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AcuteCoronarySyndrome5/98MedSWorldwideStatisticsEachyear:>4millionpatientsareadmittedwithunstableanginaandacuteMI>900,000patientsundergoPTCAwithorwithoutstent5/98MedSMyocardialIschemiaSpectrumofpresentationsilentischemiaexertion-inducedanginaunstableanginaacutemyocardialinfarction5/98MedSCumulative6-monthmortality

fromischemicheartdisease01234565100152025MonthsafterhospitaladmissionDeaths/100pts/monthAcuteMI

Unstableangina

StableanginaDukeCardiovascularDatabaseN=21,761;1985-1992Diagnosisonadmtohosp5/98MedSIschemicHeartDisease

evaluationBasedonthepatient’shistory/physicalexamelectrocardiogramPatientsarecategorizedinto3groupsnon-cardiacchestpainunstableanginamyocardialinfarction5/98MedSAcuteCoronarySyndromeIschemicDiscomfort

UnstableSymptomsNoST-segment

elevation

ST-segment

elevationUnstable Non-Q Q-Wave

angina AMI AMIECGAcute

ReperfusionHistory

PhysicalExam5/98MedSAcuteCoronarySyndromeThespectrumofclinicalconditionsrangingfrom:unstableanginanon-QwaveMIQ-waveMIcharacterizedbythecommonpathophysiologyofadisruptedatherosleroticplaque5/98MedSUnstableAngina-Definitionanginaatrest(>20minutes)new-onset(<2months)exertionalangina(atleastCCSCIIIinseverity)recent(<2months)accelerationofangina(increaseinseverityofatleastoneCCSCclasstoatleastCCSCclassIII)AgencyforHealthCarePolicyResearch-1994CanadianCardiovascularSocietyClassification5/98MedSUnstableAngina

LikelihoodofCADPrevioushistoryofCADpresenceofriskfactorsolderageST-TwaveischemicECGchangesAgencyforHealthCarePolicyResearch-19945/98MedSUnstableAngina

precipitatingfactorsInappropriatetachycardiaanemia,fever,hypoxia,tachyarrhythmias,thyrotoxicosisHighafterloadaorticvalvestenosis,LVHHighpreloadhighcardiacoutput,chamberdilatationInotropicstatesympathomimeticdrugs,cocaineintoxication5/98MedSUnstableAngina

prognosticindicatorsPresenceofST-T-wavechangeswithpainHemodynamicdeteriorationpulmonaryedema,newmitralregurgitation,3rdheartsound,hypotensionOtherpredictorsleftventriculardysfunction,extensiveCAD,age,comorbidconditions(diabetesmellitus,obstructivepulmonarydisease,renalfailure,malignancy)5/98MedSUnstableAngina

pathogenesisPlaquedisruptionAcutethrombosisVasoconstriction5/98MedSUnstableAngina

pathogenesisPlaquedisruptionPassiveplaquedisruption

softplaquewithhighconcentrationofcholesterylestersandathinfibrouscapActiveplaquedisruption

macrophage-richareawithenzymesthatmaydegradeandweakenthefibrouscap;predisposingittorupture

5/98MedSUnstableAngina

pathogenesisAcuteThrombosisVulnerableplaquedisruptedplaquewithulcerationoccurringin2/3ofunstablepatientstheexposedlipid-richcoreabundantincholesterylesterishighlythrombogenic

SystemicHypercoagulableStatedisruptedplaquewitherosionoccurringin1/3ofunstablepatients5/98MedSUnstableAngina

pathogenesisVasoconstrictiontheculpritlesioninresponsetodeeparterialdamageorplaquedisruptionareaofdysfunctionalendotheliumneartheculpritlesionplatelet-dependentandthrombin-dependentvasoconstriction,mediatedbyserotoninandthromboxaneA25/98MedSAcuteCoronarySyndromeProcessofresolutionspontaneousthrombolysisvasoconstrictionresolutionpresenceofcollateralcirculationDelayedorabsenceofresolutionmayleadtonon-Q-waveorQ-wavemyocardialinfarction5/98MedSNon-Q-WaveMI

cluestodiagnosisProlongedchestpainAssociatedsymptomsfromtheautonomicnervoussystemnausea,vomiting,diaphoresisPersistentST-segmentdepressionafterresolutionofchestpain5/98MedSPrinzmetal’sAngina

cluestodiagnosisTransientST-segmentelevationduringchestpainIntermittentchestpainoftenrepetitiveusuallyatresttypicallyintheearlymorninghoursrapidlyrelievedbynitroglycerineSyncope(rare),Raynaud’s,migraine5/98MedSUnstableAngina

RiskStratificationLowRisknew-onsetexertionalanginaminorchestpainduringexercisepainrelievedpromptlybynitroglycerineManagementcanbemanagedsafelyasanoutpatient(assumingclosefollow-upandrapidinvestigation)5/98MedSUnstableAngina

RiskStratificationIntermediateRiskprolongedchestpaindiagnosisofrule-outMIManagementobserveintheERorChestPainUnitmonitorclinicalstatusandECGobtaincardiacenzymes(troponinTorI)every8to12hours5/98MedSUnstableAngina

RiskStratificationHighRiskrecurrentchestpainST-segmentchangehemodynamiccompromiseelevationincardiacenzymesManagementmonitorintheCoronaryCareUnit5/98MedSRiskStratificationbyECG

TheriskofdeathorMIat30daysisstronglyrelatedtotheECGatthetimeofchestpain.STdepression 10%T-waveinversion 5%NoECGchanges 1-2%5/98MedSUnstableAngina

TherapeuticGoalsTherapeuticGoalsReducemyocardialischemiaControlofsymptomsPreventionofMIanddeathMedicalManagementAnti-ischemictherapyAnti-thrombotictherapy5/98MedSUnstableAngina

MedicalTherapyAnti-ischemictherapynitrates,betablockers,calciumantagonistsAnti-thrombotictherapyAnti-platelettherapyaspirin,ticlopidine,clopidogrel,

GPIIb/IIIainhibitorsAnti-coagulanttherapy

heparin,lowmolecularweightheparin(LMWH),warfarin,hirudin,hirulog5/98MedSUnstableAngina

Anti-ischemicTherapyrestrictactivitiesmorphineoxygennitroglycerinepainrelief,preventsilentischemia,controlhypertension,improveventriculardysfunctionnitratefreeperiodrecommendedafterthefirst24-48hours5/98MedSUnstableAngina

Anti-ischemicTherapybeta-blockersloweringanginathresholdpreventischemiaanddeathafterMIparticularlyusefulduringhighsympathetictonecalciumantagonistsparticularlytherate-limitingagentsnifedipineisnotrecommendedwithoutconcomitantß-blockade5/98MedSUnstableAngina

Anti-thromboticTherapyThrombolyticsarenotindicated“lyticagentsmaystimulatethethrombogenicprocessandresultinparadoxicalaggravationofischemiaandmyocardialinfarction”TIMIIIIBInvestigators

Circulation1994;89:1545-15565/98MedSPlateletsinAcuteCoronarySyndromesPlateletsplayakeyroleinACSSourcesofplateletactivation(triggers)thromboxaneA2(TXA2)ADPepinephrinecollagenthrombin

5/98MedSUnstableAngina

Anti-plateletTherapyaspirinisthe“goldstandard”irreversibleinhibitionofthecyclooxygenasepathwayinplatelets,blockingformationofthromboxaneA2,andplateletaggregationinAMI,ASAreducedtheriskofdeathby20-25%inUA,ASAreducedtheriskoffatalornonfatalMIby71%duringtheacutephase,60%at3months,and52%at2yearsbolusdoseof160-325mg,followedbymaintenancedoseof80-160mg/d5/98MedSGPIIb/IIIaReceptor

FinalPathwaytoPlateletAggregationPlateletactivationandaggregationareearlyeventsinthedevelopmentofcoronarythrombosisGPIIb/IIIa

receptorsonactivatedplateletsundergoaconformationalchangeallowingrecognitionandbindingoffibrinogenFibrinogen“actslikeglue”,bridgingGPIIb/IIIareceptorsonadjacentplatelets,leadingtoplateletaggregation5/98MedSGPIIb/IIIaReceptor

KVGFFGRThereareapproximately50,000GPIIb/IIIareceptorsoneachplateletKVGFFGRisaspecificregionwithinGPIIb/IIIareceptorthatisthoughttobeinvolvedinplateletactivation5/98MedSIncidenceofIschemicEventsNoaspirin

(early1980s)AspirinAspirin+Heparin16%12%9%IncidenceofdeathandMI5/98MedSUnstableAngina

Anti-plateletTherapyThienopyridinesticlopidine

(Ticlid;Hoffmann-LaRoche)clopidogrel

(Plavix;Bristol-MyersSquibb)

blockplateletaggregationinducedbyADPandthetransformationofGPIIb/IIIaintoitshighaffinitystate5/98MedSUnstableAngina

Anti-plateletTherapyTiclopidineinanopen-label,randomizedstudyinpatientswithunstableanginaticlopidine250mgbidvs.placeboreducedtheriskoffatalornonfatalMIby46%at6monthsbenefitnotseenat7days,butbecameapparentafter10daysoftherapy(thetimerequiredforfullantiplateletactivity)analternativeforpatientwithaspirinintoleranceCirculation1990;82:17-265/98MedSUnstableAngina

Anti-plateletTherapyClopidogrelCAPRIE(ClopidogrelversusAspirininPatientsatRiskofIschemicEvents)19,000patientsrandomlyassignedtoclopidogrel(75mg/d)ortoaspirin(325mg/d)therewasan8.7%reductioninthecombinedincidenceofstroke,MI,ordeath(P=.043)patientswithMIdidbetterwithaspirinpatientswithPVDorstrokedidbetterwithclopidogrelLancet1996;348:1329-1339

Circulation1998;97:11075/98MedSUnstableAngina

Anti-plateletTherapyGPIIb/IIIainhibitorsabciximab(monoclonalantibody)eptifibatide(peptidicinhibitor)lamifibanandtirofiban(non-peptides)

directoccupancyoftheGPIIb/IIIareceptorbyamonoclonalantibodyorbysyntheticcompoundsmimickingtheRGD

sequenceforfibrinogenbindingpreventsplateletaggregation5/98MedSUnstableAngina

Anti-plateletTherapyAbciximab

(Reo-Pro)EPICTrial

effectiveinpreventingdeath,MI,andabruptclosureassociatedwithcoronaryangioplasty(seealsoEPICslides)EPISTENTTrial

(unpublished-seeMedSlidesNews)5/98MedSUnstableAngina

Anti-plateletTherapyAbciximab

(Reo-Pro)CAPTURE

(Chimeric7E3AntiplateletinUnstableAnginaRefractorytoStandardTreatment)1,000patientswithangiographicallydocumentedunstableangina,notrespondingtoASA,nitrates,heparin,andotheranti-anginals,receivedeitherabciximaborplacebowithin18-24hoursLancet1997;349:1429-14355/98MedSUnstableAngina

Anti-plateletTherapyAbciximab

(ReoPro;Centocor)CAPTURE

At30days,therewasa29%reductionintheprimarycompositeendpointofdeath,MI,orurgentrevascularizationintheabciximabgroupAt6months,thisbenefitwasnotevidentLancet1997;349:1429-14355/98MedSUnstableAngina

Anti-plateletTherapyLamifibanPARAGON(PlateletIIb/IIIaAntagonistfortheReductionofAcuteCoronarySyndromeEventsinaGlobalOrganizationNetwork)2000patientsreceivedtwodifferentdosesoflamifibancomparedwithplacebo+heparinat6months,therewasalowereventrate(12.6%vs17.9%)withlowdoselamifiban5/98MedSUnstableAngina

Anti-plateletTherapyTirofiban

(Aggrastat;Merk&Co.)PRISM

(PlateletReceptorInhibitionforIschemicSyndromeManagement)3,200patientswithunstableanginaweretreatedwitheitherheparinortirofibanAt48hours,therewassignificantriskreduction(5.9%to3.6%)intherateofdeath,MI,orrefractoryischemia.Thebenefitwaslostat30days.NEnglJMed1998;338:1498-5055/98MedSUnstableAngina

Anti-plateletTherapyTirofibanPRISM-PLUS

(PlateletReceptorInhibitionforIschemicSyndromeManagementinPatientsLimitedbyUnstableSignsandSymptoms)randomized1,915patientswithUAandnon-Q-MItotirofibanalone,heparinalone,oracombinationofthetwo(allreceivedaspirin)NEnglJMed1998;338:1488-975/98MedSUnstableAngina

Anti-plateletTherapyTirofibanPRISM-PLUS

angiographywasperformedafter48hrofinitialmedicaltherapycombinationtherapy(tirofiban,aspirin,andheparin)reducedtheriskofdeathandMIat48hrfrom2.6%to0.9%,andat30daysfrom11.9%to8.7%NEnglJMed1998;338:1488-975/98MedSUnstableAngina

Anti-plateletTherapyTirofibanRESTORE(RandomizedEfficacyStudyofTirfibanforOutcomesandRestenosis)

evaluatetheimpactoftirofibanonangioplastyforacutecoronarysyndromestirofibanreducedthefrequencyofeventsassociatedwithinterventioninACS5/98MedSUnstableAngina

Anti-plateletTherapyEptifibatide

(Integrilin;Cor/Schering)PURSUIT(PlateletIIb/IIIaUnderpinningtheReceptorforSuppressionofUnstableIschemiaTrial)~11,000patientsadmittedwithunstableanginaornon-Q-wavemyocardialinfarctionabroad-basedtrialencompassingavarietyofclinicalpracticesandpracticestylesNEJM1998;339:436-44310/98MedSUnstableAngina

Anti-plateletTherapyEptifibatide

(Integrilin;Cor/Schering)PURSUITrandomizedtoeptifibatideorplacebo;allpatientsreceivedaspirinandheparinsignificantlyreducedtheriskofdeathandMIat30daysfrom15.7%to14.2%,a9%riskreductionNEJM1998;339:436-44310/98MedSPlateletInhibitionandBleedingTime

IMPACTII PURSUIT 135/0.5 180/2.0Inhibitionofplateletaggregation 15minutesafterbolus 69% 84% atsteadystate 40-50% >90% 4hafterinfusiondiscontinuation<30% <50%Bleeding-timeprolongation atsteadystate <5x <5x 6hafterinfusiondiscontinuation1x 1.4x5/98MedSFiban

incidenceofintracranialbleeding

Treatment(%)Study Compound PlaceboActive HeparinRESTORE Tirofiban 0.3 0.1EPIC Abciximab 0.3 0.1 0.4EPILOG Abciximab 0.0 0.1IMPACTII Integrelin 0.07 0.07 0.15TheEXCITETrialInvestigatorsBolusLowdoseHighdoseBolus+Infusion5/98MedSUnstableAngina

Anti-plateletTherapySummarythefour“Ptrials”(PRISM,PRISM-PLUS,PARAGON,PURSUIT)allshowreductionofdeathratebetween

1.3%and3.4%-inadditiontothebenefitofaspirinusefulinthemanagementofpatientswithunstableanginaandMIwithoutSTelevation5/98MedSUnstableAngina

Anti-plateletTherapySummaryThequestionisnolonger

“IsthereareasontouseGPIIb/IIIainhibitors?”but“Isthereareasonnottousethem?”

EricTopol,MD5/98MedSUnstableAngina

Anti-coagulantTherapyHeparinrecommendationisbasedondocumentedefficacyinmanytrialsofmoderatesizemeta-analyses(1,2)ofsixtrialsshoweda33%riskreductioninMIanddeath,butwithatwofoldincreaseinmajorbleedingtitratePTTto2xtheupperlimitsofnormal1.Circulation1994;89:81-882.JAMA1996;276:811-8155/98MedSUnstableAngina

Anti-coagulantTherapyLow-molecular-weightheparin

advantagesoverheparin:betterbio-availabilityhigherratio(3:1)ofanti-Xatoanti-IIaactivitylongeranti-Xaactivity,avoidreboundinduceslessplateletactivationeaseofuse(subcutaneous-qdorbid)noneedformonitoring5/98MedSUnstableAngina

Anti-coagulantTherapyLow-molecular-weightheparinESSENCETrial(EfficacyandSafetyofSubcutaneousEnoxaparininnon-Q-WaveCoronaryEventsStudy)at30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-4525/98MedSESSENCETrial

incidenceofdeath,MI,orrecurrentanginaNEngJMed1997;337:447-452heparinLovenoxheparinLovenoxn=1564n=1607n=1564n=160719.8%16.6%P=0.01923.3%19.8%P=0.016Day14Day305/98MedSUnstableAngina

CoronaryInterventionsTIMI3Bearlyinterventionvsconservativestrategy

(coronaryangiographywithin24-48hrs,followedbyangioplastyorbypasssurgery)1473patientswithUAornon-Q-waveMIwererandomized,therewerenodifferencebetweenthegroupsintheratesofdeathorMIat1yearCirculation1994;89:1545-15565/98MedSUnstableAngina

CoronaryInterventionsVANQWISH(VeteranAffairsnon-Q-WaveInfarctionStrategiesinHospital)betteroutcomewithinitialconservativetherapywithlowerratesofdeathandMI

medical invasive

Hospdischarge 3% 8%

Oneyear 18.5% 24%NEJM1998;338:1785-17925/98MedSUnstableAngina

roleofnon-ioniccontrastIoniccontrastmediaseemtoperformbetterinACSprospective,randomizedcontroltrialof211patientamuchgreaterneedforCABGwasseeninthenon-ioniccontrastmediumgroupJAmColCardiol1996;26:1381-65/98MedSTrialsUnderwayGUSTO-IV(abciximab

vsplacebo)EXCITE(EvalofOralXemilofibaninControllingThromboticEvents)OPUS(OrofibaninPatientswithUnstableCoronarySyndromes)SYMPHONY(Sibrafiban

vsAspirintoYieldMaximumProtectionfromIschemicEventsPostACS)5/98MedSReferencesAcuteCoronarySyndromes:Unstableangi

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