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7:StableIschemicHeartDisease

Overview
Thischapterreviewstheevaluationandmanagementofstableischemicheartdisease.Riskstratificationandapplicationof guidelinedirectedmedicaltherapyareemphasizedbeforeconsiderationoftheindicationsforrevascularization.Thechoice betweenPCIandCABGsurgeryisreviewedinlightoftheSYNTAXtrial.Thereisadditionalreviewofthepathophysiologyand assessmentofmyocardialviabilityanditsroleindecisionmaking,asrecentlyreportedintheSTICHtrial.Theasymptomatic patientandtheapproachtomicrovascularanginaarealsoaddressed.

Authors
PatrickT.O'Gara,MD,FACC EditorinChief ThomasM.Bashore,MD,FACC AssociateEditor JamesC.Fang,MD,FACC AssociateEditor GlennA.Hirsch,MD,MHS,FACC AssociateEditor JuliaH.Indik,MD,PhD,FACC AssociateEditor DonnaM.Polk,MD,MPH,FACC AssociateEditor SunilV.Rao,MD,FACC AssociateEditor

7.1:RiskStratification
Author(s): BenjaminM.Scirica,MD,MPH,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Recognizetheimportanceofriskstratificationinpatientswithstableischemicheartdisease(SIHD). 2. Appropriatelychooseandprioritizethevariousriskstratificationmodalitiesinordertoefficientlyandcosteffectively manageapatientwithSIHD. 3. IntegratetheresultsofmultipleclinicaltestswhenriskstratifyingapatientwithSIHD. 4. Recognizetheappropriate,andinappropriate,useofdifferentriskstratificationtechniques.

Introduction
ThediagnosisofSIHD,alsotermedchroniccoronaryarterydisease(CAD),encompassesaheterogeneouspopulation thatvariesintermsofcomorbidities,symptoms,andriskoffuturecardiovascular(CV)events.SIHDincludesany conditionthatresultsinachronicorrepetitivemismatchbetweenmyocardialoxygensupplyanddemand.Typically,SIHD isduetoatheroscleroticobstructionoftheepicardialcoronaryarterieshowever,itmayalsoarisefrommicrovascular diseaseandvasospasm,ormorerarely,congenitalanomaliesornonatheroscleroticvascularinjury.Angina,orischemic chestdiscomfort,istheclassicsymptomofSIHDhowever,patientsmaypresentwithdyspnea,heartfailure,or arrhythmiasastheironlysymptomaticmanifestation.Moreover,manypatientswithSIHDarefreeofsymptoms,eitherat thetimeofdiagnosisofSIHD,oraftersuccessfulmedicaltherapyorrevascularization. DuetothediversenatureofSIHDanddifferencesindefinitions,estimatesvaryregardingtheactualnumberofaffected people.However,itisestimatedthat16.3millionpeopleintheUnitedStatesalonehaveCAD,withapproximately9 millionreportingsymptomaticchestpainand8millionreportingapriormyocardialinfarction(MI).1 Theprevalenceof SIHDisincreasingworldwideastheburdenofriskfactorssmoking,obesity,diabetes,andhypertensionincreasesin thelargepopulationsofdevelopingnations. Giventhevariabilityinthispatientpopulation,theevaluationofpatientswithknownorsuspectedSIHDmustincorporate informationfrommultipleclinicalmodalitiestoriskstratifyeffectively,andthereby,deliverappropriateandtimelytherapy. Ingeneral,thegoalistoidentifypatientsatthehighestriskwhowillbenefitfromthemostintensetherapy,while reassuringandsparinginvasiveproceduresinpatientsatalowerrisk.Manyofthetestsortechniquesreviewedinthis chapterarealsocentraltotheinitialdiagnosisofSIHD.Thismodulewillreviewcurrentmethodstoimproverisk stratificationamongpatientswithdocumentedSIHD.DiagnosisofSIHDandtheriskstratificationofasymptomatic patientsandofpatientswithacutecoronarysyndromesarecoveredinthemoduleonAsymptomaticCADinthischapter, PatientAssessmentinChapter3,andinthemoduleonInitialManagement,RiskAssessment,andRiskStratificationof ACSinChapter6,respectively.

SpectrumofRiskforFutureCardiovascularDiseaseinPatients WithStableIschemicHeartDisease
Inprimaryprevention(patientswithoutSIHD),riskstratificationistypicallybasedon a10yearriskofMIorcoronaryheartdiseasedeath,wherea10yearriskis consideredlowat<10%(or<1%peryear),intermediateat1020%,andhighat >20%.Unfortunately,therearenosimilarlyacceptedandvalidatedrisk categorizationsforpatientswithSIHD,duelargelytothefactthatdifferentstudies includedmanytypesofpatientsatvaryingriskforCVevents. Forinstance,the1yearrateofdeathorMIinthePEACE(PreventionofEventsWith AngiotensinConvertingEnzymeInhibitionTrial)studywas<2%peryear,2 whereasit wasmorethantwiceashighamongpatientsintheCOURAGE(ClinicalOutcomes UtilizingRevascularizationandAggressiveDrugEvaluation)trial3 andtheBARI2D (BypassAngioplastyRevascularizationInvestigation2Diabetes)trial.4 Moreover, manyofthelandmarkstudiesofSIHDpredatewidespreadutilizationofstents, statins,ordualantiplatelettherapy,andtherefore,contemporaryeventratesmaybe substantiallylower. Despitethevariabilityamongthedata,categorizationofpatientsintolow, intermediate,andhighriskcategoriesshouldbeaprimarygoalintheevaluationof patientswithSIHD.Patientswithanannualmortalityrateof<1%areconsideredat lowrisk,13%areconsideredatintermediaterisk,and>3%areconsideredathigh risk(Table1).TheanalogouscategoriesforannualCVdeathratewouldbe<1%,1 2%,and>2%,respectively.

Table1

NoninvasiveRiskStratification Table1 LV=leftventricleLVEF=leftventricularejectionfraction.


aAlthoughthepublisheddataarelimited,patientswiththesefindingswillprobablynotbeatlowriskinthepresenceofeitherahighrisktreadmill

scoreorsevererestingLVdysfunction(LVEF<35%). AdaptedwithpermissionfromGibbonsRJ,ChatterjeeK,DaleyJ,etal.ACC/AHA/ACPASIMguidelinesforthemanagementofpatientswith chronicstableanginaexecutivesummaryandrecommendations:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociation TaskForceonPracticeGuidelines(CommitteeontheManagementofPatientsWithChronicStableAngina).Circulation199999:282948.

OverviewofRiskStratificationTechniquesforPatientsWith StableIschemicHeartDisease (1of3)


ThegoalofevaluatingapatientwithSIHDshouldbetosystematicallyandefficiently utilizethemultiplemodalitiestomaximizetheidentificationofhighriskfeatures withoutovertesting,buttoensurethatcriticaldatathatwouldidentifyhighrisk patientsisnotmissed.Therearefourbroadcategoriesofriskstratificationthat shouldbeconsidered5 : 1. 2. 3. 4. Clinicalevaluationandassessmentofcomorbidities Functionalcapacity/stresstest Ventricularfunction Coronaryanatomy
Figure1

Table2

Everypatientdoesnotrequireeachofthesemodalitiestobeevaluated.Nordothey needtobeassessedinsequence.Alowriskpatientmayonlyrequireaclinical evaluationandastresstestorechocardiogram,whileahighriskpatientmay proceeddirectlyfromtheclinicalevaluationtocardiaccatheterization. RiskStratificationBasedonClinicalEvaluation ClinicalHistoryandPhysicalExamination Theclinicalhistoryandphysicalexaminationremaincornerstonesintheevaluation ofpatientswithSIHD.Ingeneral,poorlycontrolledtraditionalcardiacriskfactors hypertension,dyslipidemia,smoking,anddiabetesareassociatedwithworse prognosisinpatientswithSIHD,andgiventhattheoverallriskofCVeventsishigher inpatientswithSIHD,theabsoluteriskassociatedwiththepresenceofdiabetes,for example,isevengreaterthaninprimaryprevention. Ahistoryofheartfailure,regardlessofleftventricular(LV)ejectionfunction,isalsoa markerofsignificantlyincreasedriskinalmostallSIHDpatients.Thephysical examinationshouldsupportthehistoryandidentifypatientswithevidenceofright sidedorleftsidedoverloadorstigmataofnoncoronaryatherosclerosis. PriorCardiovascularHistory Ahistoryofadocumentedsevereischemicevent,suchasaMIorstroke, substantiallyincreasestheriskofsubsequenteventscomparedtopatientswith SIHDwhohaveneverhadamajorischemicevent.IntheREACH(Reductionof AtherothrombosisforContinuedHealth)Registry,patientswithahistoryofMIor stroke(n=21,890)hadahigher4yearrateofCVdeath,MI,orstroke(18.3%) comparedtopatientswithstablevasculardiseasebutnohistoryofMIorstroke(n= 15,264)(12.2%,p<0.001)(Figure1).6 Moreover,thedetectionofvasculardisease inotherarterialbedsisalsoimportanttodocumentaspatientswithpolyvascular disease(concomitantdiseaseofthecerebrovascularorperipheralarterialbeds) areatanevenhigherrisk. AccordingtotheREACHRegistry,the1yearriskofCVdeath,MI,stroke,or hospitalizationforaCVeventrangedfrom12.6%forpatientswithanonearterial bedinvolvement,21.1%forpatientswithatwoarterialbedinvolvement,and26.3% forpatientswithathreearterialbedinvolvement(p<0.001fortrend).7 AssessingFunctionalStatusandSymptomsofStableIschemicHeartDisease AllpatientswithSIHDshouldbecloselyquestionedregardingtheirfunctionalstatus andwhethertheiractivitiesarelimitedbyanypotentialischemicsymptoms.Simple questionsregardingthepatient'susuallevelofactivity,suchaswalking,climbing stairs,carryinggrocerybags,oryardworkoffersinvaluableinsightintothepatient's physicallimitations.Acarefulunderstandingofthenatureofthelimitingsymptomin patientswithlowactivitymayofferinsightsintopotentialischemicburden.Many patientsreducetheiractivitiestopreventsymptomsofanginaandmayreporta reductionintheirpainwhenitisactuallyjustselflimitingactivity.

Ischemicchestdiscomfort,orangina,istheclassicsymptomofSIHD.The diagnosisofanginabeginswithacarefulassessmentofclinicalsymptoms.While thereissignificantvariabilityinthequalityofanginasymptoms,anginatypicallyisa thoracicdiscomfort,oftencenteredinthemidsternumthatradiatestotheneck,jaw, orarm,althoughsomedescribeitasmoreepigastricthansubsternal.Itismost commonlydescribedasapressure,squeezing,ortightness,ratherthanasharp pain.Associatedsymptomsarecommonandincludediaphoresis,dyspnea, nausea,orintensefatigue.Insomepatients,and,inparticular,inwomenandthe elderly,dyspneaordiaphoresisalone,withoutthe"typical"symptomsofsubsternal pressure,arepresentandareoftenascribedtoothercauses,delayingdiagnosis. Thepatternofanginaiscriticaltodefiningachronicversusunstableischemic syndrome.Patientswithchronicanginaexperiencesymptomsthatarepredictable, repetitive,andinduciblewithexertion.Symptomsaretypicallystableoverweeksand months.Whileexertion(e.g.,walking,climbingstairs,cleaning)isthemostcommon precipitant,anxietyandstresscanalsoelicitanginaattacks.Chronicanginaalways resolveswithrestortheuseofsublingualnitroglycerin.Manypatientsreportthe slowonsetofanginawithexertionthatrequiresthemtodiminishtheirlevelof exertionorevenstop.Often,afterthisinitialepisodesubsides,patientscancontinue theiractivitieswithoutsymptoms. Carefulquestioningofpatientswithsuspectedanginaisnecessarytodetermine howtheirqualityoflifeisaffected.Anychangeinachronicanginapattern,witheither onsetatrestoranginawithprogressivelylessexertion,requiresamoreurgent evaluation,asitmayindicateaconversiontoanunstableischemicsyndrome. PatientscanthenbeappropriatelycategorizedinadifferentCanadian CardiovascularSocietyclassificationgroup(Table2).8 Moredetailedandsensitive classificationcanbeobtainedusingmoresensitive,patientbasedsurveys,suchas theSeattleAnginaQuestionnaire. PrevalenceandRiskAssociatedWithAngina Thereportedincidenceandprevalenceofsymptomaticanginaisdirectlyrelatedto thepopulationbeingstudied.Inpopulationbasedstudies,theincidenceofangina iscloselyassociatedwithageandgender.Menbetween6585yearsoldareatthe highestrisk,withanincidenceof>10casesper1,000patientyears.Theriskwas approximatelyonehalfinyoungermenandwomenofasimilarage.1 Among patientswithestablishedCADintheREACHregistry,30%reportedahistoryof stableangina. Bydesign,clinicaltrialpopulationsarevariablyenrichedforpatientswithahistoryof angina,totheextentthattheprevalenceofahistoryofanginarangesfrom22%in theCAPRIE(ClopidogrelversusAspirininPatientsatRiskofIschemicEvents)trial toapproximately55%intheHOPE(HeartOutcomesPreventionEvaluationStudy) trial,andto70%inthePEACEtrial.Evenamongpatientswhoundergo revascularization,anginaiscommon.Almostonethirdofthepatientsinthe COURAGEtrial9assignedtopercutaneouscoronaryintervention(PCI),andonehalf ofthepatientsassignedtorevascularizationintheBARI2Dtrial,10hadanginaat1 yearafterrandomization.Alargeclinicaldatabasefoundthat30%ofpatientswho hadaPCIstillreportedangina1yearlater.11 Surprisingly,thereislittlecontemporarydatatoindicatewhetherthepresenceof anginacarriesanyincreaseinriskcomparedtopatientswithnoangina,especially whenaccountingforothercomorbiditiesandLVfunction.IntheHeartandSoulStudy ofpatientswithSIHD,129patients(14%)hadstableangina,butanginaalonewas notassociatedwithanincreased4yearriskofCHD.12

FourYearRiskofCardiovascularDeath,MyocardialInfarction,orStrokeintheREACHRegistry Figure1 Fouryearriskofcardiovasculardeath,myocardialinfarction,orstrokeintheREACHRegistryaccordingtowhetherpatientshadaprior documentedischemicevent,stableatherosclerosis,orriskfactorsonly. CV=cardiovascularMI=myocardialinfarctionmo=monthNo.=numberREACHRegistry=ReductionofAtherothrombosisforContinued HealthRegistry. ReproducedwithpermissionfromBhattDL,EagleKA,OhmanEM,etal,andtheREACHRegistryInvestigators.Comparativedeterminantsof4 yearcardiovasculareventratesinstableoutpatientsatriskoforwithatherothrombosis.JAMA2010304:13507.

GradingofAnginaPectorisbytheCanadianCardiovascularSocietyClassificationSystem Table2 ReproducedwithpermissionfromtheCanadianCardiovascularSociety.GradingofAnginaPectoris.1976.Availableat:http://www.ccs.ca. Accessed02/27/2012.

OverviewofRiskStratificationTechniquesforPatientsWith StableIschemicHeartDisease (2of3)


Resting12LeadElectrocardiogram AllpatientswithSIHDshouldreceivebaselineandregular12lead electrocardiograms(ECGs).ThepresenceofpathologicQwavesmayindicatean oldinfarct,thereforeidentifyingapatientatincreasedriskoffutureischemicevents orheartfailure.EvenintheabsenceofaknownMI,pathologicQwavesinthe absenceofaclearhistoryofMIarecommonandofferimportantprognostic information.SilentMI,identifiedbynewQwaves,accountedfor10%and36.8%of thetotalnumberofMIsobservedintworecentclinicaltrialsofdiabeticpatientsand wereassociatedwithworseoutcomes.13,14OtherECGfindingssuchasatrial fibrillation,fascicularandbundlebranchblocks,andLVhypertrophyhavealsobeen associatedwithworseoutcomesinpatientswithSIHD.15Smallerinfarctsthatdo notresultinpersistentQwavescanbeidentifiedona12leadECGbyanalyzing alteredRSR'patterns(fragmentedQRS),whichisassociatedwithincreasedCV risk.16,17 EstablishedBiomarkers PatientswithSIHDshouldhaveregularmeasurementsoflipids,fastingblood glucose,glycatedhemoglobin,andrenalfunctiontoensurethatthetraditionalrisk factorsarecloselymonitoredatgoallevels.Treatmentoftheseriskfactorsis coveredinthemoduleonPreventioninChapter4andtheMedicalTherapymodule inthischapter. OtherBiomarkers Manybiomarkers,includingthosethatassessmyocardialnecrosis,inflammation, neurohormonalactivation,metabolism,renalfunction,coagulation,andlipid traffickinghavebeenevaluatedwiththehopeofgaininggreaterinsightintothe pathogenesisofatherosclerosisandSIHD.Manybiomarkersareelevatedin patientswithSIHD,andsomeofthemaddincrementalimprovementstoother clinicalfeaturesintermsofdiscriminatingbetweenlowerriskandhigherrisk patients.Nobiomarker,though,hasbeenshowntoprovideanycleartreatment implicationsinSIHD.Forexample,anelevatedlevelofBtypenatriureticpeptide (BNP)identifiesapatientatanincreasedriskhowever,therearenoknown treatmenttherapiesthatwillreducethatrisk.Thelackoftreatmentimplicationshas limitedtheincorporationofbiomarkersintocurrenttreatmentalgorithms. Theoldergenerationsoftroponinassayswerenotsensitiveenoughtodetect elevationinpatientswithstablecardiacdisease.Theintroductionofmoresensitive cardiactroponinassaysaltersthetraditionalparadigmoftroponinbydetectinglower levelsofcirculatingtroponin,whicharecommonlyfoundinpatientswithSIHD.For example,circulatingtroponinwasdetectedin>97%ofpatientsinthePEACEtrialby usinganewhighsensitivityassay,andwasgreaterthanthe99thpercentile,the standardcutpointfordiagnosisofMI,in11.1%ofpatients.18Therewasagraded stepwiseincreaseintheriskofCVdeathandheartfailureoverthe5yearfollowup periodthatwasindependentofbaselinecharacteristics,eventhoughtheselevels aremuchlowerthantheolder,conventionaltroponinassayscoulddetect(Figure 2a).Newertroponinassayswithevenhighersensitivitythatcandetectsmall increasesduringstresstestsarenowavailableinsomecountries,buttheirrolein theevaluationofSIHDremainsverymuchanareaofdebate. MultiplestudiesexaminingthelevelsofnatriureticpeptidesinpatientswithSIHD confirmthatelevatedlevelsofhemodynamicstressareindependentlyassociated withanincreasedriskofCVdeathandheartfailure.Inonelongtermpopulation basedstudyof>1,000patientswithdocumentedCAD,patientsinthehighest quartileofNTproBNPwereata>2foldincreasedriskofCVdeathcomparedtothe lowestquartile(Figure2b).19TheseobservationswereconfirmedinboththeHOPE trialandthePEACEtrialpopulations.20,21IntheanalysesfromtheHOPEtrial,NT
Figure2a

Figure2b

Figure3

proBNPwastheonlybiomarkerthatimprovedthediscriminationfortheriskofCV deathbeyondthatprovidedbytraditionalriskfactors.Otherstudiesthatevaluated multiplenovelbiomarkersfoundthatNTproBNP,GDF15,cystatinC,midregional proadrenomedullin(MRproADM),andmidregionalproatrialnatriureticpeptide (MRproANP)weremoststronglyrelatedtoCVoutcomes,althoughincremental improvementoverestablishedriskfactorswassmall,evenaftercombining markers.22 Basedontheevidencethatbiomarkerscanofferimprovedriskstratification,current clinicalguidelinesgiveaClassIIarecommendationforthemoreestablished markers,suchashighsensitivityCreactiveprotein,23andClassIIb recommendationfornatriureticpeptidesinpatientswithstableCAD.5 The widespreadincorporationofthesebiomarkersisunlikelytooccuruntilthere becomecleartreatmentimplications,whichwillrequireprospectiveclinicaltrials. ClinicalRiskScores Incontrasttoprimarypreventionandacutecoronarysyndromes,therearefewwell validatedandacceptedintegratedclinicalriskscoresforpatientswithdocumented, butstable,CAD.Severalscores,includingonebasedon11clinicalcharacteristics andanotherwithjustfivevariablesmale,presenceoftypicalangina,evidenceof anoldMIonECG,diabetes,andinsulinusewereshowntobeassociatedwiththe severityofCADdetectedonangiography.15 Anotherclinicalscoredevelopedinpatientstreatedwithastatinaspartofaclinical trialfoundthataweightedscoringsystemincludingage,sex,tobaccouse,priorMI, revascularization,hypertension,totalcholesterol,andlowdensitylipoprotein cholesterolcategorizespatientsintoalow(<1%),intermediate(13%),andhigh (>3%)1yearriskofdeathorMI.24Itisimportanttonotethatnoneofthesescores includedeitherexercisetolerancetestorLVfunction,twoofthemostpowerfulrisk stratificationtechniques. AssessmentofRiskWithFunctionalorStressTests Stresstesting,bothbyexerciseorpharmacologicstress,providesanenormous amountofprognosticinformation,andunlesscontraindicated,shouldbeperformed inallpatientswithsuspectedorknownSIHDtoevaluatethepresenceandburdenof ischemia.25Stresstestingshouldnotbeperformedwhenurgentcatheterizationis indicated,orinothertenuoushemodynamicscenariossuchassevereaortic stenosisorunstablearrhythmias.Wheneverpossible,exercisestresstestingis preferredtopharmacologicstresstestingbecauseexercisecapacityandrecovery providesignificantincrementalprognosticinformationbeyondtheassessmentof ischemia,andbecauseitisthemorecostefficientoption. Itisimportanttorememberthatwhilestresstestsprovideanoverallassessmentof cardiopulmonaryhealth,theywillonlyidentifyhemodynamicallysignificantcoronary lesions.Theunderstandingthatmanyacutelesionsarisefromnonobstructive lesionsexplainswhyapatientwitha"negative"stresstestmaysubsequently presentwithanacutecoronarysyndrome.Diseasemodifyingtherapy,suchas bloodpressurecontrol,lipidloweringtherapy,andantiplateletdrugs,should thereforebebasedontheoverallriskassessmentandnotjustthestresstests results. ExerciseStressTests Exercisestresstestinghasbeenextensivelyvalidatedinmanyclinicalsituationsfor avarietyofindications.OnecommonindicationthediagnosisofCADinpatients withoutknownSIHDiscoveredinthemoduleonAsymptomaticCADinthis chapterandinChapter3onPatientAssessment.Ingeneral,amongpatientswith knownSIHD,thepresenceofischemia,asdetectedbySTsegmentdeviationon exercisetesting,maybelessimportantpersethanthephysiologicparameters assessedduringthetest.Maximalexerciseduration,totalexercisecapacity,timeto symptomsorSTsegmentdeviation,heartrateandbloodpressureresponseto exerciseandrecovery,andthedegreeofsymptomsareallrelatedtoprognosis. Exercisedurationandmaximalexercisecapacityaretwoofthegreatintegratorsof overallhealth.26Excellentexercisecapacity,eveninthepresenceofdocumented

ischemia,carriesagoodprognosis,whilepoorcapacity,withorwithoutischemia, identifiesapatientatahigherriskofdeath. Thereareseveralintegratedriskscoresthatcombinedifferentexercisetest parameters.TheDukeTreadmillScore(DTS),whichincludesexerciseduration, maximalSTdepression,andthepresenceandseverityofangina,isoneofthemost wellvalidatedandutilizedscoringtests(Figure3).Patientsarecategorizedaslow risk(scoreof>5)witha1yearmortalityrateof0.25%,intermediaterisk(score4to 10)witha1yearmortalityrateof1.25%,andhighrisk(score<11)witha1year mortalityrateof5.25%.27,28Othermetrics,suchasabnormalheartraterecovery pattern,prolongedSTsegmentdepression(>8minutesintorecovery),orabnormal bloodpressureresponseofferfurtherpathophysiologicinsightintotheoverallCV statusandidentifyhighriskpatients.25,29 Basedonthestrengthofevidence,cost,andease,stresstestingshould,inmost cases,bethefirstlinetestforfunctionalcapacityamongpatientswhocanexercise andhaveinterpretableECGtesting.Theindicationsforadditionalimagingare reviewedinthenextsection,butevenwhenimagingisobtained,exercisestress, ratherthanpharmacologicstress,ispreferredwheneverpossibletoobtain functionalinformation.

TroponinTandNTproBNPinStableIschemicHeartDisease(1of2) Figure2a ElevatedlevelsofhighsensitivitytroponinT ReproducedwithpermissionfromOmlandT,deLemosJA,SabatineMS,etal,andthePreventionofEventswithAngiotensinConvertingEnzyme Inhibition(PEACE)TrialInvestigators.AsensitivecardiactroponinTassayinstablecoronaryarterydisease.NEnglJMed2009361:253847, andOmlandT,SabatineMS,JablonskiKA,etal,andthePEACEInvestigators.PrognosticvalueofBTypenatriureticpeptidesinpatientswith stablecoronaryarterydisease:thePEACETrial.JAmCollCardiol200750:20514.

TroponinTandNTproBNPinStableIschemicHeartDisease(2of2) Figure2b NTproBNPareshowntobeassociatedwithincreasingriskofoverallmortalityinthePEACEtrialofpatientswithdocumentedbutstable coronaryarterydisease. ReproducedwithpermissionfromOmlandT,deLemosJA,SabatineMS,etal,andthePreventionofEventswithAngiotensinConvertingEnzyme Inhibition(PEACE)TrialInvestigators.AsensitivecardiactroponinTassayinstablecoronaryarterydisease.NEnglJMed2009361:253847, andOmlandT,SabatineMS,JablonskiKA,etal,andthePEACEInvestigators.PrognosticvalueofBTypenatriureticpeptidesinpatientswith stablecoronaryarterydisease:thePEACETrial.JAmCollCardiol200750:20514.

DukeTreadmillScore Figure3 TheDukeTreadmillScoreisthemostwellvalidatedstresstestingscorethataccuratelyclassifiespatientsintolow,intermediate,andhighrisk basedonthetimeofexercise,extentofSTdepressions,andseverityofsymptoms.Intheexample,apatientexercises8minutes,hasa1mm STsegmentdepression,andhasnonlimitingangina,whichgivesascoreof1,placingherintheintermediateriskcategory.Thesame calculationscanbeperformedusinganomogrambydrawingalinebetween1)STsegmentdeviationduringexerciseandAnginaduring exercise,and2)IschemiareadinglineandDurationofexercisetoestimatethe1yearand5yearmortalityrisk. Max=maximumMET=metabolicequivalentMI=myocardialinfarctionmin=minutes

OverviewofRiskStratificationTechniquesforPatientsWith StableIschemicHeartDisease (3of3)


MyocardialImagingTechniquestoAssessIschemia Thepresenceofischemiacanbedetectedbyradionuclide,echocardiographic,or magneticresonanceimaging(MRI)techniques,andincertainscenarios,is indicatedaspartoftheinitialstresstestorasafollowuptesttopriornoninvasive studies.Thetwomostclinicallyrelevantparametersobtainedfromthesetechniques are:1)theoverallburdenandpatternofischemia,and2)anassessmentofLV function.Consensuspracticeguidelinesrecommendthatmyocardialimagingis appropriateinthefollowingscenariosamongpatientswithknownSIHD30: Toclarifyanequivocal,borderline,ordiscordantpriorstresstestwhere obstructiveCADremainsaconcern. Toevaluateneworworseningsymptomsinapatientwithknownabnormal coronaryangiographyorpriorstressimages. Toevaluatethephysiologicconsequenceofacoronarystenosisoranatomic abnormalityofuncertainsignificance. ForfurtherevaluationofpatientswithanintermediateorhighDTS. Theappropriatenessofimaginganasymptomaticorstablepatientwithahistoryof abnormalcoronaryangiographyorabnormalstressimagingisuncertainifthelast stresstestwas>2yearsprior,andinappropriateifthelaststresstestwaswithinthe last2years.Repeatradionuclideimagingisconsideredappropriateinthesettingof incompleterevascularizationtoassessresidualischemiaandforrecurrent symptomsafterrevascularization(Figure4).30 Severalfindingsonstressimagingareimportantinriskstratification.Evidenceof reducedLVfunction(<35%)atrestorduringstress,alargeormultipleareasof stressinducedperfusiondefect(especiallyifanterior)orwallmotionabnormalities, andevidenceofstressinduceddilationorincreasedlungupdateofradionuclide traceridentifypatientsathighestrisk(>3%annualmortalityrate).ModerateLV function(3549%),moderatestressinducedperfusiondefectsorwallmotion abnormalitiesidentifyintermediateriskpatients(13%annualmortality).Lowrisk patients(<1%annualmortality)includepatientswithsmallornostressinduced perfusiondefectsorwallmotionabnormalities,althoughitisimportanttointegrate theimagingresultswithLVfunctionandthephysiologicresultsfromtheexercise tests(Table1).15 TheindicationsandprognosisobtainedfromstressechocardiographyorMRIis similartoradionuclideimaging.Thechoicebetweenthedifferentmodalitieswill dependonlocalexpertise,cost,andifthereisadditionalinformationthatisbetter assessedwithonemodalitycomparedtotheother.Forexample,stress echocardiographymaybepreferredifischemicmitralregurgitationissuspected. Oneadvantageofstressechocardiographyisthatexercisetestingcanbe performed,whereasstressMRIrequirespharmacologicstress. AssessmentofRiskbyLeftVentricularFunction Regardlessoftheclinicalsituation,LVsystolicfunctionisnotonlyoneofthemost powerfulpredictorsofshorttermandlongtermoutcomes,butitalsocarries therapeuticimplicationsregardingappropriatemedical,revascularization,and devicebasedtherapies.LVfunctionthereforeshouldbeassessedinallpatients withSIHD,evenwithoutanysignsorsymptomsofheartfailure.31 Echocardiography Inmostcases,echocardiographywillbethemodalityofchoiceforassessingLV function,becauseitiseasytoobtainandcanalsoevaluatevalvularorother structuralheartdisease.Mostradionuclidestudieswillalsoprovideaccurate measurementsofLVfunction,andifnormal,wouldnotrequireafollowup echocardiogramunlessthereisaclinicalsuspicionforstructuralorvalvularheart
Figure4

Table1

Figure5a

Figure5b

Figure5c

Figure5d

Figure6

Figure7

Table3

disease.Thecurrentappropriateusecriteriaforechocardiographyrelatedtothe evaluationofpatientswithSIHDrecommendechocardiographyinpatientswith symptomsorconditionsrelatedtosuspectedcardiacetiology,includingchestpain. RoutinesurveillancewithrepeatedechocardiographyinpatientswithknownCAD, butnochangeinsymptomsornewsignsofanyprogressionisnotindicated, however.32 MuchoftheevidencelinkingLVfunctionandoutcomescomesfromolderstudies suchastheCASS(CoronaryArterySurgeryStudy)trialwhereovertwothirdsofthe deathsat5yearswereobservedintheroughlyonethirdofpatientswithreducedLV function.IntegrationofLVfunctionandthedegreeofCADfurtherrefinesrisk stratification.Regardlessofthedegreeofatherosclerosis,worseningventricular functionisassociatedwithincreasedriskofdeath(Figures5a,b,c,d).33 AssessmentofRiskAccordingtoCoronaryAnatomy Thedecisiontodefinecoronaryanatomyisoneofthekeydecisionbranchpointsin theevaluationofpatientswithSIHD.Thedecisiontoproceedtocoronary angiographyshouldbebasedontheresultsofclinicalhistoryandnoninvasiverisk stratificationtools.ManylowtointermediateriskpatientswithSIHDmaynotrequire coronaryangiographytoappropriatelytreattheirSIHD,whileinotherpatients, catheterizationmaybethefirstdiagnostictestaftertheinitialclinicalevaluation. Definingthecoronaryanatomyshouldalsobeconsideredasanimportanttoolfor riskstratification,andnotsimplyasadiagnostictooltoidentifypotentiallesionsfor revascularization.Itisalsoimportanttorememberthatwhilecoronaryangiography isthe"goldstandard"foridentifyingflowlimitingintraluminalobstructions,itisnot sensitivetoidentifying"vulnerable"nonobstructivecoronaryplaquesthatmayrapidly progresstoacutethromboticlesions. Despitethelimitationinidentifyingtheactuallesionthatmayprecipitateanacute coronarysyndrome,theextentandburdenofatherosclerosisdetectedon angiographyclearlyidentifiesthe"vulnerablepatient"whoisatahigherriskofCV complications.Themostsimpleandwidelyusedclassificationforriskstratification isbasedonthenumberofdiseasedarteries(i.e.,leftmainorsingle,double,or triplevesseldisease).Theprognosticvalueofthisstraightforwardclassification wasmostclearlydemonstratedintheCASSregistry,wheretherewasastepwise decreaseinoverallsurvivalaccordingtothenumberofdiseasedarteries(Figures 5a,b,c,d).33 Thisrelationshipofoverallsurvivaltothenumberofdiseasedarterieshasbeen confirmedinmorerecentexperiences.IntheCOURAGEtrial,therateofdeathorMI aftera4.6yearfollowupperiodwas12.5%inpatientswithzerooronevessel disease,approximately18%inpatientswithtwovesseldisease,andapproximately 25%inpatientswiththreevesseldisease.34Moredetailedassessmentsofthe complexityofcoronarydisease,ascalculatedbytechniquessuchastheSYNTAX Score,mayprovideamorecompleteassessmentofatheroscleroticburdenand giveinsightintoactualtreatmentdecisions,however,theyarenottypicallycalculated inclinicalpractice.Inonestudyofapproximately1,400patientswithCAD undergoingPCI,the1yearriskofdeathincreasedalmosttwofoldwitheachtertileof SYNTAXscore(1.5%vs.2.1%vs.5.6%p=0.002)(Figures6,7).10,35 TheAmericanHeartAssociation/AmericanCollegeofCardiologyFoundation (AHA/ACCF)indicationsforcoronaryangiographyinpatientswithSIHDare presentedinTable3.15Eventhoughtheyaresomewhatdated,theseindications remainrelevantandareconsistentwiththerecommendationsofotherprofessional societies.5 CardiacComputedTomography Computedtomographyangiography(CTA)hasalimitedroleintheevaluationof patientswithknownSIHDorinpatientswithahighsuspicionforCAD.36Inthese cases,CTAwillpotentiallydelaycoronaryangiographyandexposepatientsto increasedcontrastandradiation.However,similartocoronaryangiography,the degreeofatherosclerosisidentifiedbyCTAisassociatedwithworseoutcomes. PatientswithanyluminalabnormalitiesdetectedonCTA(whothereforehavesome

Figure8

Figure9

degreeofatheroscleroticburden)areatahigherriskthanpatientswithnoevidence ofanyluminalobstruction.Theriskincreasesinpatientswithactualobstructive lesionsand,inparticular,amongpatientswithleftmainorleftanteriordescending arterydisease.37 Similartoangiography,thenumberofdiseasedarteriesidentifiedbyCTAisclosely associatedwithCVcomplications,withthehighestriskinpatientswithleftmain arterydisease(Figure8).38CTcalciumscanninghasnoroleinthemanagementof patientswithSIHD,asthesepatientsareknowntohaveatherosclerosis,andthe degreeofcalcificationdoesnotcorrelatewiththedegreeofstenosis.35 AnIntegratedRiskStratificationAlgorithm RiskstratificationinpatientswithSIHDshouldproceedinastepwiseandlogical progression.Theprocessbeginswiththeclinicalhistoryandexamination,andthe decisionsaboutsubsequenttestingshouldbuildoneachadditionalpieceof information(Figure9).Rarelywillonetestdriveadecisionfortherapy,butratherthe integrationofthedatafromseveralriskstratificationmodalitieswillprovidethemost completeassessmentand,therefore,themostappropriatelyguidedtherapeutic decisions.

:AppropriateUseCriteriaforCardiacRadionuclideImagingforPatientsWithIschemicSymptomsorPriorRevascularization Figure4 ACS=acutecoronarysyndromeCABG=coronaryarterybypassgraftECG=electrocardiogramPCI=percutaneouscoronaryintervention.

ReproducedwithpermissionfromHendelRC,BermanDS,DiCarliMF,etal.ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM2009appropriateuse criteriaforcardiacradionuclideimaging:areportoftheAmericanCollegeofCardiologyFoundationAppropriateUseCriteriaTaskForce,the AmericanSocietyofNuclearCardiology,theAmericanCollegeofRadiology,theAmericanHeartAssociation,theAmericanSocietyof

Echocardiography,theSocietyofCardiovascularComputedTomography,theSocietyforCardiovascularMagneticResonance,andtheSociety ofNuclearMedicine.JAmCollCardiol200953:220129.

NoninvasiveRiskStratification Table1 LV=leftventricleLVEF=leftventricularejectionfraction.


aAlthoughthepublisheddataarelimited,patientswiththesefindingswillprobablynotbeatlowriskinthepresenceofeitherahighrisktreadmill

scoreorsevererestingLVdysfunction(LVEF<35%). AdaptedwithpermissionfromGibbonsRJ,ChatterjeeK,DaleyJ,etal.ACC/AHA/ACPASIMguidelinesforthemanagementofpatientswith chronicstableanginaexecutivesummaryandrecommendations:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociation TaskForceonPracticeGuidelines(CommitteeontheManagementofPatientsWithChronicStableAngina).Circulation199999:282948.

SurvivalofMedicallyTreatedPatientsAccordingtotheNumberofDiseasedCoronaryArteriesandLeftVentricularFunction(1of4) Figure5a GraphsshowingsurvivalformedicallytreatedCASS(CoronaryArterySurgeryStudy)Registrypatients. PanelA:Patientswithone,two,orthreevesseldiseasebyejectionfraction. EJECFR=ejectionfraction. ReproducedwithpermissionfromEmondM,MockMB,DavisKB,etal.LongtermsurvivalofmedicallytreatedpatientsintheCoronaryArtery SurgeryStudy(CASS)Registry.Circulation199490:264557.

SurvivalofMedicallyTreatedPatientsAccordingtotheNumberofDiseasedCoronaryArteriesandLeftVentricularFunction(2of4) Figure5b GraphsshowingsurvivalformedicallytreatedCASS(CoronaryArterySurgeryStudy)Registrypatients. PanelB:Patientswithonevesseldiseasebyejectionfraction. EJECFR=ejectionfraction. ReproducedwithpermissionfromEmondM,MockMB,DavisKB,etal.LongtermsurvivalofmedicallytreatedpatientsintheCoronaryArtery SurgeryStudy(CASS)Registry.Circulation199490:264557.

SurvivalofMedicallyTreatedPatientsAccordingtotheNumberofDiseasedCoronaryArteriesandLeftVentricularFunction(3of4) Figure5c GraphsshowingsurvivalformedicallytreatedCASS(CoronaryArterySurgeryStudy)Registrypatients. PanelC:Patientswithtwovesseldiseasebyejectionfraction. EJECFR=ejectionfraction. ReproducedwithpermissionfromEmondM,MockMB,DavisKB,etal.LongtermsurvivalofmedicallytreatedpatientsintheCoronaryArtery SurgeryStudy(CASS)Registry.Circulation199490:264557.

SurvivalofMedicallyTreatedPatientsAccordingtotheNumberofDiseasedCoronaryArteriesandLeftVentricularFunction(4of4) Figure5d GraphsshowingsurvivalformedicallytreatedCASS(CoronaryArterySurgeryStudy)Registrypatients. PanelD:Patientswiththreevesseldiseasebyejectionfraction. EJECFR=ejectionfraction. ReproducedwithpermissionfromEmondM,MockMB,DavisKB,etal.LongtermsurvivalofmedicallytreatedpatientsintheCoronaryArtery SurgeryStudy(CASS)Registry.Circulation199490:264557.

RateofDeathorMIbyNumberofDiseaseVessels Figure6 Therateofdeathormyocardialinfarction(MI)accordingtothenumberofdiseasedarteriesamongpatientswithstableischemicheartdisease treatedwithpercutaneouscoronaryintervention(PCI)oroptimalmedicaltherapy(OMT). AdaptedwithpermissionfromDagenaisGR,LuJ,FaxonDP,etal,andtheBypassAngioplastyRevascularizationInvestigation2Diabetes(BARI 2D)StudyGroup.Effectsofoptimalmedicaltreatmentwithorwithoutcoronaryrevascularizationonanginaandsubsequentrevascularizations inpatientswithtype2diabetesmellitusandstableischemicheartdisease.Circulation2011123:1492500.

RateofDeathorMIbySYNTAXScore Figure7 Therateofdeathormyocardialinfarction(MI)accordingtothetertileofSYNTAXScore,whichquantifiestheoverallburdenandcomplexityof thedisease. AdaptedwithpermissionfromWykrzykowskaJJ,GargS,GirasisC,etal.ValueoftheSYNTAXscoreforriskassessmentintheallcomers populationoftherandomizedmulticenterLEADERS(LimusElutedfromADurableversusERodableStentcoating)trial.JAmCollCardiol 201056:2727.

RecommendationsforCoronaryAngiographyforRiskStratificationinPatientsWithChronicStableAngina Table3 AdaptedwithpermissionfromGibbonsRJ,ChatterjeeK,DaleyJ,etal.ACC/AHA/ACPASIMguidelinesforthemanagementofpatientswith chronicstableanginaexecutivesummaryandrecommendations:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociation TaskForceonPracticeGuidelines(CommitteeontheManagementofPatientsWithChronicStableAngina).Circulation199999:282948.

OverallSurvivalbyNumberofDiseasedArteries Figure8 Overallsurvivalaccordingtothenumberofdiseasedarteriesdetectedbycomputedtomographyangiography. ReproducedwithpermissionfromMinJK,ShawLJ,DevereuxRB,etal.Prognosticvalueofmultidetectorcoronarycomputedtomographic angiographyforpredictionofallcausemortality.JAmCollCardiol200750:116170.

InitialEvaluationofPatientsWithClinicalSymptomsofAngina Figure9 Algorithmfortheinitialevaluationofpatientswithclinicalsymptomsofangina. ACS=acutecoronarysyndromeCABG=coronaryarterybypassgraftCAD=coronaryarterydiseaseCV=cardiovascularCXR=chestX rayDM=diabetesmellitusECG=electrocardiogramMI=myocardialinfarctionMRI=magneticresonanceimagingPCI=percutaneous coronaryintervention. ReproducedwithpermissionfromFoxK,GarciaMA,ArdissinoD,etal.Guidelinesonthemanagementofstableanginapectoris:executive summary:theTaskForceontheManagementofStableAnginaPectorisoftheEuropeanSocietyofCardiology.EurHeartJ200627:134181.

FutureDirections
Continuedresearchintonovelbiomarkerssuchashighsensitivitytroponinassays,mayfurtherimprovetheability toidentifypatientsatthehighestrisk.Theroutineincorporationofnovelbiomarkersintoclinicalcareisunlikely though,untilspecifictreatmentsbasedontheresultsofthetestsareidentifiedinclinicaltrials. Advancesinimagingmayprovidegreaterinsightintowhichpatientmaybenefitfrommoreintensetherapy, includingrevascularization.Forexample,moredetailedassessmentsofviability,asdetectedbycardiacMRIor positronemissiontomography(PET)scansmaybetteridentifywhichpatientswillbenefitfromrevascularization. Advancedimagingtechniquesarealsobeingevaluatedtoidentifyatheroscleroticlesionsthataremostlikelyto becomeunstablepriortobecomingsymptomatic.

KeyPoints
SIHD,alsotermedCAD,encompassesaheterogeneouspopulation,whichvariesintermsofcomorbidities, symptoms,andriskoffutureCVevents. RiskstratificationinpatientswithSIHDshouldproceedinastepwiseandlogicalprogression. Categorizationofpatientsintolow,intermediate,andhighriskcategoriesshouldbeaprimarygoalinthe evaluationofpatientswithSIHD.Patientswithanannualmortalityrateof<1%areconsideredlowrisk,anannual rateof13%asintermediaterisk,and>3%ashighrisk. Fourbroadcategoriesofriskstratificationshouldbeconsidered:1)clinicalevaluationandassessmentof comorbidities,2)functionalcapacity/stressrest,3)ventricularfunction,and4)coronaryanatomy.Mostpatientswill notneedallfourdomainstested. Basedonthestrengthofevidence,cost,andease,stresstestingshouldbeinmostcasesthefirstlinetestfor functionalcapacityamongpatientswhocanexerciseandhaveaninterpretableECG.Somepatientsmayhavean indicationforadditionalimaging,butevenwhenimagingisobtained,exercisestress,ratherthanpharmacologic, ispreferredwheneverpossibletoobtainfunctionalinformation. Regardlessoftheclinicalsituation,LVfunctionisnotonlyoneofthemostpowerfulpredictorsofshortandlong termoutcomes,butalsocarriestherapeuticimplicationsregardingappropriatemedical,revascularization,and devicebasedtherapies.LVfunction,therefore,shouldbeassessedinallpatientswithSIHD,evenwithoutany signsorsymptomsofheartfailure. Coronaryangiographyshouldbeperformedbasedontheresultsofclinicalhistoryandnoninvasiverisk stratificationtools.ManylowtointermediateriskpatientswithSIHDmaynotrequirecoronaryangiography, whereasinotherpatients,catheterizationmaybethefirstdiagnostictestaftertheinitialclinicalevaluation. Definingthecoronaryanatomy,though,shouldbeconsideredanimportanttoolforriskstratification,andnot simplyasadiagnostictooltoidentifypotentiallesionsforrevascularization.

References
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24. MarschnerIC,ColquhounD,SimesRJ,etal.,onbehalfoftheLIPIDStudyInvestigators.Longtermrisk stratificationforsurvivorsofacutecoronarysyndromes.ResultsfromtheLongtermInterventionwithPravastatin inIschemicDisease(LIPID)Study.JAmCollCardiol200138:5663. 25. GibbonsRJ,BaladyGJ,BrickerJT,etal.ACC/AHA2002guidelineupdateforexercisetesting:summaryarticle.A reportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines (CommitteetoUpdatethe1997ExerciseTestingGuidelines).JAmCollCardiol200240:153140. 26. MyersJ,PrakashM,FroelicherV,DoD,PartingtonS,AtwoodJE.Exercisecapacityandmortalityamongmen referredforexercisetesting.NEnglJMed2002346:793801. 27. MarkDB,HlatkyMA,HarrellFEJr,LeeKL,CaliffRM,PryorDB.Exercisetreadmillscoreforpredictingprognosisin coronaryarterydisease.AnnInternMed1987106:793800. 28. MarkDB,ShawL,HarrellFEJr,etal.Prognosticvalueofatreadmillexercisescoreinoutpatientswithsuspected coronaryarterydisease.NEnglJMed1991325:84953. 29. ColeCR,BlackstoneEH,PashkowFJ,SnaderCE,LauerMS.Heartraterecoveryimmediatelyafterexerciseasa predictorofmortality.NEnglJMed1999341:13517. 30. HendelRC,BermanDS,DiCarliMF,etal.ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM2009appropriateuse criteriaforcardiacradionuclideimaging:areportoftheAmericanCollegeofCardiologyFoundationAppropriate UseCriteriaTaskForce,theAmericanSocietyofNuclearCardiology,theAmericanCollegeofRadiology,the AmericanHeartAssociation,theAmericanSocietyofEchocardiography,theSocietyofCardiovascularComputed Tomography,theSocietyforCardiovascularMagneticResonance,andtheSocietyofNuclearMedicine.JAmColl Cardiol200953:220129. 31. DavisRC,HobbsFD,KenkreJE,etal.Prevalenceofleftventricularsystolicdysfunctionandheartfailureinhigh riskpatients:communitybasedepidemiologicalstudy.BMJ2002325:1156. 32. DouglasPS,GarciaMJ,HainesDE,etal.ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR2011 AppropriateUseCriteriaforEchocardiography.AReportoftheAmericanCollegeofCardiologyFoundation AppropriateUseCriteriaTaskForce,AmericanSocietyofEchocardiography,AmericanHeartAssociation, AmericanSocietyofNuclearCardiology,HeartFailureSocietyofAmerica,HeartRhythmSociety,Societyfor CardiovascularAngiographyandInterventions,SocietyofCriticalCareMedicine,SocietyofCardiovascular ComputedTomography,andSocietyforCardiovascularMagneticResonance.EndorsedbytheAmericanCollege ofChestPhysicians.JAmCollCardiol201157:112666. 33. EmondM,MockMB,DavisKB,etal.LongtermsurvivalofmedicallytreatedpatientsintheCoronaryArterySurgery Study(CASS)Registry.Circulation199490:264557. 34. ManciniGB,BatesER,MaronDJ,etal.,onbehalfoftheCOURAGETrialInvestigators.Quantitativeresultsof baselineangiographyandpercutaneouscoronaryinterventionintheCOURAGEtrial.CircCardiovascQual Outcomes20092:3207. 35. WykrzykowskaJJ,GargS,GirasisC,etal.ValueoftheSYNTAXscoreforriskassessmentintheallcomers populationoftherandomizedmulticenterLEADERS(LimusElutedfromADurableversusERodableStent coating)trial.JAmCollCardiol201056:2727. 36. TaylorAJ,CerqueiraM,HodgsonJM,etal.ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR2010appropriate usecriteriaforcardiaccomputedtomography.AreportoftheAmericanCollegeofCardiologyFoundation AppropriateUseCriteriaTaskForce,theSocietyofCardiovascularComputedTomography,theAmericanCollege ofRadiology,theAmericanHeartAssociation,theAmericanSocietyofEchocardiography,theAmericanSocietyof NuclearCardiology,theNorthAmericanSocietyforCardiovascularImaging,theSocietyforCardiovascular AngiographyandInterventions,andtheSocietyforCardiovascularMagneticResonance.JAmCollCardiol 201056:186494. 37. PundziuteG,SchuijfJD,JukemaJW,etal.Prognosticvalueofmultislicecomputedtomographycoronary angiographyinpatientswithknownorsuspectedcoronaryarterydisease.JAmCollCardiol200749:6270. 38. MinJK,ShawLJ,DevereuxRB,etal.Prognosticvalueofmultidetectorcoronarycomputedtomographic angiographyforpredictionofallcausemortality.JAmCollCardiol200750:116170.

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7.2:MedicalTherapy
Author(s): RichardA.Lange,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. 2. 3. 4. Applyappropriatesecondarypreventionmeasuresofcoronaryheartdisease(CHD). Identifyantianginaldrugsthatpreventreinfarctionandimprovesurvivalinpostmyocardialinfarction(MI)patients. Identifypatientswhobenefitfromangiotensinconvertingenzyme(ACE)inhibitors. Describethegoalserumlowdensitylipoproteincholesterol(LDLC)concentrationforpatientswithstableCHD.

Introduction
Inthepatientwithchroniccoronaryarterydisease(CAD),thegoalsofmedicaltherapyaretoameliorateanginaand/or preventrecurrentmajorcardiovascular(CV)events(secondaryprevention).Theinitialapproachtoallpatientsshouldbe focuseduponeliminatingunhealthybehaviorssuchassmokingandeffectivelypromotinglifestylechangesthatreduce CVrisksuchasmaintainingahealthyweight,engaginginphysicalactivity,andadoptingahealthydiet. Inaddition,medicaltherapiesthatretardprogression(orpromoteregression)ofatherosclerosis,stabilize atheroscleroticplaques,orpreventthrombosisshouldbeadministeredtodecreasetheriskofMIanddeath.Such therapiesincludeantiplateletagents,ACEinhibitors,andlipidloweringtherapy.Inthepatientwithdiabetes,tight glycemiccontrolwasassumedtobeimportantinsecondaryCVprevention,butrecentstudiesshowthatthisapproach increasestheriskofCVdeathandcomplications.1

AntiplateletTherapy
Plateletaggregationisakeyelementofthethromboticresponsetoplaquedisruption.Hence,plateletinhibitionis recommendedinallpatientswithchronicCADunlesscontraindicated.Aspirin(acetylsalicylicacid)irreversiblyacetylates plateletcyclooxygenase,whichisrequiredfortheproductionofthromboxaneA2 ,apowerfulpromoterofplatelet aggregation.Byinhibitingthromboxaneproductionandsubsequentplateletaggregation,aspirinreducestheriskof thromboticvascularevents. Among2,920patientswithchronicCAD,theAntiplateletTrialists'Collaborationmetaanalysisshowedthataspirin treatmentwasassociatedwitha33%reductionintheriskofseriousvascularevents(nonfatalMI,nonfatalstroke,and vasculardeath).Overthecourseofacoupleofyearsoftreatment,aspirinwouldbeexpectedtopreventabout1015 vasculareventsforevery1,000peopletreated.2 Aspirindoseof75162mgdailyisequallyaseffectiveas325mginsecondaryprevention,butwithalowerriskof bleeding.Doses<75mghavelessprovenbenefit.2,3The2007ChronicAnginaFocusedUpdateoftheAmericanCollege ofCardiology/AmericanHeartAssociation(ACC/AHA)2002GuidelinesfortheManagementofPatientsWithChronic StableAnginarecommendthatallpatientswithchronicstableanginaorthosewithclinicalorlaboratoryevidenceofCAD receiveaspirin,75162mgdaily,indefinitely.3 Althoughaspirinpreventsvascularevents,itdoesnotreduceanginal episodes. Aspirinisrelativelycontraindicatedinpatientswithknownallergiestononsteroidalantiinflammatorydrugs,andin patientswiththesyndromeofasthma,rhinitis,andnasalpolyps.

Clopidogrel
Clopidogrel,athienopyridinederivative,inhibitsplateletaggregationviairreversibleinhibitionoftheadenosine diphosphateP2Y12receptor.IntheCAPRIE(ClopidogrelVersusAspirininPatientsatRiskofIschemicEvents)trial, whichenrolled19,185patientswithahistoryofMI,stroke,orperipheralvasculardisease,patientswhoreceived clopidogrelhad10%fewerseriousvasculareventsthanaspirintreatedpatients.4 Sincethemagnitudeofthedifference wassmallandnoadditionaltrialscomparingaspirinandclopidogrelinpatientswithstableCADhavebeenconducted, clopidogrelisrecommendedinpatientswithCADwhoareallergictoorcannottolerateaspirin. Theuseofdualplatelettherapywithaspirinandclopidogrelwasnomoreeffectivethanaspirinaloneinreducing vasculareventsin15,603asymptomaticpatientswithhighriskfororwithestablishedatherothromboticdisease, includingstableCAD,intheCHARISMA(ClopidogrelforHighAtherothromboticRisk,IschemicStabilization, Management,andAvoidance)study.5 AposthocanalysisshowedthatpatientswithdocumentedpriorMI,ischemic stroke,orsymptomaticperipheralarterialdiseaseappearedtoderivesignificantbenefitfromdualantiplatelettherapy withclopidogrelplusaspirin.6 Thus,treatmentwithaspirin75162mgdailyandclopidogrel75mgdailymaybe reasonableincertainhighriskpatientswithchronicCAD.

BetaBlockers
Betablockersaretheonlyantianginaldrugsproventopreventreinfarctionand improvesurvivalinpatientswhohavehadanMI.Suchbenefitshavenotbeen demonstratedinpatientswithchronicischemicheartdiseasewithoutprevious infarction.Nevertheless,betablockersremainfirstlinetherapyinthetreatmentof chronicischemicheartdisease,particularlyeffortinducedangina,withthegoalto reducethefrequencyandseverityofanginaandtoimproveexercisecapacity. Despitethefactthattheydifferwithregardtocardioselectivity,presenceofintrinsic sympathomimeticactivityorvasodilatingproperties,andrelativelipidsolubility,all betablockersappeartobeequallyefficaciousinstableischemicheartdisease.711 Betablockerdosingshouldbeadjustedtolimittheheartrateto5560bpmatrest andtonotexceed75%oftheexerciseheartrateresponseattheonsetofischemia. Betablockersimprovesurvival,preventCVhospitalizations,andimprovesymptoms andexercisetoleranceinpatientswithischemiccardiomyopathyalreadyreceiving treatmentwithconventionaltherapy(i.e.,diuretics,digoxin,andACEinhibitors). TheCIBISII(CardiacInsufficiencyBisoprololStudyII),MERITHF(MetoprololCR/XL RandomizedInterventionTrialinCongestiveHeartFailure),andCOPERNICUS (EffectofCarvedilolonSurvivalinSevereChronicHeartFailure)trialsdemonstrated anapproximately35%mortalityreductionwithbisoprolol,metoprolol,andcarvedilol, respectively(Figure1).1214Thisdoesnotappeartobeaclasseffectthatextendsto allbetablockersbecausetheBEST(BetaBlockerEvaluationofSurvivalTrial)study didnotshowareductioninmortalitywithbucindolol.15 Betablockertherapyshouldbeinitiatedandcontinuedindefinitelyinallpatientswith priorMIorleftventricular(LV)dysfunctionwithorwithoutheartfailuresymptoms unlesscontraindicated.3 Someofthemechanismsresponsibleforthebenefitsof betablockersinthesepatientsincludeincreasedmyocardialbetaadrenergic receptordensityandsensitivity,andaswitchinmyocardialsubstrateutilizationfrom freefattyacidstoglucose,whichincreasesmyocardialenergyefficiency. Althoughgenerallywelltolerated,betablockershaveseveralnotablesideeffects. Becauseoftheirnegativeinotropiceffects,betablockertherapyshouldbeadvanced cautiouslyinpatientswithimpairedLVsystolicfunction.Betablockersmay exacerbatecoronaryvasospasminpatientswithvariantangina,bronchospasmin patientswithreactiveairwaydisease,andlimbordigitischemiainpatientswith severeperipheralvasculardiseaseorRaynaud'sphenomenon.Impotencemay alsooccurwiththeiruse.Chronicbetablockertherapyleadstoanincreaseinbeta receptordensity.Thiscanbeclinicallyimportant,assuddenwithdrawalofbeta blockertherapymayresultinincreasedsensitivitytoendogenouscatecholamines, withprecipitationofanginapectoris,MI,ordeath.

Figure1

MortalityBenefitofBetaBlockersinCongestiveHeartFailure Figure1 Annualmortalityinfourstudiesofpatientswithcongestiveheartfailuremostofwhomhadanischemiccardiomyopathytreatedwitha) placeboorb)betablockersinadditiontoconventionaltherapy.Thosetreatedwithbisoprolol,metoprolol,orcarvedilolhadimprovedsurvival, whereasthosetreatedwithbucindololdidnot. References: 1. TheCardiacInsufficiencyBisoprololStudyII(CIBISII):Arandomisedtrial.Lancet1999353:913. 2. HjalmarsonA,GoldsteinS,FagerbergB,etal.Effectsofcontrolledreleasemetoprololontotalmortality,hospitalizations,andwellbeing inpatientswithheartfailure:TheMetoprololCR/XLRandomizedInterventionTrialincongestiveheartfailure(MERITHF).MERITHFStudy Group.JAMA2000283:1295302. 3. PackerM,CoatsAJ,FowlerMB,etal.Effectofcarvedilolonsurvivalinseverechronicheartfailure.NEnglJMed2001344:16518. 4. Atrialofthebetablockerbucindololinpatientswithadvancedchronicheartfailure.NEnglJMed2001344:165967.

CalciumChannelBlockers
Calciumchannelblockersmaybeusedaseffectiveantianginalagentsandforthetreatmentofhypertension(see Chapter5:Hypertension),butdonothaveadirectroleforsecondarypreventioninpatientswithstableCHD.

AngiotensinConvertingEnzymeInhibitors
ACEinhibitorsreducemortalityandmorbidityfromCVeventsinpatientswhohave heartfailureduetoLVsystolicdysfunction,andinthosewhohaveacuteMI.In addition,"highrisk"patientswithCADorothervasculardiseasemaybenefitfroman ACEinhibitorintheabsenceofLVdysfunctionorpreviousMI. Inpatientswithatheroscleroticvasculardiseaseordiabetesandatleastoneother CADriskfactor,theHOPE(HeartOutcomesPreventionEvaluation)studyshowed that,comparedtoplacebo,ramiprilsignificantlydecreasedtheprimarycomposite endpointofCVdeath,MI,andstrokeby22%over4.5yearsoffollowup.16Basedon theseresults,theFoodandDrugAdministration(FDA)approvedtheuseoframipril forthereductionofMI,stroke,anddeathinhighriskpatients.Similarly,in theEUROPA(EuropeanTrialonReductionofCardiacEventsWithPerindoprilin StableCoronaryArteryDisease)study,perindoprilreducedCVevents(CVdeath,MI, orcardiacarrest)by20%over4.2yearsoffollowupinalowerriskpopulationwith stableCHDandnoapparentheartfailure.17 Conversely,inthePEACE(PreventionofEventsWithAngiotensinConverting EnzymeInhibition)trial,whichenrolled>8,000lowriskpatientswithstableCHDand preservedLVfunctionwhowerereceivingintensivecurrentstandardtherapy,the additionoftrandolaprildidnotreduceCVdeath,MI,orcoronaryrevascularization (Figure2).18ThelackofbenefitfromACEinhibitioninthePEACEtrialhasbeen attributedtothefactthatthestudypopulationwaslowerriskandmorelikelytobe intensivelytreatedwithcoronaryrevascularizationandlipidloweringtherapythanthe patientsinthepreviousstudies. Similarly,intheQUIET(QuinaprilIschemicEventTrial)19andIMAGINE(Ischemia ManagementWithAccuprilPostBypassGraftviaInhibitionoftheConverting Enzyme)20studiesoflowrisk(LVejectionfraction[EF]>0.40)patientswhohad undergonepercutaneouscoronaryintervention(PCI)orcoronaryarterybypass grafting(CABG),quinaprildidnotreduceischemicevents. Basedonthesestudies,the2007ChronicAnginaFocusedUpdateoftheACC/AHA 2002GuidelinesfortheManagementofPatientsWithChronicStableAngina recommendthatACEinhibitorsbestartedandcontinuedindefinitelyinallpatients withLVEF0.40andinthosewithhypertension,diabetes,orchronickidneydisease unlesscontraindicated.3 Theiruseisalsorecommendedinpatientswhoarenot lowerrisk(lowerriskisdefinedasthosewithnormalLVEFinwhomCVriskfactors arewellcontrolledandrevascularizationhasbeenperformed).Finally,itis consideredreasonabletouseACEinhibitorsamonglowerriskpatientswithmildly reducedornormalLVEFinwhomCVriskfactorsarewellcontrolledand revascularizationhasbeenperformed.

Figure2

LackofBenefitofACEInhibitorin"LowRisk"StableCADPatients Figure2 Compositeoutcomeofcardiovasculardeath,myocardialinfarction,orcoronaryrevascularizationinlowriskpatientswithstablecoronary arterydisease(CAD)andpreservedleftventricularfunctiontreatedwithplaceboortrandolaprilinthePEACEstudy.Overthe4.8yearfollow up,theadditionoftrandolapriltocurrentstandardtherapywasnotbeneficialinreducingcardiovascularevents. ACEinhibitor=angiotensinconvertingenzymeinhibitor. ReproducedwithpermissionfromMassachusetsMedicalSociety.ThePEACETrialInvestigators.AngiotensinConvertingEnzymeInhibitionin StableCoronaryArteryDisease.NEnglJMed2004351:205868.Copyright2000,MassachusettsMedicalSociety.Allrightsreserved.

AngiotensinReceptorBlockers
Angiotensinreceptorblockers(ARBs)arerecommendedforindividualswhohaveindicationsforanACEinhibitor(post MI,heartfailureduetoLVsystolicfunction,ordepressedLVEF),butareintolerantofit.TheONTARGET(ONgoing TelmisartanAloneandincombinationwithRamiprilGlobalEndpointTrial)showedthattelmisartanwasnoninferiorto ramiprilforreducingmortalityandCVmorbidityovermorethan4yearsoffollowupinpatientswithvasculardiseaseor highriskdiabetesmellitus.21However,thecombinationoftelmisartanandramiprilwasassociatedwithanincreased incidenceofadverseeventswithoutadetectableincrementalbenefitaboveeitheragentalone.

InfluenzaVaccine
AnACC/AHAscienceadvisoryrecommendsannualvaccinationwithinactivatedvaccine(administeredintramuscularly) againstseasonalinfluenzatopreventallcausemortalityandmorbidityinpatientswithunderlyingCVconditions.22A recentcohortstudyin1,340elderly(i.e.,65yearsofageorolder)patientswithcongestiveheartfailureorCADshowed thatannualinfluenzavaccinationsreducedthewinterperiodmortalityby37%thenumberneededtotreattodecrease onedeathduringinfluenzaperiodis122annualvaccinations.23

LowDensityLipoproteinCholesterolLoweringTherapy (1of2)
CVdeathratesincreasewithhigherserumconcentrationsoftotalandLDL cholesterol,andtheimpactofelevatedlipidlevelsissignificantlygreaterinsubjects withpreexistingCHDthanthosewithout(Figure3).Evenmodestelevationsin serumcholesterolincreasetheriskofacardiaceventinpatientswithCHDora recentMI.Forexample,theCARE(CholesterolandRecurrentEvents)trialevaluated theroleofpravastatintherapyafterMIinpatientswithaveragelevelsoftotalandLDL cholesterol(209mg/dland139mg/dl,respectively).Intheplacebogroup,each25 mg/dlincrementinLDLCincreasedtheriskofacardiacevent(deathornonfatalMI) by28%.24Accordingly,patientswithknownCHDoraCHDequivalent(i.e.,diabetes mellitus,symptomaticcarotidarterydisease,peripheralarterialdisease,abdominal aorticaneurysm,chronicrenalinsufficiency,orFramingham10yearriskofCHD >20%)meritaggressivelipidmanagement. ThegoalserumLDLCconcentrationforpatientswithstableCHDoraCHD equivalentis<100mg/dl.25WhenLDLloweringdrugtherapyisemployedinhigh riskormoderatelyhighriskpersons,itisadvisedthattheintensityoftherapybe sufficienttoachieveatleasta3040%reductioninLDLClevels. ForindividualsconsideredtobeatveryhighriskforCHD,anLDLCgoalof<70 mg/dlisareasonabletherapeuticstrategy.25Thisgroupwouldincludeindividuals withestablishedCVdiseaseplusoneofthefollowing:1)multiplemajorriskfactors (especiallydiabetes),2)severeandpoorlycontrolledriskfactors(especially continuedcigarettesmoking),and3)multipleriskfactorsofthemetabolicsyndrome (especiallyhightriglycerides>200mg/dlplusnonhighdensitylipoprotein cholesterol[HDLC]>130mg/dlwithlowHDLC[<40mg/dl]). AllpatientswithhighserumLDLCshouldundergolifestylemodifications,suchas reducingdietarytotalandsaturatedfat(to<20%and<10%ofcaloricintake, respectively),weightlossifoverweight,andaerobicexercise.Suchchangestypically resultin<10%reductioninserumtotalandLDLcholesterollevels.However,in severalclinicaltrials,lifestylemodificationalonehasbeenassociatedwith angiographicevidenceofslowedprogressionandmodestregressionofcoronary atherosclerosisandreducedclinicalevents(angina,MI,coronaryrevascularization, ordeath).Inthesetrials,theclinicalandangiographicimprovementinducedby dietaryinterventionwasmorelikelytooccurwhenitresultedinsubstantial reductionsinLDLC.Unfortunately,dietarymodificationaloneisoftenunsuccessful inachievingtargetserumLDLCconcentrations. Lipidalteringagentsincludeseveralclassesofdrugs:bileacidsequestrants, nicotinicacid,hydroxymethylglutarylcoenzymeA(HMGCoA)reductaseinhibitors (statins),fibrates,probucol,andezetimibe.Thesedrugsdifferwithrespectto mechanismofactionandtothedegreeandtypeoflipidlowering.Thus,the indicationsforaparticulardrugareinfluencedbytheunderlyinglipidabnormality. Conventionaldosingregimensandtypicalchangesinthelipidprofilewithdrug therapyarelistedinTable1.CommonsideeffectsarelistedinTables2aandb. Cessationoftherapybecauseofadverseeffectsoccursmostcommonlywithbile acidsequestrantsandshortactingnicotinicacid,andleastcommonlywiththe statins. StatinsarethemosteffectivedrugsforloweringserumLDLC,withreductionsinthe rangeof2060%.Additionally,theylowerserumtriglyceride1535%andraise serumHDLC515%.Fluvastatinistheleastpotent,androsuvastatinisthemost potentstatin.Adversereactionsoccurlessfrequentlywiththestatinsthanwiththe otherclassesoflipidloweringagents,butpatientstakingthemshouldbemonitored forpossibleliverormuscleinjury. ThemajoreffectsofthefibratesaretolowerserumtriglycerideandraiseHDLC levels.Theyareeffectiveforthetreatmentofhypertriglyceridemiaandcombined hyperlipidemiawithorwithoutlowserumHDLC(hypoalphalipoproteinemia).The benefitsoffibratesinthecontemporaryeraofstatinuseisquestionable,since theACCORD(ActiontoControlCardiovascularRiskinDiabetes)trialofdiabetics

Figure3

Table1

Table2a

Table2b

withCVdiseasereceivingbackgroundstatintherapyreportednooverallbenefitfor fenofibrate.26 Bileacidsequestrantsareeffectiveinpatientswithmildtomoderateelevationsof serumLDLC.Theymaybeusedincombinationwithstatinsornicotinicacidin patientswithmarkedlyelevatedserumlevelsofLDLC.Theuseofabileacid sequestrantisoftenlimitedbygastrointestinalsideeffects. Nicotinicacidiseffectiveinpatientswithhypercholesterolemiaandincombined hyperlipidemiaassociatedwithnormalorlowserumHDLClevels (hypoalphalipoproteinemia).ItraisesserumHDLlevelswithdosagesaslowas1 1.5g/day,buthigherdoses(>3g/day)aretypicallyneededtolowerserumveryLDL (VLDL)andLDLcholesterol.Theuseofnicotinicacidisoftenlimitedbypoor tolerability,whichcanbeminimizedbytakingaspirinbeforehandorusingalong actingnicotinicacidpreparation.InCHDpatientswhoareatincreasedriskforCV eventsdespiteawellcontrolledLDLConstatintherapy(i.e.,thosewithlowHDLC andhightriglyceridelevels),theadditionofhighdose,extendedreleaseniacinto statintherapydoesnotreducetheriskofCVevents.27 ProbucolmodestlylowersLDLC,butmoreprominentlyreducesHDLC.Atpresent, theuseofprobucolshouldbelimitedtopatientswithrefractory hypercholesterolemiaorthosewithfamilialhypercholesterolemiaandxanthomas.

CholesterolandDeathRateinPatientsWithandWithoutCHD Figure3 Relationbetweenbaselineplasmacholesterolmeasurementand10yearcardiovasculardeathrateinpatientswithoutandwithcoronaryheart diseaseintheLipidResearchCouncilStudy.Deathratesareincreasedathigherserumcholesterolconcentrationsinbothgroups,buttheeffect ismorepronouncedinsubjectswithcoronaryheartdisease. CHD=coronaryheartdisease

ReproducedwithpermissionfromMassachusettsMedicalSociety.PekkanenJ,LinnS,HeissG,etal.Tenyearmortalityfromcardiovascular diseaseinrelationtocholesterollevelamongmenwithandwithoutpreexistingcardiovasculardisease.NEnglJMed1990322:17007.Copyright 1990,MassachusettsMedicalSociety.Allrightsreserved.

LipidLoweringDrugTherapy Table1 Conventionaldosingregimensandtypicalchangesinthelipidprofilewithdrugtherapy. HDL=highdensitylipoproteinLDL=lowdensitylipoprotein.

CommonSideEffectsofLipidLoweringDrugTherapy(1of2) Table2a

CommonSideEffectsofLipidLoweringDrugTherapy(2of2) Table2b

LowDensityLipoproteinCholesterolLoweringTherapy (2of2)
EzetimibereducesLDLCbyinhibitingabsorptionofcholesterolbythesmall intestine,leadingtoadecreaseinthedeliveryofintestinalcholesteroltotheliver. Thiscausesareductionofhepaticcholesterolstoresandanincreaseinthe clearanceofcholesterolfromtheblood.Thismechanismiscomplementarytothat ofthestatins.Hence,ezetimibeistypicallyusedincombinationwithastatinwhen cholesterolisnotreducedsufficientlybystatintherapyaloneoritisnecessaryto reducethestatindosebecauseofsideeffects.Todate,nolongtermclinical outcomestudieshavebeenperformedwithezetimibe. Severallargetrialshavedemonstratedthatlipidloweringisbeneficialinpatients withCHD.ThereisalsoampleevidencethatelderlypatientswithCHDwhodonot havelifelimitingcomorbidconditionsbenefitfromlipidloweringtherapy.28Ameta analysisof38primaryandsecondarypreventiontrialsfoundthatforeach10% reductioninserumcholesterol,CHDmortalitywasreducedby15%andtotal mortalityriskby11%.29 Inadditiontothereductioninclinicalevents,serialangiographicandintravascular ultrasoundstudieshaveshownthatcholesterolloweringcanretardtheprogression and,inmanycases,induceregressionofcoronaryatherosclerosis.30,31This benefitismostprominentwhenserumLDLClevelsarereducedbelow100mg/dl. Themechanismsofbenefitseenwithlipidloweringarenotcompletelyunderstood. Regressionofcoronaryatherosclerosisismodest.Furthermore,themagnitudeof clinicalbenefitsisdisproportionatetothemodestdegreeofregression,andtheyare seenbeforesignificantregressionofatherosclerosiscouldoccur.Otherfactorsthat mayaccountforthebeneficialeffectsoflipidloweringagentsincludeplaque stabilization,reversalofendothelialdysfunction,antioxidanteffects,decreased thrombogenicity,andantiinflammatoryeffects. CVbenefitsofcholesterolloweringwithstatinshavebeendemonstratedinpatients withCHD,withorwithouthyperlipidemia.The4S(ScandinavianSimvastatinSurvival Study)trialofpatientswithhyperlipidemia(baselineserumtotalcholesterollevels between212and309mg/dl)foundthatsimvastatintherapyversusplacebofor5.4 yearsresultedinstatisticallysignificantreductionsintotalmortality(33%reduction), majorcoronaryevents(32%reduction),CVdeaths(42%reduction), revascularizationprocedures(37%reduction),andcerebrovascularevents(37% reduction).32Thesebenefitspersistedatthe8yearfollowupperiod.33The reductioninmajorcardiaceventswashighlycorrelatedwithontreatmentserum totalcholesterolandLDLconcentrationsandwithchangesfrombaseline.Each additional1%reductioninLDLCreducedtheriskofmajorcardiaceventsby 1.7%.34 TheLIPID(LongTermInterventionWithPravastatininIschemicDiseaseTrial)study showedthatpatientswithCHDandabroadrangeofserumcholesterol concentrationsbenefitfromstatintherapy.35Thestudyrandomizedpatientswith serumcholesterolconcentrationsof155270mg/dltotherapywithpravastatinor placebo.Afterameanfollowupof60months,thestudywasterminatedprematurely because,comparedwithplacebo,pravastatintherapyloweredmorbidityand mortalityfromCVdisease,aswellasallcausemortality(Figure4).Thebenefitof pravastatinwasseeninallpredefinedsubgroups,includingthoseofanyageandat anyleveloftotalcholesterol,LDLC,HDLC,ortriglycerides. TheCAREtrialshowedthatstatintherapywasbeneficialinCHDpatientswithhigh normallevelsofserumcholesterol.36Inthisstudy,patientswithaveragecholesterol levels(meanserumtotalcholesterolconcentrationof209mg/dl)weretreatedwith pravastatin(40mg)orplacebo.At5years,benefitswithpravastatincomparedwith placeboincludedsignificantreductionsinthecombinedincidenceofcoronarydeath andnonfatalMI(31%reduction),theneedforrevascularization(25%reduction),and thefrequencyofstroke(32%reduction).Thebenefitswereseenonlyinpatientswith LDLClevelsabove125mg/dl.

Figure4

TheHeartProtectionStudy(HPS)questionedwhetheratargetLDLgoal<100mg/dl issufficientinhighriskindividuals.37Inthisstudyof>20,000patientswith establishedCVdisease,diabetes,orhypertension,simvastatin(40mg/day) reducedmortality(13%),cardiovascularmortality(18%),majorCVevents(24%),and ischemicstroke(25%)comparedtoplacebooverthe5.5yearfollowup.Importantly, subgroupanalysissuggestedthatsimvastatintherapyproducedsimilarreductions inrelativeriskregardlessofthebaselinelevelsofLDLC,includingsubgroupswith baselineLDLClevels>135mg/dl,<116mg/dl,or<100mg/dl. ThePROSPER(ProspectiveStudyofPravastatinintheElderlyatRisk)trialextends theuseofstatinstotheolderpopulation.28Approximately6,000subjectsages70 82yearswithahistoryofvasculardiseaseorCVdiseaseriskfactorswere randomizedtopravastatin(40mg/day)orplaceboandfollowedfor3.2years.Major coronaryevents,definedasnonfatalMIandCHDdeath,werereducedby19%and CHDmortalityby24%withpravastatintherapy.

MortalityBenefitWithStatinTherapyinPatientsWithaBroadRangeofSerumCholesterolConcentrations Figure4 KaplanMeierestimatesofmortalityduetocoronaryheartdiseaseinthepravastatinandplacebogroupsintheLIPIDStudy. CHD=coronaryheartdisease ReproducedwithpermissionfromMassachusettsMedicalSociety.Preventionofcardiovasculareventsanddeathwithpravastatininpatients withcoronaryheartdiseaseandabroadrangeofinitialcholesterollevels.TheLongTermInterventionwithPravastatininIschaemicDisease (LIPID)StudyGroup.NEnglJMed1998339:134957.Copyright1998,MassachusettsMedicalSociety.Allrightsreserved.

KeyPoints
Unlesscontraindicated,allpatientswithevidenceofCADshouldreceiveaspirintopreventMI. Betablockersaretheonlyantianginaldrugsproventopreventreinfarctionandimprovesurvivalinpatientswho havehadanMI. StableCADpatientsreceivingintensivemedicaltherapywhoareatlowriskforaCVeventdonotbenefitfromACE inhibitortherapy.Conversely,ACEinhibitorsreduceCVmortalityandmorbidityin"highrisk"patientswithvascular disease(i.e.,thosewithpoorlycontrolledriskfactorsordiabetesandotherCVriskfactors). StatinsarethemosteffectivedrugsforloweringserumLDLC.ThegoalserumLDLCconcentrationforpatients withstableCHDoraCHDequivalentis<100mg/dl,andforthoseat"veryhighrisk"(i.e.,establishedCHDand multipleriskfactors),theLDLCgoalis<70mg/dl.

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27. BodenWE,ProbstfieldJL,AndersonT,etal.,onbehalfoftheAIMHIGHInvestigators.Niacininpatientswithlow HDLcholesterollevelsreceivingintensivestatintherapy.NEnglJMed365:225567. 28. ShepherdJ,BlauwGJ,MurphyMB,etal.Pravastatininelderlyindividualsatriskofvasculardisease(PROSPER): arandomisedcontrolledtrial.Lancet2002360:162330. 29. GouldAL,RossouwJE,SantanelloNC,HeyseJF,FurbergCD.Cholesterolreductionyieldsclinicalbenefit: impactofstatintrials.Circulation199897:94652. 30. NissenSE,NichollsSJ,SipahiI,etal.Effectofveryhighintensitystatintherapyonregressionofcoronary atherosclerosis:theASTEROIDtrial.JAMA2006295:155665. 31. NissenSE,TuzcuEM,SchoenhagenP,etal.Effectofintensivecomparedwithmoderatelipidloweringtherapyon progressionofcoronaryatherosclerosis:arandomizedcontrolledtrial.JAMA2004291:107180. 32. [Noauthorslisted].Randomisedtrialofcholesterolloweringin4444patientswithcoronaryheartdisease:the ScandinavianSimvastatinSurvivalStudy(4S).Lancet1994344:13839. 33. PedersenTR,WilhelmsenL,FaergemanO,etal.FollowupstudyofpatientsrandomizedintheScandinavian simvastatinsurvivalstudy(4S)ofcholesterollowering.AmJCardiol200086:25762. 34. PedersenTR,OlssonAG,FaergemanO,etal.Lipoproteinchangesandreductionintheincidenceofmajor coronaryheartdiseaseeventsintheScandinavianSimvastatinSurvivalStudy(4S).Circulation199897:145360. 35. TheLongTermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup.Preventionof cardiovasculareventsanddeathwithpravastatininpatientswithcoronaryheartdiseaseandabroadrangeof initialcholesterollevels.TheLongTermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup. NEnglJMed1998339:134957. 36. SacksFM,PfefferMA,MoyeLA,etal.Theeffectofpravastatinoncoronaryeventsaftermyocardialinfarctionin patientswithaveragecholesterollevels.CholesterolandRecurrentEventsTrialinvestigators.NEnglJMed 1996335:10019. 37. HeartProtectionStudyCollaborativeGroup.MRC/BHFHeartProtectionStudyofcholesterolloweringwith simvastatinin20,536highriskindividuals:arandomisedplacebocontrolledtrial.Lancet2002360:722.

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7.3:IndicationsforRevascularization
Author(s): JohnMcPherson,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Utilizeappropriatemedicaltherapyinthemanagementofpatientswithsymptomaticobstructivecoronaryarterydisease (CAD). 2. ReferappropriatepatientswithsignificantleftmainormultivesselCADforsurgicalorpercutaneousrevascularization. 3. Compareandcontrastthemanagementofpatientswithstableischemicheartdisease(SIHD)andacutecoronary syndromes(ACS)withrespecttotheneedforrevascularization. 4. ManageasymptomaticpatientswithobstructiveCADaccordingtocurrenttreatmentguidelines.

Introduction
Despitemanyadvancesintheprimarypreventionofcardiovascular(CV)disease, SIHDcontinuestobeasignificantcauseofmorbidityanddisability.Itisestimated that10millionAmericanshaveSIHD,with500,000newcasesofanginadiagnosed eachyear.1 UnlikepatientswithACS,patientswithSIHDareprimarilymanagedin theoutpatientsetting,withafocusonfourmajoraspectsofcare:1)identification andtreatmentofassociateddiseasesthatcanprecipitateangina,2)reductionof coronaryriskfactorsandmodifyinglifestylefactors,3)administeringmedicaltherapy (seemoduleonMedicalTherapyinthischapter),and4)revascularizationby percutaneouscoronaryintervention(PCI)orbycoronaryarterybypassgrafting (CABG). Throughthiscomprehensiveapproach,theprevalenceofmajorCVriskfactors, suchastobaccouse,hypercholesterolemia,andhypertension,hasdecreased,and withtheuseofevidencebasedtherapies(includingantiplateletagents,beta blockers,angiotensinconvertingenzyme[ACE]inhibitors,statins,andmyocardial revascularization),mortalityfromCADhasdecreasedbynearly50%overthepast severaldecades.2,3 In1964,Garrett,Dennis,andDeBakeyreportedonthefirstCABGsurgery.4 Inthe followingtwodecades,myocardialrevascularizationwithCABGinpatientswith SIHDwasamajorfocusofinvestigation.StudiesincludingthelandmarkCASS (CoronaryArterySurgeryStudy)5 andVACS(VeteransAdministrationCooperative Study)6 demonstratedamortalitybenefitwithCABGinspecificanatomicsubsetsof patients,primarilyduetotheuseoftheleftinternalmammarygrafttorevascularize theleftanteriordescending(LAD)coronaryartery.7 Withimprovementinsurgical techniquesandperioperativemanagement,clinicaloutcomesfollowingelective CABGhavecontinuedtoimprove,withanapproximate2%majoradverseeventrate anda1%hospitalmortalityrate.8 PCIintheformofballoonangioplastywasfirstperformedbyGruentzigin1977for thetreatmentofproximal,noncalcifiedlesionsinvolvingasinglecoronaryartery.9 Refinementofpercutaneoustechniqueshasalsoadvancedoverthepasttwo decades,allowingfortheabilitytotreatawiderangeofpatientswithsignificant comorbiditiesandcomplexCAD.Inaddition,advancesinadjunctive pharmacologicaltherapywithdualantiplatelettherapy,antithromboticagents, vascularclosuredevices,andradialarterialaccesshavealsoledtoareductionin periproceduralischemiceventsandreducedbleedingcomplications.10Datafroma highvolumePCIcenteronpatientsundergoingelectivePCIfrom20033006 demonstratedaproceduralsuccessrateof96%,amajorcardiacadverseeventrate of0.6%,andamortalityrateof0.1%.11 Alongwithrefinementinrevascularizationtechniquesofthepastthreedecades, understandingofthepathogenesisandtriggersofadverseCVeventsinpatients withSIHDhasadvancedinparallel.AnimportantfindingisthatthemajorityofACS arecausedbynonobstructive,clinicallysilentcoronaryplaques.Severalstudies, includingtheCOURAGE(ClinicalOutcomesUtilizingRevascularizationand AggressiveDrugEvaluation)trial,12havedemonstratedthatsuccessfulPCIof severe,clinicallystablecoronarystenosesdoesnotreducetherateofdeathor myocardialinfarctioncomparedwithoptimalmedicaltherapy.IntheCOURAGEtrial, 2,287patientswererandomizedtoPCIplusoptimalmedicaltherapyoroptimal medicaltherapyalone.At4.6yearfollowup,ratesofdeathandnonfatalmyocardial infarctionweresimilar(19.0%and18.5%,respectively)(Figure1,panelA).With someexceptions,theprimarybenefitofrevascularizationinSIHDpatients,therefore, isreliefofischemicsymptomsratherthanpreventionofmajorcardiacevents. In2009,theAmericanCollegeofCardiologyFoundation,theSocietyfor CardiovascularAngiographyandIntervention,andtheSocietyofThoracicSurgeons, alongwithotherkeyspecialtyandsubspecialtysocieties,published appropriatenesscriteriaforcoronaryrevascularization.13Thesecriteriaandthe availableevidenceguidingtheselectionofpatientswhoarecandidatesfor revascularizationisdiscussedlaterinthismodule.

Figure1

KaplanMeierSurvivalCurves Figure1 Theestimated4.6yearrateofthecompositeprimaryoutcomeofdeathfromanycauseandnonfatalmyocardialinfarctionwas19.0%inthePCI groupand18.5%inthemedicaltherapygroup.InPanelB,theestimated4.6yearrateofdeathfromanycausewas7.6%inthePCIgroupand 8.3%inthemedicaltherapygroup.InPanelC,theestimated4.6yearrateofhospitalizationforacutecoronarysyndrome(ACS)was12.4%in thePCIgroupand11.8%inthemedicaltherapygroup.InPanelD,theestimated4.6yearrateofacutemyocardialinfarctionwas13.2%inthePCI groupand12.3%inthemedicaltherapygroup. CI=confidenceintervalPCI=percutaneouscoronaryintervention. ReproducedwithpermissionfromBodenWE,ORourkeRA,TeoKK,etal.OptimalmedicaltherapywithorwithoutPCIforstablecoronary disease.NEnglJMed2007356:150316.

AcuteCoronarySyndromes
TheevidencesupportingrevascularizationasthefundamentaltreatmentofpatientswithACSandSTsegmentelevation myocardialinfarction(STEMI)isdiscussedindetailinChapter6:AcuteCoronarySyndromes.Inpatientspresentingwith STEMI,revascularizationforprimaryreperfusionisappropriateunlessthepresentationis>12hoursfromsymptomonset andtherearenoongoingischemicsymptomsorhemodynamicinstability.Followingthrombolytictherapy, revascularizationisindicatedinpatientswithheartfailureorongoingischemiaandshouldbeconsideredinpatientswith STEMIandhighriskfeatures,suchasextensiveSTsegmentelevation,newleftbundlebranchblock,anteriorinfarction, anddepressedleftventricular(LV)function.13Followingsuccessfulreperfusiontherapy,therevascularizationof nonculpritarteriesbeforehospitaldischargeshouldbeperformedonlyinpatientswithclinicalinstability,recurrentor provokableischemia,ordepressedLVfunction.Ingeneral,revascularizationshouldbeconsideredinpatients presentingwithunstableanginaornonSTsegmentelevationmyocardialinfarctionandhighriskfeatures,asoutlinedin Chapter6:AcuteCoronarySyndromes.

StableIschemicHeartDisease
TherearetwoprincipalobjectivesofrevascularizationinpatientswithSIHD: improvementofsurvivalandreliefofischemicsymptoms.Ingeneral,allpatients withSIHDshouldreceiveappropriatemedicaltherapybeforerevascularizationis considered.ThedecisiontoreferSIHDpatientsforrevascularizationgenerally shouldbebasedonfiveclinicalfactors:1)thepresenceofsignificantleftmain disease,2)noninvasiveriskstratification,3)severityofischemicsymptoms,4)the anatomicalseverityofCADburden,and5)theintensityofmedicaltherapy.Fora discussionregardingthechoiceofrevascularizationstrategy(i.e.,surgicalvs. percutaneous)inpatientswithSIHD,refertothemoduleonPercutaneousCoronary InterventionversusCoronaryArteryBypassGraftinginthischapter. LeftMainDisease Revascularizationinpatientswithleftmaincoronarystenosis50%wasprimarily studiedinthe1970sand1980s.Multiplestudiesfromthatera,includingdatafrom theVACS6 andtheCASSregistry,5 demonstratedthatCABGsignificantlyimproved survivalcomparedwithmedicaltherapyinpatientswithsignificantleftmaincoronary disease.TherearecurrentlynorandomizedstudiescomparingPCIwithmedical therapyinleftmaindisease.Basedonavailablesurgicaldata,revascularizationis indicatedinallpatientswithsignificantleftmaindisease,regardlessofsymptoms ornoninvasivefindings.14,15 NoninvasiveRiskAssessment CriteriafornoninvasiveriskstratificationaresummarizedinTable1.Inpatients referredfornoninvasivetesting,theannualmortalityriskisdirectlyrelatedto exercisecapacity,severityofischemicsymptoms,theamountofischemia demonstratedonimaging,andthedegreeofventriculardysfunction. Inpatientswithmoderatetosevereinducibleischemia(involving10%oftotal myocardium),patientstreatedwithrevascularizationhaveasignificantlylower mortalityratecomparedwiththosetreatedmedically.16Thus,revascularizationis recommendedinnearlyallpatientswithhighrisknoninvasivefindingsthereis uncertaintyinasymptomaticorminimallysymptomaticpatientswithoutproximalLAD coronarydisease(Table2).Inpatientswithintermediateriskonnoninvasivetesting, nearlyallpatientswithischemicsymptomsdespitemaximalmedicaltherapyshould bereferredforrevascularization(Table3).Ingeneral,patientswithproximalLAD diseaseorthreevesseldiseaseregardlessoftherapyalsobenefitfrom revascularization. Intermediaterisk,asymptomaticpatientswithalowburdenofCADgenerallyare inappropriatecandidatesforrevascularization.Inpatientswithlowrisknoninvasive findings,onlypatientswithischemicsymptomsdespitemaximalmedicaltherapy shouldbereferredforrevascularization.Anexceptiontothisrecommendation involvespatientswithseveresymptomsandalargediseaseburdentherapeutic uncertaintyexistsregardingpatientswithnosymptomsorwithonlymildsymptoms (Table4). SeverityofIschemicSymptoms TheCanadianCardiovascularSociety(CCS)classificationmethodismost commonlyusedtoevaluatetheseverityofischemicsymptoms(Table5).As expected,theseverityofanginalsymptomscorrelateswithmortalityrisk.Inpatients withclassIIIorIVsymptoms,revascularizationwithCABGhasbeendemonstrated toimprovesurvivalcomparedwithmedicaltherapy.5 Althoughrelativelylittledataare availablethatcomparePCItomedicaltherapyinthesepatients,revascularizationis recommendedinnearlyallpatientswithsevere(CCSclassIIIorIV)angina(Table 2). InpatientswithSIHDwhohavemildersymptoms(CCSclassIorII),thedecisionto revascularizeshouldincludeconsiderationoftheintensityofmedicaltherapy, noninvasiveriskassessment,andtheanatomicalextentofCAD.Thus,
Table4

Table1

Table2

Table3

Table5

Table6

revascularizationisindicatedinpatientswhohavehighrisknoninvasivefindings, symptomsdespitemaximalmedicaltherapy,andsignificantdiseaseburden (Tables2,3).Ingeneral,asymptomaticpatientsshouldbeconsideredfor revascularizationonlywhennoninvasivefindingsarehighrisk,orforseverethree vesseldisease(Table4). AnatomicalCoronaryArteryDiseaseBurden Fromananatomicalstandpoint,itiswellestablishedthattheextentofCADpredicts outcomesinpatientswithSIHD.Ingeneral,CVriskisassociatedwiththeamountof myocardiumsuppliedbythediseasedarteries(Table6).IntheCASSstudy,a mortalitybenefitwasobservedwithrevascularizationinpatientswiththefollowing conditions: Leftmaincoronaryarterystenosisorleftmainequivalentdisease ThreevesselCAD,particularlywithareducedLVejectionfraction(40%) TwovesselCADincludinga>75%stenosisintheproximalLADartery Intheabsenceoftheaboveconditions,thedecisiontorevascularizeapatientwith SIHDshouldtakeintoaccountthedegreeofCADinthecontextoftheseverityof symptomsonmaximalmedicaltherapy,thedegreeofischemiapresenton noninvasivetesting,andtheamountofmyocardiumsuppliedbythediseased vessels.Thus,thereisagradientfortheappropriatenessofrevascularizationbased onthesethreefactors.ForpatientswithsinglevesselCADnotinvolvingtheproximal LADartery,revascularizationisonlyindicatedinthepresenceofclassIII/IVanginaor intermediatetohighriskfindingsonnoninvasivestresstesting(Tables2,3).

NoninvasiveRiskStratification Table1 LV=leftventricularLVEF=leftventricularejectionfraction.

ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

AppropriatenessRatingsbyHighRiskFindingsonNoninvasiveImagingStudyandSeverityofAngina Table2 CTO=chronictotalocclusionLAD=leftanteriordescending. ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

AppropriatenessRatingsbyIntermediateRiskFindingsonNoninvasiveImagingStudyandSeverityofAngina Table3 CTO=chronictotalocclusionLAD=leftanteriordescending. ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

AppropriatenessRatingsbyLowRiskFindingsonNoninvasiveImagingStudyandAsymptomaticPatients Table4 CTO=chronictotalocclusionLAD=leftanteriordescending. ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

GradingofAnginaPectorisbytheCanadianCardiovascularSocietyClassificationSystem Table5 ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

PrognosisbyExtentofAnatomicalCoronaryArteryDisease Table6 *Assumingmedicaltreatmentonly. CAD=coronaryarterydiseaseLAD=leftanteriordescending. ReproducedwithpermissionfromPatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009appropriatenesscriteriafor coronaryrevascularization.JAmCollCardiol200953:53053.

SpecialPatientSubsets
PreviousCoronaryArteryBypassGrafting Ingeneral,theindicationsforrevascularizationinpatientswithpriorCABGarethesameasforpatientswithoutprior CABGpatientswithhighrisknoninvasivefindingsorthosewithobstructivediseasesubtendingalargemyocardial territoryareexpectedtoderiveamortalitybenefitwithrevascularization.Bycontrast,patientswithapatentinternal mammarygrafttotheLADarteryandlowrisknoninvasivefindingsshouldbereferredforrevascularization,primarilyfor symptomaticreliefdespitemaximalmedicaltherapy.However,withtheincreasedlevelofcomplexityofCVdiseaseand limitedevidenceregardingrepeatrevascularizationinthesepatients,thethresholdforappropriatenessisgenerallylower thanforpatientswithoutpriorCABG.13 ElderlyPatients AlthoughincreasingageisknowntobeastrongpredictorofadverseeventsinpatientswithCAD,itisalsoclearthat elderlypatientsareathigherriskforadverseeventsafterrevascularizationfrombothCABGandPCI.17,18Inaddition, mostlargerandomizedtrialsofrevascularizationexcludedelderlypatients.Withimprovementsinbothsurgicaland percutaneousrevascularizationtechniques,therisksofrevascularizationproceduresinelderlypatientsaredeclining, anddatafrommorerecentstudiesindicatethatselectedelderlypatientsderivesimilarifnotmorerelativebenefitfrom revascularizationcomparedwithyoungerpatients.1719 ThecurrentpracticeguidelinesforPCIandCABGaswellastheAppropriatenessCriteriaforRevascularizationapplyto alladultpatientswithSIHD,regardlessofage.However,carefulconsiderationofpatientspecificproceduralrisksand comorbiditiesisofparticularimportanceinthetreatmentofelderlypatients. Diabetes PatientswithdiabeteswhohaveSIHDareatincreasedriskforadverseCVeventscomparedwithnondiabeticpatients. However,thereisnoevidencethatamoreaggressiveapproachtorevascularizationinthesepatientsimproves outcomes.IntheBARI2D(BypassAngioplastyRevascularizationInvestigation)trial,patientswithdiabetesrandomizedto revascularizationhadnoimprovementin5yeardeathrate,myocardialinfarction,orstrokecomparedwiththosetreated withoptimalmedicaltherapy.20However,ifthedecisionismadetorevascularizeapatientwithdiabetes,thereis evidencethatoutcomesarebetterwithCABGthanwithPCI.Intheeraofbaremetalstents,alargemetaanalysis demonstratedimprovedlongtermsurvivalwithCABGcomparedwithPCI.21 CurrentdataontheuseofdrugelutingstentsfromtheSYNTAX(SynergyBetweenPercutaneousCoronaryIntervention WithTaxusandCardiacSurgery)studyfoundthatpatientswithdiabeteshadhigherratesofrevascularizationfollowing PCIthanwithCABG,particularlyinthosewithmorecomplexdisease.22 ChronicKidneyDisease CVdiseaseistheprimarycauseofmortalityinpatientswithchronickidneydisease.Althoughdatafromrandomized trialsarenotavailable,findingsfromobservationalstudiessuggestanimprovedsurvivalratewithrevascularizationin patientswithmultivesselCADandchronickidneydisease.23 LeftVentricularDysfunction EarlydatafromrandomizedtrialsdemonstratedasurvivalbenefitwithCABGcomparedwithmedicaltherapyinpatients withmildtomoderateLVsystolicdysfunction.5,6However,morerecentdatafromtheSTICH(SurgicalTreatmentfor IschemicHeartFailure)trialdidnotdemonstrateanoverallsurvivalbenefitwithCABGinpatientswithischemic cardiomyopathyandLVejectionfraction35%.24BecausemultiplesecondaryendpointsfromSTICHdidindicate improvedoutcomeswithCABG,thestudyfollowuphasbeenextendedto10yearstoevaluatelongtermoutcomes. TherearecurrentlynorandomizeddataontheuseofPCIinthispopulation,andcurrentguidelinesstatethatCABGto improvesurvivalisreasonableinpatientswithmildtomoderateLVsystolicdysfunctionandsignificantCADwith evidenceofviablemyocardiumintheregionofintendedrevascularization.14,15

HybridCoronaryRevascularization
TherationalebehindhybridcoronaryrevascularizationistocombinetheadvantagesofCABG(durabilityoftheleftinternal mammaryartery[LIMA]graft)andPCIinpatientswithmultivesselCAD.25Typically,theLADarteryissurgicallybypassed usingtheLIMA,andPCIisperformedofoneormoreothercoronaryarteries.Patientsparticularlysuitedforthehybrid approachincludethosewithchronictotalocclusionsorpatentvesselsunfavorableforPCIandpatientswithalackof surgicalgraftconduitorheavilycalcifiedaortasinwhichsaphenousveingraftingwouldbedifficult.Hybridprocedures maybeperformedinasuitablehybridoperativesuiteinonesetting,ortheymaybestaged.Inastagedprocedure,the PCIusuallyfollowstheLIMAbypasstominimizeperioperativebleedingfromantiplatelettherapyandalsosothat angiographicevaluationoftheLIMAgraftcanbeperformed.

PreoperativeCoronaryRevascularization
Ingeneral,decisionsonrevascularizationinpatientswithSIHDundergoingnoncardiacsurgeryareconsistentwiththose regardingotherpatientswithSIHD.PatientswithsignificantleftmainorseverethreevesselCADshouldbetreatedwith revascularizationpriortoelectivenoncardiacsurgery.Intheabsenceoftheseindications,thereisnoevidencethat routinepreoperativerevascularizationimprovesoutcomesafternoncardiacsurgery.IfPCIisperformedinapatientin whomnoncardiacsurgeryislikely,theoperatorshouldconsidercarefullythetimingoftheoperation,thefeasibilityof continuingdualantiplatelettherapyduringsurgery,andthetypeofstentusedinthePCI. Noncardiacsurgeryperformedwithin4weeksofstentimplantationisassociatedwithhighratesofstentthrombosisand deathinthiscase,balloonangioplastyisrecommendedwheneverpossible.Ifsurgeryisanticipatedwithin112months followingPCI,itrecommendedthatbaremetalstentsbeused,suchthatdualantiplatelettherapycanbediscontinued safelybeforesurgery.Ifadrugelutingstentisplaced,electivesurgeryshouldbedelayedforatleast12months,if possible.15

AdjunctiveAssessmentofthePhysiologicSignificanceofCoronaryArteryStenoses
Itiswellknownthatangiographyhaslimitationsintheassessmentofcoronarystenoses,particularlyintheevaluationof intermediate(4070%obstructive)lesions.Fractionalflowreserve(FFR)hasemergedasausefultoolinthe assessmentofsuchlesions.FFRvalues<0.75correlatewellwithischemiaonnoninvasivetesting,andthefindings fromtheDEFER(DeferralVersusPerformanceofBalloonAngioplastyinPatientsWithoutDocumentedIschemia)study demonstratedthatpatientswithangiographiclesionsassociatedwithanFFR>0.75hadbetteroutcomeswithmedical therapycomparedwithPCI.26 TheevaluationandtreatmentofpatientswithmultivesselCADusingFFRwasstudiedintheFAME(FractionalFlow ReserveVersusAngiographyforMultivesselEvaluation)study.27InFAME,PCIwasdeferredinlesionswithanFFRof >0.80.Despiteloweroveralluseofstentsandrevascularization,clinicaloutcomeswereimprovedintheFFRgroup comparedwiththegrouptreatedwithangiographyalone.Intravascularultrasound(IVUS)canprovidesignificant additionalinformationaboutcoronarylesions,suchasluminaldiameters,crosssectionalarea,andplaquesizeand characteristics.IVUShasbeenusedtoassistintheevaluationofangiographicallyindeterminatecoronarylesions. Ingeneral,inleftmaincoronarystenoses,aminimalluminalareaof<6mm2 isbelievedtobeconsistentwithaflow limitinglesionthatmaybenefitfromrevascularization.Inothercoronarystenoses,thecorrelationbetweenminimum luminalareaandischemiaismoreproblematic,asotherfactorsincludingvesselsize,lesionlength,andtheextentof myocardiumsubtendedbythelesionmayinfluencetheischemicpotentialandchoiceoftreatment.

Summary
SIHDisoneofthemostcommonmanifestationsofCVdisease,anditsprevalenceundoubtedlywillincreaseovertime. TreatmentofpatientswithSIHDinitiallyshouldfocusonsecondarypreventionwithmedicaltherapyandcontrolof modifiablecoronaryriskfactors.ThetwofundamentalgoalsofrevascularizationinSIHDaretoimprovesurvivalandto providereliefofischemicsymptoms.InSIHD,patientswithimprovedsurvivalwithrevascularizationincludethosewith significantleftmaindisease,alargeamountofischemicmyocardium,andsevereanginalsymptomsdespitemaximal medicaltherapy.Instablesymptomaticpatients,theanatomicaldegreeofCADburden,theamountofischemiaon noninvasivestresstesting,theseverityofsymptoms,theintensityofmedicaltherapy,andassociatedcomorbiditiesare allimportantconsiderationsindeterminingtheclinicalbenefitsofsurgicalorpercutaneousrevascularization.

KeyPoints
Medicaltherapywithantiplateletagents,lipidloweringtherapy,andantianginalagentsisthemainstayof treatmentinpatientswithSIHD. Thegoalsofrevascularizationaretoimprovesurvivalandtoprovidereliefofischemicsymptoms. Revascularizationisindicatedinpatientswithsignificantleftmainstenosisandinpatientswithmultivessel diseaseinvolvingtheproximalLADartery,particularlywithsubnormalLVsystolicfunction. FactorsinfluencingthedecisiontoperformcoronaryrevascularizationincludetheanatomicaldegreeofCAD burden,theamountofprovokableischemiaonnoninvasivetesting,theseverityofsymptoms,theintensityof medicaltherapy,andassociatedcomorbidities.

References
1. LloydJonesD,AdamsR,CarnethonM,etal.Heartdiseaseandstrokestatistics2009update:areportfromthe AmericanHeartAssociationStatisticsCommitteeandStrokeStatisticsSubcommittee.Circulation2009119:e21 181. 2. FoxCS,EvansJC,LarsonMG,KannelWB,LevyD.Temporaltrendsincoronaryheartdiseasemortalityand suddencardiacdeathfrom1950to1999:theFraminghamHeartStudy.Circulation2004110:5227. 3. FordES,AjaniUA,CroftJB,etal.ExplainingthedecreaseinU.S.deathsfromcoronarydisease,19802000.N EnglJMed2007356:238898. 4. GarrettHE,DennisEW,DeBakeyME.Aortocoronarybypasswithsaphenousveingraft.Sevenyearfollowup. JAMA1973223:7924. 5. AldermanEL,BourassaMG,CohenLS,etal.Tenyearfollowupofsurvivalandmyocardialinfarctioninthe randomizedCoronaryArterySurgeryStudy.Circulation199082:162946. 6. TheVACoronaryArteryBypassSurgeryCooperativeStudyGroup.EighteenyearfollowupintheVeteransAffairs CooperativeStudyofCoronaryArteryBypassSurgeryforstableangina.Circulation199286:12130. 7. SabikJF3rd,BlackstoneEH,GillinovAM,BanburyMK,SmediraNG,LytleBW.Influenceofpatientcharacteristics andarterialgraftsonfreedomfromcoronaryreoperation.JThoracCardiovascSurg2006131:908. 8. WijnsW,KolhP,DanchinN,etal.Guidelinesonmyocardialrevascularization.TaskForceonMyocardial RevascularizationoftheEuropeanSocietyofCardiology(ESC)andtheEuropeanAssociationforCardioThoracic Surgery(EACTS).EurHeartJ201031:250155. 9. GruentzigAR,SenningA,SiegenthalerWE.Nonoperativedilatationofcoronaryarterystenosis:percutaneous transluminalcoronaryangioplasty.NEnglJMed1979301:618. 10. MarsoSP,AminAP,HouseJA,etal.Associationbetweenuseofbleedingavoidancestrategiesandriskof periproceduralbleedingamongpatientsundergoingpercutaneouscoronaryintervention.JAMA2010303:2156 64. 11. HilliardAA,FromAM,LennonRJ,etal.Percutaneousrevascularizationforstablecoronaryarterydisease. Temporaltrendsandimpactofdrugelutingstents.JACCCardiovascInterv20103:1729. 12. BodenWE,O'RourkeRA,TeoKK,etal.OptimalmedicaltherapywithorwithoutPCIforstablecoronarydisease.N EnglJMed2007356:150316. 13. PatelMR,Dehmer,GJ,HirshfeldJW,etal.ACCF/SCAI/STS/AHA/ASNC2009AppropriatenessCriteriaforCoronary Revascularization:areportbytheAmericanCollegeofCardiologyFoundationAppropriatenessCriteriaTask Force,SocietyforCardiovascularAngiographyandInterventions,SocietyofThoracicSurgeons,American AssociationforThoracicSurgery,AmericanHeartAssociation,andtheAmericanSocietyofNuclearCardiology. EndorsedbytheAmericanSocietyofEchocardiography,theHeartFailureSocietyofAmerica,andtheSocietyof CardiovascularComputedTomography.JAmCollCardiol200953:53053. 14. HillisLD,SmithPK,AndersonJL,etal.2011ACCF/AHAguidelineforcoronaryarterybypassgraftsurgery:areport oftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines. DevelopedincollaborationwiththeAmericanAssociationforThoracicSurgery,SocietyofCardiovascular Anesthesiologists,andSocietyofThoracicSurgeons.JAmCollCardiol201158:e123210. 15. LevineGN,BatesER,BlankenshipJC,etal.2011ACCF/AHA/SCAIguidelineforpercutaneouscoronary intervention.AreportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForce onPracticeGuidelinesandtheSocietyforCardiovascularAngiographyandInterventions.JAmCollCardiol 201158:e44122. 16. HachamovitchR,HayesSW,FriedmanJD,etal.Comparisonoftheshorttermsurvivalbenefitassociatedwith revascularizationcomparedwithmedicaltherapyinpatientswithnopriorcoronaryarterydiseaseundergoing stressmyocardialperfusionsinglephotonemissioncomputedtomography.Circulation2003107:29007. 17. GrahamMM,GhaliWA,FarisPD,etal.Survivalaftercoronaryrevascularizationintheelderly.Circulation 2002105:237884. 18. SinghM,PetersonED,RoeMT,etal.Trendsintheassociationbetweenageandinhospitalmortalityafter percutaneouscoronaryintervention:NationalCardiovascularDataRegistryexperience.CircCardiovascInterv 20092:206. 19. TIMEInvestigators.Trialofinvasiveversusmedicaltherapyinelderlypatientswithchronicsymptomaticcoronary arterydisease(TIME):arandomizedtrial.Lancet2001358:9517. 20. FryeRL,AugustP,BrooksMM,etal.Arandomizedtrialoftherapiesfortype2diabetesandcoronaryartery disease.NEnglJMed2009360:250315. 21. HlatkyMA,BoothroydDB,BravataDM,etal.Coronaryarterybypasssurgerycomparedwithpercutaneouscoronary interventionsformultivesseldisease:acollaborativeanalysisofindividualpatientdatafromtenrandomised trials.Lancet200937311907. 22. BanningAP,WestabyS,MoriceMC,etal.Diabeticandnondiabeticpatientswithleftmainand/or3vessel coronaryarterydisease:comparisonofoutcomeswithcardiacsurgeryandpaclitaxelelutingstents.JAmColl Cardiol201055:106775. 23. HemmelgarnBR,SouthernD,CulletonBF,etal.Survivalaftercoronaryrevascularizationamongpatientswith kidneydisease.Circulation2004110:18905.

24. VelazquezEJ,LeeKL,DejaMA,etal.Coronaryarterybypasssurgeryinpatientswithleftventriculardysfunction.N EngJMed2011364:160716. 25. ZhaoDX,LeaccheM,BalaguerJM,etal.Routineintraoperativecompletionangiographyaftercoronaryartery bypassgraftingand1stophybridrevascularization:resultsfromafullyintegratedhybridcatheterization laboratory/operatingroom.JAmCollCardiol200953:23241. 26. PijlsNH,vanSchaardenburghP,ManoharanG,etal.Percutaneouscoronaryinterventionoffunctionally nonsignificantstenosis:5yearfollowupoftheDEFERstudy.JAmCollCardiol200749:210511. 27. PijlsNH,FearonWF,ToninoPA,etal.,onbehalfoftheFAMEStudyInvestigators.Fractionalflowreserveversus angiographyforguidingpercutaneouscoronaryinterventioninpatientswithmultivesselcoronaryarterydisease: 2yearfollowupoftheFAME(FractionalFlowReserveVersusAngiographyforMultivesselEvaluation)study.JAm CollCardiol201056:17784.

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7.4:PercutaneousCoronaryInterventionVersusCoronaryArteryBypass Grafting
Author(s): JohnMcPherson,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Identifypatientswithcoronaryarterydisease(CAD)inwhomrevascularizationwithcoronaryarterybypassgrafting (CABG)confersasurvivalbenefit. 2. Comparetheefficacyofpercutaneouscoronaryintervention(PCI)withthatofCABGinthetreatmentofpatientswith multivesselCAD. 3. Identifypatientswithspecificclinicalcharacteristicswhowouldbenefitfromsurgicalrevascularizationasopposedto percutaneousrevascularization. 4. Identifypatientswithspecificclinicalcharacteristicswhowouldbenefitfrompercutaneousrevascularizationasopposed tosurgicalrevascularization. 5. Reviewtherationaleandpossibleclinicalbenefitsofhybridcoronaryrevascularization.

Introduction
AsmentionedinthemoduleonIndicationsforRevascularizationinthischapter,themanagementofstableischemic heartdisease(SIHD)focusesonreductionofcoronaryriskfactors,aggressivemedicaltherapy,and,whenappropriate, revascularizationbyPCIorwithCABG.Thismodulereviewstheconsiderationsimplicitinthechoiceofrevascularization modeinpatientswithSIHD.

CoronaryArteryBypassGrafting
ThedevelopmentofCABGforthetreatmentofsymptomaticCADoccurredinthe1960s.1 Intwodecadesthatfollowed, myocardialrevascularizationwithCABGinpatientswithSIHDwasamajorfocusofinvestigation,evaluatedinstudies includingtheCoronaryArterySurgeryStudy(CASS)andregistry,2 andtheVeteransAdministrationCooperativeStudy.3 In thesestudies,themajorbenefitofCABGcomparedwithmedicaltherapywasinreliefofanginalsymptoms,although therewasalsoademonstrablemortalitybenefitwithCABGinspecificsubsetsofpatients,suchasthosewithleftmain coronaryartery(LMCA)disease,threevesselCAD,andthosewithleftventricular(LV)dysfunction.4 Withimprovementinsurgicaltechniquesandperioperativemanagement,clinicaloutcomesfollowingelectiveCABG havecontinuedtoimprove,withanapproximate2%majoradverseeventrateanda1%hospitalmortalityratereportedin recentstudies.5 SpecificrefinementstoCABGincludetheuseofarterialconduits(leftandrightinternalmammaryartery, radialartery),"offpump"(beatingheart)CABG,andsternalsparing,minimallyinvasivetechniques.

PercutaneousCoronaryIntervention
Dr.AndreasGruentzigfirstperformedPCIintheformofballoonangioplastyin1977forthetreatmentofstableangina causedbyproximal,noncalcifiedsinglevesselCAD.6 Majoradvancesinpercutaneoustechniques,includingthe developmentofbaremetalanddrugelutingcoronarystents,adjunctivepharmacologicaltherapywithdualantiplatelet therapyandnewerantithromboticagents,vascularclosuredevices,andradialarterialaccesshaveenabledtheuseof PCIinthetreatmentofawiderangeofpatientswithsignificantcomorbiditiesandcomplexCAD. PCIisnowperformedinapproximately600,000patientsperyearintheUnitedStates,inhospitalswithandwithout onsitecardiacsurgicalcapabilities.AswithCABG,advancesinPCIhavealsoledtoareductioninperiprocedural complicationsdespitethetreatmentofolder,higherriskpatients.7 DatafromahighvolumePCIcenteronpatients undergoingelectivePCIfrom20032006demonstratedaproceduralsuccessrateof96%,amajorcardiacadverseevent rateof0.6%,andamortalityrateof0.1%.8 Recently,a"hybrid"approachtorevascularizationhasbeendeveloped,inwhichthebenefitsofCABGandPCIare combinedtoprovidepatientswithadurable,completerevascularizationandaminimallyinvasiveprocedure.Although longtermdataregardingthisapproacharelimited,initialresultsappearpromising,anditislikelythatahybridapproach willemergeasareasonabletherapeuticalternativetotraditionalCABGandPCIinpatientswithSIHD.9,10 Regardlessofthetechniqueused,itisnowclearthatcoronaryrevascularizationisonlyonecomponentofa comprehensivestrategyintheoptimalmanagementofSIHD.Theuseoflongtermantiplateletagents,controlof hypertensionandhypercholesterolemia,referralforcardiacrehabilitation,andlifestylecounselingareallimportant elementsinimprovingoutcomesfollowingrevascularization.Withsomeexceptionsinpatientswithahighburdenof CAD,theprimarybenefitofrevascularizationinpatientswithSIHDisreliefofischemicsymptomsratherthanprevention ofmajorcardiacevents. GiventherapidadvancementsinbothCABGandPCItechniquesandpostproceduralcare,muchdebatesurroundsthe choiceofsurgicalversuspercutaneousrevascularizationforanygivenpatient.Severalrandomizedtrialscomparing CABGandPCIhaveattemptedtoanswerthisquestion,butprogressinthisareahasbeenhamperedbyenrollmentof onlyasmallproportionofscreenedpatientsandlimitedgeneralizabilityduetotherapidtechnologicaladvancementsin bothfields.Theavailableevidenceandcurrentrecommendationsguidingtheapproachtorevascularizationinpatients withSIHDisdiscussedinthefollowingsections.

AnatomicalandFunctionalConsiderations
SingleVesselCAD Todate,norandomizedtrialhasdemonstratedasurvivalbenefitinrevascularization ofpatientswithstable,singlevesselCADnotinvolvingtheproximalleftanterior descending(LAD)coronaryartery.Thus,theobjectiveofeitherCABGorPCIinthese patientsisreliefofischemicsymptomsdespitemaximalmedicaltherapy.Inthese cases,PCIisgenerallythepreferredapproachbecauseofitslowerprocedural morbidity,particularlywhenamoredurableinternalmammaryarterialconduitisnot plannedorusedattimeofCABG.Arareexceptionmaybeahighlysymptomatic, large,chronicallyoccludedarteryinwhichthedistalvesselisareasonabletargetfor surgicalgraftingandthelikelihoodofsuccessfulPCIislow. SeveralstudieshavesuggestedthatCABGforisolatedproximalLADdiseaseis associatedwithimprovedsurvivalcomparedwithmedicaltherapy.11 Revascularizationforthesepatientsisrecommendedintheappropriatenesscriteria forcoronaryrevascularization,publishedbytheAmericanCollegeofCardiology Foundation(ACCF),theSocietyforCardiovascularAngiographyandIntervention, andtheSocietyofThoracicSurgeons,alongwithotherkeyspecialtyand subspecialtysocieties.12 Inalargemetaanalysisofninerandomizedtrials,CABGandPCIforproximalLAD diseaseresultedinsimilarratesofstroke,myocardialinfarction,and5yearsurvival CABGwasassociatedwithmorereliefofanginaandlowerratesofrepeat revascularization,whereasPCIwasassociatedwithshorterhospitalstaysandless needforbloodtransfusion.13Thus,eitherapproachisconsideredreasonablein thiscase. LeftMainCoronaryArteryDisease PatientswithdiseaseoftheLMCA(definedasa50%angiographicstenosis)areat particularlyhighriskofcardiovascularmorbidityandmortality.Clearly,CABGfor LMCAdiseaseimprovessurvivalcomparedwithmedicaltherapy,2,3,11and revascularizationisindicated.UnlikeCABG,norandomizeddatademonstratea survivalbenefitinpatientswithPCIoftheLMCA,andcurrentlyPCIforLMCAdisease isconsideredinappropriatewhenCABGisareasonableoption.12,14However,with theadventofbaremetalanddrugelutingstents,PCIoftheLMCAinpatientswithout priorCABG("unprotected"LMCA)isincreasinglyconsideredarevascularization option. ImprovedoutcomeswithcontemporaryPCIandrecentdatacomparingLMCAPCI withCABGarechallengingthestandardofcareinpatientswithLMCAdisease. RegistriescomparingPCIandCABGinpatientswithLMCAdiseasehaveshown similarratesofsurvival,decreasedratesofstroke,andincreasedratesofrepeat revascularizationwithPCIcomparedwithCABG.15 IntheSYNTAX(SynergyBetweenPercutaneousCoronaryInterventionWithTaxus andCardiacSurgery)trial,arandomizedstudycomparingCABGtoPCIwithdrug elutingstentsinpatientswithmultivesselCAD,40%ofthepatientshadsignificant LMCAdisease.16Inthissubgroup,majoradversecardiovasculareventrateswere similartherateofrepeatrevascularizationwassignificantlyhigherinthePCIgroup (11.8%vs.6.5%)andthestrokeratewassignificantlyhigherintheCABGgroup (2.7%vs.0.3%).Ongoinglarge,randomizedtrialscomparingLMCAPCIwithCABG willinformtheoptimaltreatmentapproachforthesehighriskpatients. MultivesselDisease Improvementsinrevascularizationtechniqueshaveallowedbothinterventional cardiologistsandcardiacsurgeonstotreateffectivelymorepatientswithincreasing levelsofCADdiseaseburdenandcomorbidities.Notsurprisingly,revascularization witheitherCABGorPCIisnowtechnicallyfeasibleinthevastmajorityofthese patients.InpatientswithSIHD,PCIofmultivesseldiseasehasnotbeen demonstratedtoimprovesurvivalcomparedwithmedicaltherapy.14Thisisin
Figure1

Figure2

Figure3

Figure4a

Figure4b

contrasttomucholdersurgicaldata,inwhichCABGwasshowntoimprovesurvival insubsetsofpatientswithmultivesselCAD,particularlyinpatientswiththreevessel CADandinvolvementoftheproximalLADcoronaryartery,orwithLVdysfunction.2,3 Giventhesignificantchangesinbothsurgicaltechniquesandmedicaltherapy,itis unclearwhethertheseresultswouldbereplicatedinacontemporarysetting. Withfewexceptions,comparingCABGwithPCIinrandomizedtrialshasbeen challengingbecauseofinherentdifficultiesinenrollingtypical"realworld"patients, giventhenecessarystudyinclusion/exclusioncriteriaandphysicianbiases.In addition,thedataarenotalwaysapplicableduetotherapidadvancesinbothCABG andPCItechniques(i.e.,offpumpCABG,drugelutingstents).Thus,manyofthe currentlyavailabledataarecontainedinseverallargeregistriesandafew randomizedtrials,withsignificantvariationsintechniques. IntheNewYorkStateRegistry,treatmentofmultivesselCADwascomparedin 22,000patientsundergoingPCIusingbaremetalstentsand15,000patients treatedwithCABG.17LowermortalitywithCABGwasobservedinpatientswithmore complexCAD,includingthosewiththreevesselCADandproximalLADdisease. Similardifferencesinmortalitywerereportedwiththeuseofdrugelutingstentsin thesameregistry.18 Althoughotherregistrieshavenotreporteddifferencesinsurvival,findingsof increasedrepeatrevascularizationfollowingPCIandincreasedincidenceofstroke followingCABGhavebeenconsistent.Inametaanalysisof24,000patientswith multivesselCADtreatedwithdrugelutingstentsorCABG,ratesofmyocardial infarctionandsurvivalweresimilar,butratesofrepeatrevascularizationwerefour timeshigherinpatientstreatedwithPCI.19 InthefirstrandomizedtrialofPCIversusCABGforthetreatmentofmultivesselCAD, theBARI(BypassAngioplastyRevascularizationInvestigation)researchers randomized1,829patientswithmultivesselCADtoballoonangioplastyorCABG.20 At5years,infarctfreesurvivalwassimilarinthetwogroups(80%vs.79%),but patientstreatedwithangioplastyhadamuchhigherrateofrepeatrevascularization (54%vs.8%).Furthermore,the5yearsurvivalratewassignificantlyhigherinthe subgroupofdiabeticpatientstreatedwithCABG(81%vs.66%)(Figure1). SeveralsimilarrandomizedtrialscomparedPCIusingbaremetalstentswithCABG, andHlatkyandcolleagues15performedalargemetaanalysisincorporatingthese studiesalongwithearlierdata.Intheiranalysis,althoughoverallmortalitywasagain similarbetweenthetwogroups,patientswithdiabetesandthoseolderthan65 yearshadimprovedsurvivalwithCABG(Figure2). TheSYNTAXtrialwasthefirstlargerandomizedtrialtocomparetreatmentwithPCI usingdrugelutingstentstoCABGinpatientswithmultivesselCAD.16Inthe SYNTAXtrial,patientswerealsostratifiedaccordingtothepresenceofLMCA diseaseanddiabetes.Theinvestigatorsalsointroducedthe"SYNTAXscore"21to objectivelyevaluateindetailthecomplexityofCAD.At3years,thecomposite endpointofdeath,MI,stroke,andrepeatrevascularizationwashigherinthePCIarm (28.0%vs.20.2%),primarilydrivenbyadifferenceinrepeatrevascularization(19.7% vs.10.7%).MortalityratesweresimilarinpatientstreatedwithCABGandPCI. TheSYNTAXstudyalsoreaffirmedthenotionthatclinicaloutcomesfollowingPCIfor multivesselCADareinverselyproportionaltotheoverallburdenandcomplexityof CAD:inpatientswithlowSYNTAXscores(definedas022)andintermediate SYNTAXscores(2332),eventratesweresimilarinpatientstreatedwithPCIor CABGwhereaspatientswithhighSYNTAXscores(33)hadsignificantlylower adverseeventratesfollowingCABG(Figure3).22 PreviousCoronaryArteryBypassGrafting InpatientswithpreviousCABGreferredforrevascularization,itisimportantto considerthetypeandnumberofremainingfunctionalgrafts,thedegreeofviable myocardiumsuppliedbythediseasedvessels,thecomplexityofthediseaseinthe involvedvessels,andpatientcomorbidities.Inpatientswithapatentinternal mammarygrafttotheLADcoronaryarteryandpoordistalsurgicaltargets,PCIis generallypreferred.Bycontrast,CABGispreferredinpatientswithextensive

disease,reasonablesurgicaltargets,andtheavailabilityofaninternalmammary conduittoanoccludedartery.14 CompletenessofRevascularization InthetreatmentofpatientswithSIHD,theabilitytoprovidefullrevascularizationmay affectpatientoutcomes.Ratesofcompleterevascularizationtypicallyarehigherin patientsundergoingCABGthaninthoseundergoingPCI,asdemonstratedinrecent studiesincludingtheSYNTAXtrial.16FollowingPCI,incompleterevascularization hasbeenassociatedwithaslightincreaseinlongtermmortalityandincreased ratesofsubsequentCABG(Figures4a,b).23

SurvivalAmongPatientsWithandWithoutDiabetesandMultivesselCADintheBARIStudy Figure1 Survivalamongpatientswhowerebeingtreatedfordiabetesatbaseline(heavylines)andallotherpatients(lightlines). PatientsassignedtoCABGareindicatedbysolidlines,andthoseassignedtoPTCAbydashedlines.Thenumbersofpatientsatriskareshown belowthegraphatbaseline,threeyears,andfiveyears. BARI=BypassAngioplastyRevascularizationInvestigationCABG=coronaryarterybypassgraftingCAD=coronaryarterydiseasePTCA= percutaneoustransluminalcoronaryangioplasty. ReproducedwithpermissionfromTheBypassAngioplastyRevascularizationInvestigation(BARI)Investigators.Comparisonofcoronary bypasssurgerywithangioplastyinpatientswithmultivesseldisease.NEnglJMed1996335:21725.

MortalityinPatientsAfterCABGorMultivesselPCIAccordingtoDiabetes Figure2 *Numberofpatientsavailableforfollowup.Datashowoverallunadjustedmortalityratesforpatientswithdiabetesandwithoutdiabetes.PanelA includespatientsfromalltentrials.PanelBexcludespatientsfromtheBARItrial. BARI=BypassAngioplastyRevascularizationInvestigationCABG=coronaryarterybypassgraftingPCI=percutaneouscoronaryintervention. ReproducedwithpermissionfromHlatkyMA,BoothroydDB,BravataDM,etal.Coronaryarterybypasssurgerycomparedwithpercutaneous coronaryinterventionsformultivesseldisease:acollaborativeanalysisofindividualpatientdatafromtenrandomizedtrials.Lancet 200937311907.

RatesofMajorAdverseCardiacorCerebrovascularEventsAccordingtoSYNTAXScore Figure3 CABG=coronaryarterybypassgraftingPCI=percutaneouscoronaryinterventionSYNTAX=SynergyBetweenPercutaneousCoronary InterventionWithTaxusandCardiacSurgery. ReproducedwithpermissionfromSerruysPW,MoriceMC,KappeteinAP,etal.,onbehalfoftheSYNTAXInvestigators.Percutaneouscoronary interventionversuscoronaryarterybypassgraftingforseverecoronaryarterydisease.NEnglJMed2009360:96172.

KaplanMeierSurvivalCurvesforPatientsWithCompleteandIncompleteRevascularizationAfterCoronaryStenting(1of2) Figure4a IR=incompleterevascularization. ReproducedwithpermissionfromWuC,DyerAM,KingSB,etal.Impactofincompleterevascularizationonlongtermmortalityaftercoronary stenting.CircCardiovascInterv20114:41321.

KaplanMeierSurvivalCurvesforPatientsWithCompleteandIncompleteRevascularizationAfterCoronaryStenting(2of2) Figure4b IR=incompleterevascularization. ReproducedwithpermissionfromWuC,DyerAM,KingSB,etal.Impactofincompleterevascularizationonlongtermmortalityaftercoronary stenting.CircCardiovascInterv20114:41321.

SpecialPatientSubsets
Diabetes PatientswithdiabetesandSIHDclearlyareatincreasedriskforadverse cardiovasculareventscomparedwithnondiabeticpatients.Patientswithdiabetes referredforrevascularizationoftenhavemorediffuseandcomplexCADachieving completerevascularizationwithPCIcanbemorechallenging.Asmentionedearlier, patientswithdiabetesenrolledintheBARItrialhadalowermortalityratefollowing CABGwhencomparedwithmultivesselangioplasty(Figure1).20 Intheeraofbaremetalstents,alargemetaanalysisdemonstratedimprovedlong termsurvivalanddecreasedrepeatrevascularizationinpatientswithdiabetes treatedwithCABGcomparedwithPCI(Figure2).15Themostrecentavailabledata arefromtheSYNTAXtrial.WiththeuseofdrugelutingstentsformultivesselPCI, patientswithdiabeteshadhigherratesofrevascularizationfollowingPCIthanwith CABG,particularlythosewithmorecomplexdisease.16Overall,ratesofdeath, myocardialinfarction,andstrokeweresimilarbetweenthetwogroups.However,in thesubsetofdiabeticswithSYNTAXscoresof33,mortalitywassignificantlyhigher followingPCIthanafterCABG(13.5%vs.4.1%)(Figure5).Thus,similarto nondiabeticpatients,thedecisionregardingmodeofrevascularizationshould includeconsiderationofCADcomplexityanddiseaseburden,whichisoftengreater inpatientswithdiabetes.Inpatientswithextensivedisease,CABGisthepreferred treatment. LeftVentricularSystolicDysfunction DatafromCASSandotherstudiesestablishedthatmortalityisimprovedfollowing revascularizationwithCABGinpatientswithLVdysfunctionandmultivesselCAD.2 DataintheliteraturearescarceregardingoutcomesaftercontemporaryPCIinthis patientpopulation,althoughsomestudieshavedemonstratedsimilarmortality ratesinpatientstreatedwithPCIandCABG.14Atpresent,decisionsregardingthe approachtorevascularizationinthesepatientsshouldalsobemadebasedonother factors,suchasdiseasecomplexity,presenceofdiabetes,andpatient preferences.14
Figure1

Figure2

Figure5

SurvivalAmongPatientsWithandWithoutDiabetesandMultivesselCADintheBARIStudy Figure1 Survivalamongpatientswhowerebeingtreatedfordiabetesatbaseline(heavylines)andallotherpatients(lightlines). PatientsassignedtoCABGareindicatedbysolidlines,andthoseassignedtoPTCAbydashedlines.Thenumbersofpatientsatriskareshown belowthegraphatbaseline,threeyears,andfiveyears. BARI=BypassAngioplastyRevascularizationInvestigationCABG=coronaryarterybypassgraftingCAD=coronaryarterydiseasePTCA= percutaneoustransluminalcoronaryangioplasty. ReproducedwithpermissionfromTheBypassAngioplastyRevascularizationInvestigation(BARI)Investigators.Comparisonofcoronary bypasssurgerywithangioplastyinpatientswithmultivesseldisease.NEnglJMed1996335:21725.

MortalityinPatientsAfterCABGorMultivesselPCIAccordingtoDiabetes Figure2 Numberofpatientsavailableforfollowup.Datashowoverallunadjustedmortalityratesforpatientswithdiabetesandwithoutdiabetes.PanelA includespatientsfromalltentrials.PanelBexcludespatientsfromtheBARItrial.

ReproducedwithpermissionfromHlatkyMA,BoothroydDB,BravataDM,etal.Coronaryarterybypasssurgerycomparedwithpercutaneous coronaryinterventionsformultivesseldisease:acollaborativeanalysisofindividualpatientdatafromtenrandomizedtrials.Lancet 200937311907.

ClinicalOutcomesat1YearinPatientsWithDiabetesintheSYNTAXStudy Figure5 CABG=coronaryarterybypassgraftingCVA=cerebrovascularaccidentMI=myocardialinfarctionPES=paclitaxelelutingstentsSYNTAX= SynergyBetweenPercutaneousCoronaryInterventionWithTaxusandCardiacSurgery. ReproducedwithpermissionfromBanningAP,WestabyS,MoriceMC,etal.Diabeticandnondiabeticpatientswithleftmainand/or3vessel coronaryarterydisease:comparisonofoutcomeswithcardiacsurgeryandpaclitaxelelutingstents.JAmCollCardiol201055:106775.

HybridCoronaryRevascularization
HybridcoronaryrevascularizationtypicallyischaracterizedbyelectiverevascularizationoftheLADcoronaryarterywitha leftinternalmammaryarterialgraftandPCIofoneormoremajorepicardialvessels.Otherexamplesincludeminimally invasivevalvesurgerycombinedwithPCItocoronarylesions(valve/PCI),to"convert"ahighriskvalve/CABGprocedure intoalowerrisk,isolated,minimallyinvasivevalveprocedure. Potentialbenefitsofahybridprocedureinclude:1)providesadurablerevascularizationtotheLADcoronaryartery2) allowsforaminimallyinvasivesurgicalapproach3)providesangiographicconfirmationofbypassgraftpatencyduring hybridPCI4)enablestreatmentofpatientswithinadequategraftconduitand/orheavilycalcifiedaortasand5)allows effectivetreatmentofpatientswithmultiplecomorbidities.14Emergingdatasuggestthat,inselectedpatients,outcomes followinghybridcoronaryrevascularizationaresimilartothosefollowingstandardCABG.9,10 Dependingonthecapabilitiesofthehospitalandtheneedsofthepatient,hybridproceduresmaybeperformedina hybridoperatingroomorasastagedprocedure,withinitialCABGorPCIfollowedbytheotherwithin23days.Instaged hybridprocedures,theCABGcomponentisusuallyperformedfirstinordertodelaythenecessarypostPCIdual antiplatelettherapyuntilafterthesurgeryandthusminimizebleedingrisk,andalsotoallowforbypassgraftangiography.

HeartTeamApproachtoRevascularization
ManypatientswithSIHDreferredforrevascularizationhavecomplexanatomicalCADandmultipleclinicalvariablesthat requirecarefulconsiderationwhenchoosingarevascularizationstrategy,particularlywhenbothCABGandPCIare technicallyfeasible.RecentrandomizedtrialscomparingCABGwithPCI,includingtheSYNTAXstudy,havemandatedthe formationofamultidisciplinaryHeartTeamintheevaluationofpatientswithcomplexCAD. TheHeartTeam,composedofaninterventionalcardiologist,cardiacsurgeon,andoccasionallyanoninvasive cardiologist,cannotonlyprovideacomprehensiveevaluationofthepatient'scoronaryanatomyandsuitabilityforPCIor CABG,butalsocanassessthepatient'scomorbiditiesandtreatmentpreferences.ThemostrecentACCFendorsed guidelinesforbothPCIandCABGhaverecommendedaHeartTeamapproachtorevascularizationinallpatientswith unprotectedLMCAdiseaseorcomplexCAD.11,14

Summary
Patientswithstable,symptomaticCADshouldbetreatedwithacomprehensiveapproachfocusingonreductionof coronaryriskfactorsandaggressivemedicaltherapy.Theprimarygoalsofrevascularizationarereliefofischemic symptomsrefractorytomedicaltherapyandimprovementinsurvivalwhenextensiveCADispresent. BothCABGandPCIhavespecificadvantages:CABGgenerallyismoredurable,resultinginmorereliefofanginal symptomsandfewerrepeatrevascularizationprocedures,whereasPCIisassociatedwithlessproceduralmorbidity, shorterhospitalstays,andfasterrecovery.ForuncomplicatedCAD,CABGandPCIhavesimilarlongtermoutcomes.As CADcomplexityandburdenincrease,theincidenceofcontinuedanginasymptomsandneedforrepeatrevascularization increasetoagreaterextentafterPCIcomparedwithCABG. RecentstudieshavedemonstratedsimilarlongtermsurvivalratesafterCABGandPCI,eveninpatientswithextensive CAD.However,improvedsurvivalafterrevascularizationhasonlybeenshownwithCABGinthesepatients,andthus, CABGiscurrentlythepreferredapproachforpatientswithsignificantleftmainorcomplexthreevesselCAD.Other factors,suchaspatientage,LVfunctionandthepresenceofdiabetesareimportantconsiderationsindeterminingthe optimaltreatmentforindividualswithcomplexCAD,andtheinvolvementofamultidisciplinaryHeartTeamshouldbea fundamentalcomponentoftheircare.

FutureDirections
Recently,theNationalCardiovascularDiseaseRegistryworkinggroupoftheACCwasawardedaGrandOpportunities grantbytheNationalHeart,Lung,andBloodInstitutetostudythecomparativeeffectivenessofPCIandCABGforthe treatmentofstableCAD.24Inthisstudy,theexistingACCandSocietyofThoracicSurgerydatabaseswillbeusedto compareproceduraloutcomesinaddition,longtermoutcomeswillbeanalyzedusingtheCentersforMedicare& MedicaidServices'100%denominatorfiledata.Itisanticipatedthatmorethan100,000patientswillbeincludedinthis study,whichundoubtedlywillprovidevaluableinformationoftheoptimalapproachtorevascularizationinawidearrayof patients.

KeyPoints
RevascularizationwithCABGtoimprovesurvivalisindicatedinpatientswithsignificantLMCAdiseaseorsevere threevesselCADinvolvingtheproximalLADcoronaryartery. InpatientswithsinglevesselCAD,longtermoutcomesfollowingsuccessfulPCIandCABGaresimilar. InpatientswithmultivesselCADwithoutahighlevelofcomplexity(e.g.,lowtointermediateSYNTAXscore), successfulrevascularizationwithCABGorPCIresultsinsimilarlongtermoutcomes. InpatientswithcomplexmultivesselCAD(highSYNTAXscore),revascularizationwithCABGresultsinfewer repeatrevascularizationproceduresandimprovedlongtermsurvivalcomparedwithmultivesselPCI. PatientswithsignificantleftmainorcomplexmultivesselCADideallyshouldbeevaluatedbyamultidisciplinary HeartTeamtodeterminethemostappropriatemethodofrevascularization.

References

1. GarrettHE,DennisEW,DeBakeyME.Aortocoronarybypasswithsaphenousveingraft.Sevenyearfollowup. JAMA1973223:7924. 2. AldermanEL,BourassaMG,CohenLS,etal.Tenyearfollowupofsurvivalandmyocardialinfarctioninthe randomizedCoronaryArterySurgeryStudy.Circulation199082:162946. 3. TheVACoronaryArteryBypassSurgeryCooperativeStudyGroup.EighteenyearfollowupintheVeteransAffairs CooperativeStudyofCoronaryArteryBypassSurgeryforstableangina.Circulation199286:12130. 4. YusufS,ZuckerD,PeduzziP,etal.Effectofcoronaryarterybypassgraftsurgeryonsurvival:overviewof10year resultsfromrandomisedtrialsbytheCoronaryArteryBypassSurgeryTrialistsCollaboration.Lancet 1994344:56370. 5. WijnsW,KolhP,DanchinN,etal.Guidelinesonmyocardialrevascularization.TheTaskForceonMyocardial RevascularizationoftheEuropeanSocietyofCardiologyandtheEuropeanAssociationforCardioThoracic Surgery.EurHeartJ201031:250155. 6. GruentzigAR,SenningA,SiegenthalerWE.Nonoperativedilatationofcoronaryarterystenosis:percutaneous transluminalcoronaryangioplasty.NEnglJMed1979301:618. 7. MarsoSP,AminAP,HouseJA,etal.Associationbetweenuseofbleedingavoidancestrategiesandriskof periproceduralbleedingamongpatientsundergoingpercutaneouscoronaryintervention.JAMA2010303:2156 64. 8. HilliardAA,FromAM,LennonRJ,etal.Percutaneousrevascularizationforstablecoronaryarterydisease. Temporaltrendsandimpactofdrugelutingstents.JACCCardiovascInterv20103:1729. 9. ZhaoDX,LeaccheM,BalaguerJM,etal.Routineintraoperativecompletionangiographyaftercoronaryartery bypassgraftingand1stophybridrevascularization:resultsfromafullyintegratedhybridcatheterization laboratory/operatingroom.JAmCollCardiol200953:23241. 10. HalkosME,VassiliadesTA,DouglasJS,etal.Hybridcoronaryrevascularizationversusoffpumpcoronaryafter bypassgraftingforthetreatmentofmultivesselcoronaryarterydisease.AnnThoracSurg201192:1695702. 11. HillisLD,SmithPK,AndersonJL,etal.2011ACCF/AHAGuidelineforCoronaryArteryBypassGraftSurgery.A reportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPractice Guidelines.DevelopedincollaborationwiththeAmericanAssociationforThoracicSurgery,Societyof CardiovascularAnesthesiologists,andSocietyofThoracicSurgeons.JAmCollCardiol201158:e123210. 12. PatelMR,DehmerGJ,HirshfeldJW,etal.ACCF/SCAI/STS/AATS/AHA/ASNC2009AppropriatenessCriteriafor CoronaryRevascularization:areportbytheAmericanCollegeofCardiologyFoundationAppropriatenessCriteria TaskForce,SocietyforCardiovascularAngiographyandInterventions,SocietyofThoracicSurgeons,American AssociationforThoracicSurgery,AmericanHeartAssociation,andtheAmericanSocietyofNuclearCardiology. EndorsedbytheAmericanSocietyofEchocardiography,theHeartFailureSocietyofAmerica,andtheSocietyof CardiovascularComputedTomography.JAmCollCardiol200953:53053. 13. KapoorJR,GiengerAL,ArdehaliR,etal.Isolateddiseaseoftheproximalleftanteriordescendingartery: comparingtheeffectivenessofpercutaneouscoronaryinterventionsandcoronaryarterybypasssurgery.JACC CardiovascInterv20081:48391. 14. LevineGN,BatesER,BlankenshipJC,etal.2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronary Intervention.AreportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForce onPracticeGuidelinesandtheSocietyforCardiovascularAngiographyandInterventions.JAmCollCardiol 201158:e44122. 15. HlatkyMA,BoothroydDB,BravataDM,etal.Coronaryarterybypasssurgerycomparedwithpercutaneouscoronary interventionsformultivesseldisease:acollaborativeanalysisofindividualpatientdatafromtenrandomised trials.Lancet2009373:11907. 16. BanningAP,WestabyS,MoriceMC,etal.Diabeticandnondiabeticpatientswithleftmainand/or3vessel coronaryarterydisease:comparisonofoutcomeswithcardiacsurgeryandpaclitaxelelutingstents.JAmColl Cardiol201055:106775. 17. HannanEL,RaczMJ,WalfordG,etal.Longtermoutcomesofcoronaryarterybypassgraftingversusstent implantation.NEnglJMed2005352:217483. 18. HannanEL,WuC,WalfordG,etal.Drugelutingstentsvs.coronaryarterybypassgraftinginmultivesselcoronary disease.NEnglJMed2008358:33141. 19. BenedettoU,MelinaG,AngeloniE,etal.Coronaryarterybypassgraftingversusdrugelutingstentsinmultivessel coronaryarterydisease:ametaanalysison24,268patients.EurJCardiothoracSurg200936:6115. 20. TheBypassAngioplastyRevascularizationInvestigation(BARI)Investigators.Comparisonofcoronarybypass surgerywithangioplastyinpatientswithmultivesseldisease.NEnglJMed1996335:21725. 21. SianosG,MorelMA,KappeteinAP,etal.TheSYNTAXScore:anangiographictoolgradingthecomplexityof coronaryarterydisease.EuroIntervention20051:21927. 22. SerruysPW,MoriceMC,KappeteinAP,etal.,onbehalfoftheSYNTAXInvestigators.Percutaneouscoronary interventionversuscoronaryarterybypassgraftingforseverecoronaryarterydisease.NEnglJMed 2009360:96172. 23. WuC,DyerAM,KingSB3rd,etal.Impactofincompleterevascularizationonlongtermmortalityaftercoronary stenting.CircCardiovascInterv20114:41321. 24. KleinLW,EdwardsFH,DeLongER,RitzenthalerL,DangasGD,WeintraubWS.ASCERT:theAmericanCollegeof CardiologyFoundationTheSocietyofThoracicSurgeonscollaborationonthecomparativeeffectivenessof revascularizationstrategies.JACCCardiovascInterv20103:1246.

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7.5:Hibernation,Stunning/Viability
Author(s): AnnaLisaCrowleyMD,FACC RaymondJ.KimMD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. 2. 3. 4. Definemyocardialhibernation,stunning,andviability. Identifythetechniquescurrentlyavailabletoassessmyocardialviability. DescribetheSTICH(SurgicalTreatmentforHeartDisease)trial. Examinetheunderlyingassumptionsinviabilitytesting.

Introduction
Background Theconceptthatdysfunctionalmyocardiummaybeviablehasbeenknownfordecades.Specificphysiologicstatesthat canresultindysfunctional,yetviablemyocardiumarestunningandhibernation."Myocardialstunning"describesthe stateofpostischemicmyocardialdysfunctioninthepresenceofrelativelynormalbloodflow.1 Onlightmicroscopy, stunnedmyocardiumappearsnormal.However,thereisdecreasedadenosinetriphosphateandsubtleultrastructural abnormalities.2 Themechanismunderlyingstunningisnotcompletelyunderstood.Ithasbeenproposedthatstunninginvolves myofilamentdesensitizationtocalcium,possiblybyinitialcalciumoverloadduringreperfusion,leadingtotroponinI proteolysisand/oroxygenradicalformationduringischemiareperfusiondamagingthecontractilecellmembranes.In general,stunnedmyocardiumhasbeenshowntorecoverfunctionwithinhourstodays,andrecoverymaytakelongerin casesoflongerischemicepisodespriortorevascularization.3 Theterm"myocardialhibernation"describesthestateofchronicmyocardialdysfunctionatrestthatcanbepartiallyor completelyrestoredtonormaleitherbyimprovingbloodflowand/orbyreducingdemand.4 Thisphysiologywasfirst notedwhenventricularwallmotionabnormalitiesimprovedaftercoronaryarterybypassgrafting(CABG).57Biopsy specimensfromregionsofdysfunctionalmyocardiumthatrecoveredfunctionafterCABGshowedthat90%ofthevolume consistedofviablecells.8,9However,increasedglycogenisseeninareaspreviouslyoccupiedbymyofilaments,and smallmitochondriaarepresent.10Themechanismunderlyinghibernatingmyocardiumisnotcompletelyunderstood,but manyinvestigatorsbelieveitisduetoachronicreductioninrestingcoronarybloodflow.Otherssuggestthatbloodflowis normalinhibernatingmyocardium,andthatthedysfunctionresultsfromrepetitiveepisodesofstunning.10Incontrastto therelativelyearlyrecoveryoffunctionseenwithmyocardialstunning,recoveryoffunctionhasbeenshowntotakeupto1 yearafterrevascularizationinmyocardialhibernation.3 Thus,myocardialstunningandhibernationbothrepresent myocardiumthatisalive(orviable),ratherthandead(ornonviable). ClinicalImportanceofViability Inpatientswithcoronaryarterydisease(CAD)andleftventricular(LV)systolicdysfunction,determiningwhichpatients maybenefitmostfromrevascularizationisclinicallyimportant.Guidelinesforrevascularizationareprovidedbythe AmericanCollegeofCardiologyFoundationandtheAmericanHeartAssociation(ACCF/AHA),whichwaslastupdatedin 201111 InpatientswithpoorLVfunction,surgicalrevascularizationisgivenaClassIrecommendation(evidence/agreementthat treatmentisuseful/efficacious)forpatientswiththefollowingcoronaryanatomy:1)significantleftmainstenosisor2) proximalLADstenosiswithtwoorthreevesseldisease. Theserecommendationsarebasedlargelyondatafromolderrandomizedtrialsthatfocusedprimarilyonthe angiographicappearanceofCADanddidnottakeotherfactorssuchasmyocardialviabilityintoconsideration.While thesestudiesshowedbenefitintheoverallpopulationwithsevereangiographicdisease,fromamechanisticpointof view,onewouldexpectthatadditionalinformation,suchasthepresenceorabsenceofextensiveviablemyocardium, couldimprovepatientriskstratificationforrevascularization. Thepotentialimportanceofmyocardialviabilitytestinginreferencetoprognosisafterrevascularizationhasbeen evaluatedinmanysmall,singlecenterstudies,includingametaanalysisdemonstratingdecreasedannualmortalityin patientswithviabilitywhowereundergoingrevascularizationcomparedtothosewhowerenotundergoing revascularization.12 Allmanetal.,inametaanalysisof24studies,whichincluded3,088patientswithameanLVejectionfraction(EF)of 32%,concludedthat,inpatientswithsignificantviability(asdeterminedbythalliumperfusionimaging,F18 fluorodeoxyglucosemetabolicimaging,ordobutamineechocardiography),revascularizationwasassociatedwitha 79.6%reductioninannualmortalitycomparedwithmedicaltreatment(3.2%vs.16%p<0.0001).13Conversely,in patientswithoutviability,mortalityratesweresimilarforrevascularizationandmedicaltherapy(7.7%vs.6.2%p=not significant). Basedondatasuchasthese,theACCF/AHAguidelinesonthediagnosisandmanagementofheartfailurefrom2009 andCABGsurgeryfrom2011statethatCABG,inadditiontothosewiththecoronaryanatomydescribedearlier,maybe performedinpatientswithpoorLVfunctionandsignificantCADifthereissignificantviablemyocardium(ClassIIa recommendation[weightofevidence/opinionisinfavorofusefulness/efficacy]).11,14Incontrast,CABGisnot recommendedinpatientswithoutevidenceofintermittentischemiaandsignificantviablemyocardium(ClassIII recommendation[evidence/agreementthattreatmentisnotuseful/efficaciousormaybeharmful]).

However,theevidencefortheserecommendationshaslimitations.First,studiesweresmall,notrandomized, observational,andretrospective,leadingtopotentialpatientselectionbias.Second,themethodologyandcriteriafor definingviability,aswellasthetreatmentregimens,werenotstandardizedamongthedifferentstudies.Finally,the successandcompletenessofmyocardialrevascularizationwasnotinvestigatedbyfollowupangiographyorstress imagingdatainmoststudies.12Giventheseflaws,metaanalysesincorporatingthesedataaresubjecttothesame limitations.Inpart,duetotheselimitations,theSTICHtrialwasundertaken.15 STICHwasarandomized,multicenter,nonblindedtrialfundedbytheNationalHeart,Lung,andBloodInstitute.15 PatientswithangiographicdocumentationofCADamenabletosurgicalrevascularizationandLVsystolicdysfunction(EF 35%)wereeligibleforenrollment.Exclusioncriteriawereleftmainstenosis>50%,cardiogenicshock,myocardial infarction(MI)within3months,andneedforaorticvalvesurgery.Inhypothesis1,enrolledpatientswererandomly assignedtoreceivemedicaltherapyaloneormedicaltherapyplusCABG.Inhypothesis2,enrolledpatientswere randomlyassignedtoreceivemedicaltherapyplusCABGormedicaltherapyplusCABGandsurgicalventricular reconstruction. Between2002and2007,1,212patientsfrom99centersin22countrieswereenrolledinhypothesis1.Theprimary endpointwasdeathfromanycause.IntheinitialdesignoftheSTICHtrial,viabilitytestingwithsinglephotonemission computedtomography(SPECT)wasrequired.However,thisrequirementprovedtobeanimpedimenttostudy enrollment.Therefore,theprotocolwasrevisedin2004tomakeviabilitytestingoptional,andthedecisiontoperformthe testwasleftuptotherecruitinginvestigators.Inaddition,theviabilitytestoptionswereexpandedtoincludeSPECT(four separateprotocols),dobutaminestressechocardiography(DSE),orboth.16 Overall,therewasnosignificantdifferencebetweenpatientswithmedicaltherapyaloneandmedicaltherapyplusCABG withrespecttotheprimaryendpointofdeathfromanycauseatamedianof5.1yearsoffollowup.15Inthe601patients whoreceivedaviabilitystudy,therewasasignificantassociationbetweenviabilityandoutcomeonunivariateanalysis, butnotonmultivariateanalysis.Surprisingly,theassessmentofmyocardialviabilitydidnotidentifypatientswitha differentialsurvivalbenefitfromCABG,ascomparedwithmedicaltherapyalone,incontrastwiththepriorliterature.16 TheauthorspointoutthatconclusionsdrawnfromSTICHarelimitedbyanumberoffactors.16First,slightlylessthan halfofthe1,212patientsenrolledinthehypothesis1comparisonunderwentviabilitytesting.Second,patientswerenot randomizedtoviabilitytesting,andthird,testingcouldhavebeenperformedpriorto,onthedayof,orafterstudy enrollment.Thesefactorsmayhaveledtopatientselection/enrollmentbiasandmayhaveinfluencedsubsequentclinical decisionmaking.Additionally,onlyasmallpercentageofpatientsweredeemednottohaveviablemyocardium(19%), whichlimitedthepoweroftheanalysistodetectadifferentialeffectofCABG,ascomparedtomedicaltherapyalone,in patientswithmyocardialviabilityascomparedtothosewithoutmyocardialviability.Lastly,theviabilityanalyseswere limitedtoSPECTandDSEimaging.WhiletheresultsweresimilarforSPECTandforDSE,cautionshouldbetakento notextrapolatetheseresultstootherimagingmodalitiesthatwerenottestedinSTICH,suchaspositronemission tomography(PET),delayedenhancementcardiacmagneticresonance(DECMR),anddelayedenhancement multidetectorcomputedtomography(DEMDCT). Despitethestudylimitations,theSTICHtrialisalandmarkinvestigationthatraisesanimportantquestion:Isviability assessmentimportant?Fromapathophysiologicviewpoint,itwouldbedifficulttointerprettheSTICHresultsas concludingthatalivemyocardiumisthesameasdeadmyocardium.Ontheotherhand,fromaclinicalviewpoint,the STICHresultsshowthatusing"statusquo"viabilitymethodstodeterminewhowillbenefitfromCABGishighly problematic.Asaresult,thereclearlyisaneedtoreassesstheunderlyingmechanismsregardinghowviabilitytestsare assumedtoworkandhowtheyareinterpreted. Thefollowingsectionswillfocusonthecurrenttechniquesusedtoassessmyocardialviabilityandtheirunderlying pathophysiologicbasis,andexplorewhatmightconstitutean"ideal"technique.GiventheresultsfromSTICH,the numeroussmallstudiespublishedpriortoSTICHrelatingviabilityimagingtofunctionalrecoveryandprognosiswillnot besummarized.Instead,fundamentalconceptsinviabilityassessmentwillbeexamined.Additionally,DECMRasa paradigmwillbeusedtodiscussmanyoftheunderlyingassumptionsinviability.

PhysiologicalBasisOfViabilityTesting
Morphology SimplemorphologicalcharacteristicsoftheLVmayprovideusefulinformationabout viability.Forinstance,ventricularwallthinninghasbeenusedasamarkerforthe absenceofviability,basedonthehypothesisthatathinnedregionrepresentsscar tissueandchronicMI.Cwajgetal.studied45patientswithstableCADandLV dysfunctionusingechocardiography.andconcludedthat"asimplemeasurementof enddiastolicwallthickness6mmvirtuallyexcludesthepotentialforrecoveryof function."17Similarly,Baeretal.studied43patientswithchronicMIandLV dysfunctionwithcardiacmagneticresonance(CMR)andconcludedthat"the depictionofsignificantlyreducedenddiastolicwallthickness(<5.5mm)excludesa clinicallyrelevantamountofpersistentviablemyocardium."18 However,therearesomelimitationswiththisapproach.First,itisnotintendedto examineviabilityinthesettingofacuteMIwherewallthicknessmaybenormalor evenincreasedbyasmuchas50%despitethelackofviablemyocytes.19Second, thetimerequiredforacutemyocardialnecrosistohealandturnintocollagenous scarwithresultantwallthinningmaybesubstantialandintheorderof68weeks. Third,eveninthechronicsetting,althoughitisclearthattransmuralinfarctionis frequentlyassociatedwithmyocardialthinning,therearelessdatainthesettingof nontransmuralinfarction,andthetransmuralityofinfarctionthatisnecessaryforwall thinningisunknown. Function Bydefinition,thepresenceofcontractionorsystolicwallthickeninginaregion demonstratessubstantialviablemyocardium.However,theconversemaynotbe true.Absentrestingcontractiondoesnotnecessarilymeanthatthemyocardiumis dead.Obviousexamplesofthisincludethephenomenaofmyocardial"stunning" and"hibernation"inwhichcontractionisabsentdespitepreservedviability. Clinically,dysfunctional,butviable,myocardiummaybedifferentiatedfrominfarction byassessingcontractilereserve,asonlyviablemyocardiumwillrespondto inotropicstimulationbydemonstratingenhancedcontractionandsystolicthickening. Basedonthisprinciple,bothDSEandCMRhavebeenusedtoassesscontractile reserveandthusviability.Ingeneral,bothDSEandCMRdemonstratelower sensitivitythanspecificityforpredictingfunctionalimprovement.18,20,21 Theobservationthatcontractilereservemayhaverelativelymodestsensitivityfor predictingfunctionalimprovementhighlightstheindirectrelationshipbetween contractilereserveandviability.Experimentalstudiesofchroniclowflowischemia haveshownthatsomeviableregionsaresodelicatelybalancedbetween reductionsinflowandfunction,withexhaustedcoronaryflowreserve,thatany inotropicstimulationmerelyresultsinischemiaandprecludestheabilitytoenhance contractility.22 Perfusion Myocardialperfusionisrelatedtomyocardialviabilityinthatchronicabsenceof bloodflow,ofcourse,isincompatiblewithviability.However,itisimportantto recognizethatperfusiondoesnothaveadirectonetoonerelationshipwithviability. Forexample,myocardialischemiaiscausedbyreducedperfusion,butthis pathophysiologicstate,bydefinition,requiresviablemyocardium.Reperfusedacute infarctionisanotherpathophysiologicstatewhereperfusionandviabilityare dissociated.Theentireinfarctedregionisbydefinitionnonviablehowever,tissue perfusionmayrangefromnearlyzeroincentralregionsoftheinfarctwithprofound microvasculardamagetonearlynormalinotherregionsinwhichthe microvasculatureisintact.23 Theheterogeneityofperfusioninreperfusedinfarctionhasbeendemonstratedin humansusingcontrastechocardiography,24andmeasuredinanimalmodelsusing radioactivemicrospheres.25Additionally,thepathophysiologyofhibernating
Figure1

myocardiumitselfsuggestsadiscordance.Althoughtherearesomeconflicting data,hibernatingmyocardium,whichrepresentsviabletissue,isbelievedtobedue tochronicallyreducedperfusion.Thesediscrepanciesintherelationshipbetween perfusionandviabilityunderscorethepotentiallimitationsinutilizingatechnique thatmeasuresperfusionforassessingviability. MetabolismandCellMembraneIntegrity Techniquesthatexaminethemetabolicactivityorcellmembraneintegrityof myocytesshouldprovide,atleasttheoretically,themostdirectmeansfor determiningwhethermyocytesarealiveordead.Scintigraphictechniquesusing PETorSPECTareexamplesofsuchmethods.26Specifically,preservedglucose metabolismcanbeexaminedbyF18fluorodeoxyglucose(FDG)PET,cell membraneintegritybythallium201SPECT,andintactmitochondriabytechnetium 99msestamibiSPECT.Forthelattertwotechniques,however,myocardialperfusion probablyalsoaffectstraceractivitytosomedegree. Overall,radionuclidetechniquesdemonstratemoderatetogoodsensitivity(8193%) butpoorspecificity(5066%)forpredictingfunctionalimprovement.20Ingeneral, SPECThaslowerdiagnosticaccuracythanPETandismoreproneto underestimateviability,27mostlikelybecauseoftechnicallimitations,suchaslower spatialresolution,useoflowerenergytracers,andlackofbuiltinattenuation correction.Thepoorspecificityofbothtechniquesmayalsorelatetotechnical limitationshowever,theuseoffunctionalimprovementafterrevascularizationasthe truthstandardforviabilitymayresultinanartificiallylowspecificity. DECMRisanothertechniquethatcanindexcellmembraneintegrity.Althoughthe gadoliniumbasedcontrastmediausedforDECMRisinert,andactivetransport processesacrosscellmembranessuchasforthalliumarenotpresent,there appearstobeadirect,butinverserelationshipbetweengadoliniumconcentration andthepercentageofviablemyocyteswithinanygivenregionofmyocardialtissue. Themechanismislikelybasedonthefollowing:1)tissuevolumeinnormal myocardiumispredominantlyintracellular(7580%ofthewaterspace)28and2) currentlyavailablegadoliniumcontrastmediaare"extracellular"agentssincethey donotcrosscellmembranes.29Thus,thevolumeofdistributionofgadolinium contrastinnormalmyocardiumisquitesmall(approximately20%ofwaterspace), andonecanconsiderviablemyocytesasactivelyexcludingcontrastmedia.30 Pathophysiologicstatesthatresultinareduceddensityofviablemyocyteswillthen haveincreasedvolumeofdistributionofgadoliniumandhigherconcentration.31 Notethatthismechanismisindependentofthecauseoretiologyfornonviable myocardium.Whetherthetissueconsistsofcontractionbandnecrosisinthesetting ofacuteMI,collagenousscarinchronicMI,orfibrosisinvariousnonischemic cardiomyopathies,theregionwillhaveincreasedgadoliniumconcentrationifthere isareduceddensityofviablemyocytes.30 DECMRhasbeenshowntobehighlyeffectiveinidentifyingthepresence,location, andextentofMIinboththeacuteandchronicsettingsinbothanimalandhuman studies.3135Additionally,ithasbeenusedtopredictreversiblemyocardial dysfunctioninthoseundergoingrevascularizationprocedures.3638 RecentlythedelayedenhancementconcepthasbeenextendedtoMDCT.The interpretationofcontrastenhancementpatternsonMDCTappearsquitesimilarto thatforDECMR,andislikelybasedonthesameunderlyingmechanismbecause theiodinatedcontrastmediausedforMDCThasnearlyidenticalpharmacokinetics asthatof"extracellular"gadoliniumcontrast.39 Likewise,inanimalmodels,DEMDCTassessmentofacuteandchronicMIhas beenshowntoaccuratelyreflecttrueinfarctsizeandmorphologyasdeterminedby histopathology.40Althoughcurrentlytherearefewstudiesinhumans,39,41these initialstudieshavedemonstratedanexcellentagreementbetweenDEMDCTand CMR,albeitwithreducedcontrasttonoiseratioandimagequalityfor MDCT.39Figure1showsacomparisonbetweenDEMDCTandDECMRinthree patients.

DelayedEnhancementImagesFromCardiacMagneticResonanceandMultidetectorComputedTomographyin3DifferentPatientsWithAcute MyocardialInfarctions Figure1 Shortaxisdelayedenhancementcardiacmagneticresonance(panelsa,c,e)anddelayedenhancementmultidetectorcomputedtomography images(panelsb,d,f)inthreedifferentpatientswithacutemyocardialinfarctionattributabletoleftanteriordescendingartery(panelsa,b),right coronaryartery(panelsc,d),andleftcircumflexartery(panelse,f)occlusionaftersuccessfulrevascularization.Thereisexcellentagreement betweenhyperenhancedregions(arrows)onthetwotechniques. AdaptedwithpermissionfromMahnkenAH,KoosR,KatohM,etal.Assessmentofmyocardialviabilityinreperfusedacutemyocardialinfarction using16slicecomputedtomographyincomparisontomagneticresonanceimaging.JAmCollCardiol200545:20427.

The"Ideal"Technique
KnowingHowMuchIsAliveIsNotEnough Ausefulexerciseistoconsiderwhatmightconstitutean"ideal"techniquefor assessingviability.Certainly,itwouldbeimportantforthetechniquetobefastand safe,andtoprovidereproducibleresults.However,whatmightnotbesoapparentis thatevenifatechniquewereavailablethatcouldofferprecisequantificationof viabilitywithouttechnicallimitations(e.g.,infinitespatialresolution,noartifacts),this wouldstillbeinsufficienttoprovideacompletecharacterizationofviability,andthus, wouldbeinsufficienttoprovidethehighestaccuracyinpredictingwallmotion improvementorclinicalbenefitaftercoronaryrevascularization.42 Certainly,thereareadditionalfactorsthatarenotrelatedtolimitationsinnoninvasive testingthatcouldreduceaccuracyinpredictingfunctionalimprovement.Thesehave beenwelldescribedandincludeperioperativeorpostoperativeoccultMI,43 incompleterevascularizationasaresultofdiffusedisease,44ortetheringofregions withextensivescarringadjacenttoviableregions.45Forthepurposesofthis section,theseclinicalfactorswillnotbeconsideredinstead,itwillfocusonissues relatedtothenoninvasiveassessmentofviabilityandwillexaminetheconceptthat "knowinghowmuchisaliveisnotenough." Acentraltenetofthisconceptisthatatechniquethatoffersevenaperfect assessmentofwhatisalive(viable)hassubstantialandpracticallimitations comparedwithatechniquethatoffersbothanassessmentofwhatisaliveandwhat isdead(nonviable).Thistenetmaybecounterintuitive,becauseitwouldseemthat byknowingexactlyhowmuchisalive,bydeductivelogic,oneshouldknowhow muchisdead.However,thisisanincorrectassumption,andthepatientexamples inFigure2maybeillustrative. TheleftpanelinthetoprowofFigure3(PatientA)showsamidventricular,shortaxis DECMRimageofanormalheartindiastole.WithDECMR,nonviableregionssuch asinfarctionappearbright(hyperenhanced),whereasviableregionsappearblack. First,consideronlya"nonviability"orbrightregionassessment.Aquickvisual inspectionshowsnoevidenceofmyocardialbrightregionsthus,onerapidly concludesthatnoinfarctionispresent.Incomparison,nowconsideronlya"viability" orblackregionassessment.Onecantracetheendocardialandepicardialborders ofviablemyocardium(centerpanel),andthenplotthetransmuralextentofviability asafunctionofposition,startingfromtheanteriorwallat12:00andmoving counterclockwisearoundtheLV(rightpanel). Fromtheplot,itisobviousthatthereismarkedheterogeneityinthetransmural extentofviability,withasmuchas12mmofviablemyocardiumintheportionofthe inferiorwalladjacenttotheposteriorpapillarymuscleandaslittleas7mminthe anteroseptalwallattheRVinsertionsite.Concerningthisfinding,itisimportantto notethatithasbeenlongknownthattherecanbesignificantvariationindiastolic wallthicknessatdifferentpointsaroundtheLV,evenifpapillarymusclesare excludedandhealthyvolunteersarestudied.46Thisobservationthennaturally proceedstotheconclusionthattherecanbesignificantvariabilityinthetransmural extentofviablemyocardiumatdifferentlocationsofthenormalLV,aswasfoundin PatientA. Theprinciplethatnormalheartscanhavesignificantheterogeneityintheextentof viablemyocardiumhasdirectclinicalimplications.Forexample,inaregionwith 70%,theviabilityoftheregionwiththemaximumamountofviabilitymayrepresent eitheranormalregionwith70%thewallthicknessofthethickestregionoraregion withasubendocardialMI.TheimagesfromPatientB(Figure2)underscorethis concept.ThisparticularpatienthadaclinicallydocumentedMIduetoocclusionof therightcoronaryartery(RCA),whichwasreopenedduringprimaryangioplasty. Again,considerfirstonlya"nonviability"assessment.Fromaquickvisualperusal (leftpanel),onecandeterminethatthereisasubendocardialbrightregioninthe inferoseptalwallconsistentwiththepatient'spriorMIintheRCAperfusionterritory. Next,consideronlya"viability"assessment,similartotheassessmentperformedin
Figure2

Figure3

Figure4

Figure5

PatientA.Again,endocardialandepicardialcontoursaretraced(centerpanel) however,onedifferenceshouldbenoted.Theendocardialcontourisalongthe borderofviable(black)myocardium,andtheinfarctedregionisnotincluded.The plotshowingtheextentofviablemyocardium(rightpanel)oncemoreshowsmarked regionalvariability,andfromthisassessment,thepresenceand/orlocationof infarctionisnotevident.Thus,inthispatient,theintrinsicvariationintheextentof viablemyocardiumfornoninfarctedregionsisgreaterthanthereductioninviable myocardiumfortheregionwithsubendocardialinfarction.Thisrendersthe subendocardialinfarction"invisible"foranytechniquethatcanassessonlyviable myocardium,evenifthetechniquehasperfectaccuracyandhasinfinitespatial resolution. Thesetwopatientexampleshighlightthedifferencesbetweentechniquesthatcan visualizeonlyviablemyocardium,asopposedtotechniquesthatcanvisualizeviable andnonviablemyocardium.Additionally,itisimportanttorecognizethattheuseof differenttechniquesoftenleadtodifferencesinthewayinwhichviabilityis quantified,althoughthenomenclatureusedmaybethesame.Forinstance,when onlyviablemyocardiumcanbevisualized,thepercentageofviabilityinanygiven segmentisassessedindirectlyandgenerallyreferstotheamountofviabilityinthe segmentnormalizedtothesegmentwiththemaximumamountofviabilityortodata fromagenderspecificdatabaseofcontrols.Conversely,whenbothviableand nonviablemyocardiumcanbevisualized,thepercentageofviabilitycanbe assesseddirectlyandexpressedastheamountofviabilityinthesegment normalizedtotheamountofviabilityplusinfarctioninthesamesegment(Figure3). Thedifferencesinthewayinwhichviabilityismeasuredcanalterclinical interpretation.ForthenormalheartinPatientA,theindirectmethodwouldshowthat thereissignificantregionalvariabilityintheextentofviablemyocardium:60100%of maximumviabilitywhereas,thedirectmethodwouldshowessentiallynovariability becauseallofthesegmentswouldbeclassifiedas100%viable.Likewisefor PatientB,theindirectmethodwouldnotbeabletoidentifytheregionof subendocardialinfarctionbecausetheextentofviablemyocardiuminthissectoris withinthenormalvariationwhereas,thedirectmethodwouldclearlyidentifythe regionwithsubendocardialinfarctionbecausethisregionwouldbetheonlyregion withlessthan100%viablemyocardium. Thesepatientexamplesalsoclarifythemechanismbywhichsubendocardial infarctsareroutinelymissedbytechniquessuchasSPECTandPET(Figure4).4749 Althoughitisoftenreportedthatlimitedspatialresolutionisthereason,itshouldbe evidentthateveninfinitespatialresolutionwouldnotimprovethedetectionof subendocardialinfarctionbytheseorothermethodologiesbasedonassessing onlyviablemyocardium.Conversely,amethodologywithpoorspatialresolution (e.g.,asinglevoxelacrosstheLVwall)wouldstillbeabletodetectsubendocardial infarctionifithadtheabilitytoassessbothaliveanddeadtissue. Is'Thinned'MyocardiumAlwaysDead? Asdiscussedearlierinthemodule,priorstudiesreportthat,inpatientswith coronarydiseaseandLVdysfunction,regionswiththinnedmyocardiumrepresent scartissueandcannotimproveincontractilefunctionafterrevascularization.17 Somerecentobservationsappeartorefutethisconcept.17,50,51 Figure5showsCMRimagesoftwopatients(PatientCandPatientD)whohave severeCADandchronicLVdysfunction.Theleftpanelsrepresentlongaxisviews acquiredbeforecoronaryrevascularization.Twopointsshouldbenotedonthecine images.First,bothpatientshaveseverecontractiledysfunctionoftheanteriorwall. Second,PatientDhasassociatedthinningoftheanteriorwall(diastolicwall thickness,5.0mm),whereasPatientCdoesnot(diastolicwallthickness,8.0mm). Basedonthesecineimagesandtheexistingliterature,onemightexpectthatthere ismoreviablemyocardiumintheanteriorwallofPatientCthaninPatientD,and,in fact,questiontheneedforviabilitytestingatallinPatientDbecausethethinned, akineticanteriorwallmustundoubtedlybescartissueandthusnonviable. TheDECMRimagesacquiredbeforerevascularization,however,indicateadifferent clinicalinterpretation.InPatientC,thereisabrightendocardialrimof hyperenhancement(infarction)thatmeasures,onaverage,4.5mminthickness.

Theremainingepicardialrimoftissue,whichisblack(viable),measures3.5mmin thickness(totalthickness,8mm).InPatientD,thereisalsoanendocardialrimof hyperenhancementhowever,itmeasuresonaverageonly1.5mminthickness.The epicardialrim,whichisviablemeasures3.5mminthickness(totalthickness,5 mm).Notethat,inbothpatients,theabsoluteamountofviablemyocardiumisthe same(3.5mm),however,whentheextentofviabilityisexpressedasapercentage ofthetotalamountofmyocardiuminthesegment,PatientChaslessthan50% viablemyocardium(3.5/8=44%),whereasPatientDhas>50%viablemyocardium (3.5/5=70%). Therightmostpanelsrepresentcineimagesacquired2monthsaftercoronary revascularization.PatientCexhibitsnoimprovementincontractilefunctioninthe anteriorwalland,infact,developsdiastolicwallthinninginthisregion.Conversely, PatientDexhibitsnotonlysignificantimprovementinanteriorwallcontractile function,butalsorecoveryofdiastolicwallthicknessinthisregion(from5mmto9 mm). Threefundamentalpointsareraisedbythesepatientexamples.First,itisapparent thatamethodthatcanquantifyonlyviablemyocardium,eveniftechnicallyflawless (e.g.,infinitespatialresolution,noartifacts),providesinsufficientinformationtoallow acomprehensiveassessmentofmyocardialviability.Becausebothpatientshadthe same,reducedamountofviablemyocardium(3.5mmthickness),wewouldhave predicted,incorrectlyasitturnsout,thatbothpatientswouldnotimprovein contractilefunctionfollowingrevascularization. Second,itisevidentthattheabsoluteamountofviablemyocardiuminagivenregion isdynamicandcanincreaseordecreaseasaresultofventricularremodeling. Whereasitiscommonknowledgethatmyocardialviabilitycandecrease,for exampleduetoMIwithassociatedwallthinning,thereverseprocessinwhich regionsofthinmyocardiumbecomethickwithanabsoluteincreaseinthe transmuralextentofviability(asinPatientD)hasnotbeendescribed. Third,itappearsthatquantificationofnonviable,inadditiontoviable,myocardiumis importantinpredictingcontractileimprovementfollowingrevascularization.For instance,incorporatinginformationregardingnonviablemyocardiumintoaratioof viabletototalmyocardium(viableplusnonviable)withinthesameregionwouldlead totheconclusionthattheanteriorwallofPatientDhasahigherpercentageofviable myocardium(70%)thanPatientC(44%),andthus,ismorelikelytoimprovein contractilefunction.Thefollowupcineimagesinthefiguredemonstratethatthis predictioniscorrect.Futureinvestigationsarenecessarytoexploreandvalidate theseconcepts.

RegionalVariationinDeterminingtheExtentofViableMyocardium Figure2 Leftpanelsshowdelayedenhancementimagesofanormalsubject(PatientA)andapatientwithasubendocardial,inferiorwallmyocardial infarction(PatientB).Thecenterpanelsshowtracingofthebordersofviablemyocardium.Therightpanelsplottheextentofviability(thickness) asafunctionofleftventricularlocation.Notethatthereissignificantregionalvariationintheextentofviablemyocardium. AdaptedwithpermissionfromKimRJ,ShahDJ.Fundamentalconceptsinmyocardialviabilityassessmentrevisited:whenknowinghowmuchis "alive"isnotenough.Heart200490:13740.

DifferencesBetweenanIndirectandDirectMethodofQuantifyingRegionalMyocardialViability Figure3 Cartoonhighlightingdifferencesbetweenanindirectanddirectmethodofquantifyingregionalviability.Theindirectmethodisbasedon assessmentofviableregionsonly.Thedirectmethodisbasedonassessmentofviableandnonviableregions.Viablemyocardiumisblack,and infarctiswhite.Remotezonerepresentssegmentwithmaximumamountofviability. ReproducedwithpermissionfromFusterV,KimRJ.Frontiersincardiovascularmagneticresonance.Circulation2005112:13544.

ShortAxisViewsFromThreeCaninesWithSubendocardialMyocardialInfarctions Figure4 Comparisonofamethodthatindexescellmembraneintegrityanddetectsonlyviablemyocardium(singlephotonemissioncomputedtomography [SPECT])andamethodthatindexescellmembraneintegrityanddetectsbothviableandnonviablemyocardium(delayedenhancementcardiac magneticresonance[DECMR])withhistologyinthreecanineswithsubendocardialinfarcts(arrows).Notethattheinfarctsarenotevidenton SPECT. AdaptedwithpermissionfromWagnerA,MahrholdtH,HollyTA,etal.ContrastenhancedMRIandroutinesinglephotonemissioncomputed tomography(SPECT)perfusionimagingfordetectionofsubendocardialmyocardialinfarcts:animagingstudy.Lancet2003361:3749.

CardiacMagneticResonancein2PatientsBeforeandAfterRevascularization Figure5 Delayedenhancementcardiacmagneticresonance(CMR)andcineimagesoftwopatients(CandD)beforecoronaryrevascularizationandcine images2monthsafterrevascularization. AdaptedwithpermissionfromKimRJ,ShahDJ.Fundamentalconceptsinmyocardialviabilityassessmentrevisited:whenknowinghowmuchis "alive"isnotenough.Heart200490:13740.

CommonAssumptions
IntermediateLevelsofViability Viabilitytestingisthoughttobelesshelpfulwhenintermediatelevelsofviabilityare measured(i.e.,levelsofviabilitythatresultinonlyapproximately50%ofthese regionsrecoveringfunctionafterrevascularization).Thisviewisaresultofa commonassumptionregardingfunctionalrecovery.First,itisimportantto distinguishbetweenwhatwouldbedesirableclinicallyfromwhatcanactuallyoccur physiologically.Whilewemayaskforanimprovedtechniquewithbetterpredictive value,perhapsinreality,weareaskingforadifferentphysiologicalrelationshipan abruptthresholdofviability,belowwhichthereisvirtuallynochanceforfunctional recovery,andabovewhichnearlyallhavefunctionalrecovery.Figure6,PanelA demonstratesthat,withanabruptthreshold,theproblemofpredictingan intermediatelikelihoodforfunctionalrecoveryisgreatlyminimized.Unfortunately, thisphysiologicalrelationshipmaynotexist. Second,itisessentialtorememberthatfunctionalrecoveryisacontinuum(asis viabilityitself),andnotsimplyabinaryyesornofunction.Thus,partofthe problemwithintermediatelevelsofviabilityisexpectingthattheseregionswillorwill nothavefunctionalrecoveryinthisbinaryfashion.Becauseitmorecloselyreflects reality,itmaybebettertoconsidermostregionswithintermediatelevelsofviability ashavingahighchanceforanintermediateamountofimprovementratherthan 50%likelytohavecompleterecoveryandtheother50%likelytohaveno improvementwhatsoever. Complicatingthisissueisthebeliefthatathresholdphenomenonexistsbetween thetransmuralextentofinfarctionandsystolicthickening.Thisassumptionisbased primarilyonresultsbyLiebermanetal,52whodemonstratedinacaninemodelof acuteinfarctionthatakinesiaisexpectedifinfarctioninvolves20%ofthewall thickness.However,theanimalmodelinvolvedpermanentcoronaryligationand likelyincludedeffectsfrommyocardialstunningand/orongoingischemia. Evaluationinhumanswithchronicinfarctionsuggeststhatathresholdphenomenon doesnotexist.53,54Thesedataindicatethatitisproblematictoextrapolatethe resultsofLieberman'sstudy,whichdidnotconsidertheeffectsofstunningand/or ongoingischemia,tohumansfollowingrevascularizationinwhomsubstantial stunning,ischemia,orhibernationmaynolongerbepresent. Thefindingthattwotechniquescandemonstrateasimilarrelationshipbetweenthe amountofviabilityandthelikelihoodoffunctionalrecoverydoesnotmeanthatthe techniqueshavethesamediagnosticcapability.Forexample,bothanaccurateand alessaccuratetechniquemayshowthat,foragivenintermediatelevelofviability,on average,50%ofsegmentsrecoverfunction.However,partoftheproblemagainis definingfunctionalrecoveryasabinomialvariable.Figure6,PanelBdemonstrates theutilityofexpressingfunctionalrecoveryasacontinuousvariable(e.g.,millimeters ofimprovementinsystolicwallthickening).Althoughtheoverallrelationshipisthe same,foranygivenlevelofviability,thebettertechniquewillprovideasmaller variability(smallererrorbars)intheabsoluteamountoffunctionalimprovementthan theworsetechnique. FunctionalRecoveryastheStandardofTruth Theidealreferencestandardforevaluatingviabilityimagingtechniqueswouldbe histopathologicalexamination.However,forthevastmajorityofclinicalstudies,this isnotfeasible,andfunctionalrecoveryfollowingrevascularizationhasbecomethe defactostandard.Thisclinicalendpointmakessenseforavarietyofreasons. BecauseLVdysfunctionportendspoorprognosis,onewouldexpectthatfunctional recoverywouldbeanimportantandbeneficialclinicaloutcomeofrevascularization. Additionally,ifamyocardialregionrecoversfunction,thenonemightconfidently assumethattheregionhasasubstantialamountofviablemyocytes. Indeed,thishasbeenconfirmedbyhistopathologicalexamination.In33patients withLADdisease,Maesetal.tooktransmuralneedlebiopsiesfromtheLVanterior wallduringCABG.Thebiopsiesfromregionsthatweredysfunctionalpriorto
Figure6

revascularization,butrecoveredafterwards,showed89%6%ofthevolume consistedofviablecells.8 Similarly,Dakiketal.reportedthatamong21biopsied dyssynergicmyocardialsegments,the11whichrecoveredfunctionafterCABGhad 93%4%viabilitybyvolume.9 However,acommonmisconceptionisthat,ifa regiondoesnothavefunctionalimprovement,thenthisregionisnonviable.Infact, Maes8 andDakik9 observedthatbiopsyspecimensfromregionsthatdidnot improveafterrevascularizationstillhad65%25%and69%21%viabilityby volume,respectively. Thereareseveralreasonswhyregionsthatarepredominantlyviablemaynot recoverfunctionfollowingrevascularization.First,revascularizationmayoftenbe incompleteinpatientswithextensiveatherosclerosis.44Therefore,theremaybe persistentareasofhibernatingmyocardium.Second,viablemyocardiummaybe juxtaposedtoregionswithextensivescarringandunabletorespondto revascularizationbecauseoftethering.45Third,theuseofasingleevaluationof ventricularfunctionsoonafterrevascularizationmayleadtoanunderestimationof thetruerateoffunctionalrecovery.Baxandcolleaguesevaluatedfunctionalrecovery in26patientsat3and14monthsfollowingCABG.3 At3months,only31%of hibernatingsegmentsrecovered,whereasat14months,anadditional61% recovered. Evenwiththeselimitations,onecouldarguethatfunctionalrecoveryisan appropriatetruthstandardforviabilitybecausewithoutrecoverytheremaybeno benefittothepatientforundergoingrevascularization.Onthispoint,theresultsby Samadyetal.areinstructive.55Ofthe104consecutivepatientswhounderwentpre andpostCABGLVEFassessment,68patientshadimprovementinLVEF(>5% increase)and36patientshadnosignificantchange.Surprisingly,thetwogroups hadsimilarpostoperativeimprovementinanginaandheartfailurescores,andthere wasnodifferenceinCVmortality,withameanfollowupperiodof32months.The authorsconcludedthatalackofimprovementinLVEFafterCABGisnotassociated withpooreroutcome,andspeculatedthatmanypatientswithoutimprovementin LVEFmaynonethelesshavesubstantialviablemyocardiumthatcanrespondto effectiverevascularizationwithbeneficialeffectsonprognosis. Thus,functionalrecoveryisaflawedtruthstandardforevaluatingviabilityimaging techniques.Theprimaryproblemisthatregions(orpatients)withoutfunctional recoverymayhavesubstantialviabilitythatmaybeimportanttodetectclinically.This hasimplicationsforthepublishedstudiesthathaveusedfunctionalrecoveryasthe standardforevaluatingtestsofviability.Poorspecificity(forfunctionalrecovery) shouldbeconsideredlessimportantthanpoorsensitivity,becausefortheformer,a numberof"falsepositives"(testshowedviabilitybuttherewasnofunctional recovery)mayrepresentaproblemwiththetruthstandardratherthanthetechnique. AfutureSTICHsubstudywilladdresswhetherfunctionalrecoverycanpredictother clinicallyrelevantendpointssuchasdeath(E.Velazquez,personalcommunication, 2011). Thedecisionforrevascularizationisdependentonseveralfactorsbesidesthe amountofviability,includingspecificsregardingthecoronaryanatomy,thepresence ofanginaorischemia,andpatientcomorbidities.Additionally,viablemyocardium canbeindifferentstates(i.e.,normal,ischemic,hibernating,cardiomyopathicfroma nonischemicprocess,etc.),anditislikelythatdifferentiatingbetweenthesestates maybeimportantforrevascularizationdecisionsinsomepatients.

Assumptionsinevaluatingviabilitytechniques Figure6 PanelA:Atechniquethatdemonstratesasmoothlinearrelationshipbetweenviabilityandfunctionalrecoverymaybeconsideredlimitedinthat intermediatelevelsofviabilitypredictintermediatelikelihoodforfunctionalrecovery.Withanabruptthresholdrelationshipbetweenviabilityand functionalrecovery,theproblemofpredictingintermediatelikelihoodforfunctionalrecoveryisgreatlyminimized. PanelB:Twotechniqueswithdifferentdiagnosticcapabilitymayshowasimilaroverallrelationshipbetweenviabilityandfunctionalimprovement. However,iffunctionalimprovementisexpressedasacontinuous,ratherthanbinomial,variable,thebettertechniquemayreducethevariability (smallererrorbars)inpredictingtheabsoluteamountoffunctionalimprovement. ReproducedfromDiCarliMandKwongR(editors).NovelTechniquesforImagingtheHeart:CardiacMRandCT.1stedition.WestSussex:Wiley Blackwell2008.

Summary
Thismoduleprovidedareviewthepathophysiologyofmyocardialviabilityanddescriptionofitsclinicalimportance. Methodstoassessmyocardialviabilityarevariedandmayonlyindirectlyberelatedtowhethermyocytesarealiveor dead.Therearemanyassumptionsregardingviabilitytesting.Severalarise,inpart,fromconsideringviabilityand/or functionalrecoveryasasimplebinaryyesornofunction,ratherthanasacontinuum,whichbetterreflectsreality. Althoughanimportantclinicalendpoint,functionalrecoveryafterrevascularizationisaflawedtruthstandardforevaluating viabilitytechniques,becausemyocardiumthatdoesnotrecovermaybepredominantlyviableratherthannonviable. Understandingtheunderlyingassumptionsinviabilitytestingisimportant,astheresultsoftherecentSTICHtrial highlight.Incontrasttoearlier,smallerstudies,STICHfoundthatcommonclinicalmethodssuchasDSEandSPECT havenotidentifiedpatientswithadifferentialsurvivalbenefitfromCABG,ascomparedwithmedicaltherapyalone.16 Ultimately,thedecisionforrevascularizationstillinvolvesmanyfactorsbesidestheamountofviability(andnonviability).

KeyPoints
Theterm"myocardialstunning"describesthestateofpostischemicmyocardialdysfunctioninthepresenceof relativelynormalbloodflow. Theterm"myocardialhibernation"describesthestateofchronicmyocardialdysfunctionatrestthatcanbe partiallyorcompletelyrestoredtonormaleitherbyimprovingbloodflowand/orbyreducingdemand. Severalnoninvasiveimagingmethodsareavailablethatassessmyocardialviabilityeitherindirectly(by measuringmorphologyorcontractilereserve)ordirectly(bymeasuringmetabolicactivityorcellmembrane integrity). IntheSTICHtrial,theassessmentofmyocardialviabilitywithDSEand/orSPECTdidnotidentifypatientswitha differentialsurvivalbenefitfromCABG,ascomparedwithmedicaltherapyalone,incontrastwiththeprior literature. Understandingtheunderlyingassumptionsincurrentviabilityassessmentmethodsisimportant.

SuggestedReading
1. BonowRO,MaurerG,LeeKL,etal,andtheSTICHTrialInvestigators.Myocardialviabilityandsurvivalinischemic leftventriculardysfunction.NEnglJMed2011364:161725. 2. SchinkelAF,BaxJJ,DelgadoV,PoldermansD,RahimtoolaSH.Clinicalrelevanceofhibernatingmyocardiumin ischemicleftventriculardysfunction.AmJMed2010123:97886. 3. PartingtonSL,KwongRY,DorbalaS.Multimodalityimagingintheassessmentofmyocardialviability.HeartFail Rev201116:38195.

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MahrholdtH,WagnerA,ParkerM,etal.Relationshipofcontractilefunctiontotransmuralextentofinfarctionin patientswithchroniccoronaryarterydisease.JAmCollCardiol200342:50512. 54. NelsonC,McCrohonJ,KhafagiF,RoseS,LeanoR,MarwickTH.Impactofscarthicknessontheassessmentof viabilityusingdobutamineechocardiographyandthalliumsinglephotonemissioncomputedtomography:a comparisonwithcontrastenhancedmagneticresonanceimaging.JAmCollCardiol200443:124856. 55. SamadyH,ElefteriadesJA,AbbottBG,MatteraJA,McPhersonCA,WackersFJ.Failuretoimproveleftventricular functionaftercoronaryrevascularizationforischemiccardiomyopathyisnotassociatedwithworseoutcome. Circulation1999100:1298304.

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7.6:MicrovascularAngina
Author(s): AshishGupta,MD,PhD C.NoelBaireyMerz,MD,FACC CarlJ.Pepine,MD,MACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Reviewnewdataregardingtheprevalenceofmicrovascularcoronarydysfunction. 2. Discussemergingdataregardingpathophysiologicalmechanismsofmicrovascularcoronarydysfunction. 3. Evaluatediagnosticstrategiesformicrovascularcoronarydysfunction.

BackgroundandPrevalenceofMicrovascularCoronary Dysfunction

Theexactprevalenceofmicrovascularcoronarydysfunctionasthebasisforangina andotherfindingssuggestingischemicheartdisease(IHD)isunknown.Butitis estimatedthatover9millionAmericanshaveanginapectoris,whichsignificantly impactsqualityoflife,abilitytowork,andcoststosociety.1 Amongpatients undergoingcoronaryangiographyforevaluationofchestpainthoughttorepresent anginapectoris,asignificantproportionhasangiographically"normal"epicardial vesselsorinsufficientobstructivediseasetoexplainischemia.TheCASS(Coronary ArterySurgeryStudy)registryfoundthatamong25,000patientsundergoingcoronary angiography,39%offemalesand11%ofmenhadwhatappearedtobe"normal" epicardialarteries.2 TheAmericanCollegeofCardiology(ACC)NationalCardiovascularDataRegistry (NCDR)databaseof>375,886patientsfoundthat"nonobstructivecoronaryartery disease(CAD)"wasconsiderablymorefrequentthanthatreportedfromtheCASS, andthefrequencywassignificantlyhigheramongwomen(51%)versusmen (32%).3 TheWISE(Women'sIschemiaSyndromeEvaluation)prospectivecohort foundthat62%offemalesreferredtoangiographyforanginahadnonobstructive CAD,4 andapproximatelyonehalfofthesepatientswhohadcoronaryflow measuredhadevidenceofmicrovasculardysfunction(reducedflowreserveto adenosine).Amongpatientspresentingwithbiomarkerconfirmedacutecoronary syndromeinmultipleclinicaltrials,womenwerefoundtohaveahigherprevalence ofnonobstructivediseaseversusmen(Figure1).5 Angina,ingeneral,alsoappears tobemoreprevalentinwomenthanmen,basedoncomparisonsfrom31countries: 6.7%inwomenversus5.6%inmen.6 HistoricalConsiderations,Definitions,andNomenclature Intheirclassicalreportontherelationshipbetweenclinicalmanifestationsand pathologicfindings,Blumgartandcolleagues7 notedthatuncomplicatedangina pectoriswasusuallyassociatedwithocclusionsofatleasttwoofthemain epicardialcoronaryarteries.Withtheintroductionofcoronaryangiography,this conceptwasreinforcedbymultiplereports.Usingthisbackgroundin1967,Likoff andcolleagues8 firstcalledattentiontothe"paradoxofanginawithunmistakable normalcoronaryangiograms"inagroupof15womenwithischemic electrocardiogram(ECG)abnormalitieswithoutdiabetesorhypertension.Theyalso suggestedthepossibilityofmicrovascularabnormalities.Referringtoagroupof patientswithnormalcoronaryangiogramsplusECGandtransmyocardiallactate evidenceofmyocardialischemiareportedbyArbogastandBourassa,Kempand colleaguescoinedthedescriptor"syndromeX"in1973.9,10 Cannonandcolleagues11introducedtheterm"microvascularangina"in1983after documentingevidenceformicrovasculardysfunctionasaninappropriatecoronary flowresponsetovariousstimuli,despiteangiographicallynormalepicardial vessels.However,insubsequentstudiestheyquestionedthepresenceofischemia whentheycouldnotdetectleftventricular(LV)wallmotionabnormalitiesby echocardiography. In1991,Maseriandcolleaguesproposedthatfocalischemia,insmallregions scatteredthroughoutthemyocardiumcausedbyprearteriolardysfunction,could explaintheabsenceofLVwallmotionchanges.12Usingcardiacmagnetic resonanceimaging,whichprovidessuperiorresolutiontoevaluateperfusion, Panting,Pennell,andcolleaguesthendocumentedarelativefailureof subendocardialperfusiontoincreasewithadenosineinfusioninthesepatientsthat couldalsoaccountforanabsenceofmajorchangesinLVwallmotion.13 Morerecently,CamiciandCrea14furtherrefinedthedefinitionofcoronary microvasculardysfunctionas"adysregulationofcoronarybloodflow,not attributabletoobstructiveCAD,thatresultsfromeitherstructuralorfunctional mechanismsinthecoronarymicrovasculature."Theyalsodevelopedaclinical classification(Table1),andsummarizedthepossiblepathogeneticmechanisms basedonalterationsobservedandtheirpossiblecauses(Table2).

Figure1

Table1

Table2

PrevalenceofNormalorNonobstructiveCoronaryArteriesinAcuteCoronarySyndromeTrialsReportingResultsofEarlyAngiography Figure1 ReproducedwithpermissionfromAndersonRD,PepineCJ.Howtomanageanginawithnormalcoronaryarteries(update).In:FauciA, BraunwaldE,KasperD,HauserS,LongoD,JamesonJ,LoscalzoJ,eds.HarrisonsPrinciplesofInternalMedicine.17thed.NewYork:McGraw HillProfessional2009.

ClinicalClassificationofCoronaryMicrovascularDysfunction Table1 AdaptedwithpermissionfromCamiciPG,CreaF.Coronarymicrovasculardysfunction.NEnglJMed2007356:83040.

PathogeneticMechanismsofCoronaryMicrovascularDysfunction Table2 ACS=acutecoronarysyndrome. AdaptedwithpermissionfromCamiciPG,CreaF.Coronarymicrovasculardysfunction.NEnglJMed2007356:83040.

ClinicalFindings
Clinically,thesyndromeofmicrovascularanginaischaracterizedbypredominantlyeffortorstressrelatedchest symptoms(discomfort,dyspnea)thatoftenareindistinguishablefromsymptomsattributabletoanginapectoris associatedobstructiveCAD.Whilemicrovascularanginamayoccurinmen,mostpatientswiththissyndromeare women.Theexamisusuallynormal,asistheECG,otherthanoccasionalminorSTTwavealterations.Thesepatients oftenhavesomeSTsegmentdepressionand/orperfusionstudiessuggestiveofmyocardialischemiaduring spontaneousorprovokedanginathatisnotattributabletoobstructiveCAD.Theseabnormalities,however,arewidely variableintheirreproducibilityonrepeatedtesting,butthisfindingisalsonotunusualformanypatientswithobstructive CAD. Althoughtestingforepicardialcoronaryarteryspasmisimportant,becauseitcanbespecificallytreated,the overwhelmingmajorityofpatientswithmicrovascularanginahavenoevidenceforspontaneousorprovokedcoronary arteryspasmorcardiac(e.g.,hypertrophicordilatedcardiomyopathy,transplantvasculopathy)orsystemic(e.g., amyloidosis)diseasesknowntobeassociatedwithmicrovascularcoronarydysfunction.TheWISEcohortidentifieda highprevalenceofatherosclerosisriskconditions(e.g.,hypertension,diabetes,andobesity),andexceptinpatientswith leftbundlebranchblock,LVsystolicfunctionisusuallynormalormayevenbehyperdynamic.Nevertheless,whilethereis usuallyimportantfunctionaldisability,thissyndromewasbelievedtoberarelyassociatedwithsuddendeathor myocardialinfarction(MI),untilthemorerecentWISEfindingsdiscussedinthenextsection.

Pathophysiology
AtherosclerosisRiskFactors Numeroussmallstudiesinitiallysuggestedthatwomenwithatherosclerosisrisk factorswereusuallypostmenopausal,whilelargerconsecutivecohorts,including theWISEstudy,suggestedthatthesewomentendtobeyoungerandfrequently premenopausalcomparedwiththosewithobstructiveCAD.4 Traditionalriskfactors likehypertension,obesity,hypertriglyceridemia,anddiabetes,aswellasthe Framinghamriskscoretendtounderestimatetheriskforadverseoutcomes. Severalconditionsfoundonlyinfemales,includingearlymenopause,gestational diabetes,peripartumvasculardissection,preeclampsiaandeclampsia,polycystic ovariansyndrome,lowbirthweightchildren,andhypothalamichypoestrogenemia, carryincreasedriskforCADlaterinlife,15butitisunknownifsuchconditions portendmicrovascularanginabeforethesewomendevelopclinicallymanifestCAD. DatafromtheWISEstudydemonstratedthatcoronarymicrovasculardysfunctionis presentinatleast50%ofwomenwithchestpainintheabsenceofobstructiveCAD andcannotbecompletelyexplainedbyriskfactorsforatherosclerosis,hormone levels,orinflammatorymarkers. Thediagnosisofmicrovasculardysfunctionshouldbeconsideredinpatientswith chronicchestpainsyndromesresemblingangina,whodonothaveevidenceof obstructiveCAD.Womenalsosufferdisproportionatelyfromavarietyofgeneralized vasculardisordersthatareknowntobeassociatedwithCAD,aswellas microvasculardisease,includingsystemiclupuserythematosus(SLE),rheumatoid arthritis,migraine,Raynaud'sphenomenon,andautoimmunearthritis.These observationssupporttheinfluenceoflifelong,varyingreproductivehormonelevels relatedtoovariancycling,pregnancy,peripartum,andmenopausethatarelikelyto influencevascularfunction. Therolethatabnormalcoronaryreactivityplaysinischemiaamongwomenwithout obstructiveCADhasbeendescribed,buttherelativeimportanceofendothelialand microvasculardysfunctionhasbeeninsufficientlyexplored.Anintegratedworking understandingofthecascadeofmechanismsandmanifestationsofischemia impactingIHDriskinwomenisreviewedinFigure2.16 Ithasbeenproposedthatmicrovascularcoronarydysfunctionleadingtochronic stableangina(e.g.,microvascularangina)ismoreprevalentinwomenthanmenas aresultofriskfactorclustering,vascularinflammationandremodeling,and hormonalalterations.1518Abnormalcoronaryreactivityoccursinthesettingof atherosclerosisriskfactorsandisusuallyassociatedwithunderlyingatheroma vulnerabletoclinicalinstabilityandmoreprogressivediseasestates.Itisforthis reasonthatidentifyingnonobstructiveatheromamayprovidegreaterrisk stratificationinwomen.Anoverarchingworkingmodelofthisproposedfemale specificIHDpathophysiologyisdepictedinFigure3.16 Althoughtherelationshipbetweenmicrovasculardysfunctionandepicardial atherosclerosisisnotfullyunderstood,aleadinghypothesisisthatitisasingle diseaseprocess.Thisisbasedonobservationsfromanimalmodelsdocumenting thatmostatherosclerosisriskconditions(e.g.,increasedlowdensitylipoprotein cholesterol[LDLC],glucose)injurethemicrovessels.Theresponsetovascular wallinjurymayvaryrelatedtosexdifferencesinvascularremodelingandvascular reactivity.
Figure2

Figure3

CascadeofMechanismsandManifestationsofIschemiaHavinganImpactonIschemicHeartDiseaseRiskinWomen Figure2 AdaptedwithpermissionfromShawLJ,BugiardiniR,MerzCN.Womenandischemicheartdisease:evolvingknowledge.JAmCollCardiol 200954:156175.

OverarchingModelofIschemicHeartDiseasePathophysiologyinWomen Figure3 CAD=coronaryarterydiseasePCOS=polycysticovariansyndrome. AdaptedwithpermissionfromShawLJ,BugiardiniR,MerzCN.Womenandischemicheartdisease:evolvingknowledge.JAmCollCardiol 200954:156175.

RegulationoftheMicrovascularCoronaryCirculation
Variousregulatorymechanismsofthemicrovascularcoronarycirculationand experimentalevidencesupportingthesemechanismshavebeenreviewedindetail byPatelandFisher.19Thecomplexinterplayoftheseregulatorypathwaysis outlinedinFigure4,andabriefsynopsisofkeyregulatorymechanismsfollows. MetabolicFactors Broadlyspeaking,coronaryflowislinearlyrelatedtomyocardialoxygen requirements.Anincreaseinmyocardialmetabolismmustbebalancedbyan increasedsupplyofnutrientsandoxygenfromblood,otherwiseischemiaresults. Thesupplyincreaseisprimarilyaresultofmicrovascularendotheliummediated dilationvianitricoxide,adenosine,andadenosinetriphosphatesensitiveK+ channels. MyogenicFactors Maintenanceofintraluminalpressurewithinfinelimitsinthemicrocirculationis necessarytoensureadequatetransportofsubstancesacrossthevascularlumen tothetissues.Withelevatedintraluminalpressure,thereisariskoftissuedamage duetoedema.Inthemediumsizedarterioles,themainmechanisminvolvedin regulationofthemicrovascularcirculationisalterationofsmoothmuscletonein responsetochangesinintraluminalpressure,andthisisindependentof endothelialfunction.Thesemyogenicresponsesarereducedinthe subendocardiumcomparedwiththesubepicardium,whichmayalsoexplainwhy thesubendocardiumismorepronetoischemicinjury,particularlygiventhe increasedphysicalstressesinthesubendocardiumduringthecardiaccycle. EndothelialFactors Threemajormediatorsincludenitricoxide,endothelialderivedhyperpolarizing factor,andprostacyclin.Productionandreleaseofthesemediatorsistriggeredby shearstressdetectedattheendothelialcellsurfacereceptor.Inaddition, endothelialcellsareresponsibleforproductionofpotentvasoconstrictorsincluding thromboxaneA2,someprostaglandins,angiotensinII,andendothelin1. Maintenanceofsmoothmuscletoneisdependentonafinebalancebetween endothelialderivedvasoconstrictorsandvasodilators. OtherFactors Manyotherfactorsplayaroleincontrolofthemicrocirculation.Theseincludethe autonomicnervoussystemandextravascularphysicalforcesofthebeatingheart. Subendocardialperfusion,inparticular,isreducedbyphysicalforcesrelatedtothe contractingheartmuscle,whichexplainswhythesubendocardiumismostproneto ischemicinjury.

Figure4

MechanismsResponsibleforRegulationofMyocardialMicrovascularResistance Figure4 Factorsinvolvedinregulatingtoneofthemicrocirculation.Endothelialdependentregulation,mediatedbyreleaseofmediatorsfromendothelial cellsinresponsetostimulisuchasshearstressandplateletderivedfactors,isthedominantmechanisminlargerarterioles.Myogenicregulation utilizessmoothmusclecellstretchreceptorsinactivationofmembraneboundionicchannelstorespondtochangesinintraluminalpressureand isdominantinmediumsizedmicrovessels.Metabolicfactors(e.g.,changeinPCO2,pH,andadenosine)contributetodilationinresponseto increasingmetabolicactivity,andthisismostprominentinthesmallestmicrovessels.Inaddition,neurallymediatedfactorsandextravascular mechanicalforcesareinvolvedinregulationofmyocardialmicrovascularresistance. ACh=acetylcholineEDHF=endothelialderivedhyperpolarizingfactorK+ATP=adenosinetriphosphatesensitiveK+channelLVEDP=left ventricularenddiastolicpressureNO=nitricoxidePKC=proteinkinaseCPLC=phospholipaseCRVEDP=rightventricularenddiastolic pressure. AdaptedwithpermissionfromPatelB,FisherM.Therapeuticadvancesinmyocardialmicrovascularresistance:unravelingtheenigma. PharmacolTher2010127:13147

PathogeneticMechanismsofMicrovascularCoronary Dysfunction
Onthebasisoftheclinicalsettingsinwhichitoccurs,microvascularcoronary dysfunctioncanbeclassifiedintofourtypes:1)dysfunctionoccurringintheabsence ofCADandmyocardialdiseases,2)dysfunctioninthepresenceofmyocardial diseases,3)dysfunctioninthepresenceofobstructiveepicardialCAD,and4) iatrogenicdysfunction.VariousclinicalscenarioshavebeenreviewedbyCamiciand Crea,14andaresummarizedinTable2. Severalpathophysiologicmechanismsincludingstructuralandfunctional aberrationsofthecoronarymicrovasculature,aswellastheextravascularchanges, mayaccountformicrovascularcoronarydysfunction.

Table2

PathogeneticMechanismsofCoronaryMicrovascularDysfunction Table2 ACS=acutecoronarysyndrome. AdaptedwithpermissionfromCamiciPG,CreaF.Coronarymicrovasculardysfunction.NEnglJMed2007356:83040.

AssessmentofMicrovascularFunction
Asaresultofthesmallsizeofthecoronarymicrocirculationandlimitedresolutionof availableimagingtechniques,directvisualizationandmorphologicassessmentof humancoronarymicrovasculatureinvivoisnotpossiblewithcurrenttechniques. Therefore,assessmentisusuallybasedonevaluatingphysiologicandfunctional properties.20Bothnoninvasiveandinvasivemethodsareavailable(Table3).In general,thesetechniquesmaybegroupedintothreecategories:1)techniquesfor assessmentofinduciblemyocardialischemia(e.g.,magneticresonanceimaging [MRI]perfusion,positionemissiontomography[PET],singlephotonemission computedtomography[SPECT]),2)myocardialperfusionabnormality,and3) assessmentofcoronaryflowresponsetomaximalhyperaemia. IntheabsenceofobstructiveCAD,induciblemyocardialischemiaormyocardial perfusiondefectorimpairedcoronaryflowreserve(CFR)maybeusedasindicators ofcoronarymicrovasculardysfunction.Theabilitytoquantifymicrovascularblood flowinrestingandstressstatesallowsforthedeterminationofCFR,theratioof maximalhyperemictorestingflowrates.Mildvariationsinanormalcutoffexist betweendifferentquantificationmethods,suchthataCFR<2.0and2.5isgenerally consideredabnormal.21CFRistypicallydecreasedwhenmeasuredinavessel withepicardialstenosis,butintheabsenceofthis,decreasedCFRisrepresentative ofmicrovascularcoronarydysfunction.

Table3

AvailableMethodstoAssessCoronaryMicrovascularFunction Table3 CFR=coronaryflowreserveCT=computedtomographyFFR=fractionalflowreserveIMR=indexofmicrocirculatoryresistanceMRI= magneticresonanceimagingPET=positionemissiontomographySPECT=singlephotonemissioncomputedtomographyTIMI=Thrombolysisin

MyocardialInfarction. AdaptedwithpermissionfromLeungDY,LeungM.Noninvasive/invasiveimaging:significanceandassessmentofcoronarymicrovascular dysfunction.Heart201197:58795.

ManagementConsiderations
Chronicanginainapatientwithmicrovascularcoronarydysfunctionisassociated withdiversespectraofclinicaldisordersandinvolvesmultiplemechanismswith variousclinicalconsequences.Inapproachingapatientwithchronicangina,the followingspecificconditionsneedtobeconsideredforappropriatemanagement afterobstructiveCADandcoronaryspasmhavebeenexcludedwithreasonable certainty: Insulinresistancestates(e.g.,diabetes,metabolicsyndrome). Associatedmyocardialdisorders(e.g.,primarycardiomyopathies[e.g., dilatedandhypertrophic]andsecondarycardiomyopathies[e.g.,long standinghypertension,severevalvulardisease]). Inflammatory/immune/connectivetissuedisorder(e.g.,SLE,rheumatoid arthritis,progressivesystemicsclerosis,giantcellarteritis). Knowndiseasesofthemyocardium(e.g.,myocarditis). Earlyinfiltrativeheartdisease(e.g.,amyloidosis,hemochromatosis). Ifnoneoftheprecedingstructuralmechanismsforcoronarymicrovasculatureare likely,thepatientshouldbeconsideredtohaveafunctionaldisordertoexplain "microvascularangina"andothermanifestationsofmyocardialischemia.Although largeoutcomestudiesareneeded,sometreatmentshavebeenshowntobe effectiveinsmalltrialsforreductionofsymptomsandevenimprovementin microvascularcoronaryfunction.Therapeuticapproachestopatientswithchronic stableanginainpatientswithnormalepicardialcoronaryarteriesforthe improvementoffunction,angina,andqualityoflifeareoutlinedinTable4.19,22 Whetherthesetreatmentsmodifytheintermediatetolongtermcourseorreducethe frequencyofadverseoutcomesisunknownatthistime.

Table4

TherapeuticApproachestoPatientsWithAnginaandNormalCoronaryArteries Table4 ACE=angiotensinconvertingenzymeARB=angiotensinreceptorblockerCAD=coronaryarterydiseaseEECP=enhancedexternal counterpulsationVSMC=vascularsmoothmusclecell.

KeyPoints
Chronicstableangina,evenamongpatientswithnormalappearingcoronaryangiography,carriesasignificant burdenintermsofmorbidityandoveralladverseoutcome. Microvascularcoronarydysfunctionisanimportantprognosticfactorinawiderangeofdiseases. Microvascularcoronarydysfunctionmaybepresentintheabsenceofovertobstructivediseaseinconduitand epicardialarteries. Microvascularcoronarydysfunctioncanbedetectedinthepresenceofvascularriskfactorsandmaybereversible withlifestylemodificationandtreatmentofriskfactors. Microvascularcoronarydysfunctionmayleadtomyocardialischemia,asseeninpatientswithmicrovascular angina. Assessmentofcoronarymicrocirculationdependsonevaluationofitsfunctionalaspects.Bothinvasiveand noninvasivemethodsareavailabletoassessmicrovascularcoronaryfunction. Mostavailablemethodsdonotassessmicrovascularcoronaryfunctioninisolation.Theyassessthetotalimpact ofbothepicardialcoronarydiseaseandmicrovasculardysfunctiononcoronaryflowormyocardialperfusion reserve. ACFR<2.5isgenerallyconsideredabnormal.DecreasedCFRinthesettingofnormalepicardialvesselsis representativeofmicrovascularcoronarydysfunction. Assessmentofmicrovascularcoronaryfunctionmayallowearlyidentificationofatriskpatients,monitoringof treatment,oropennewtherapeuticintervention. Managementincludestraditionalantianginaldrugsandnoveltherapiesincludingpotassiumchannelopeners, metabolicagents,kinaseinhibitors,angiotensinconvertingenzymeinhibitors,latesodiumchannelmodifiers, andstatins.

ReferencesandSuggestedReading
References 1. RosamondW,FlegalK,FurieK,etal.Heartdiseaseandstrokestatistics2008update:areportfromthe AmericanHeartAssociationStatisticsCommitteeandStrokeStatisticsSubcommittee.Circulation2008117:e25 146. 2. DavisKB,ChaitmanB,RyanT,BittnerV,KennedyJW.Comparisonof15yearsurvivalformenandwomenafter initialmedicalorsurgicaltreatmentforcoronaryarterydisease:aCASSregistrystudy.CoronaryArterySurgery Study.JAmCollCardiol199525:10009. 3. ShawLJ,ShawRE,MerzCN,etal.Impactofethnicityandgenderdifferencesonangiographiccoronaryartery diseaseprevalenceandinhospitalmortalityintheAmericanCollegeofCardiologyNationalCardiovascularData Registry.Circulation2008117:1787801. 4. ShawLJ,MerzCN,PepineCJ,etal.Theeconomicburdenofanginainwomenwithsuspectedischemicheart disease:resultsfromtheNationalInstitutesofHealthNationalHeart,Lung,andBloodInstitutesponsored Women'sIschemiaSyndromeEvaluation.Circulation2006114:894904. 5. AndersonRD,PepineCJ.Howtomanageanginawithnormalcoronaryarteries(update).In:FauciA,Braunwald E,KasperD,etal.Harrison'sPrinciplesofInternalMedicine.17thed.NewYork:McGrawHillProfessional2009. 6. HemingwayH,LangenbergC,DamantJ,FrostC,PyrlK,BarrettConnorE.Prevalenceofanginainwomen versusmen:asystematicreviewandmetaanalysisofinternationalvariationsacross31countries.Circulation 2008117:152636. 7. BlumgartHL,SchlesingerMJ,DavisD.Studiesontherelationoftheclinicalmanifestationsofanginapectoris, coronarythrombosis,andmyocardialinfarctiontothepathologicfindings.Withparticularreferencetothe significanceofthecollateralcirculation.AmHeartJ194019:190. 8. LikoffW,SegalBL,KasparianH.Paradoxofnormalselectivecoronaryarteriogramsinpatientsconsideredto haveunmistakablecoronaryheartdisease.NEnglJMed1967276:10636. 9. ArbogastR,BourassaMG.Myocardialfunctionduringatrialpacinginpatientswithanginapectorisandnormal arteriograms.Comparisonwithpatientshavingsignificantcoronaryarterydisease.AmJCardiol197332:25763. 10. KempHGJr,VokonasPS,CohnPF,GorlinR.Theanginalsyndromewithnormalcoronaryarteriograms.Report ofasixyearexperience.AmJMed197354:73542. 11. CannonRO3rd,WatsonRM,RosingDR,EpsteinSE.Anginacausedbyreducedcoronaryvasodilatorreserveof thesmallcoronaryarteries.JAmCollCardiol19831:135973. 12. MaseriA,CreaF,KaskiJC,CrakeT.MechanismsofanginapectorisinsyndromeX.JAmCollCardiol 199117:499506. 13. PantingJR,GatehousePD,YangGZ,etal.AbnormalsubendocardialperfusionincardiacsyndromeXdetected bycardiovascularmagneticresonanceimaging.NEnglJMed2002346:194853. 14. CamiciPG,CreaF.Coronarymicrovasculardysfunction.NEnglJMed2007356:83040. 15. PepineCJ,KerenskyRA,LambertCR,etal.Somethoughtsonthevasculopathyofwomenwithischemicheart disease.JAmCollCardiol200647(3Suppl):S305. 16. ShawLJ,BugiardiniR,MerzCN.Womenandischemicheartdisease:evolvingknowledge.JAmCollCardiol 200954:156175. 17. RobinsonJG,WallaceR,LimacherM,etal.Cardiovascularriskinwomenwithnonspecificchestpain(fromthe Women'sHealthInitiativeHormoneTrials)AmJCardiol2008102:6939. 18. GulatiM,CooperDeHoffRM,McClureC,etal.Adversecardiovascularoutcomesinwomenwithnonobstructive coronaryarterydisease:areportfromtheWomen'sIschemiaSyndromeEvaluationStudyandtheStJames WomenTakeHeartProject.ArchInternMed2009169:84350. 19. PatelB,FisherM.Therapeuticadvancesinmyocardialmicrovascularresistance:unravelingtheenigma. PharmacolTher2010127:13147. 20. LeungDY,LeungM.Noninvasive/invasiveimaging:significanceandassessmentofcoronarymicrovascular dysfunction.Heart201197:58795. 21. KernMJ,deBruyneB,PijlsNH.Fromresearchtoclinicalpractice:currentroleofintracoronaryphysiologically baseddecisionmakinginthecardiaccatheterizationlaboratory.JAmCollCardiol199730:61320. 22. BeltrameJF,CreaF,CamiciP.Advancesincoronarymicrovasculardysfunction.HeartLungCirc200918:1927. SuggestedReading 1. ShimokawaH,YasudaS.Myocardialischemia:currentconceptsandfutureperspectives.JCardiol200852:67 78. 2. CamiciPG.IsthechestpainincardiacsyndromeXduetosubendocardialischemia?EurHeartJ200728:1539 40. 3. PriesAR,HabazettlH,AmbrosioG,etal.Areviewofmethodsforassessmentofcoronarymicrovasculardisease inbothclinicalandexperimentalsettings.CardiovascRes200880:16574. 4. DeanfieldJE,HalcoxJP,RabelinkTJ.Endothelialfunctionanddysfunction.Circulation2007115:128595. 5. PaulyDF,JohnsonBD,AndersonRD,etal.Inwomenwithsymptomsofcardiacischemia,nonobstructive

coronaryarteries,andmicrovasculardysfunction,angiotensinconvertingenzymeinhibitionisassociatedwith improvedmicrovascularfunction:adoubleblindrandomizedstudyfromtheNationalHeart,LungandBlood InstituteWomen'sIschemiaSyndromeEvaluation(WISE).AmHeartJ2011162:67884. 6. JespersenL,HvelplundA,AbildstrmSZ,etal.Stableanginapectoriswithnoobstructivecoronaryarterydisease isassociatedwithincreasedrisksofmajoradversecardiovascularevents.EurHeartJ2011Sep11:[Epubahead ofprint].

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7.7:AsymptomaticCoronaryArteryDisease
Author(s): MichaelS.Lauer,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Citecriteriaforvalidscreeningtestsforchronicdiseasesothatphysicianscanworkwiththeirpatientstomakeinformed decisionsaboutwhethertoundergotesting. 2. Appraisethevalueofnovelriskmarkersofasymptomaticdisease,appreciatingthatstatisticalindependencealoneis inadequateevidence. 3. Describeassessmentsthatshouldbeundertakeninallasymptomaticadults,assessmentsthatshouldnotbe undertakeninanyasymptomaticadult,andassessmentsthatmightbereasonableinintermediateriskasymptomatic adults.

Introduction
Perhapsnoothertypeofmedicaltechnologybettercapturesthepublicimaginationthanscreening.Catchitearly,the thinkinggoes,becausebycatchingitearly,onecannipitinthebud,literallystoppingpotentiallydeadlydiseaseinits tracksbeforeitevenhasachancetostrike.Thereisnoquestionthatscreeningforasymptomaticdiseasecan,when properlyapplied,savelives.Largescalerandomizedtrialshaveshown,forexample,thatscreeningcanlowerdeath ratesrelatedtocertaincancers(e.g.,breast,colon,andlung)andrelatedtoabdominalaorticaneurysm.1 However,in othercases,screeninghasnotworked,andhasinsteadledtoprobableharm,withmanypatientssubjecttounneeded andinsomecasesdangerousdownstreamtestsandprocedures.25 Coronaryarterydisease(CAD)potentiallylendsitselfwelltoscreening.Ithaslongbeenknownthatthereisanextended asymptomaticlatentperiod,aperiodthatcanlastfordecades.Onehalfofallmajorcoronaryevents,includingfatal events,comewithoutwarning.Despiteimprovementsinmedicaltherapyandprevention,therecontinuestobeahigh prevalenceofatheroscleroticriskfactorsintheUnitedStates.Thecombinationofnewandpotentiallypowerfulscreening tests,alongwitheffectivetreatmentsforriskfactors,givescredencetoroutineCADscreeningamongadultsdeemedto beatintermediaterisk.6

ScreeningforChronicDisease:GeneralConsiderations
TheUnitedStatesPreventiveServicesTaskForce(USPSTF)haslistedfourcriteria forwhenscreeningisvaluable(Table1):tworelatedtodiseaseandtworelatedtoa candidatetest.7 Foradiseasetobeworthwhilescreening,itmustbecommonand serious,anditmusthaveaprolongedasymptomaticphasebothofthesecriteria areclearlymetforCAD. Forascreeningtesttohavevalue,itmusthavealowfalsepositiverate,anditsuse mustleadtoimprovedclinicaloutcomes.Whenexaminingthesetwocriteria, screeningtestsforCADfallshort.Forexample,evenamongadultswhowere enrolledintheMESA(MultiEthnicStudyofAtherosclerosis)andwhohadhigh coronarycalciumscores,wellover90%experiencednocoronaryeventsduringa median3.8yearsoffollowup.8 Todate,norandomizedtrialshavedefinitivelyshown alinkbetweenuseofascreeningtestandreducedriskofmyocardialinfarction(MI) orcoronarydeath. Ofnote,noneofthefourUSPSTFcriteriamentionprediction.Theliteraturelinking variousnoninvasiveteststoclinicaleventsisextensive,butitisimportanttokeepin mindthatpredictiondoesnotnecessarilyimplyprevention. Itistemptingtouseobservationaldatatoshowthatpatientswhoundergoscreening testshavebetterclinicaloutcomes.However,itisimportantforcliniciansto recognizeseriousbiasesthatcloudinterpretationofobservationalanalyses,andto beabletoexplainthemtotheircolleaguesandpatients,whomaybeoverly influencedbyaggressivedirecttoconsumeradvertising.3 Threemajorbiasesinobservationalscreeningstudiesare9 : 1. Leadtimebias:Diseaseisdetectedatanearlierstage,butdeath(ora majorclinicalevent)occurswheneveritwasdestinedtooccur,leadingtoan increaseinapparentsurvival. 2. Lengthtimebias:Patientswithindolentdiseasethatoccursovera prolongedperiodwithoutmanifestingsymptomsaremorelikelytobe detectedwhenundergoingascreeningtest,becauseaggressivedisease strikesbeforethetestisperformed.Detectinglessaggressivediseaseby screeningtestsleadstoanapparentincreaseinsurvivalinthisgroup. 3. Overdiagnosisbias:Thisisrelatedtolengthtimebias.Diseaseisdetected byscreeningtests,butthediseaseneverwouldhaveclinicallymanifested haditneverbeenfound.Thisissometimescalledpseudodisease. Sometimesdiseaseregressesspontaneouslyothertimesitprogressesso slowlythatanotherpathologicalprocesskillsthepatientfirst.10

Table1

UnitedStatesPreventiveServicesTaskForceCriteriaforaValidScreeningTest Table1 ReproducedwithpermissinofromU.S.PreventiveServicesTaskForce.GuidetoClinicalPreventiveServices(2ndEdition):ReportoftheU.S. PreventiveServicesTaskForce.McLean,VA:InternationalMedicalPublishing2009.

AssessingtheValueofNovelPrognosticTests
Intheabsenceofrandomizedtrials,mostdataonnovelprognostictestsarebased oncohortstudiesinwhichinvestigatorshaveattemptedtoshowthattestsare independentlypredictiveofriskafteraccountingforknownpredictors.Typically, investigatorsuseregressionmodels(e.g.,Coxregression)andpronounceatestto beindependentlypredictiveiftheadjustedpvalueis<0.05.AnAmericanHeart Association(AHA)ScientificStatementonevaluationofnovelmarkersof cardiovascularriskdescribesmorestringentcriteria.11Theseincludethefollowing: Statisticalindependenceoverandaboveexistingdata(e.g.,age,gender, standardriskfactors). Discrimination:Theabilitytodistinguishbetweenpeoplewhodevelop diseaseandthosewhodonot.Thisistypicallyassessedbycalculatingac statistic,orcindex,whichisanalogoustotheareaunderareceiver operatingcharacteristic(ROC)curve.Avalueof1.0impliesperfect discrimination,whereasavalueof0.5impliesnodiscriminativeabilityany betterthanchance. Reclassification:Theabilityofatesttoaccuratelyreclassifypeoplefromone riskcategorytoanother.Forexample,ifapersonwhoultimatelydevelops diseaseisreclassifiedfromintermediatetohighrisk,thetestreclassifies correctlyconversely,ifapersonwhoultimatelydevelopsdiseaseis reclassifiedfromhightointermediaterisk,thetesthasyieldedmisleading information.MeasurestoassessreclassificationincludetheNet ReclassificationImprovement. Otherimportanttestcharacteristicstoconsiderinclude: Accuracyandreproducibility:Doesthetestcorrectlymeasurewhatitclaims tomeasure,andwillitdosoinaconsistentmanner? Costs:Whenaphysicianordersatest,heorshecancausethepatientand societytoincuravarietyofcosts,includingthoseofthetestitselfaswellas thecostsofdownstreamtests,procedures,andcomplications. Testimpact:Beyondcostsandprocedures,testscanleadtolifestyle changesandpharmacologicalinterventions.Thesemaybereasonable,but onlyiftheyleadtoimprovedclinicaloutcomes.Intheabsenceofrandomized trials,oneoftencannotdeterminewhetheratesthasasalutaryimpact.12 TheprecedingcriteriaandcharacteristicsaresummarizedinTable2.

Table2

CharacteristicsbyWhichNovelRiskStratificationTestsAreAssessed Table2 References: 1. HlatkyMA,GreenlandP,ArnettDK,etal.onbehalfoftheAmericanHeartAssociationExpertPanelonSubclinicalAtherosclerotic DiseasesandEmergingRiskFactorsandtheStrokeCouncil.Criteriaforevaluationofnovelmarkersofcardiovascularrisk:ascientific statementfromtheAmericanHeartAssociation.Circulation2009119:240816. 2. LordSJ,IrwigL,SimesRJ.Whenismeasuringsensitivityandspecificitysufficienttoevaluateadiagnostictest,andwhendoweneed randomizedtrials?AnnInternMed2006144:8505.

CurrentGuidelines:GeneralApproachandRecommendationson SpecificTests
TheAmericanCollegeofCardiologyFoundationandtheAHA(ACCF/AHA)recently releasedguidelinesonassessmentofcardiovascularriskinasymptomaticadults.6 Theguidelinesrecommendthefollowingapproach. First,cliniciansshouldcalculateaglobalriskscoreforalladults(ClassIB).Avariety ofriskscoresareavailable(Table3)allusemultipletraditionalcardiovascularrisk factors.Thescoresareusefulforderivingasinglequantitativeestimatetoclassify subjectsasbeinglowrisk(<10%risk/10years),intermediaterisk(1020%/10 years),orhighrisk(>20%/10years)forexperiencingmajorcoronaryevents.To furthermodifyrisk,theguidelinesrecommendobtainingfamilyhistoryforpremature atherothromboticcardiovasculardisease(ClassIB).Forsubjectswhoaredeemed tobeatloworhighrisk,nofurthertestingisneeded. Second,clinicianscanconsiderperformingfurthertestsinadultswho,basedon globalriskscoresandfamilyhistory,areatintermediaterisk(1020%10yearrisk). Amongtheteststhatcliniciansmightconsider(ClassIIA)inthisintermediaterisk groupare: HighsensitivityCreactiveprotein(hsCRP):Inadultswhomeettheinclusion andexclusioncriteriaoftheJUPITER(JustificationfortheUseofStatinsin Prevention:AnInterventionTrialEvaluatingRosuvastatin)trial,13(i.e.,men ages>50yearswomenages>60yearslowdensitylipoproteincholesterol <130mg/dlnotonlipidlowering,hormonereplacement,or immunosuppressanttherapywithoutclinicalcoronaryheartdisease, diabetes,chronickidneydisease,severeinflammatoryconditions,or contraindicationstostatins)todetectelevatedlevels. Urineanalysis:Inadultswithhypertensionordiabetes,todetect microalbuminuria. Restingelectrocardiogram(ECG):Inadultswithhypertensionordiabetes,to detectleftventricularhypertrophy,silentQwaves,intraventricularconduction delays,andSTTabnormalities. Carotidintimamediathickness:Publishedrecommendationsonrequired equipment,technicalapproach,andoperatortrainingandexperiencefor performanceofthetestmustbecarefullyfollowedtoachievehighquality results. Anklebrachialindex:Reasonableforasymptomaticadults. Coronarycalcium:Reasonableforasymptomaticadults. Theguidelineslistagroupofteststhatmaybereasonable(ClassIIB).These includehsCRPinyoungeradultsthanthoseenrolledintheJUPITERtrial,urine analysisintheabsenceofhypertensionordiabetes,lipoproteinassociated phospholipaseA2,restingECGsintheabsenceofhypertensionordiabetes, echocardiographyintheabsenceofhypertension,exerciseECG(e.g.,insedentary adultsconsideringstartingavigorousexerciseprogram)withparticularattentionto nonECGmarkerssuchasexercisecapacity,andstressmyocardialperfusion imaging(MPI)inpeoplewithdiabetes,astrongfamilyhistory,andhighcoronary calciumscore. Finally,theguidelinesdelineateteststhatshouldNOTbedone(ClassIII): genotypes,lipidmeasuresbeyondthoseprovidedbyastandardprofile,natriuretic peptide,arterialflowdilatation,arterialstiffness,stressechocardiography,stress MPI(exceptasnotedearlier),computedtomography(CT)angiography,and magneticresonance(MR)angiography.

Table3

GlobalRiskScores Table3 CHD=coronaryheartdiseaseCVD=cardiovasculardiseaseHDL=highdensitylipoproteinhsCRP=highsensitivityCreactiveproteinLDL= lowdensitylipoproteinMI=myocardialinfarction. Reproducedwithpermissionfrom:GreenlandP,AlpertJS,BellerGA,etal.2010ACCF/AHAguidelineforassessmentofcardiovascularriskin asymptomaticadults:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.J AmCollCardiol201056:e50103.

SpecialCircumstances
TheACCF/AHAguidelinesaddressspecificapproachestoasymptomaticadultswithdiabetesandapproachesto women.6 Forpeoplewithdiabetes,itisreasonable(ClassIIA)tomeasurecoronarycalcium,whileitmaybeconsidered (ClassIIB)toobtainglycosylatedhemoglobinandstressMPI.Itisnoteworthythatinvestigatorshaveperformeda randomizedtrialofMPIindiabetesandfoundthat,althoughMPIabnormalitiespredictedcoronaryevents,theuseofMPI didnotreducerisk.14Thistrial,knownasDIAD(DetectionofIschemiainAsymptomaticDiabetics),demonstratesthe principlethatpredictiondoesnotnecessarilyimplyprevention. Theguidelinesrecommendthataglobalriskscoreandfamilyhistorybeobtainedinallasymptomaticwomen(ClassIB forboth).

UnmetNeeds
ItisnoteworthythattheACCF/AHAguidelinesdonotgiveanyClassIArecommendationforcliniciansassessing cardiovascularriskinasymptomaticadults.Thisisbecauseitisnotknownwhetheranymeasurementortest(including globalriskscores)improvesoutcomes.Onemightthinkthatriskassessmentandscreeningtestscouldleadto improvedadherenceandmotivationtointerventionsthattreatriskfactors,butatleastonerandomizedUSArmytrialof coronaryarterycalciumscoringwasnegative.15 Similarly,itisnotknownwhetheracquisitionofglobalriskscores,familyhistory,orfindingsfromscreeningtestsguide therapyorlongtermmonitoringinsuchawayastoimprovehealthoutcomes,mainlybecauserandomizedtrialsonthis topicarefew.12,16TherecentlycompletedNLST(NationalLungScreeningTrial)servesasanexample.17

KeyPoints
Itcannotbeautomaticallyassumedthatdiagnosingdiseaseinanearly,asymptomaticstatepreventsclinical diseaseorimproveshealth. Itcannotbeautomaticallyassumedthatifatestpredictsclinicalevents,itsroutineusewillpreventevents. Althoughatestmayindependentlypredicteventsbystandardstatisticalcriteria,itmayfailtoimproveclinicians abilitytodiscriminatepatientswhowilldevelopdiseasefromthosewhowillnot,andtoproperlyreclassify patientsrisk. Moreimportantly,althoughatestmaypredictevents,itmaynotpredictresponsetopreventiveinterventions. Allasymptomaticadultsshouldbecheckedforglobalriskbasedonstandardcardiovascularriskfactors,andfor familyhistoryofprematureCAD. Physiciansmayreferintermediateriskpatientsforanumberoftests,buttheyshouldinformtheirpatientsthatitis notknownwhetherobtaininginformationfromadditionaltestswillleadtobetterhealth.Thesetestsincludehs CRP(forthosemeetingJUPITERcriteria),urineanalysisandrestingECG(inpeoplewithhypertensionor diabetes),carotidintimamediathickness,anklebrachialindex,andcoronarycalciumscores. Randomizedtrialsareneededtoimprovephysiciansabilitytoworkwithpatientsandmakeinformedevidence baseddecisionsaboutscreeningforCADinasymptomaticadults.

References
1. AshtonHA,BuxtonMJ,DayNE,etal.onbehalfoftheMulticentreAneurysmScreeningStudyGroup.The MulticentreAneurysmScreeningStudy(MASS)intotheeffectofabdominalaorticaneurysmscreeningonmortality inmen:arandomisedcontrolledtrial.Lancet2002360:15319. 2. GrimesDA,SchulzKF.Usesandabusesofscreeningtests.Lancet2002359:8814. 3. LeeTH,BrennanTA.Directtoconsumermarketingofhightechnologyscreeningtests.NEnglJMed 2002346:52931. 4. LauerMS.Screeningforcoronaryheartdisease:hasthetimeforuniversalimagingarrived?CleveClinJMed 200774:64550,6534,656 5. AndrioleGL,CrawfordED,GrubbRL3rd,etal.onbehalfofthePLCOProjectTeam.Mortalityresultsfroma randomizedprostatecancerscreeningtrial.NEnglJMed2009360:13109. 6. GreenlandP,AlpertJS,BellerGA,etal.2010ACCF/AHAguidelineforassessmentofcardiovascularriskin asymptomaticadults:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociation TaskForceonPracticeGuidelines.JAmCollCardiol201056:e50103. 7. U.S.PreventiveServicesTaskForce.GuidetoClinicalPreventiveServices(2ndEdition):ReportoftheU.S. PreventiveServicesTaskForce.McLean,VA:InternationalMedicalPublishing2009. 8. DetranoR,GuerciAD,CarrJJ,etal.Coronarycalciumasapredictorofcoronaryeventsinfourracialorethnic groups.NEnglJMed2008358:133645. 9. PatzEF,Jr.,GoodmanPC,BeplerG.Screeningforlungcancer.NEnglJMed2000343:162733. 10. BlackWC,CzumJM.ScreeningcoronaryCTangiography:notimesoon.JAmCollRadiol20074:2959. 11. HlatkyMA,GreenlandP,ArnettDK,etal.onbehalfoftheAmericanHeartAssociationExpertPanelonSubclinical AtheroscleroticDiseasesandEmergingRiskFactorsandtheStrokeCouncil.Criteriaforevaluationofnovel markersofcardiovascularrisk:ascientificstatementfromtheAmericanHeartAssociation.Circulation 2009119:240816. 12. LordSJ,IrwigL,SimesRJ.Whenismeasuringsensitivityandspecificitysufficienttoevaluateadiagnostictest, andwhendoweneedrandomizedtrials?AnnInternMed2006144:8505. 13. RidkerPM,DanielsonE,FonsecaFA,etal.onbehalfoftheJUPITERStudyGroup.Rosuvastatintoprevent vasculareventsinmenandwomenwithelevatedCreactiveprotein.NEnglJMed2008359:2195207. 14. YoungLH,WackersFJ,ChyunDA,etal.onbehalfoftheDIADInvestigators.Cardiacoutcomesafterscreeningfor asymptomaticcoronaryarterydiseaseinpatientswithtype2diabetes:theDIADstudy:arandomizedcontrolled trial.JAMA2009301:154755. 15. O'MalleyPG,FeuersteinIM,TaylorAJ.Impactofelectronbeamtomography,withorwithoutcasemanagement,on motivation,behavioralchange,andcardiovascularriskprofile:arandomizedcontrolledtrial.JAMA2003289:2215 23. 16. BonowRO.Clinicalpractice.Shouldcoronarycalciumscreeningbeusedincardiovascularpreventionstrategies? NEnglJMed2009361:9907. 17. TheNationalLungScreeningTrialResearchTeam.Reducedlungcancermortalitywithlowdosecomputed tomographicscreening.NEnglJMed2011Jun30:[Epubaheadofprint].

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Chapter7Exam
Visittheonlineversionoftheproducttoseethecorrectanswerandcommentary.

1.Apaperinamedicaljournalreportsonanewdiagnosticscreeningtestthatisa statisticallysignificantindependentpredictorofmajorcardiovasculareventsin asymptomaticadults,evenafteraccountingforstandardriskfactors.Theauthors arguethatcliniciansshouldusethetest. Whichofthefollowingisthemostimportantreasonwhytheauthorsargumentis notvalid? A. Failuretoaccountfordiscrimination. B. Failuretoaccountforimpactonoutcome. C. Failuretoaccountforreclassification. D. Failuretoaccountforcalibration.

2. WhichofthefollowingstatementsisTRUEregardingthetreatmentofmultivessel CAD? A. RoutinerevascularizationinpatientswithischemiccardiomyopathyandLV ejectionfractionbelow35%improvessurvival. B. PercutaneousrevascularizationguidedbyFFRisassociatedwithsimilar numbersofstentsperprocedurebutimprovedoutcomesat2yearscompared withrevascularizationguidedbyangiography. C. PatientswithdiabetesandmultivesselCADhaveimprovedsurvivalwith CABGcomparedwithPCIusingbaremetalstentsmortalitydatacomparing surgerywithdrugelutingstentsinpatientswithdiabetesareinconclusive. D. ApatientwithseverestenosesintheproximalLADarteryandproximalright coronaryarteryshouldbetreatedwithmaximalmedicaltherapyandreferredfor revascularizationonlyforreliefofanginalsymptoms.

3. Inwhichofthefollowingsituationsisrevascularizationassociatedwithimproved survival? A. Chronicocclusionofalargedominantcircumflexarteryintermediateriskon noninvasivetestingclassIIangina. B. SeverestenosesofthemidLADandproximalcircumflexarteries intermediateriskonnoninvasivetestingasymptomaticonmetoprolol. C. Chronicocclusionofadominantrightcoronaryarteryseverestenosisofthe midcircumflexclassIIanginaonmaximalmedicaltherapy. D. 80%stenosesoftheproximalLADandproximalcircumflexarteriesnormal ventricularfunctionclassIangina.

4. WhichofthefollowingtestsisLEASTlikelytoprovideanyincrementalprognostic informationinpatientswithestablishedSIHD? A. Echocardiography. B. CardiacMRI. C. NTproBNPorBNP. D. Computedtomographycalciumscore.

5. WhenevaluatingpatientswithSIHDandcategorizingthemintoanappropriaterisk group,whichofthefollowingarethecorresponding1yearmortalityratesforlow, intermediate,orhighrisk? A. <5%(low),58%(intermediate),>8%(high). B. <1%(low),13%(intermediate),>3%(high). C. <3%(low),34%(intermediate),>5%(high). D. <10%(low),1020%(intermediate),>20%(high).

6. WhichofthefollowingstatementsisTRUEregardingrevascularization? A. Comparedwithstenting,CABGforisolatedproximalLADdiseaseis associatedwithimproved1yearsurvival. B. InpatientswithmultivesselCAD,1yearmortalityratesaresimilarfollowing PCIwithdrugelutingstentscomparedwithCABG. C. InpatientswithmultivesselCAD,1yearrepeatrevascularizationratesare similarfollowingPCIwithdrugelutingstentscomparedwithCABG. D. IntheSYNTAXstudy,patientswithsignificantLMCAdiseasehadsimilar1 yearratesofsurvivalandrepeatrevascularizationafterPCIcomparedwith CABG.

7.A45yearoldmanwithdiabetesisevaluatedforchronicCanadian CardiovascularSocietyclassIIIanginadespitetreatmentwithaspirin,metoprolol, ranolazine,andatorvastatin.Oncardiaccatheterization,hisventricularfunctionis normal,andhehasfocal90%stenosesinhismidLADcoronaryartery,midright coronaryartery,andalargefirstobtusemarginalbranch. WhichofthefollowingstatementsisTRUEregardingthispatientstreatment?

A. Continuedmedicaltherapywithadditionofalongactingnitrateisindicated, givenhisnormalLVfunction. B. MultivesselPCIwithdrugelutingstentsisassociatedwithanincreasedrisk ofmortalityat1yearcomparedwithCABG,regardlessofhisSYNTAXscore. C. Inpatientswithdiabetes,multivesselPCIwithdrugelutingstentsis associatedwithanincreasedriskofrepeatrevascularizationat1yearcompared withCABG. D. Thepatientshouldbefurtherevaluatedwithmyocardialperfusionimaging andundergorevascularizationifmoderateorhighriskfindingsare demonstrated.

8.A64yearoldmanwithangiographicdocumentationofCADamenabletosurgical revascularizationandaLVEFof30%isbeingevaluatedintheclinicforroutine followup.HismostrecentMIwas6monthsago.Hedoesnothaveleftmainor aorticvalvediseaseandhasneverhadcardiogenicshock.Youareconsidering whetherornotaviabilitystudywillhelpyoutodetermineifthispatientwillbenefit fromsurgicalrevascularization. WhichofthefollowingstatementsisTRUEregardingtheprognosticvalueofa viabilitystudyinthispatient? A. ViabilityassessmentbySPECTand/orDSEwillidentifypatientswitha greaterlikelihoodofsurvival,independentofotherbaselineprognosticvariables. B. ViabilityassessmentbySPECTissuperiortoDSEinidentifyingpatientswith adifferentialsurvivalbenefitfromCABG. C. ViabilityassessmentbySPECTand/orDSEwillidentifypatientswitha differentialsurvivalbenefitfromCABG. D. ViabilityassessmentbyDSEissuperiortoSPECTinidentifyingpatientswith adifferentialsurvivalbenefitfromCABG. E. ViabilityassessmentbySPECTand/orDSEwillnotidentifypatientswitha differentialsurvivalbenefitfromCABG.

9.A62yearoldwomanpresentstoyourofficecomplainingofchestdiscomfort, whichhasbeenincreasinginfrequencyoverthepast2years.Atfirstshenoticedthe discomfortwithextremeexertion,whilerunningwithhergrandchildren.The discomfortbeganinhersubsternalregionandradiatedtoherbackandleft shoulder,andresolvedwithrest.Sheattributedthesesymptomstogettingoldand beingoutofshape.About9monthsago,shenoticedthattheseepisodeswere occurringaboutonceaweekandnowwereprecipitatedbyeitherphysicalactivity (walkingupordownthestairs,doinghouseholdchoreswithherarms)oremotional stressrelatedtoherjobasateacherofautisticchildren. Althoughtheseepisodescontinuetoresolvewithrest,sheisconcernedabout whethersheshouldretire.Shehasa50packyearsmokinghistoryandquit2years agowhentheseepisodesfirststarted.Sheadmitstopoordietaryhabits,historyof hypertension,andinfrequentmigrainebothdiagnosedinherlate40sandcurrently treatedwithenalapril10mgdailyandhydrochlorothiazide12.5mgdaily.Shehas dyslipidemiatreatedwithlovastatin20mgdailyfor2yearswithtotalcholesterolof 215mg/dl,lowdensitylipoprotein(LDL)of125mg/dl,highdensitylipoproteinof32 mg/dl,andtriglyceridesof178mg/dl.Shedoesnothavediabetes.Shehasnever

seenacardiologistandhasneverhadanECGoranyothercardiovasculartesting. Herfatherdiedofafatalmyocardialinfarctionattheageof62,andhermotherdied oflungcancerattheageof58.Herolderbrotherhashadcoronaryarterybypass grafting,andheryoungersisterhasdyslipidemiaanddiabetes. Otherthanbeingoverweight(5feet3inches,174lbs)withabloodpressuretodayof 162/89mmHg,herexamisunremarkable. Hercardiologistdeterminesthatshehasstableangina,andthatherbloodpressure andLDLneedbettercontrol.Beforeaddressingherretirementquestionandper ACC/AmericanHeartAssociation(AHA)guidelines,thecardiologistdiscussesthe needforadditionalnoninvasivecardiacriskstratification.HerrestingECGwas normal,andenalaprilwasincreasedto20mg,hydrochlorothiazideto25mgdaily, andlovastinto40mgdaily.Afteralengthydiscussion,thepatientwasnotinterested intakingalongactingnitrate,fearingthatitwouldprovokehermigraine.Likewise, shedidnotwanttotakeabetablockerorcalciumantagonistbecauseshehad experiencedfatigueandedemawhenshehadbeenprescribedtheseagentsover thepreviousyearsforhypertension. Thepatientreturnstotheofficenurseforbloodpressurechecksoverthenext3 weeks.ThenanexercisestresstestwasdoneusingtheBruceprotocolwithDuke treadmillscoring.Herstresstestresultsareasfollows: Restingheartrate:80bpmrestingbloodpressure128/78mmHg. Timeontreadmill:9minutesand30secondswithoutchestdiscomfort. Peakheartrate:142bpmpeakbloodpressure185/92mmHg. Atpeakexercise,sheexhibitsa1.5mmhorizontaltodownslopingSTdepressionin inferiorleads,consistentwithischemiawithfairlyhighworkload.Shedidnothave anysymptoms.Animmediatepostexerciseechocardiogramrevealsanejection fractionof65%andnowallmotionabnormalities.HerSTsegmentdepression resolvedcompletelyin1minute. WhichofthefollowingisNOTaprimarygoaloftherapyforpatientswithchronic stableangina? A. Reducecoronaryperfusionpressure. B. Increasequalityoflifebyreducingischemiaandpreventingsymptoms. C. Increasequantityoflifebydiseasemodificationandpreventionofmyocardial infarctionanddeath.

PleasevisittheonlineversiontoengageinthisExam. 1.ThecorrectanswerisB.Forascreeningtesttobeofvalue,itsusemustleadtoan improvementinclinicaloutcome. 2.ThecorrectanswerisC.Inalargemetaanalysisofstudiescomparingcoronaryartery bypasssurgerywithmultivesselPCI,lowermortalitywasobservedinpatientswithdiabeteswho weretreatedwithsurgery.1 Thesestudieswereconductedbeforetheadventofdrugeluting stents.TheSYNTAXstudycomparedmultivesselPCIwithdrugelutingstentstosurgery.2 In SYNTAX,althoughtherewasnodifferenceinmortalityinthediabeticsubgroup,thepatients treatedwithPCIhadincreasedratesofrepeatrevascularizationatfollowup. TheSTICHtrialcomparedroutinerevascularizationtooptimalmedicaltherapyinpatientswith ischemiccardiomyopathyandsevereLVdysfunction(definedasaLVejectionfractionbelow 35%).3 InSTICH,overallmortalitywasnodifferentbetweenthetwogroups,althoughsecondary endpointswereimprovedinthesurgicalarm.ThefollowupinSTICHwillbeextendedto examinetheeffectofrevascularizationonlongtermmortality.

IntheFAMEstudy,theuseofFFRinguidingpercutaneousrevascularizationinpatientswith multivesselCADresultedinlowerratesofstentuseandimprovedoutcomesat2years.4 PatientswithmultivesselCADincludingseverediseaseoftheproximalLADarteryshouldbe consideredforrevascularizationtoimprovesurvival.ThisrecommendationisbasedontheCASS study.5 References


1. HlatkyMA,BoothroydDB,BravataDM,etal.Coronaryarterybypasssurgerycomparedwith percutaneouscoronaryinterventionsformultivesseldisease:acollaborativeanalysisofindividual patientdatafromtenrandomizedtrials.Lancet199037311907. 2. BanningAP,WestabyS,MoriceMC,etal.Diabeticandnondiabeticpatientswithleftmainand/or3 vesselcoronaryarterydisease:comparisonofoutcomeswithcardiacsurgeryandpaclitaxeleluting stents.JAmCollCardiol201055:106775. 3. VelazquezEJ,LeeKL,DejaMA,etal.Coronaryarterybypasssurgeryinpatientswithleft ventriculardysfunction.NEngJMed2011364:160716. 4. PijlsNH,FearonWF,ToninoPA,etal.Fractionalflowreserveversusangiographyforguiding percutaneouscoronaryinterventioninpatientswithmultivesselcoronaryarterydisease:2year followupoftheFAMEstudy.JAmCollCardiol201056:17784. 5. AldermanEL,BourassaMG,CohenLS,etal.Tenyearfollowupofsurvivalandmyocardial infarctionintherandomizedCoronaryArterySurgeryStudy.Circulation199082:162946.

3.ThecorrectanswerisD.Dataonthemortalitybenefitofrevascularizationinpatientswith multivesselCADisprimarilyfromthestudiesfromthreedecadesagocomparingCABGwith medicaltherapy.IntheCASSstudy,1 amortalitybenefitwasobservedwithrevascularizationin patientswiththefollowingconditions: Leftmaincoronaryarterystenosisorleftmainequivalentdisease ThreevesselCAD,particularlywithareducedLVejectionfraction(40%) TwovesselCADincluding>75%stenosisintheproximalLAD ThereisnoevidencethatsurvivalisimprovedinpatientswithsinglevesselCADnotinvolvingthe proximalLAD.PatientswithmildtomoderateanginafrommultivesselCADnotinvolvingthe proximalLADmayderivesymptomaticrelieffromrevascularization,butthereisnoevidencethat survivalisimproved. References
1. AldermanEL,BourassaMG,CohenLSetal.Tenyearfollowupofsurvivalandmyocardialinfarction intherandomizedCoronaryArterySurgeryStudy.Circulation199082:162946.

4.ThecorrectanswerisD.AssessmentofLVfunctioniscriticalintheevaluationofpatients withSIHD,andthus,echocardiographyprovidesimportantinformationregardingprognosis. CardiacMRIisalsoareasonabletestinpatientswithSIHD.Inadditiontoprovidingquantifiable dataregardingLVfunction,itmayofferinsightintomyocardialviability,whichmayhelpguide therapy.NTproBNPorBNPhavebeenshowntoidentifypatientsatgreaterriskofdeathand heartfailureamongpatientswithSIHD,andtherefore,doaddincrementalprognostic information.Calciumscoring,asassessedwithCT,hasnoroleinthemanagementofpatients withSIHD,asthesepatientsareknowntohaveatherosclerosisandthedegreeofcalcification doesnotcorrelatewiththedegreeofstenosis. References
1. DouglasPS,GarciaMJ,HainesDE,etal.ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011Appropriateusecriteriaforechocardiography.areportoftheAmericanCollegeofCardiology FoundationAppropriateUseCriteriaTaskForce,AmericanSocietyofEchocardiography,American HeartAssociation,AmericanSocietyofNuclearCardiology,HeartFailureSocietyofAmerica,Heart RhythmSociety,SocietyforCardiovascularAngiographyandInterventions,SocietyofCriticalCare Medicine,SocietyofCardiovascularComputedTomography,andSocietyforCardiovascular MagneticResonanceEndorsedbytheAmericanCollegeofChestPhysicians.JAmCollCardiol 201157:112666. 2. OmlandT,SabatineMS,JablonskiKA,etal,andthePEACEInvestigators.PrognosticvalueofBType natriureticpeptidesinpatientswithstablecoronaryarterydisease:thePEACETrial.JAmCollCardiol 200750:20514. 3. TaylorAJ,CerqueiraM,HodgsonJM,etal.ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010appropriateusecriteriaforcardiaccomputedtomography.AreportoftheAmericanCollegeof CardiologyFoundationAppropriateUseCriteriaTaskForce,theSocietyofCardiovascularComputed

Tomography,theAmericanCollegeofRadiology,theAmericanHeartAssociation,theAmerican SocietyofEchocardiography,theAmericanSocietyofNuclearCardiology,theNorthAmerican SocietyforCardiovascularImaging,theSocietyforCardiovascularAngiographyandInterventions, andtheSocietyforCardiovascularMagneticResonance.JAmCollCardiol201056:186494.

5.ThecorrectanswerisB.WhiletheriskcategoriesinSIHDarenotaswellvalidatedand acceptedasinprimaryprevention,inSIHD,lowriskisconsidereda1yearmortalityrateof<1%, intermediateriskisconsidereda1yearmortalityrateof13%,andhighriskisconsidereda1 yearmortalityrateof>3%.Inprimaryprevention,theratesaremuchlower,witha10yearriskof deathandMIof<10%(or<1%peryear)inlowriskpatients,1020%inintermediaterisk patients,and>20%inhighriskpatients. References


1. GibbonsRJ,AbramsJ,ChatterjeeK,etal.ACC/AHA2002guidelineupdateforthemanagementof patientswithchronicstableanginasummaryarticle:areportoftheAmericanCollegeof Cardiology/AmericanHeartAssociationTaskForceonpracticeguidelines(Committeeonthe ManagementofPatientsWithChronicStableAngina).JAmCollCardiol200341:15968.

6.ThecorrectanswerisB.TheSYNTAXstudywasthefirstrandomizedtrialtocompare treatmentwithPCIusingdrugelutingstentswithCABGinpatientswithmultivesselCAD.Overall ratesofmortalityat12monthsweresimilarinthetwogroups,whereasrepeatrevascularization procedureswereincreasedinpatientstreatedwithPCI.InSYNTAX,the40%ofpatientswith significantLMCAdiseasewerestratifiedatrandomizationtoPCIorCABG.Inthisgroup,mortality ratesweresimilar,andrepeatrevascularizationrateswereincreasedfollowingPCI. Inalargemetaanalysis,CABGandPCIforproximalLADdiseaseresultedinsimilarratesof stroke,myocardialinfarction,and5yearsurvivalCABGwasassociatedwithmorereliefof anginaandlowerratesofrepeatrevascularization,whereasPCIwasassociatedwithshorter hospitalstaysandlessneedforbloodtransfusion. References
1. SerruysPW,MoriceMC,KappeteinAP,etal.,onbehalfoftheSYNTAXInvestigators.Percutaneous coronaryinterventionversuscoronaryarterybypassgraftingforseverecoronaryarterydisease.N EnglJMed2009360:96172. 2. KapoorJR,GiengerAL,ArdehaliR,etal.Isolateddiseaseoftheproximalleftanteriordescending artery:comparingtheeffectivenessofpercutaneouscoronaryinterventionsandcoronaryartery bypasssurgery.JACCCardiovascInterv20081:48391.

7.ThecorrectanswerisC.TheSYNTAXstudywasthefirstrandomizedtrialtocompare treatmentwithPCIusingdrugelutingstentsversusCABGinpatientswithmultivesselCAD.In SYNTAX,patientswithdiabeteswerestratifiedatrandomizationtoPCIorCABG.Inthisgroup, mortalityratesweresimilar,whereasrepeatrevascularizationrateswereincreasedfollowing multivesselPCI.However,inthesubsetofpatientswithdiabeteswithSYNTAXscoresof33, mortalitywassignificantlyhigherfollowingPCIthanwithCABG(13.5%vs.4.1%). Revascularizationisindicatedinthispatient,givenhissevereanginalsymptomsdespite medicaltherapyinthepresenceofsignificantCAD. References


1. BanningAP,WestabyS,MoriceMC,etal.Diabeticandnondiabeticpatientswithleftmainand/or3 vesselcoronaryarterydisease:comparisonofoutcomeswithcardiacsurgeryandpaclitaxeleluting stents.JAmCollCardiol201055:106775. 2. SerruysPW,MoriceMC,KappeteinAP,etal.,onbehalfoftheSYNTAXInvestigators.Percutaneous coronaryinterventionversuscoronaryarterybypassgraftingforseverecoronaryarterydisease.N EnglJMed2009360:96172. 3. PatelMR,DehmerGJ,HirshfeldJW,etal.ACCF/SCAI/STS/AATS/AHA/ASNC2009Appropriateness CriteriaforCoronaryRevascularization:areportbytheAmericanCollegeofCardiologyFoundation AppropriatenessCriteriaTaskForce,SocietyforCardiovascularAngiographyandInterventions, SocietyofThoracicSurgeons,AmericanAssociationforThoracicSurgery,AmericanHeart Association,andtheAmericanSocietyofNuclearCardiology.EndorsedbytheAmericanSocietyof Echocardiography,theHeartFailureSocietyofAmerica,andtheSocietyofCardiovascular ComputedTomography.JAmCollCardiol200953:53053.

8.ThecorrectanswerisE.OptionCisincorrectbecauseSPECTandDSEwillNOTidentify

patientswithadifferentialsurvivalbenefitfromCABG,basedontheSTICHviabilitytrialresults. OptionsBandDareincorrectbecausethereisnosignificantdifferencebetweenDSEand SPECTintermsoflackofidentifyingpatientswithadifferentialsurvivalbenefitfromCABG,based ontheSTICHviabilitytrialresults.OptionAisincorrectbecauseviabilitystatusisnotsignificantly associatedwiththerateofdeathafteradjustmentforothersignificantbaselinevariablessuchas LVEF,enddiastolicvolume,andendsystolicvolumeindex.1 References


1. BonowRO,MaurerG,LeeKL,etal,andtheSTICHTrialInvestigators.Myocardialviabilityand survivalinischemicleftventriculardysfunction.NEnglJMed2011364:161725.

9.ThecorrectanswerisA.Therearetwoprimaryobjectivesinmanagingpatientswithchronic stableangina:1)increasequantityoflifebydiseasemodificationtopreventmyocardialinfarction anddeath,and2)increasequalityoflifebyreducingischemiaandpreventinganginaandrelated symptoms.Seethe2007ChronicAnginaFocusedUpdateoftheACC/AHA2002Guidelinesfor theManagementofPatientsWithChronicStableAngina.Treatingherhighbloodpressuretothe 120130mmHgsystolicand6085mmHgdiastoliclevelwillnotimpaircoronaryperfusion,but willreducemyocardialoxygendemandtolessenthepossibilityofischemia. References


1. FrakerTDJr,FihnSD2002ChronicStableAnginaWritingCommitteeAmericanCollegeof CardiologyAmericanHeartAssociationGibbonsRJ,AbramsJ,ChatterjeeK,etal.2007chronic anginafocusedupdateoftheACC/AHA2002guidelinesforthemanagementofpatientswithchronic stableangina:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForce onPracticeGuidelinesWritingGrouptodevelopthefocusedupdateofthe2002guidelinesforthe managementofpatientswithchronicstableangina.JAmCollCardiol200750:226474.

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