AcuteCoronarySyndromes:

ManagementofUA/NSTEMIAcuteCoronarySyndromes:

MaOverviewof2003Updatestothe

ACC/AHAGuidelineforUA/NSTEMIAssesslikelihoodofCADRiskstratificationTargettherapy:moreaggressivetreatmentin

higher-riskpatientsAnti-ischemic,antithrombotictherapyInvasivevsconservativestrategyDischargeplanning(riskfactormodificationand

long-termmedicaltherapy)ACC/AHA,AmericanCollegeofCardiology/AmericanHeartAssociation;UA,unstableangina;

NSTEMI,non–ST-segmentelevationmyocardialinfarction.

BraunwaldE,etal.JAmCol.Cardiol.2000;36:970-1062.Overviewof2003UpdatestothAcuteManagementofUA/NSTEMIAnti-IschemicTherapyOxygen,bedrest,ECGmonitoringNitroglycerin-BlockersACEinhibitorsUA,unstableangina;NSTEMI,non-ST-segmentelevationmyocardialinfarction;ECG,electrocardiogram;ACE,angiotensin-convertingenzyme.BraunwaldE,etal.JAmCollCardiol.2000;36:970-1062.AntithromboticTherapyAntiplatelettherapyAnticoagulanttherapyAcuteManagementofUA/NSTEMIAPossible

ACSAspirinAspirin+IVHeparin+IVPlatelet

GPIIb/IIIaAntagonistDefiniteACSWithInvasiveStrategy(Catheterization/PCI)orHighRisk(IIa)*ClopidogrelAspirin+SQLMWH*orIVHeparinLikely/Definite

ACSClopidogrel* ClassIIa:enoxaparinpreferredoverUFHunlessCABGplannedwithin24hours.

ACC,AmericanCollegeofCardiology;AHA,AmericanHeartassociation;ACS,acutecoronary syndrome;PCI,percutaneouscoronaryintervention;SQLMWH,subcutaneouslowmolecular-weight heparin;IV,intravenous.

BraunwaldE,etal.JAmCollCardiol.2000;36:970-1062.ACC/AHAClassIRecommendationsforAntithromboticTherapy*Possible

ACSAspirinAspirinDef17.16.5*PlaceboASA05101520Patients(%)UnstableAngina

25.011.0*ASA01020303.31.9*ASA0123411.89.4*ASA051015AcuteMIAspirininAcuteCoronarySyndromes*P<.0001DeathorMI*P=.003Reocclusion*P=.012MI*P<.001DeathN= 397 399 513 419 8587 8600 8587 8600MI,myocardialinfarction;ASA,acetylsalicylicacid;RISC,ResearchonInStabilityinCoronaryarterydisease.RISCGroup.Lancet.1990;336:827-830.RouxS,etal.JAmCollCardiol.1992;19:671-677.ISIS-2.Lancet.1988;2:349-360.PlaceboPlaceboPlacebo17.16.5*PlaceboASA05101520PatiAspirininAcuteCoronarySyndromes12.93.9*ASA05101511.93.3*ASA05101512.96.2*ASA0510152.21.3*ASA00.511.522.5UA/NSTEMIPrimary

PreventionStable

Angina*P<.0001

MI*P=.0003

MI*P=.008

DeathorMI*P=.012

DeathorMIN= 11034 11037 155 178 279 276 118 121MI,myocardialinfarction;ASA,acetylsalicylicacid;RISC,ResearchonInStabilityinCoronaryarterydisease;ISIS-2,SecondInternationalStudyofInfarctSurvival.PHS.NEnglJMed.1989;321:129-35.RidkerPM,etal.AJC.1991;114:835-839.CairnsJA,etal.NEnglJMed.1985;313:1369-1375.TherouxP,etal.NEnglJMed.1988;319:1105-1111.PlaceboPlaceboPlaceboPlaceboPatients(%)AspirininAcuteCoronarySyndIndirectComparisonsofASADosesonVascularEventsinHigh-RiskPatients* Oddsreduction. TreatmenteffectP<.0001. ASA,acetylsalicylicacid. AdaptedwithpermissionfromBMJPublishingGroup.AntithromboticTrialists’Collaboration. BMJ.2002;324:71-1.52.0500-1500mg 34 19160-325mg 19 2675-150mg 12 32<75mg 3 13Anyaspirin 65 23AntiplateletBetterAntiplateletWorse AspirinDose No.ofTrials(%)OddsRatio0OR*IndirectComparisonsofASADoBRAVO:BleedingByASAdoseTopolEJ,etal.Circulation.2003;108:399-406.(withpermission)OutcomesbyAspirinDoseinPlaceboStudyDrugPatientsLowDose,

75-162mg/d

(n=2410)HigherDose,

>162mg/d

(n=2179)Primaryendpoint 16.4 18.6Death,MI,stroke 6.2 6.1Death 2.8 1.7MI 2.0 2.1Stroke 2.1 2.8Urgenthospitalcare 9.5 10.6Urgentresuscitation 7.3 10.0Internalbleeding 2.4 3.3Anybleeding 11.1 15.4Transfusion 1.0 2.0BRAVO:BleedingByASAdoseToClopidogrel+ASA?(N=6259)Placebo+ASA*(N=6303)CURE:MajorBleedingat1yearbyASADose

<100mg(N=5320) 1.9% 3.0% 100-199mg(N=3109) 2.8% 3.4%

>200mg(N=4110) 3.7% 4.9%

Pvaluefortrend .0001 .0009* P=.0001.? P=.0009.AdaptedfromPetersRJG,etal.Circulation.2003;108:1682-1687.ASADoseClopidogrelPlaceboCURE:MajorRR:Death/MIASAAlone68/655=10.4%Heparin+ASA55/698=7.9%BBBBBBB0.1110SummaryRelativeRisk0.67(0.44-0.1.02)TherouxRISCCohen1990ATACSHoldrightGurfinkelComparisonofHeparin+ASAvsASAAloneASA,acetylsalicylicacid;RISC,ResearchonInStabilityinCoronaryarterydisease;ATACS,AntithromboticTherapyinAcuteCompanySyndromes;RR,relativerisk;MI,myocardialinfarction.OlerA,etal.JAMA.1996;276:811-815.(withpermission)RR:ASAAlone68/655=10.4%HepaTIMI,ThrombosisinMyocardialInfarction;ESSENCE,EfficacyandSafetyofSubcutaneousEnozapaminNon–Q-WaveCoronaryEvents;UHF,unfractionatedheparin;ENOX,enoxaparin;MI,myocardialinfarction;OR,oddsratio.AntmanEM,etal.Circulation.1999;100:1602-1608.(withpermission)TIMIIIB/ESSENCEMetanalysis:

EnoxaparinvsUnfractionatedHeparin 8.67.1 0.82(0.69-0.97)18.02 6.55.2 0.79(0.65-0.96)21.02 5.34.1 0.77(0.62-0.95)23.02 1.8 1.4 0.80(0.55-1.16)20.240.512Day281443UFH

(%)ENOX

(%)OR

(95CI)FavorsENOXFavors

UFHPORDeathorMI%TIMI,ThrombosisinMyocardial

0123456789081624324048566472Patients(%)HoursfromRandomization7.3%5.5%RRR24%P=.026UFH(n=1957)ENOX(n=1953)UHF,unfractionatedheparin;ENOX,enoxaparin;RRR,relativeriskratio.AntmanEM.Circulation.1999;100:1593-1601.(withpermission)TIMIIIB:EarlyPhase

Death/MI/UrgentRevasc0123456789081624324048566472Patients(%)HoursfromRandomization7.3%5.5%RRR24%P=.026UFH(n=1957)ENOX(n=1953)0123456789081624324048566472UFHEnoxaparinP=.03MajorBleeds—96HoursINTERACT:EnoxaparinvsUnfractionatedHeparinWithGPIIb/IIIaInhibitorsGoodmanSG,etal.Circulation.2003;107:238-244.Death/MI—30DaysP=.031UFHEnoxaparinPercentUFHEnoxaparinP=.03MajorBleedsA-PhaseStudyDesignUA/NSTEMIFinalAvisit30daysRandomize-24hours

Chestpain

Min0hour Max120hour

Tirofiban+ASA

Hour0Aggressiveorconservativecareperlocalpractice20261961ENOX1mg/kgq12hrUFHWeight-adjustedZZTreat&Evaluate

forZ-Phase2018195239871endpoint7daysBlazingM.presentedatACC2003.A-PhaseStudyDesignUA/FinalA0102030024681012UFHEnoxaparinUFHENOXDaysFromRandomizationEventRates(%)Day78.4%(169events)9.4%(184events)7-and30-DayPrimaryEndpoint

CompositeDeath,MIandRefractoryIschemiaBlazingM.presentedACC2003.0102030024681012UFHEnoxaparinUEnoxTestvsOutcomesMoliternoDJ,etal.JACC.2003;42:1132-1139.(withpermission) Death/MI/UrgTVR Bleeding302520151050200250300350400450500550600200250300350400450500550600ProbabilityofMACE(%)ProbabilityofAnyBleeding(%)302520151050ENOXTime(sec)ENOXTime(sec)EnoxTestvsOutcomesMoliternoDirectThrombinInhibitorTrialists'CollaborationDirectThrombinInhibitorTrialists’CollaborativeGroup.

Lancet.2002;359:294-302.(withpermission)11RCTS36,000PtsACS,PCIDeathor

Myocardial

InfarctionDirectThrombin

Inhibitor Heparin

(N=18,736) (N=17,184)OR (95%Cl)Endoftreatment7days30daysEndoftreatment7days3daysDeathMyocardial

InfarctionEndoftreatment7days30daysEndoftreatment7days30daysStrokeMajorbleeding

duringtreatment

Intracranial

bleedingduring

treatment 815(4.3%) 883(5.1%) 947(5.0%) 990(5.8%) 1399(7.4%) 1409(8.2%) 355(1.9%) 346(2.0%) 422(2.2%) 395(2.3%) 685(3.6%) 642(3.7%) 522(2.8%) 596(3.5%) 601(3.2%) 672(3.9%) 876(4.7%) 917(5.3%) 62(0.33%) 60(0.35%) 72(0.38%) 70(0.41%) 120(0.64%) 110(0.64%)360(1.90%) 403(2.30%)

21(0.11%) 28(0.16%)0.01.02.0Direct

Thrombin

InhibitorHeparin

Better0.85 (0.77-0.94%)0.88 (0.80-0.96%)0.91 (0.84-0.99%)0.97 (0.83-1.13%)1.00 (0.87-1.16%)1.01 (0.90-1.12%)0.80 (0.71-0.90%)0.81 (0.72-0.91%)0.87 (0.79-0.95%)0.95 (0.66-1.35%)0.94 (0.68-1.31%)1.01 (0.78-1.31%)0.75 (0.65-0.87%)

0.72 (0.42-1.23%)DirectThrombinInhibitorTriaEarlyinvasivestrategy+/-GPIIb/IIIa

Catheterizationwithin

8hoursoflast

subcutaneousdoseUA/NSTEMIIdentified,LMWH-GPIIb/IIIa+GPIIb/IIIaCatheterizationbetween8-12hours

oflastsubcutaneousdoseNoadditionalUFHorLMWHAdditionalEnoxaparin0.3mg/kgIVbolusSupplementwithUFH<50U/kg,aimforACT200-250SupplementwithUFH<60U/kg,aimforACT250-300AdditionalEnoxaparin0.3-0.5mg/kgIVKereiakesDJ,etal.AmHeartJ.2002;144:615-624.(withpermission)ExpertPanelConsensusEarlyinvasivestrategy+/-GPGPIIb/IIIaInhibitorDuringMedicalManagementandAfterPCI:CAPTURE,PURSUIT,PRISM-PLUS0%2%4%6%8%10%PCIN=2754P=.001N=12,296P=.001+24h+48h+72h+24h+48hBoersmaE,etal.Circulation.1999;100:2045-2048.(withpermission)4.3%2.9%8.0%4.9%DeathorMIMedicalRxPostPCIControlGPIIb/IIIainhibitor0GPIIb/IIIaInhibitorDuringMMeta-analysisofIIb/IIIaInhibitioninPCIfor30-DayMortalityKongDF,etal.AmJCardiol.2003;92:651-655.(withpermission)P=.024OREPICEPILOGRAPPORTCAPTUREImpactIImpactIIRestoreEpistentEspiritISAR2AdmiralCadillacCombinedN2099279248312651504010214123992064401300208220186Trt1.01.00.42.0Ctrl1.32.02.31.3IIb/IIIaInhibitorBetterPlaceboBetter0.73(0.55,0.96)0.1110Meta-analysisofIIb/IIIaInhiIVGPIIb/IIIaInhibitorsinACS:DeathorMIat30Days(N=31,402) PRISM 7.1% 5.8%*

0.80 0.60-1.06 PRISM-PLUS 12.0% (*) 8.7% 0.70 0.50-0.98

(?) 13.6%*

1.17 0.80-1.70 PARAGON-A 11.7% (l) 10.3% 0.87 0.58-1.29

(h) 12.3% 1.06 0.72-1.55PURSUIT 15.7% (l) 13.4% 0.83 0.70-0.99

(h) 14.2% 0.89 0.79-1.00 PARAGON-B 11.4% 10.6% 0.92 0.77-1.09

GUSTO-IV 8.0% (24h) 8.2% 1.02 0.83-1.24

(48h) 9.1% 1.15 0.94-1.39

Overall 11.8% 10.8%t 0.91 0.85-0.98OddsRatioPlaceboIVGpIIb/IIIa95%CIPlaceboBetterGpIIb/IIIaBetter01.02.0StudyP=.015* Withoutheparin.?With/withoutheparin.(l),Lowdose;(h),High-dose.

BoersmaE,etal.Lancet.2002;359:189-198.IVGPIIb/IIIaInhibitorsinABenefitofIIb/IIIainhibitorsin

UA/NSTEMIbyTroponinUA,unstableangina;NSTEMI,non–ST-segmentelevationmyocardialinfarction;CAPTURE,Chimeric-7E3AntiPlateletTherapyinUnstableanginaREfractorytostandardtreatment;PRISM,PlateletReceptorInhibitionforIschemicSyndromeManagementStudy;TnT,tropponinTlevel;TnI,troponinIlevel.HammCW,etal.NEnglJMed.1999;340:1623-1629.HeeschenC,etal.Lancet.1999;354:1757-1762.TnI>0.1g/LCAPTUREPRISM14.805101520TnI0.1g/LP<.001TnT0.1TnT>0.1P<.0014.90510152025HeparinTirofibanHeparinAbciximab+HeparinDeathorMIat30days(%)BenefitofIIb/IIIainhibitorsGPIIb/IIIaInhibitioninTnI+PatientsbyRevascularization:PRISMStudyTnI,troponinI;PRISM,PlateletReceptorInhibitionforIschemicSyndromeManagementstudy;

MI,myocardialinfarction.

HeeschenC,etal.Lancet.1999;354:1757-1762.(withpermission)Death/MIat30Days0.37(0.15-0.93)P

=.020.30(0.10-0.84)P

=.0041612840051015202530Eventrate(%)Follow-up(days)NorevascularizationRevascularizationHeparinHeparinTirofibanTirofibanGPIIb/IIIaInhibitioninTnIGPIIb/IIIaInhibitioninDiabetics RoffiM,etal.Circulation.2001;104:2767-2771.(withpermission)30-DayMortalityinDiabeticPatients2163687362167741211576458PURSUITPRISMPRISM-PLUSGUSTOIVPARAGONAPARAGONBPooled6.1%4.2%6.7%7.8%6.2%4.8%6.2%5.1%1.8%3.6%5.0%4.6%4.9%4.6%P=.33P=.07P=.17P=.022P=.51P=.93P=.007Trial N OddsRatio&95%Cl Placebo IIb/IIIaBreslow-Day:P=.50 IIb/IIIaBetter PlaceboBetter OR=0.740 0.5 1 1.5 2GPIIb/IIIaInhibitioninDiabIntravenousGPIIb/IIIaAntagonistsinACS:DeathorMI(at30Days)inPCI/CABG<5DaysCohortandinMedicalTreatmentCohort17.310.514.310.102468101214161820InterventionMedicalTreatmentDeathorMIPlaceboIVGPIIb/IIIaP=.001P=NS(N=5847)(N=25,555)ACS,acutecoronarysyndrome;MI,myocardialinfarction;PCI,percutaneouscoronaryintervention;

CABG,coronaryarterybypassgraft;NS,notsignificant.BoersmaE,etal.Lancet.2002;359:189-198.InteractionP<.02IntravenousGPIIb/IIIaAntagoGPIib/IIIaInhibitorNSTEACSTrialsAnalysis

Risk-AdjustedMortalityat30DaysPetersonED,etal.JAmCollCardiol.2003;42:45-53.

BoersmaE,etal.Lancet.2002;359:189-1.0NRMI1Boersma20.83-1.010.910.79-0.970.8895%CIOddsRatioOddsRatioforMortalityat30DaysGPIIb/IIIaInhibitorFavored

(aspirin+heparin)ControlArm

Favored

(aspirin+heparin)GPIib/IIIaInhibitorNSTEACSMortalitybyHospitals’UseofEarly

GPIIb/IIIaInhibitors(N=1189Hospitals)HospitalUseofEarlyGPIIb/IIIainhibitorsinNRMI(%)In-HospitalMortality(%)<55-1516-30>3014121086420NRMI,NationalRegistryofMyocardialInfarction.PetersonED,etal.JAmCollCardiol.2003;42:45-53.(withpermission)In-HospitalMortality(%)MortalitybyHospitals’UseofEfficacyofClopidogrelorTiclopidineinReducingCoronaryEventsAfterStentingCLASSICS,ClopidogrelAspirinStentInterventionCoopoerativeStudy.

BhattDL,etal.JAmCollCardiol.2002;39:9-14.(withpermission)30-DayMajorAdverseCardiacEventsOddsRatio&95%CITiclopidineBetterClopidogrelBetterTrialClopid.(%)Ticl.(%)NOverall13,9552.03.90.1110TOPPSCLASSICS1016100.9LenoxHillCCF25652368.9Müller7003.11.7Wessex-3613.45.2N.Memorial13780.82.2S.Illinois8752.11.4Wash.Hosp.8442.00.5Mayo28270.61.6OR=.73,P=.003EfficacyofClopidogrelorTic CURE,ClopidogrelinUnstableAnginatoPreventRecurrentIschemicEvents;MI,myocardialinfarction; CV,cardiovascular;RRR,relativeriskreduction.? Plavix?[packageinsert];2002.

Adaptedwithpermission(2002)fromtheMassachusettsMedicalSociety.

YusufS,etal.NEnglJMed.2001;345:494-502.0.000.020.040.060.04CumulativeHazardRateClopidogrel

+Aspirin369Placebo

+AspirinFollow-up(mo)P=.00009?(N=12,562)01220%RRRCURE:PrimaryEndPoint

MI/Stroke/CVDeath CURE,ClopidogrelinUnstableCURE:MI/Stroke/CVDeath/Severe

IschemiaWithin24HoursofRandomization CURE,ClopidogrelinUnstableAnginatoPreventRecurrentIschemicEvents;MI,myocardialinfarction;

CV,cardiovascular;RRR,relativeriskreduction;RR,relativerisk.

AdaptedfromYusufS,etal.Circulation.2003;107:966-972.HoursAfterRandomizationCumulativeHazardRates0.00.0050.0100.0150.0200.025024681012141618202224RR=0.67P=.003Placebo+AspirinClopidogrel+Aspirin33%RRRCURE:MI/Stroke/CVDeath/Sever CURE,clopidogrelinUnstableAnginatoPreventIschemicEvents;TIMI,ThrombosisinMyocardialInfarction; CV,cardiovascular;MI,myocardialinfarction;RRR,relativeriskreduction;ARR,Absoluteriskreduction.* Inadditiontootherstandardtherapies. BudajA,etal.Circulation.2002;106:1622-1626.(withpermission)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+AspirinAcrossAllTIMIRiskScoreGroups CURE,clopidogrelinUnstablePCI-CURE:StudyDesignCLOPIDOGREL+ASA*PCIPLACEBO+ASA*Open-labelthienopyridinePretreatmentOpen-label

thienopyridinePretreatmentN=2658patientsundergoingPCIN=1345N=1313CUREPCI-CURERMehtaSR,etal.Lancet.2001;358:527-533.30days

post-PCIEndoffollow-upupto

12monthsafterrandomizationPCI-CURE:StudyDesignCLOPIDOGPCICURE:BenefitofPretreatmentWithClopidogrelat30Days051015202530Follow-up(days)0.00.020.040.060.0830%RRRP=.03N=2658CumulativeHazardRateMehtaSR,etal.Lancet.2001;358:527-533.(withpermission)6.4%4.5%Clopidogrel

+ASAPlacebo

+ASACardiovascularDeath,MI,or

UrgentRevascularizationPCICURE:BenefitofPretreatAdaptedfromMehtaSR,etal.Lancet.2001;358:527-533.(withpermission)CVDeathorMIFromRandomization

toEndofFollow-upPCI-CURE:Long-termResults50.00100200300400Follow-up(days)12.6%8.8%P=.002

N=2658Clopidogrel+AspirinPlacebo+AspirinCumulativeHazardRates31%RelativeRisk

ReductionAdaptedfromMehtaSR,etal.SteinhublS,etal.JAMA.2002;288:2411-2420.CredoStudy:StudyDesignClopidogrelArmPlaceboArmPCI28DaysPlacebo+

aspirin(325mg)Pretreatment

3-24hbeforePCIClopidogrel300mg

+aspirin(325mg)Clopidogrel75mgQD

+aspirin325mgQDClopidogrel75mgQD

+aspirin325mgQD12MonthsPlaceboQD

+aspirin(81-325mg)QDClopidogrel75mgQD

+aspirin(81-325mg)QDRObjective:Toassessthebenefitof1yearvs1monthofclopidogrelplusaspirininpatientsundergoingPCISteinhublS,etal.JAMA.2002EffectofTimingofLoadingDose:

28-DayEndpoint—Death,MI,UTVR1.01.2Hazardratio(95%CI)3to<6hrs 7.9 7.0 8936to24hr 5.8 9.4 851RRR-13.4P=NSRRR38.6P=.05RRR18.5P=.23OverallCREDOResultsNPT-Clopidogrel*No-PT*Events(%)No-PTBetterPT-ClopidogrelBetter PT,pretreatment;UTVR,urgenttargetvesselrevascularization.* PlusASAandotherstandardtherapies. SteinhublS,etal.JAMA.2002;288:2411-2420.EffectofTimingofLoadingDoCREDO:BenefitsofClopidogrelPlusAspirinto1YearFollowingPCICVDeath,MIorStroke* PlusASAandotherstandardtherapies. SteinhublS,etal.JAMA.2002;288:2411-2420.(withpermission)CombinedEndpointOccurrence(%)MonthsFromRandomization27%RRRP=.02Placebo*Clopidogrel*0510158.5%11.5%036912CREDO:BenefitsofClopidogrelCURE:BleedingResults CURE,

ClopidogrelinUnstableAnginatoPreventIschemicEvents;* Otherstandardtherapieswereusedasappropriate.? Life-threateningandothermajorbleeding. Plavix?[packageinsert]2003.EventClopidogrel

+Aspirin*

(n=6259)

(%)Placebo

+Aspirin*

(n=6303)

(%)PValueMajorbleeding?01Life-threatening

bleeding3Minorbleeding5.12.4<.001CURE:BleedingResultsEventClPlacebo

+ASA(%)Clopidogrel

+ASA(%)FromPCIto30days Major 1.4 1.6?

Lifethreatening 0.7 0.7?

Minor 0.7 0.9?

FromPCItoendoffollow-up Major 2.5 2.7?

Lifethreatening 1.3 1.2?

Minor 2.1 3.5?? P=NS,?P=0.03

AdaptedfromMehtaSR,etal.Lancet.2001;358:527-533.PCI-CURE:BleedingOutcomesPlacebo

+ASA(%)ClopidogrelMajor/Life-ThreateningBleedsWithin7DaysofCABGSurgeryPlaceboClopidRRPStopped<5dayspriortoCABGN=476N=436PtswithMaj/LTBld

TIMIMajor6.3%

2.7%9.6%

2.5%1.53

0.92.06

NSStopped>5dayspriortoCABGN=454N=456PtswithMaj/LTBldTIMIMajor5.3%

2.4%4.4%

1.8%0.83

0.72.53

NSCUREinvestigators.NEnglJMed.2001;FoxKM.PresentedatESC2002.Major/Life-ThreateningBleedsCURE:OutcomesbyCABGinInitialHospitalization(CVdeath/MI/Stroke PlaceboClopidogrelN(%)N(%)RRCICABGDuringInitialHospitalization:No.ofPatients528485CVdeath/MI/stroke16.713.20.780.57-1.08NoCABG:No.ofPatients57755774CVdeath/MI/stroke11.08.90.800.71-0.89CUREinvestigators.NEnglJMed.2001;FoxKM.PresentedatESC2002.CURE:OutcomesbyCABGinIniEarlyClopidogrelTiminginACSPCI-CUREandCREDO:Needtostartclopidogrelearly(>6h)togetpost-PCIbenefit50%-60%ofpatientsgetPCI,8%-20%getCABG

(halfofwhomare>5dpostcatheterizationanyway)Tradeoffper1000UA/NSTEMIpatientRx:EarlyRxpreventsadditional~10majorcardiaceventsvscreating1.5TIMIminorbleedpost-CABGACS,acutecoronarysyndrome;PCI,percutaneouscoronaryintervention;CURE,

ClopidogrelinUnstableAnginatoPreventRecurrentEvents;CREDO,ClopidogrelforReductionofEventsDuringObservation;

CABG,coronaryarterybypassgraft;UA,unstableangina;NSTEMI,non–ST-segmentmyocardialinfarction;

TIMIThrombosisinMyocardialInfarction.BoersmaE,etal.Lancet.2002;359:189-198.EarlyClopidogrelTiminginACPRONTOStudy:EffectofCo-Administration

ofVariousStatinsWithClopidogrelPRONTOStudy—100PatientsUndergoingElectiveStentingBaselineDay2Day5Atorvastatin(n=9)60.810.440.48.638.18.0Anystatin(n=26)58.710.736.0Nostatin(n=74)59.411.538.710.535.87.7InducedPlateletAggregation%SD

(5MADPinducedPlateletAggregation)PRONTO,PlavixReductionOfNewThrombusOccurrence.GurbelPA,etal.AmHeartJ.2003;145:239-247.PRONTOStudy:EffectofCo-AdmNoInteractionofClopidogrelandAtorvastatinSawP,etal.Circulation.2003;108:921-924.(withpermission)Clopidogrel(%)Control(%)181614121084201-YearDeath/MI/StrokeEventRate(%)Allpatients

(n=2116)Nostatin

(n=944)Anystatin

(n=1172)CYP3A4-MET

statin

(n=1001)Atorvastatinstatin

(n=564)Prevastatin

(n=142)Non-CYP3A4-METstatin

(n=158)RRR26.9%

P=.02RRR12.4%

P=.51RRR38.6%

P=.01RRR36.4%

P=.03RRR60.6%

P=.11RRR49.8%

P=.02RRR63.3%

P=.13NoInteractionofClopidogrel2159low-riskpatientsundergoingelectivestenting,

excludingpatientswith:Abciximab(n=1079)Placebo(n=1080)Endpoints:Primary:30daydeath/MI/urgenttargetvesselrevascularizationSecondary:30-daybleedingcomplicationsISAR-REACTTrialACC2003,LateBreakingTrials.AcutecoronarysyndromeAcuteMIwith14daysST-segmentdepressionPositivebiomarkersInsulin-dependentdiabetesChronictotalocclusionsEF<30%ThrombuspresenceLesionsinbypassgraftsClopidogrel(600-mgloadingdose,2x75mg/dthroughdischarge,75mg/dfor4weeks)2159low-riskpatientsundergoISAR-REACT:30DayEndpoints4.04.20246Death/MI/UrgentTVR(%)

P=.82AbciximabPlaceboACC2003,LateBreakingTrials.Death(%)

P=NS0.30.30246AbciximabPlaceboUrgentTVR(%)

P=NS0.90.70246AbciximabPlaceboISAR-REACT:30DayEndpoints4.CRP,C-reactiveprotein;MI,myocardialinfarction;PCI,percutaneouscoronaryintervention;

RRR,relativeriskratio.ChewDP,etal.AmJCardiol.2001;88:672-674.DeathorMIbyDay30inPatientsUndergoing

PCIWithStenting58%RRRP=.0020510152025TotalPopulation

0<11mg/LHighestQuartile

>11mg/L13(n=295)10(n=565)24(n=74)10.2(n=136)PercentThienopyridine

pretreatmentNoThienopyridine

pretreatmentClopidogrelTherapyMayReducethe

RiskAssociatedWithElevatedBaseline

CRPStatusCRP,C-reactiveprotein;MI,m30-DayDeathorMIinPatientsUndergoing

PCIwithStentingAdaptedfromChewDP,etal.AmJCardiol.2001;88:672-674.ClopidogrelTherapyAttenuatestheRiskAssociatedWithBaselineCRPStatus7.97.724.012.35.711.812.510.205101520251stQuartile2ndQuartile3rdQuartile4thQuartilen=216n=218n=22758%RRRP=.002n=216

ClopidogrelpretreatmentNopretreatmentCRPQuartiles(mg/dl)Patients(%)30-DayDeathorMIinPatientsInvasivevsConservativeStrategy

forUA/NSTEMIUA,unstableangina,NSTEMI,non–ST-segmentmyocardialinfarction;ISAR,IntracoronaryStentingand

AntithrombicRegimenTrial;RITA,RandomizedInterventionTreatmentofAngina;VANQWISH,VeteransAffairsNon-Q-WaveInfarctionStrategiesinHospitalstudy;MATE,MedicinevsAngioplastyforThrombolyticExclusionstrial;TACTICS-TIMI18,TreatAnginawithAggrestat?andDetermineCostofTherpaywithInvasiveorConservativeStrategy;FRISC,FragminduringInStabilityinCoronaryarterydisease.TIMIIIIB2003ConservativeInvasiveVANQWISHMATEFRISCIITACTICS-

TIMI18VINORITA-3No.ofPatients:920 1674 7018TRUCSISAR-

COOLInvasivevsConservativeStratTnT,troponinT;ST,STsegment.MorrowDA.JAMA.2001;286:2405-2412;CannonCP.NEnglJMed.2001;344:1879-1887.BenefitofInvasiveStrategybyTroponin

andSTChangesDeath,MI,RehospACSat6Months12.425.0*16.015.3*051015202530TnT-TnT+CVEvents(%)P=NS15.124.5*16.616.4*051015202530NoSTchangeSTchangeP=NSP<.001P<.001ConservativeInvasiveTnT,troponinT;ST,STsegmen2000ACC/AHAUA/NSTEMIGuidelines:

EarlyInvasiveStrategyClassIAnyofthehigh-riskindicators(LevelofEvidence:A)a)Recurrentanginaatrest/low-levelactivitydespiteRxb)ElevatedTnTorTnIc)NewST-segmentdepressiond)Rec.angina/ischemiawithCHFsymptoms,rales,MRe)Positivestresstestf) EF<0.40g)BPh)SustainedVTi)PCI<6mos,priorCABG BraunwaldE,etal.JAmColCardiol.2000;36:970-1062.2000ACC/AHAUA/NSTEMIGuideli$13,2660.079$10,1750.103$1048Troponin

T0.01$39820.217$38060.227$864STchanges$13,0220.045$12,7390.046$586OverallpopulationCERatio$

perlife-yeargainedLife-years(I-C)CERatio$perlife-yeargainedLife-years(I-C)Costs(I-C)FraminghamPURSUITAdaptedfromMahoneyEM,etal.JAMA.2002;288:1851-1858.Long-TermCost-EffectivenessAnalysis$13,2660.079$10,1750.103$1048TSIRIUS:DrugElutingStentsMoses,etal.NEnglJMed.2003;349:1315-1323.(withpermission)ActuarialRateofSurvivalFreefromTarget-VesselFailure

AmongPatientsWhoReceivedEithera

Sirolimus-ElutingStentoraStandardStentTherateofevent-freesurvivalwassignificantlyhigherinthesirolimus-stentgroupthaninthestandard-stentgroup(P<.001bytheWilcoxonandlog-ranktests).Event-freeSurvival(%)DaysAfterInitialProcedureNo.atRiskSirolimusStentStandardStentSirolimus-stentgroupStandard-stentgroup91.1%100908000 30 60 90 120 150 180 210 240 270533 529 527 524 520 515 509 505 493 477525 523 521 514 506 481 474 465 451 43678.6%SIRIUS:DrugElutingStentsMos0123456Time(months)048121620%PatientsCONSINVO.R0.7895%CI(0.62,0.97)P=.02519.4%15.9%TACTICSPrimaryEnd