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Introductionto

AspirinResistance.Introductionto

AspirinResis1AspirinHistoryFirstsynthesizedinpureformbyFelixHoffmanofFriedr.Bayer&Co.in1897.(FromtheGermanacetylspirsaure+chemicalsuffix–in)AspirinHistoryFirstsynthesiz2AspirinHistoryDuetoproblemswiththeoriginalAspirinpowderbeingcounterfeited,itbecamethefirstpharmaceuticalagenteversoldinpillforminearly1900’s.FirstpillinUSAwas5grains(~325mg).AspirinHistoryDuetoproblems3阿司匹林抵抗英文課件4MetabolicPathwaysof

ArachadonicAcidMembranePhospholipidsARACHIDONICACIDProstaglandinH2COX-1ThromboxaneA2PlateletAggregationVasoconstrictionProstacyclinPlateletAggregationVasodilitationAspirinMetabolicPathwaysof

Arachado5AspirinintheTreatmentofACSWallentinLC,etal.JACC1991;18:1587-93.0.000.000.25036912MonthsProbability

ofDeathorMIPlaceboAspirin75mgRiskratio0.52

95%CL0.37-0.72AspirinintheTreatmentofAC6AspirininAcuteMyocardialInfarction:ISIS-21002003004005006000714212835Placeboalone:568/4300(13.2%)Aspirinalone:461/4295(10.7%)Streptokinasealone:448/4300(10.4%)Streptokinaseplusaspirin:343/4292(8.0%)CumulativeNumberofVascularDeathsDaysFromRandomizationAspirininAcuteMyocardialIn7RandomizedTrialsofAspirininPTCASchwartz,NEnglJMed1988;318:1714White,CoronaryArteryDisease1991;2:75704812SchwartzetalN=376WhiteetalN=337%MajorIschemicComplications6.912.6Heparin10,000units2.4Ticlopidine+Heparin1.6ASA/Dipyridamole+Heparin77%P=0.01133.275%P<0.001RandomizedTrialsofAspirini8Whatis“AspirinResistance?”InabilityofASAtopreventtreatedpatientsfromhavingthromboticevents.InabilityofASAtherapytoprolongbleedingtime.InabilityoftreatmentwithASAtopreventthromboxanebiosynthesis.InabilityofASAtoachieveapre-definedeffectonanexvivoorinvitromeasureofplateletfunction.PatronoC.JThrombHaemost2003;1:1710-3Whatis“AspirinResistance?”I9Inter-IndividualVariabilityinResponsetoAspirinQuickAJ.AmericanJournalofMedicalScienceSept1966:265-9N=10Inter-IndividualVariabilityi10InterpatientVariabilityinAspirinResponse-BleedingTimeAspirin,325mgdailyin40CABGpatientsBuchanan,CanJCardiol1995;11(3):221100300500700900100300500700900BleedingTime,Pre-ASABleedingTimePost-ASAResponders(58%)MeanBT58+10%Non-responders(42%)MeanBT2+4%InterpatientVariabilityinAs11AspirinResponsivenessand

ClinicalOutcome181patients,followingCVA.Aspirin500mgTID.Followed-upfor24months.10075506121824%ofPatientsWithoutEventMonthsofObservationAspirinRespondersN=114AspirinNon-respondersN=6060%95%P<0.0001Grotemeyer,ThrombosisResearch1993;71:397AspirinResponsivenessand

Cl12ThromboxaneBiosynthesisonAspirinandCVEvents1.0012<15.115.1-21.821.9-33.8>33.8Uninary11-dehydrothromboxaneB2(ng/mmolecreatinine)OddsRatioforMI,StrokeorCVDeathEikelboomCirc2002;105:1650HOPETrialN=488,with5yrf/uThromboxaneBiosynthesisonAs13AspirinResponsivenessBy

PFA-100andAggregometry23.8%5.5%70.7%AspirinSensitiveResistantPartialResponders9.5%90.5%AspirinSensitive325patientswithstableASCADAggregometryResponsetoADPandAAPFA-100GumP.AmJCardiol2001;88:230-235AspirinResponsivenessBy

PFA14ClinicalOutcomes:AspirinResponsive-nessbyAggregometryAndPFA-100

0204000200200400400600600800800DaysafterTreatmentNotAspirinResistant,N=309AspirinResistant,N=17%Death,MI,CVALogrank2=5.05,p=0.03Gum,P.JACC2003;41:961-505101520ASAResponderN=294ASANon-ResponderN=3212.915.1%Death,MI,CVAP=0.4ClinicalOutcomesbasedonPFA-100ResultsClinicalOutcomes:AspirinRes15PossibleMechanismsfor

VariabilityinResponsetoAspirinDecreasedbioavailabilityNon-complianceConcomitantNSAIDsPlateletfunctionAcceleratedplateletturnoverIncreasedplateletCOX-2PlateletReceptorPolymorphismsOtherfactorsDeGaetanoG.JThrombHaemost2003;1:2048-50PossibleMechanismsfor

Varia16MetabolicPathwaysof

ArachadonicAcidMembranePhospholipidsARACHIDONICACIDProstaglandinH2COX-1ThromboxaneA2PlateletAggregationVasoconstrictionProstacyclinPlateletAggregationVasodilitation12-Lipoxygenase12-HETE,12-HPETE-PlateletAdhesivityNon-EnzymaticLipidPeroxidationCatalyzedbyFreeRadicalsIsoprostanesAmplifiesplateletresponsetootheragonists.VasoconstrictorPlasmalevels1-2ordersofmagnitude>COX-derivedmetabolites.AspirinMetabolicPathwaysof

Arachad17PlA2Polymorphismand

AspirinResistance0204060800.1110100%AggregationAspirinμmol/LP=0.02P=0.01PlA1/A1PlA1/A2Cooke,Lancet1998;351:PlA2PolymorphismSinglenucleotidepolymorphism-Prolineforaleucineatposition33of3subunit.~25%ofindividualsofN.EuropeanancestryarePlA2+.

PlA2Polymorphismand

Aspirin18AspirinResistance:RoleofCOX-2?WeberA-ALancet1999;353:900Aspirinis170-foldmorepotentinhibitorofCOX-1thanCOX-2.Plateletsfrom20differentdonorswereCOX-2positive.COX-2expressioninplateletsincreased16-foldin9post-CABGpatients.(ZimmermannAHA1999)AspirinResistance:RoleofC19ConclusionsEverystudythathaseverevaluatedindividualresponsivenesstoASAhasfoundmarkedvariability.Moststudieshavebeenabletocorrelatethisvariabilitywithaclinicallysignificantincreaseinthromboticevents.TheabilitytoidentifythesubstantialproportionofpatientswhoareunabletoachieveanadequateresponsetoASAhasthepotentialtodramaticallyimprovetheirantithromboticregimenandwithit,long-termoutcomes.ConclusionsEverystudythatha20Introductionto

AspirinResistance.Introductionto

AspirinResis21AspirinHistoryFirstsynthesizedinpureformbyFelixHoffmanofFriedr.Bayer&Co.in1897.(FromtheGermanacetylspirsaure+chemicalsuffix–in)AspirinHistoryFirstsynthesiz22AspirinHistoryDuetoproblemswiththeoriginalAspirinpowderbeingcounterfeited,itbecamethefirstpharmaceuticalagenteversoldinpillforminearly1900’s.FirstpillinUSAwas5grains(~325mg).AspirinHistoryDuetoproblems23阿司匹林抵抗英文課件24MetabolicPathwaysof

ArachadonicAcidMembranePhospholipidsARACHIDONICACIDProstaglandinH2COX-1ThromboxaneA2PlateletAggregationVasoconstrictionProstacyclinPlateletAggregationVasodilitationAspirinMetabolicPathwaysof

Arachado25AspirinintheTreatmentofACSWallentinLC,etal.JACC1991;18:1587-93.0.000.000.25036912MonthsProbability

ofDeathorMIPlaceboAspirin75mgRiskratio0.52

95%CL0.37-0.72AspirinintheTreatmentofAC26AspirininAcuteMyocardialInfarction:ISIS-21002003004005006000714212835Placeboalone:568/4300(13.2%)Aspirinalone:461/4295(10.7%)Streptokinasealone:448/4300(10.4%)Streptokinaseplusaspirin:343/4292(8.0%)CumulativeNumberofVascularDeathsDaysFromRandomizationAspirininAcuteMyocardialIn27RandomizedTrialsofAspirininPTCASchwartz,NEnglJMed1988;318:1714White,CoronaryArteryDisease1991;2:75704812SchwartzetalN=376WhiteetalN=337%MajorIschemicComplications6.912.6Heparin10,000units2.4Ticlopidine+Heparin1.6ASA/Dipyridamole+Heparin77%P=0.01133.275%P<0.001RandomizedTrialsofAspirini28Whatis“AspirinResistance?”InabilityofASAtopreventtreatedpatientsfromhavingthromboticevents.InabilityofASAtherapytoprolongbleedingtime.InabilityoftreatmentwithASAtopreventthromboxanebiosynthesis.InabilityofASAtoachieveapre-definedeffectonanexvivoorinvitromeasureofplateletfunction.PatronoC.JThrombHaemost2003;1:1710-3Whatis“AspirinResistance?”I29Inter-IndividualVariabilityinResponsetoAspirinQuickAJ.AmericanJournalofMedicalScienceSept1966:265-9N=10Inter-IndividualVariabilityi30InterpatientVariabilityinAspirinResponse-BleedingTimeAspirin,325mgdailyin40CABGpatientsBuchanan,CanJCardiol1995;11(3):221100300500700900100300500700900BleedingTime,Pre-ASABleedingTimePost-ASAResponders(58%)MeanBT58+10%Non-responders(42%)MeanBT2+4%InterpatientVariabilityinAs31AspirinResponsivenessand

ClinicalOutcome181patients,followingCVA.Aspirin500mgTID.Followed-upfor24months.10075506121824%ofPatientsWithoutEventMonthsofObservationAspirinRespondersN=114AspirinNon-respondersN=6060%95%P<0.0001Grotemeyer,ThrombosisResearch1993;71:397AspirinResponsivenessand

Cl32ThromboxaneBiosynthesisonAspirinandCVEvents1.0012<15.115.1-21.821.9-33.8>33.8Uninary11-dehydrothromboxaneB2(ng/mmolecreatinine)OddsRatioforMI,StrokeorCVDeathEikelboomCirc2002;105:1650HOPETrialN=488,with5yrf/uThromboxaneBiosynthesisonAs33AspirinResponsivenessBy

PFA-100andAggregometry23.8%5.5%70.7%AspirinSensitiveResistantPartialResponders9.5%90.5%AspirinSensitive325patientswithstableASCADAggregometryResponsetoADPandAAPFA-100GumP.AmJCardiol2001;88:230-235AspirinResponsivenessBy

PFA34ClinicalOutcomes:AspirinResponsive-nessbyAggregometryAndPFA-100

0204000200200400400600600800800DaysafterTreatmentNotAspirinResistant,N=309AspirinResistant,N=17%Death,MI,CVALogrank2=5.05,p=0.03Gum,P.JACC2003;41:961-505101520ASAResponderN=294ASANon-ResponderN=3212.915.1%Death,MI,CVAP=0.4ClinicalOutcomesbasedonPFA-100ResultsClinicalOutcomes:AspirinRes35PossibleMechanismsfor

VariabilityinResponsetoAspirinDecreasedbioavailabilityNon-complianceConcomitantNSAIDsPlateletfunctionAcceleratedplateletturnoverIncreasedplateletCOX-2PlateletReceptorPolymorphismsOtherfactorsDeGaetanoG.JThrombHaemost2003;1:2048-50PossibleMechanismsfor

Varia36MetabolicPathwaysof

ArachadonicAcidMembranePhospholipidsARACHIDONICACIDProstaglandinH2COX-1ThromboxaneA2PlateletAggregationVasoconstrictionProstacyclinPlateletAggregationVasodilitation12-Lipoxygenase12-HETE,12-HPETE-PlateletAdhesivityNon-EnzymaticLipidPeroxidationCatalyzedbyFreeRadicalsIsoprostanesAmplifiesplateletresponsetootheragonists.VasoconstrictorPlasmalevels1-2ordersofmagnitude>COX-derivedmetabolites.Aspirin

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