 1 LDL-C level 2 2 2 HDL-C level 1 1 1 1 1 TC:HDL-C ratio 1 1 1 1 Smoking 1 1 1 1 1 Glucose levels 2 2 Underlying risk factors Overweight/obesity 2 1 2 1 Physical inactivity 2 2 1 Atherogenic diet Socioeconomic factors 2 1 2 Family history of 2 1 2 3 1 premature CVD Genetic/racial factors 2 1 2 1 1 Diabetes 2 1 1 1 1 Antihypertensives 2 1 1 Emerging risk factors TG levels 2 2 2 Renal function 2 1 2 1 NR Framingham/ Reynolds Risk Score, CHD/stroke at 10 y
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 40-75 y with 10 y CHD/stroke risk 7.5% and LDL-C 70-189 mg/dl; 40-75 y with DM and LDL-C 70-189mg/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 70-189 mg/dl; DM1 or DM2; LDL-C level 190 mg/dl NR
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.
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 http://www.aafp.org/online/en/home.html Physicians (AAFP) American Association of Clinical United States www.aace.com Endocrinologists American College of Cardiology United States http://www.acc.org/ American College of Physicians United States http://www.acponline.org/ American College for United States http://www.acpm.org/ Preventive Medicine American Diabetes Association United States http://www.diabetes.org/ (ADA) American Geriatrics Society United States http://www.americangeriatrics.org/ (AGS) American Heart Association United States http://www.americanheart.org/ (AHA) American Medical Association United States http://www.ama-assn.org/ (AMA) American Stroke Association United States http://www.strokeassociation.org/ Australian Diabetes Society Australia https://www.diabetessociety.com.au/ (ADS) Australian Medical Association Australia http://www.ama.com.au/web.nsf/ (AMA) British Cardiac Society (BCS) United Kingdom http://www.bcs.com/pages/default.asp British Hypertension Society United Kingdom http://www.bhsoc.org/default.stm (BHS) Canadian Diabetes Association Canada http://guidelines.diabetes.ca/ Canadian Hypertension Society Canada http://www.hypertension.ca/ (CHS) Canadian Task Force on Canada http://canadiantaskforce.ca/ Preventive Health Care (CTFPHC) Cardiac Society of Australia and Australia http://www.csanz.edu.au/ New Zealand (CSANZ) Centers for Disease Control and United States http://www.cdc.gov/ Prevention (CDC)/ AHA Department of Health (DOH) United Kingdom http://www.dh.gov.uk/en/index.htm European Society of Cardiology Europe http://www.escardio.org/ International Diabetes International http://www.idf.org/ Federation (IDF) International Society of International http://www.ish-world.com/ Hypertension National Health and Medical Australia http://www.nhmrc.gov.au/index.htm Research Council (NHMRC) National Heart Foundation Australia http://www.heartfoundation.org.au/index.htm National Heart Lung and Blood United States http://www.nhlbi.nih.gov/guidelines/index.htm Institute National Institute for Health United Kingdom http://www.nice.org.uk/ and Clinical Excellence (NICE) New Zealand Guidelines Group New Zealand http://www.nzgg.org.nz/index.cfm? Royal College of General Practitioners (RCGP) United Kingdom http://www.rcgp.org.uk/default.aspx