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ASAResistanceand

ClinicalOutcomesASAResistanceand

ClinicalOu1ASAResistance:KeyQuestionsDoesastandardizeddefinitionexist?Aretherereliableteststodiagnosethisphenomenon?Whatarethepossiblemechanismsandfutureimplications?Doesithaveanyclinicalsignificance?HowdowemanagepatientswithAspirinresistance?ASAResistance:KeyQuestionsD2EstablishedPlateletFunctionTestsHarrisonP.BrJHematology2000;111:733-744PlateletFunctionTestBleedingtimeAggregometry-turbidometricmethodsAggregometry-impedancemethodsAggregometry&luminescenceAdeninenucleotidesThromboelastography(TEG)GlassfilterometerPlateletreleasemarkersInVivoscreeningtestResponsivenesstopanelagonistsResponsivenesstopanelagonistsCombinedaggregationandADPreleaseStoredandreleasedADPGlobalHemostasisHighshearplateletfunctionInvivoplateletactivationmarkersAdvantagesPhysiologicalDiagnosticWholebloodtestMoreinformationSensitivePredictsbleedingSimpleSimple,systemicmeasureofplateletactivationDisadvantagesInsensitive,invasive&highvariabilityLaborintensive&non-physiologicalInsensitiveSemi-quantitativeSpecializedequipmentMeasuresclotpropertiesonly,insensitivetoASARequiresbloodcounterPronetoartifactPltFunctionTestDisadvantagesAdvantagesAssayEstablishedPlateletFunction3NewerPlateletFunctionTests(PFA)-100 Wholeblood + Primary Limitedrange-mostpts hemostasis afterGPIIb/IIIainhibitorshave (highshear closuretimes>300sec,somay adhes/aggreg) notbeabletodiscerndiff.Used toassayADPantagonist

ClotSignature Wholeblood + Adhesion, LargeinstrumentforroutineuseAnalyzer aggregation andinterpretationofresultsis complexRapidplatelet Wholeblood + Aggregation GPIIb/IIa:baselinesamplereq.functionassay Clinicaloutcomedata(GOLD) Aspirin:AA-likeagonistHarrisonP.BrJHematology2000;111:733-744MukherjeeD&MoliternoDJ.ClinPharmacokinet2000;39(6):445-458Flowcytometry

Wholeblood - PlateletGP, Flexible&powerful.Requires activationmarkers, specializedoperator.Expensive PlateletfunctionAssay SubstrateBedside Principle CommentsNewerPlateletFunctionTests(4PrevalenceofASAResistanceGumPAetal.AmJCardiol2001;88:230-235ASA-R:meanaggregation≥70%withμM10ADP&≥20%with0.5mg/mlAA325patientswithstableCVDtakingASA325mg>7daysPrevalenceofASAResistanceG5WangJCetal.AmerJCardiol2003;92:1492-4422patientspresentingtocardiaccathlabonASA81-325mg>7dPrevalenceofAspirinResistance23.4%Aspirinnon-responsiveAccumetricsVerifyNowAspirinDefinition:ARU>550Multivariateanalysis:historyofCADassociatedwithtwicetheoddsofbeingASAnon-responder(oddsratio2.09,95%CI1.189-3.411,p=0.009)Noassociationwithgender,DM,smoking,ASAdoseWangJCetal.AmerJCardiol6ClinicalStudiesClinicalStudies7ASAResistance:Long-termClinicalStudiesStroke1 1500mg PltReactivity 24m Stroke/MI/ 10-foldlower(n=180) Vasculardeath riskinASA respondersPVD2 100mg Wholeblood 18m Arterial 87%higherrisk(n=100) aggregometry Occlusion inASA-R

CVD/CVA3 100mg PFA-10 >60m RecurrentCVA/ RecurrentCVA34%(n=53)TIA TIA ASA-Rvs.0%no recurrenteventsSubgroup 75-325mg Urinary11-dehydro 5yrs MI/Stroke/ 1.8timesHOPE4

TXB2CVDeath higherriskin(n=967) uppervs.lower quartileCVD5 325mg Opticalplatelet 679±185 Death/MI/CVA 24%ASA-Rvs.(n=326) aggregation days 10%ASA-S[HR 3.12(95%CI1.1- 8.9,p=0.03)GrotemeyerKH,etal.ThrombRes1993;71:397-403MuellerMR,etal.ThrombHaemost1997;78:1003-1007GrundmannK,etal.JNeurol2003;250:63-66EikelboomJW,etal.Circulation2002;105:1650-1655GumPA,etal.JAmCollCardiol2003;41:961-965Pts ASAdose Test F/U End-point ResultsASAResistance:Long-termClin8ASAResistanceandClinicalOutcomeinCADPatientsEikelboomJW,etal.Circulation2002;105:1650-1655HOPETrialSubstudy:ASA75-325mgASAResistanceandClinicalOu9ASAResistanceandClinicalOutcomeinCVDPatientsGumPA,etal.JAmCollCardiol2003;41:961-965ASA-R:meanaggregation≥70%with10μMADP&≥20%with0.5mg/mlAA326CVDpatientsonASA325mg>7daysp=0.03ASAResistanceandClinicalOu10ASAResistanceandClinicalOutcomeinPVDPatientsMuellerMRetal.ThrombHaemost1997;78:1003-1007ASAResistanceandClinicalOu11ASAResistanceandClinicalOutcomeinStrokePatientsGrotemeyerKHetal.ThrombRes1993;71:397-403ASAResistanceandClinicalOu12ASAResistanceandClinicalOutcomeinStrokePatientsGrundmannKetal.JNeurol2003;250:63-6653CVAptsonASA100mgforsecondaryprevention>60monthsASAResistanceandClinicalOu13Chenetal.JAmerCollCardiol2004;43:1122-6ASAResistanceinPCIRPFA-ASA,ASA/clopidogrel(n=151),19.2%ASAresistantChenetal.JAmerCollCardi14

OralAntiplateletAgentsCollagen

Thrombin

TXA2AspirinADP(FibrinogenReceptor)clopidogrelbisulfateTXA2ADPDipyridamolePhosphodiesteraseADPGpIIb/IIIaActivationCOXticlopidineHClADP=adenosinediphosphate,TXA2=thromboxaneA2,COX=cyclooxygenase.SchaferAI.AmJMed1996;101:199–209.OralAntiplateletAgentsColla15ClopidogrelinUnstableAnginatoPreventRecurrentIschemicEventsTheCURETrialInvestigators.NEnglJMed.2001;345:494-502.Aspirin75-325mgAspirin75-325mg

PlaceboClopidogrel300mgloadingdosePatientswithNon-STelevation

AcuteCoronary

SyndromeR

136 912 Months3months￡double-blindtreatment￡12monthsClopidogrel75mgq.d.+ASA75-325mgq.d.*(6259patients)Placebo+ASA

75-325mgq.d.*(6303patients)ClopidogrelinUnstableAngina16*IncombinationwithstandardtherapyTheCURETrialInvestigators.NEnglJMed.2001;345:494-502.0.140.000.020.040.060.080.100.12CumulativeHazardRateClopidogrel

+ASA*369Placebo

+ASA*MonthsofFollow-Up11.4%9.3%20%RRRP<0.001N=12,562012PrimaryEndpoint:MI/Stroke/CVDeath*Incombinationwithstandard17PCIPLACEBO+ASA*CLOPIDOGREL300mg3-24hpre-PCI+ASA*30dayspostPCIEndoffollow-upUpto12monthsafterrandomizationClopidogrel75QDPretreatmentClopidogrel75QDPretreatmentN=2,116patientsundergoingelectivePCI*IncombinationwithstandardtherapyN=1345N=1313RCREDOPCIPLACEBOCLOPIDOGREL30daysp18Steinhubletal.JAMA2002CREDO:PrimaryEndpoint26.9%relativeriskreduction(CI3.9-44.4%;P=0.02)Absolutereduction=3%Steinhubletal.JAMA2002CRE19

AspirinResistantPatientManagementEliminateinterferingsubstances(ibuprofen)IncreaseaspirindoseUseotheranti-plateletmedicationssuchasclopidogreltopreventrecurrentischemiceventsEducatepatientonimportanceofcompliance

AspirinResistantPatientMan20ConclusionsASAuseassociatedwith23%reductionintheoddsofvasculareventsBeneficialanti-thromboticeffectofASAmediatedbyirreversibleacetylationofCOX-1ASAresistance5-60%ASAresistanceassociatedwithincreasedriskofmajoradversecardiovasculareventsConclusionsASAuseassociated21ASAResistanceand

ClinicalOutcomesASAResistanceand

ClinicalOu22ASAResistance:KeyQuestionsDoesastandardizeddefinitionexist?Aretherereliableteststodiagnosethisphenomenon?Whatarethepossiblemechanismsandfutureimplications?Doesithaveanyclinicalsignificance?HowdowemanagepatientswithAspirinresistance?ASAResistance:KeyQuestionsD23EstablishedPlateletFunctionTestsHarrisonP.BrJHematology2000;111:733-744PlateletFunctionTestBleedingtimeAggregometry-turbidometricmethodsAggregometry-impedancemethodsAggregometry&luminescenceAdeninenucleotidesThromboelastography(TEG)GlassfilterometerPlateletreleasemarkersInVivoscreeningtestResponsivenesstopanelagonistsResponsivenesstopanelagonistsCombinedaggregationandADPreleaseStoredandreleasedADPGlobalHemostasisHighshearplateletfunctionInvivoplateletactivationmarkersAdvantagesPhysiologicalDiagnosticWholebloodtestMoreinformationSensitivePredictsbleedingSimpleSimple,systemicmeasureofplateletactivationDisadvantagesInsensitive,invasive&highvariabilityLaborintensive&non-physiologicalInsensitiveSemi-quantitativeSpecializedequipmentMeasuresclotpropertiesonly,insensitivetoASARequiresbloodcounterPronetoartifactPltFunctionTestDisadvantagesAdvantagesAssayEstablishedPlateletFunction24NewerPlateletFunctionTests(PFA)-100 Wholeblood + Primary Limitedrange-mostpts hemostasis afterGPIIb/IIIainhibitorshave (highshear closuretimes>300sec,somay adhes/aggreg) notbeabletodiscerndiff.Used toassayADPantagonist

ClotSignature Wholeblood + Adhesion, LargeinstrumentforroutineuseAnalyzer aggregation andinterpretationofresultsis complexRapidplatelet Wholeblood + Aggregation GPIIb/IIa:baselinesamplereq.functionassay Clinicaloutcomedata(GOLD) Aspirin:AA-likeagonistHarrisonP.BrJHematology2000;111:733-744MukherjeeD&MoliternoDJ.ClinPharmacokinet2000;39(6):445-458Flowcytometry

Wholeblood - PlateletGP, Flexible&powerful.Requires activationmarkers, specializedoperator.Expensive PlateletfunctionAssay SubstrateBedside Principle CommentsNewerPlateletFunctionTests(25PrevalenceofASAResistanceGumPAetal.AmJCardiol2001;88:230-235ASA-R:meanaggregation≥70%withμM10ADP&≥20%with0.5mg/mlAA325patientswithstableCVDtakingASA325mg>7daysPrevalenceofASAResistanceG26WangJCetal.AmerJCardiol2003;92:1492-4422patientspresentingtocardiaccathlabonASA81-325mg>7dPrevalenceofAspirinResistance23.4%Aspirinnon-responsiveAccumetricsVerifyNowAspirinDefinition:ARU>550Multivariateanalysis:historyofCADassociatedwithtwicetheoddsofbeingASAnon-responder(oddsratio2.09,95%CI1.189-3.411,p=0.009)Noassociationwithgender,DM,smoking,ASAdoseWangJCetal.AmerJCardiol27ClinicalStudiesClinicalStudies28ASAResistance:Long-termClinicalStudiesStroke1 1500mg PltReactivity 24m Stroke/MI/ 10-foldlower(n=180) Vasculardeath riskinASA respondersPVD2 100mg Wholeblood 18m Arterial 87%higherrisk(n=100) aggregometry Occlusion inASA-R

CVD/CVA3 100mg PFA-10 >60m RecurrentCVA/ RecurrentCVA34%(n=53)TIA TIA ASA-Rvs.0%no recurrenteventsSubgroup 75-325mg Urinary11-dehydro 5yrs MI/Stroke/ 1.8timesHOPE4

TXB2CVDeath higherriskin(n=967) uppervs.lower quartileCVD5 325mg Opticalplatelet 679±185 Death/MI/CVA 24%ASA-Rvs.(n=326) aggregation days 10%ASA-S[HR 3.12(95%CI1.1- 8.9,p=0.03)GrotemeyerKH,etal.ThrombRes1993;71:397-403MuellerMR,etal.ThrombHaemost1997;78:1003-1007GrundmannK,etal.JNeurol2003;250:63-66EikelboomJW,etal.Circulation2002;105:1650-1655GumPA,etal.JAmCollCardiol2003;41:961-965Pts ASAdose Test F/U End-point ResultsASAResistance:Long-termClin29ASAResistanceandClinicalOutcomeinCADPatientsEikelboomJW,etal.Circulation2002;105:1650-1655HOPETrialSubstudy:ASA75-325mgASAResistanceandClinicalOu30ASAResistanceandClinicalOutcomeinCVDPatientsGumPA,etal.JAmCollCardiol2003;41:961-965ASA-R:meanaggregation≥70%with10μMADP&≥20%with0.5mg/mlAA326CVDpatientsonASA325mg>7daysp=0.03ASAResistanceandClinicalOu31ASAResistanceandClinicalOutcomeinPVDPatientsMuellerMRetal.ThrombHaemost1997;78:1003-1007ASAResistanceandClinicalOu32ASAResistanceandClinicalOutcomeinStrokePatientsGrotemeyerKHetal.ThrombRes1993;71:397-403ASAResistanceandClinicalOu33ASAResistanceandClinicalOutcomeinStrokePatientsGrundmannKetal.JNeurol2003;250:63-6653CVAptsonASA100mgforsecondaryprevention>60monthsASAResistanceandClinicalOu34Chenetal.JAmerCollCardiol2004;43:1122-6ASAResistanceinPCIRPFA-ASA,ASA/clopidogrel(n=151),19.2%ASAresistantChenetal.JAmerCollCardi35

OralAntiplateletAgentsCollagen

Thrombin

TXA2AspirinADP(FibrinogenReceptor)clopidogrelbisulfateTXA2ADPDipyridamolePhosphodiesteraseADPGpIIb/IIIaActivationCOXticlopidineHClADP=adenosinediphosphate,TXA2=thromboxaneA2,COX=cyclooxygenase.SchaferAI.AmJMed1996;101:199–209.OralAntiplateletAgentsColla36ClopidogrelinUnstableAnginatoPreventRecurrentIschemicEventsTheCURETrialInvestigators.NEnglJMed.2001;345:494-502.Aspirin75-325mgAspirin75-325mg

PlaceboClopidogrel300mgloadingdosePatientswithNon-STelevation

AcuteCoronary

SyndromeR

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