急性冠脈綜合征：從病理到治療講座

煩惱有何懼怕，既然躲不掉，就調(diào)好心態(tài)與它共存。心向陽(yáng)光，何懼風(fēng)霜。

茫茫人海你我相遇就是緣分，歡迎下載！2021/8/121AcuteCoronarySyndrome:

FromPathophysiologytoManagement2021/8/122STEMIClinicalfindingEKGSerummarkersRiskassessmentNon-cardiac

chestpainStable

anginaUANSTEMINegativePositiveST-Twave

changesSTelevationLow

probabilityMedium-highriskThrombolysis

PrimaryPCIAspirin+GPIIb/IIIainhibitorclopidogrel+heparin/LMWH+anti-ischemicRx

EarlyinvasiveRxDischargeNegativeDiagnostic

ruleoutMI/ACSpathwaySTEMI

NegativeAtypical

painLowriskAspirin,heparin/low-molecular-weightheparin(LMWH)+clopidogrel

Anti-ischemicRx

EarlyconservativetherapyOngoingpainDM=diabetesmellitus.Cannon,Braunwald.HeartDisease.2001.Restpain,Post-MI,DM,PriorAspirinExertional

painTheSpectrumofACS2021/8/123InconsistentApproachtoACSMultiplicityofinterpretationofClinicaltrialsProtocolvariationPropensityofPCIinclinicalstudiesPersonalpreferenceofphysiciansUnclearguidelines2021/8/124InflammationAtherosclerosisThrombosisThrombusQuiescentplaquePlateletsandthrombinPlaqueruptureAcuteCoronarySyndromes

EvolvingUnderstandingofPathophysiology2021/8/125RelativeRiskofCardiovascularEventsAccordingtoSeveralBiochemicalMarkersRelativeRiskofFutureCVEvents01.02.04.06.0Lipoprotein(a)LDL-cholesterolHomocysteineTotalcholesterolApolipoproteinBTC:HDL-Cratiohs-CRPhs-CRP+TC:HDL-CRatioAdaptedfromRidkerPM,etal.NEnglJMed.2000;342:836-843.2021/8/126ThrombosisofaDisruptedAtheromaWeakeningofthefibrouscapThrombogenicityofthelipidcoreThesignalsthatregulatethesefeaturesoftheplaqueremainuncertain2021/8/127CollagenaseexpressionandcircumferentialstressinhumancoronaryatheromaMMP-1LeeRTetal.ArtThrombVascBiol1996;16:10702021/8/128PercentageDistributionofCoronaryAtheroscleroticPlaqueRupturesOtherThantheCulpritLesion%#ofRupturedPlaqueDistinctFromtheCulpritLesionRioufolG.etal.,Circulation2002;106:804-8.

0123452021/8/1292021/8/1210MarkersofIncreasedRiskinACSSTsegmentchangesSerummarkersNecrosisInflammationLVdysfunctionHemodynamicinstability2021/8/12119、人的價(jià)值，在招收誘惑的一瞬間被決定。2023/2/32023/2/3Friday,February3,202310、低頭要有勇氣，抬頭要有低氣。2023/2/32023/2/32023/2/32/3/20234:35:32PM11、人總是珍惜為得到。2023/2/32023/2/32023/2/3Feb-2303-Feb-2312、人亂于心，不寬余請(qǐng)。2023/2/32023/2/32023/2/3Friday,February3,202313、生氣是拿別人做錯(cuò)的事來(lái)懲罰自己。2023/2/32023/2/32023/2/32023/2/32/3/202314、抱最大的希望，作最大的努力。03二月20232023/2/32023/2/32023/2/315、一個(gè)人炫耀什么，說(shuō)明他內(nèi)心缺少什么。。二月232023/2/32023/2/32023/2/32/3/202316、業(yè)余生活要有意義，不要越軌。2023/2/32023/2/303February202317、一個(gè)人即使已登上頂峰，也仍要自強(qiáng)不息。2023/2/32023/2/32023/2/32023/2/32021/8/121203060901201501801086420DaysST↓ACST-waveinversionGUSTO-IIbStudy:Correlationof6-MonthMortalityWithBaselineECGFindingsinPatientsWithACSCumulativeMortalityAt6Months,%SavonittoS,etal.JAMA.1999;281:707-713.Copyrighted1999,AmericanMedicalAssociation.2021/8/1213AssociationofTroponinElevationwithRiskofMortalityinACSMortalityat42Days8311741481345067%%%%%%AntmanEM.NEnglJMed1996;335:12342-1349.2021/8/1214*xupperlimitofnormalRelationshipBetweenElevatedCK-MBandMortalityat6monthsAlexanderJHetal.Circulation.1999;Suppl1:1-629.4.9%5.7%9.2%12.6%14.5%19.9%

(n=5,681) (n=1,098) (n=294) (n=302)(n=249)(n=211)

Normal

1-2*

2-3*

3-5*

5-10*

10*CK-MBlevelsduringhospitalization2021/8/1215TACTICS:OutcomebyTroponinStatusand CADonCathat6monthsTnnegNoCADTnnegCADTnPosNoCADTnPosCADP-valueDeath(%)00.082Re-MI(%)00.003Death/Re-MI05.05.511.2<0.001ACS-Hosp2.27.014.611.40.005AllCause2.210.518.519.1<0.0012021/8/1216LindahlB,etal.NEnglJMed.2000;343:1139-1147.PredictiveValueofTroponinTandhs-CRPforMortalityFromACSinFRISCII201000612182430364248CumulativeProbabilityofDeath,%MonthsTroponinT>0.60μg/L(n=377)TroponinT0.60-0.59μg/L(n=367)TroponinT<0.60μg/L(n=173)P=.007P=.001CRP2-10mg/L(n=294)201000612182430364248CRP>10mg/L(n=309)CRP<2mg/L(n=314)P=.001P=.292021/8/1217TroponinI(TnI),C-ReactiveProtein(CRP),andB-typeNatriureticPeptide(BNP)asDeterminantsof30-DayMortalityinACSSabatineMS,etal.Circulation.2002;105:1760-1763.P=.014P<.0001671501557830-DayMortalityRisk(%)50471732490OPUS-TIMI1611.83.5601234560123TACTICS-TIMI1812.15.713024681012140123No.ofElevatedBiomarkersNo.ofElevatedBiomarkersn=67n=150n=155n=78n=504n=717n=324n=902021/8/1218InflammationinACS:MyeloperoxidaseCirculation20032021/8/1219InflammatoryMarkerPredictsInvasiveSuccessinFRISCIILindmarketal.JAMA2001;286:2107-132021/8/1220GoalsinACSManagementRelievesymptomsMinimizelossofmuscleReducemortalityTreatspecificcomplications2021/8/1221Therefore….ReducethrombusburdenLimitthrombusprogressionPreventmicro-embolizationPromotehealingandhomeostasisoftheinjuredvesselwall2021/8/1222Eventincidence(%)DayCohen,etal.AmHeartJ2002;143:63.00.816111621Recurrentangina*MIDeath*LeadingtourgentrevascularizationPeak-Day2Peak-Day8Peak-Day300.511.52.5161116212Day

In-HospitalEventsinACSESSENCE/TIMI11b(N=7,081)2021/8/1223ACSTreatmentStrategiesMedicalTheapyRiskModificationCABGPCIAntithrombotictherapyOthermedicaltherapyADPantagonistsNitratesBBsSTATINSACE-IOTHERSReperfusion/RevascularizationtherapyHeparinASAGPIIb/IIIas2021/8/1224FRISCIIInvestigators.Lancet.1999;354:708-715.CannonC,etal.NEnglJMed.2001;344:1879-1887.

FRISCII TACTICS-TIMI18 Dalteparin TirofibanDay7:OR=0.59P=0.033Day30:OR=0.51P=0.0020306090Time(days)1201501800.000.020.040.060.04ProbabilityofDeath/MIInvasiveConservativeConservativeInvasiveUA/NSTEMI:BenefitofEarlyInvasiveStrategy00.080.060.040.0200 30 60 90 120 150 180Timesincestartofopenphase(days)2021/8/1225Conservative+tirofibanEarlyintervention+tirofiban6-monthDeath/MI/

Re-hospitalization(%)11.820.312.816.119.530.605101520253035Low0–2Intermediate3–4High5–7TACTICS-TIMI18:

EarlyInterventionversusConservativeCannonC,etal.NEnglJMed.2001;344:1879-1887.2021/8/1226TMPGPost-stentandCompositeEventsby48Hrs&1YrCompositeEvent(%)1YearDeath,MI,UrgentTVRp=0.0132.4%4.2%1/2411/34AllPatientsHaveTIMI3FlowatCompletionofStentingStainSlowPaleNormalGibsonCMetal,AmHeartJ.2002Jan;143(1):106-110.2021/8/1227TroponinElevationsonAdmissionareAssociatedwithTissueLevelPerfusionFollowingPCI:TACTICSTIMI18p=0.004p=0.013%TMPG0/1%TMPG0/1Circulation20022021/8/1228SitesofAnti-thromboticDrugActionIntrinsicPathwayExtrinsicPathwayPlasmaclottingcascadeProthrombinThrombinFibrinogenFibrinThrombusPlateletaggregationConformational

activationofGPIIb/IIIaPlateletAgonistsThromboxaneA2ADPATIIIFactorXaCoagulationcascadePlateletcascadeBivalirudinHirudinArgatrobanXimelagatranUFHeparinFondaparinuxThrombo-lyticsEnoxaparinAspirinTiclopidineClopidogrelGPIIb/IIIainhibitors42021/8/1229RiskReductionWithAspirinTherapy1.AntithromboticTrialists’Collaboration.BMJ2002;324:71–86.Category %oddsreductionAcuteMIPriorMI Priorstroke/TIA Otherhighrisk*

Alltrials

34%(p<0.0001)1.00.50.01.52.0ControlbetterAntiplateletbetter*Coronaryarterydisease,peripheralarterialdisease,highriskofembolismandotherhigh

riskconditions(includinghemodialysis,diabetesmellitus,carotiddisease)

2021/8/1230WhatistheRightDoseofAspirin?AdaptedwithpermissionfromtheBMJPublishingGroup.AntithromboticTrialists’Collaboration.BMJ.2002;324:71-86.00.51.01.52.0500–1500mg 34 19160–325mg 19 2675–150mg 12 32<75mg 3 13Anyaspirin 65 23AntiplateletBetterAntiplateletWorseAspirinDose #TrialsOR*(%)*Oddsreduction.TreatmenteffectP<0.0001.OddsRatio2021/8/1231ADP-ReceptorActivation

MechanismofAction

AdaptedfromSaviPetal.BiochemBiophysResCommun2001;283:379–83,andFergusonJJ.ThePhysiologyofNormalPlateletFunction.In:FergusonJJ,ChronosN,HarringtonRA(Eds).AntiplateletTherapyinClinicalPractice.London:MartinDunitz;2000:15–35.ADP/ATPP2Y1P2X1P2T12Gi2coupledGqcoupledCa2+Ca2+cAMPPlateletshapechange

TransientaggregationNoeffectonfibrinogenreceptorCationinfluxCalciummobilizationFibrinogenreceptoractivationThromboxaneA2generationSustainedaggregationresponse2021/8/1232PrimaryEndPoint—MI/Stroke/CVDeathClopidogrel

+ASA*369Placebo

+ASA*MonthsofFollow-UpP=0.00009?N=12,562012CURETrialInvestigators.NEnglJMed.2001;345:494-502.20%RelativeRisk

ReductionCUREStudyTheprimaryoutcomeoccurredin9.3%ofpatientsintheclopidogrel+ASAgroupand11.4%intheplacebo+ASAgroup.2021/8/1233ARR=Absoluteriskreduction;RRR=relativeriskreduction.*Inadditiontootherstandardtherapies.BudajA,etal.Circulation.2002;106:1622-1626.PrimaryCompositeEndPoint(CVDeath,MI,Stroke)0510152025304.19.815.95.711.420.7Low(0-2)Intermediate(3-4)High(5-7)Patients(%)TIMIRiskStratification29%RRRP<.04ARR 1.6 1.6 4.815%RRRP<.0327%RRRP<.004

Placebo+Aspirin* Clopidogrel+Aspirin*

CURE:BenefitofClopidogrel+AspirinAcrossAllTIMIRiskScoreGroups2021/8/1234CardiovascularDeath,MI,Stroke,andSevereIschemiaWithinFirst24HoursAfterRandomizationCumulativeHazardRatesHoursAfterRandomizationYusufS.etal.,Circulation2003;107:966-72.p=0.003PlaceboClopidogrel2021/8/1235?Upto12months.?PlusAspirinandotherstandardtherapies.PCI-CURE:Long-termEfficacyofClopidogrelCompositeofCVdeathorMIfromrandomizationtoendoffollow-up?MehtaSR,etal.Lancet.2001;358:527-533.Placebo?

Clopidogrel?50.00100200300400DaysofFollow-up12.6%8.8%P=0.002

N=2658CumulativeHazardRate31%Relative-risk

Reduction2021/8/1236Placebo+Aspirin*(%)Clopidogrel+Aspirin*(%)CURE:MajorBleedingbyAspirinDose

<100mg 2.6 2.0 100-200mg 3.5 2.3 >200mg 4.9 4.0

Aspirin

Dose*Otherstandardtherapieswereusedasappropriate.Plavix?(clopidogrelbisulfate)prescribinginformation.2021/8/1237PrimaryEfficacyandExcessinLife-ThreateningBleedinginClopidogrelGroupComparedtoPlaceboGroupDifferenceinNoofEvents/1000PatientsTreatedMonthsofFollow-upYusufS.etal.,Circulation2003;107:966-72.LifeThreateningBleedsCVDeath,MI,Strokes2021/8/1238CURE:BenefitsofCombinationTherapyinPatientsUndergoingCABGClopidogrelAspirinRR95%CICABG14.5%16.2%0.890.71-1.11PCI9.6%13.2%0.720.57-0.90MedRX9.1%10.0%0.800.69-0.922021/8/1239CURE:BleedinginCABGPatientsClopidogrelAspirinP-valueLife-Threateningbleeding7.0%5.7%0.20MajorBleeding9.6%7.5%0.0952021/8/1240nnnnGPIIb/IIIaInhibitioninPCI

OddsRatio&95%CITrialPlaceboIIb/IIIaNEPILOG11.7%5.3%

279212.8%EPIC8.3%

2099012CAPTURE15.4%11.3%

125211.2%RAPPORT5.8%

48910.5%RESTORE8.0%213911.4%IMPACTII9.5%4010PlaceboBetterIIb/IIIaBetter30DayDeath,MI,orUrgentRevascularizationEPISTENT*10.8%5.3%

1603*Stentarmsonlynn10.5%ESPRIT6.8%

20640.65(0.54,0.79)P<0.001Overall15,92372021/8/1241

EfficacyofGPIIb/IIIaInhibitorsinACS

2021/8/124230-DayMortalityAmongNondiabeticPatientswithACSRoffiM.etal.,Circulation2001;104:2767-71.TrialNPURSUIT7291PRISM2545PRISM-PLUS1208GUSTOIV6094PARAGONA1870PARAGONB4064Pooled23072PlaceboIIb/IIIa3.0%3.0%3.5%2.4%3.8%3.6%2.8%3.5%2.5%3.3%2.9%2.4%3.0%3.0%IIb/IIIaBetterPlaceboBetterP=0.07P=0.10P=0.88P=0.18P=0.37P=0.37P=0.992021/8/124330-DayMortalityAmong

DiabeticPatientswithACSRoffiM.etal.,Circulation2001;104:2767-71.TrialNPURSUIT2163PRISM687PRISM-PLUS362GUSTOIV1677PARAGONA412PARAGONB1157Pooled5458PlaceboIIb/IIIa6.1%5.1%4.2%1.8%6.7%3.6%7.8%5.0%6.2%4.6%4.8%4.9%6.2%4.6%IIb/IIIaBetterPlaceboBetterP=0.33P=0.07P=0.17P=0.022P=0.51P=0.23P=0.0072021/8/1244UnstableAngina:RoleofUFH1.00.60.003691215183090FreedomfromEventsrefractoryangina,MI,deathDaysofFollow-UpAspirin+HeparinHeparinAspirinPlaceboThérouxetal.NEnglJMed.1992;327:141–145.52021/8/1245ORand95%CIEikelboomJ,etal.Lancet.2000;355:1936-1910.0FavorsHeparinFavorsControlControl

%UFHor

LMWH%03.1Cohen4.5Grandtotal7.40.53(0.38-0.73)7.910.4UFHvsplacebo0.67(0.45-0.99)5.74.8FRISCI0.39(0.22-0.68)1.65.2LMWHvsplacebo0.34(0.20-0.58)5.79.6Gurfinkel(UFH)0.58(0.17-1.98)27.330.5Holdright0.85(0.51-1.43)09.6Gurfinkel(LMWH)0.13(0.03-0.60)1.43.7RISC0.40(0.11-1.39)0.12(0.01-5.89)3.88.2Cohen0.46(0.15-1.41)1.63.3Theroux0.50(0.10-2.53)OR

95%CIUFHorLMWHinUA/NSTEMI2021/8/1246

DayFRIC 6(dalteparin;n=1,482) p=0.33FRAXIS 14(nadroparin;n=2,357) p=0.24ESSENCE P=0.032 14(enoxaparin;n=3,171)TIMI11B P=0.029 14(enoxaparin;n=3,910)0.75 1 1.5

LMWHbetter UFHbetter*Tripleendpoint:death,MI,recurrentischemiaurgentrevascularizationLMWHinUA/NQMI

EffectsonTripleEndpoints*BraunwaldE,etal.JAmCollCardiol2002;40:1366.2021/8/1247

ManypatientsinthepreviousLMWHACSstudiesdidnotundergointerventionsorreceiveGPIIb/IIIainhibitors!2021/8/1248Atleast2of3required:Age60STortransientST+CK-MBorTroponinEnoxaparinIVHeparinPrimaryendpoint:DeathorMIat30daysSYNERGYHigh-RiskACSPatientsRandomized

(n=10,027)ASAEarlyinvasivestrategyanduseofGPIIb/IIIaencouragedOthermedicaltherapyperAHA/ACCGuidelines(-Blocker,ACE-I,clopidogrel,etc.)60IU/kg12IU/kg/hr(PTT1.5–2xULNoraPTT50-70sec)1mg/kgSCQ12HIfPCI<8hrssincelastdosenoIVdoseneeded8hrssincelastdose0.3mg/kgIVSYNERGYExecutiveCommitteeAmHeartJ2002;143:952-60.2021/8/1249SYNERGY

PrimaryEfficacyOutcome0510152025300.80.850.90.951.0FreedomfromDeath/MIDaysfromRandomizationUFHEnoxaparinn30-DayDeath/MI0.80.8111.21.2HazardRatio(95%CI)EnoxaparinBetterUFHBetter1.1

MahaffeyK,FergusonJ.ACCScientificSessions;Mar7-10,2004;NewOrleans,LA.2021/8/1250SYNERGY

PrimaryEfficacyEndpointsp=0.705p=0.135p=0.396Patients(%)

MahaffeyK,FergusonJ.ACCScientificSessions;Mar7-10,2004;NewOrleans,LA.2021/8/1251SYNERGY

BleedingEvents

Enoxaparin UFH p-value (n=4993) (n=4985) GUSTOsevere 2.9 2.4 0.106AnyRBCtransfusion 17.0 16.0 0.155TIMImajorTotal 9.1 7.6 0.008

CABG-related 6.8 5.9 0.081

Non-CABG-related 2.4 1.7 0.025ICH <0.1 <0.1 NS

MahaffeyK,FergusonJ.ACCScientificSessions;Mar7-10,2004;NewOrleans,LA.2021/8/1252SYNERGYisasuperioritytrialthatshowednon-inferiority2021/8/1253NewPotentialTherapyofACSNewADPantagonists:AZD6140(AZ)FactorXaInhibitors:Otamixiban(direct)Fondaparinux(indirect)DierctThrombinInhibitors:Ximelgatran,Argatroban2021/8/1254PROVE-IT:MedianLDLCholesterolLevelsLDLCholesterol(mg/dL)TimeofVisit40mgofpravastatin80mgofatorvastatinPravastatin1973

18441761164714451883Atorvastatin2003

18561758164514611910No.ofPatientsCannonC.etal.,NEnglJMed2004;350(15):Epubaheadofprint.2021/8/1255PROVE-IT:Kaplan-MeierEstimatesoftheIncidenceofthePrimaryEndPointofDeathoraMajorCVEventDeathorMajorCardiovascularEvent(%)MonthsofFollow-Up40mgofpravastatin80mgofatorvastatinPravastatin2063168815361423810138Atorvastatin2099173615911485842133No.atRiskP=0.005CannonC.etal.,NEnglJMed2004;350(15):Epubaheadofprint.2021/8/1256Howmightlipidloweringimprovepatientoutcomepost-acutecoronarysyndromes?PlaqueregressionReducingthrombogenicityOpposingvasospasmDecreasinginflammationStabilizingfibrouscap2021/8/1257OtherPotentialTherapiesAntibioticsPROVE-IT:Gatifloxacinvs.Placebo(2yrs)Cvevents23.7%gatifloxacinvs.25.1%Placebo,P=0.41ACES:Azithromycinvs.placebo(4yrs)CVevents22.3%vs.22.4%p=ns2021/8/1258SpectrumoftherapytrialsforpreventionofplaqueruptureEpidemiologicalmodelSpecificplaquemodelIdentifyhighrisklesionsandthentreatjustthoseIdentifyhighriskpatients2021/8/1259Morphologyvs.ActivityImagingInactiveandnon-inflamedplaqueActiveandinflamedplaqueIVUSVHOCTMRIMorphologyActivityThermography,Spectroscopy,MRIwithtargetedCM2021/8/1260Vulnerableplaques:

PreventiveStrategiesSystemicCholesterol-loweringAnti-inflammatoryagentsMetalloproteinaseinhibitionMechanicalinterventionBalloonStentCABGEnergyBrachytherapyPhotodynamictherapyLocationSafetyEfficacy2021/8/12612021/8/1262Invasivevs.ConservativeStrategyforACSConservative

920PatientsInvasive

7,018PatientsTIMIIIIBVANQWISHMATEFRISCIITACTICS-

TIMI18VINORITA-3

TRUCS

ISAR-COOLAdaptedfromCannonCP.Cardiology.2002;8(specialedition):29-37.Conservative

1,674Patients2021/8/1263IndependentVariablesAssociatedWithNeedforCABGinACS

(SadanandanetalJACC44.2004)0.0011.2-2.21.6Male0.0381.1-2.61.6PAD<0.00011.3-2.21.7STDev0.0011.3-2.61.8Angina<0.00012.7-5.53.9Tnpos<0.00010.2-0.50.35HxCABGP-value95%CIORVariables2021/8/1264Ratesofin-hospitalCABGAccordingtoRiskScore2021/8/1265LMWHLimitationsIndirectinhibition:dependentonantithrombinInabilitytoinhibitclot-boundthrombinCatheterizationlab:sloweronset,longerhalf-life,andwithenoxaparin,nostandardtesttomeasurelevels/effectCABG:concernsregardingthelonghalf-lifeMonitoringforFactorXa:possible,butwhatisthetherapeutictarget,increasedtime,expense?NotallLMWHsarethesameCABG=coronaryarterybypassgraft.2021/8/1266LMWH:PotentialAdvantagesIncreasedanti-Xatoanti-IIaactivity

inhibitsthrombingenerationmoreeffectivelyDalteparin2:1,enoxaparin3.8:1 Lessbindingtoplasmaproteins(eg,acute-phasereactantproteins)

moreconsistentanticoagulationLowerrateofthrombocytopeniavsunfractionatedheparin(UFH)SubcutaneousadministrationNoneedtomonitoritseffects2021/8/1267WhichkindofHeparintoUse?

PotentialAdvantagesofLMWHsOverUFHMorepredictableanticoagulantresponseLongerhalf-lifeBetterbioavailabilityatlowdosesLowerincidenceofHITNoneedtomonitoraPTTIncreasedAnti-Xa/IIaratioSubcutaneousadministration2021/8/1268p=0.0029RRR=17.9NSp=0.0039RRR=16.4p=0.045SYNERGY

EfficacyandSafetywithConsistentTherapy*Patients(%)PerProtocolIntent-to-treatn=3398n=2740n=2627n=3010NS

DatapresentedatACCScientificSessions;Mar7-10,2004;NewOrleans,LA.* Consistenttherapy=nopre-randomizedtherapy,orrandomizedtothesametherapytheyhadbeenreceivingNS2021/8/1269

Enoxaparin UFH AllPatients

(n=4993) (n=4985) (n=9978)Pre-randomization(%):

Noantithrombin 24.3 24.6 24.5

UFHonly 28.6 30.3 29.5

Enoxaparinonly 43.8 42.3 43.0

UFHandenoxaparin 3.3 2.8 3.1SYNERGY

Pre-randomizationTherapy

p=NS

MahaffeyK,FergusonJ.ACCScientificSessions;Mar7-10,2004;NewOrleans,LA.2021/8/1270ThrombosisInflammation2021/8/1271HospitalAdmissionsforACS:

UA/NSTEMIversusSTEMIACS2.3millionhospitaladmissionsACSUA/NSTEMI1.43millionadmissionsperyearNationalCenterforHealthStatistics.2001.STEMI829,000

admissionsperyear2021/8/1272StentsorBypassinsertionXMechanicaloptions2021/8/1273SIRIUS–9MonthClinicalEventsIn-hospitalMACEOut-of-hospdeath|MITVR(Non-TL)TLR2.4%1.5%In-hospMACE2.3%1.4%Out-of-hospdeath|MI3.2%4.8%TVR(Non-TL)7.0%8.6%3.9%16.6%TLRP<0.001Sirolimus(n=533)Control(n=525)%2021/8/1274

>90%of“Normal”Arteries HaveSignificantPlaqueBurdenbyIVUS2021/8/1275HigherresolutionIVUSOpticalcoherencetomographyInfraRedSpectroscopyThermalimagingEndovascularMRIRamanspectroscopyPulselaserirradiationFluorescence-mediatedtomography(FMT)FutureTechnologiestopredict“vulnerable”plaque2021/8/1276OCTFibrocalcificPlaqueYabushitaetal.,Circ,20022021/8/1277Oil-red-O(lipid)Lumen

Lumenlumen

fibrouscapEndovascularMRIH&EYeghiazariansetal.2002EndovascularMRIcorrelateswellwiththehistologyofanadvancedex-vivohumaniliacartery2021/8/1278Fluorescence-mediatedTomography:

Invivoimagingofproteolyticactivity

inatherosclerosisChenetal.Circulation2002;105:2766SudanIVNIRF2021/8/1279Thermography:Inflammationishot0102040305000.00PA007Unstableangina–DCAwithabundantmacrophagesandlipids2021/8/1280SubtherapeuticUFHTherapeuticUFHSupratherapeuticUFHMeanaPTTvalues020406080100612244872Hours34.838.252.352.448.027.231.536.83125.426.89.8MeanaPTT(s)41(±30)92(±47)84(±43)71(±29)72(±30)73(±27)OASIS-2:MeanaPTTValuesOverTimeAnandSS,etal.Circulation2003;107:2884-88.2021/8/1281OASIS-2:aPTTandRecurrentCVEvents**CVdeath,MI,refractoryanginaPercentrecurrentCVeventsRR=1.22

(0.87-1.22)RR=1.84

(1.25-2.70)

P<0.005RR=2.21

(1.47-3.31)P<0.0001PersistencewithinaPTTrange(hours)AnandSS,etal.Circulation2003;107:2884.8854,1234334,5493324,6542021/8/1282StudyDesign:ISAR-COOLPTT=partialthromboplastintime.AdaptedfromNeumannFJ,etal.JAMA.2003;290:1593-1599.528assessedforeligibility118excluded207assignedtoreceiveantithrombotictherapy*

+catheterizationwithin72-120hours203assignedtoreceiveantithrombotictherapy*

+catheterizationwithin6hours207includedin

primaryanalysis203includedin

primaryanalysis*UFH60μ/kgbolustheninfusionadjustedtoPTT60-85seconds;aspirin500mgIVthen100mgPOBIDclopidogrel600mgLDthen75mgBID;tirofiban100μg/kgbolusthen0.10μg/kg/min410randomized2021/8/1283ISAR-COOL:BenefitofEarlyInvasiveversusProlongedMedicalTreatmentCoolingOffEarlyInterventionDeath/

NonfatalMI

within30Days(%)11.6%5.9%NeumannFJ,etal.JAMA.2003;290:1593-1599.PrimaryEndpoint:Death,MIwithin30Days2021/8/1284P2Y1GPCRGq

PLC/IP3

[Ca2+]iShapechangetransientaggregationReceptorsubtype2°messengersystemMolecularstructureFunctionalresponseP2X1Intrinsicionchannel

Na+/Ca2+]i?P2Y12GPCRGi

AC

[cAMP]SustainedaggregationsecretionActivemetaboliteClopidogrelADPReceptorSubtypes2021/8/1285LeonC,etal.Blood.2004;103:594-600.Ex-vivoinhibitionoftheP2Y12ADPreceptorbyclopidogreladministrationdiminishedtherapidexposureoftissuefactor,themajorinitiatorofcoagulation,inconjugatesofplateletswithleukocytesestablishedbythecontactofwholebloodwithfibrillarcollagen.02040PlateletADPReceptorsContributetotheInitiationofIntravascularCoagulationTissue-factor-positiveCellsClopidogrelPostPre2021/8/1286AndréP,etal.Circulation.2003;108:2697-2703.MeanThrombusVolume(μm3/μm2)WT+GPIIb/IIIaInhibitor+Aspirin+BivalirudinWTP2Y12-/-Anticoagulants(ThrombinInhibitors)andAspirinSynergizewithP2Y12ReceptorAntagonisminThrombosisWTP2Y12-/-WTP2Y12-/-Untreated0201030402021/8/1287AfterLibbyP.Circulation1995++++++–SynthesisBreakdownLipidcoreIL-1

TNF-

MCP-1

M-CSFFibrous

capIFN-γCD-40LCollagenase

GelatinasesStromelysin

Otherproteases +peptidasesMatrixmetabolismandintegrityoftheplaque’sfibrouscap2021/8/1288AbsoluteReductionin30-dayDeath

orMIwithEptifibatidevsPlacebo(%)

(n=2522) (n=2041) (n=3803) (n=1105)1.7%

0%2.3%TimefromOnsetofSymptomsBhattD,TopolE.JAMA.2000;284:1549-1558.

0.00.51.01.52.02.53.0

<6hours6–12hours12–24hours>24hours1.7%2.3%

2.8%GPIIb/IIIaInhibitors:ReductioninDeath/MIAssociatedwithTimeofAdministrationfromSymptomOnset2021/8/1289In-hospitalEventsbyEarlyversusIn-labOnlyGPIIb/IIIaInhibitorUseAdjustedOR0.95;(95%CI0.60–1.15)AdjustedOR0.83;(95%CI0.63–1.09)PetersonE.CRUSADEregistrydata.ACCScientificSession;March30-April2,2003;Chicago,Il.4.15%5.02%1.65%1.32%0%1%2%3%4%5%6%DeathDeath/MIIn-labOnly

GPIIb/IIIa

(n=3642)EarlyGP

IIb/IIIa

(n=2191)PatientsreceivingPCI<48hours+GPIIb/IIIa;n=5833Patients2021/8/1290DorsamR,KunapuliS.JClinInvest.2004;113:340-345.2021/8/1291Modifiedfrom:PhippsR.ProcNatlAcadSci.2000;97:6930-6932.MacrophagePlateletsTCellAdventitiaSMCEC=CD40=CD40LigandSMC=SmoothMuscleCellEC=EndothelialCellCD40/CD40Ligand2021/8/1292AndréP,etal.Circulation.2002;106:896-899.SheddingofCD40LigandCD40ligandADPThrombinCollagenPDGFTGFPF4TSPGPIIb/IIIaAntagonistsCD40ligandsCD40LPDGF=platelet-derivedgrowthfactor.TGFβ=transforminggrowthfactor-β.PF4=plateletfactor4.TSP=thrombospondin.2021/8/1293GoodmanSG,etal.JACC2000;36:693.0102030402468101214MonthsCumulativeEventRate(%)OR=0.87p=0.022

UFH

EnoxaparinESSENCE

1-YearFollow-upResultsDeath/MI/RecurrentAngina2021/8/1294TIMI11b:PrimaryEndpoint

0481216200816243240P=0.048

RRR=12%UFHENOX19.7%17.3%%DaysAntmanEM,etal.Circulation1999;100:1593-1601.2021/8/1295ACC/AHAGuideline

RecommendationsforAnti-thromboticTherapyBraunwaldE,eta