2010循环杂志残余血小板活性预测心血管风险

Cardiovascular Death and Nonfatal Myocardial Infarction in Acute CoronarySyndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay: A 12-Month

Follow-Up

Rossella Marcucci, Anna Maria Gori, Rita Paniccia, Betti Giusti, Serafina Valente,Cristina Giglioli, Piergiovanni Buonamici, David Antoniucci, Rosanna Abbate and

Gian Franco Gensini

Circulation 2009;119;237-242; originally published online Dec 31, 2008;

DOI: 10.1161/CIRCULATIONAHA.108.812636

Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX

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CoronaryHeartDisease

CardiovascularDeathandNonfatalMyocardialInfarctioninAcuteCoronarySyndromePatientsReceivingCoronaryStentingArePredictedbyResidualPlateletReactivityto

ADPDetectedbyaPoint-of-CareAssay

A12-MonthFollow-Up

RossellaMarcucci,MD;AnnaMariaGori,BS;RitaPaniccia,BS;BettiGiusti,BS;

SerafinaValente,MD;CristinaGiglioli,MD;PiergiovanniBuonamici,MD;DavidAntoniucci,MD;

RosannaAbbate,MD;GianFrancoGensini,MD

Background—Theclinicalimpactofplateletaggregationassessedbypoint-of-careassaysisunknown.Wesoughttoevaluatewhetherhighresidualplateletreactivity(RPR)toADPduringclopidogreltherapy,measuredbyapoint-of-careassay,predictsadverseclinicaleventsinacutecoronarysyndromepatientsundergoingpercutaneouscoronaryintervention.

MethodsandResults—WeusedtheVerifyNowP2Y12assay(AccumetricsInc,SanDiego,Calif)todetermineRPRtoADPin683patientswithacutecoronarysyndromeundergoingdual-antiplatelettherapywhounderwentpercutaneouscoronaryinterventionwithbare-metalordrug-elutingstentimplantation.Allpatientsreceivedasingle600-mgclopidogrelloadingdosefollowedby75mgofclopidogreldailyand100to325mgofaspirindaily.Theendpointsofthestudyatfollow-upof12monthswerecardiovasculardeath,nonfatalmyocardialinfarction(MI),andtarget-vesselrevascularization.Ata12-monthfollow-up,wefound51ischemicevents(24cardiovasculardeaths[3.5%],27nonfatalMIs[3.9%])and40target-vesselrevascularizations(5.8%).Byreceiveroperatingcharacteristiccurve(ROC)analysis,theoptimalcutoffvalueinpredicting12-monthcardiovasculardeathandnonfatalMIwasP2Y12reactionunitvalues 240.RPR,definedinthepresenceofP2Y12reactionunitvaluesabovethiscutoff,wasfoundtobeasignificantandindependentpredictorofcardiovasculardeathandnonfatalMIinamodelthatadjustedforcardiovascularriskfactors,renalfailure,reducedleftventricularejectionfraction,multivesseldisease,totalstentlength,bifurcationlesions,numberoflesionstreated,typeofstent,anduseofglycoproteinIIb/IIIainhibitors(cardiovasculardeath:hazardratio2.55,95%CI1.08to6.07,P 0.034;nonfatalMI:hazardratio3.36,95%CI1.49to7.58,P 0.004).NosignificantassociationwasfoundbetweenhighRPRandtheriskoftarget-vesselrevascularization.

Conclusions—RPRtoADPwithclopidogreltherapy,measuredbythepoint-of-careassayVerifyNowP2Y12,isabletodetectacutecoronarysyndromepatientsatriskof12-monthcardiovasculardeathandnonfatalMI.Theoptimalcutoffvaluewasidentifiedasbeing240P2Y12reactionunits.(Circulation.2009;119:237-242.)

KeyWords:aspirinⅢclopidogrelⅢplateletsⅢbedsidetestingⅢacutecoronarysyndrome

ual-antiplatelettreatmentwithaspirinandclopidogrelinpatientsundergoingpercutaneouscoronaryintervention(PCI)hasdramaticallyreducedtherateofmajoradversecardiacevents.1,2Agrowingbodyofevidencedemonstratesthataninvitrohighresidualplateletreactivity(RPR)inpatientsundergoingdual-antiplatelettreatmentisassociatedwithanincreasedriskofadversecardiovasculareventssuchasstentthrombosisandcardiovasculardeath.3–8

D

ClinicalPerspectivep242

Clopidogrelnonresponsivenessasassessedbylighttrans-mittanceaggregometryinducedbyADP10 mol/Lisanindependentpredictorofdrug-elutingstent–implantationthrombosis.7Lighttransmittanceaggregometryisconsideredtobethestandardmethodforassessmentofplateletfunction,butlogisticproblemsmakeitsroutineusedifficult.Inrecent

ReceivedAugust6,2008;acceptedOctober23,2008.

FromtheDepartmentofMedicalandSurgicalCriticalCareandtheCenterfortheStudyattheMolecularandClinicalLevelofChronic,DegenerativeandNeoplasticDiseasestoDevelopNovelTherapies(R.M.,A.M.G.,R.P.,B.G.,R.A.,G.F.G.),UniversityofFlorence,Florence,Italy;DepartmentofHeartandVessels(R.M.,A.M.G.,R.P.,B.G.,S.V.,C.G.,P.B.,D.A.,R.A.,G.F.G.),AziendaOspedaliero-UniversitariaCareggi,Florence,Italy;andCentroS.MariaagliUlivi(G.F.G.),FondazioneDonCarloGnocchiOnlusIRCCS,Impruneta,Florence,Italy.

CorrespondencetoRossellaMarcucci,DepartmentofMedicalandSurgicalCriticalCare,UniversityofFlorence,UniversityofFlorence,VialeMorgagni85,50134FlorenceItaly.E-mailrossella.marcucci@unifi.it©2009AmericanHeartAssociation,Inc.Circulationisavailableat

DOI:10.1161/CIRCULATIONAHA.108.812636

238CirculationJanuary20,2009

arrhythmia,orrefractorycongestiveheartfailure;2)nonfatalmyo-cardialinfarction(MI;ariseinserumtroponinIoranincreaseincreatinekinase-MBisoenzymeatleasttwicetheuppernormallimitswithatleast1ofthefollowing:acuteonsetofprolonged[ 20minutes]typicalischemicchestpain;ST-segmentelevationofatleast1mmin2ormorecontiguousECGleads,orST-segmentdepression 0.5mmin 2contiguousleads;orT-waveinversion 1mminleadswithpredominantRwaves);and(3)target-vesselrevascularizationbyrepeatPCIorCABG.

years,point-of-careassaysofplateletfunctionhavebecomeavailable,includingtheVerifyNowsystem,whichprovidesvaluesofRPRafterADPstimuluscorrelatedwiththosefoundbyADPlighttransmittanceaggregometry.9Onestudybasedon380patientsundergoingPCIandclopidogreltreat-menthasdemonstratedthathighADPRPR,asmeasuredbyVerifyNow,isassociatedwithpostdischarge(6-monthfollow-up)adverseeventsafterPCIwithdrug-elutingstents.8TheaimofthepresentstudywastoevaluatewhethertheVerifyNowassayisabletopredict12-monthclinicalrecur-rencesinalargesampleofpatientswithacutecoronarysyndrome(ACS)treatedbyPCI.

StatisticalAnalysis

Continuousvariablesarepresentedasmedian(range).Categoricaldataarereportedasfrequencies.DifferencesincontinuousvariableswerecomparedbytheStudentttestorMann–WhitneyUtest,asappropriate.Dichotomousvariableswerecomparedby 2testorFisher’sexacttest,asappropriate.

AreceiveroperatingcharacteristiccurveanalysiswasusedtodeterminetheabilityoftheVerifyNowP2Y12assaytodistinguishbetweenpatientswithandwithoutpostdischargeeventsafterPCI.Theoptimalcutoffpointwascalculatedbydeterminingthepost-treatmentPRUthatprovidedthegreatestsumofsensitivityandspecificity.CumulativesurvivalcurvesforpatientswithandwithouthighRPR(RPRasdefinedbyPRU 240)wereconstructedbytheKaplan–Meiermethod,andthelog-ranktestwasusedtoassessstatisticaldifferencesbetweenthese2survivalcurves.Afterassess-mentoftheproportionalhazardassumption,univariateandmulti-variatehazardregressionmodelsofCoxwereused,respectively,toidentifyriskfactorsforclinicalendpointsandtoadjustforpotentialconfoundersthatwereassociatedwithclinicalendpointsonunivar-iateanalysis(cardiovascularriskfactors,renalfailure,leftventricu-larejectionfraction 40%,multivesseldisease,totalstentlength,bifurcationlesions,numberoflesionstreated,typeofstentused,anduseofglycoproteinIIb/IIIainhibitors).

AsignificancelevelwasdefinedasP 0.05.AllanalysiswasperformedwithSPSS14.0(SPSSInc,Chicago,Ill).

Theauthorshadfullaccesstoandtakefullresponsibilityfortheintegrityofthedata.Allauthorshavereadandagreetothemanuscriptaswritten.

Methods

StudyPopulation

rmedwrittenconsentwasobtainedfromallpatients,andthestudywasapprovedbythelocalethicsreviewboard.

PCIandAntiplateletManagement

Allinterventionswereperformedaccordingtocurrentstandardguidelines,andthetypeofstentimplantedandtheuseofglycopro-teinIIb/IIIainhibitorswereatthediscretionoftheoperator.Allpatientsreceived1clopidogrelloadingdoseof600mgfollowedbyadailydoseof75mg.Allpatientsreceivedunfractionatedheparin70IU/kgduringtheprocedureandacetylsalicylicacid500mgIVfollowedbyadailydoseof100to325mgPO.

RPRAssessment

Venousbloodsamplesanticoagulatedwithsodiumcitrate0.109mol/L(ratio9:1)weretakenfromeachpatientwithin24hoursafter600-mgclopidogrelloading.ForpatientswhoreceivedboththeloadingdoseofclopidogrelandaglycoproteinIIb/IIIainhibitorinthecatheterizationlaboratory,bloodsampleswereobtained6daysafterward,whilethepatientwastakingthe75-mgmaintenancedoseofclopidogrel.

TheVerifyNowsystem(Accumetrics,SanDiego,Calif)isaturbidimetry-basedopticaldetectiondevicethatmeasuresplatelet-inducedaggregationinasystemcontainingfibrinogen-coatedbeads.Theinstrumentmeasureschangesinlighttransmissionandthustherateofaggregationinwholeblood.InthecartridgeoftheVerifyNowP2Y12assay,thereisachannelinwhichinhibitionoftheADPP2Y12receptorismeasured.ThischannelcontainsADPasplateletagonistandprostaglandinE1asasuppressorofintracellularfreecalciumlevels,toreducethenonspecificcontributionofADPbindingtoP2Y1receptors.ResultsareexpressedasP2Y12reactionunits(PRU).

Thereferenceintervalinasampleof98healthyvolunteersobtainedinourlaboratoryis244to382PRU(5thto95thpercentileofcontroldistribution,n 98).Samplesfrom5controlsubjectsand5coronaryarterydiseasepatientstakingdual-antiplatelettherapyandtheVerifyNowassaywetqualitycontrol(level1 normalandlevel2 abnormal)wereassessed4timestodetermineourlabora-torycoefficientofvariationfortheassay.Themeancoefficientsofvariationwere3.5%incontrolsubjects,3.2%incoronaryarterydiseasepatients,and2.5%and3.4%forlevel1and2qualitycontrols,respectively.9

Results

FromJanuary2005toMarch2006,683patientswereenrolledinthepresentstudy.Baselinecharacteristicsinclud-ingRPRareshowninTable1.PRUvalueswerenormallydistributed.Themeanplateletreactivitywas193.6 86.9PRU.Table2showsclinicaloutcomesat12months.The1-yearfollow-upratewas100%.Therewere51adverseevents:24cardiovasculardeaths(3.5%),27nonfatalMIs(3.9%),and40target-vesselrevascularizations(5.8%).

Receiveroperatingcharacteristiccurveanalysisdemon-stratedthatPRUwasabletodistinguishbetweenpatientswithandwithoutsubsequentischemicevents(namely,car-diovasculardeathsandnonfatalMI)at12-monthfollow-up(areaunderthecurve0.66,95%CI0.57to0.78,P 0.001;Figure1).Table3showsthattheadditionofRPRtoamodelthatincludedclassicandproceduralriskfactorsmoderatelybutsignificantlyimprovedtheareaunderthecurveforthedetectionof12-monthfollow-upcardiovasculardeathsandnonfatalMIs.APRU 240wasidentifiedastheoptimalcutofftopredictcardiovasculardeathandnonfatalMIat12-monthfollow-up,providingasensitivityof61%(95%CI47.0%to75.8%),aspecificityof70%(95%CI66.4%to73.5%),anegativepredictivevalueof96%(95%CI94.6%to98.0%),andapositivepredictivevalueof12%(95%CI0.7%to1.6%).PatientswithRPRPRUabovetheoptimalcutoffvalueweresignificantlyolder,morelikelytobefemale,more

DataCollectionandFollow-Up

Alldatawerecollectedprospectivelyandenteredintoacentraldatabase.Clinicalfollow-upinformationwasobtainedbycontactingallpatientsat12months,andsourcedocumentsofpotentialeventswereobtained.

Theendpointsofthestudywereasfollows:(1)Cardiovasculardeath,definedasdeathinthepresenceofACS,significantcardiac

Marcuccietal

Table1.

Age,y

Malegender,n(%)Diabetes,n(%)Smoking,n(%)Hypertension,n(%)Dyslipidemia,n(%)BMI 25kg/m2,n(%)FamilyhistoryofCAD,n(%)LVEF 40%,n(%)Renalfailure,*n(%)STEMI,n(%)ACEinhibitors,n(%)

PlateletReactivityandIschemicEvents239

ClinicalCharacteristicsofPatientsInvestigated

OverallGroup(n 683)

69(29–94)517(75.6)178(26.0)210(30.8)460(67.3)357(52.3)250(36.6)132(19.3)174(25.5)69(10.1)191(28)444(65)271(39.6)410(60)635(92.9)205(30)13141154121(17.7)248(36.3)37 26

RPR*(n 219)73(46–93)141(64.3)75(34.2)68(31.1)154(70.3)124(56.6)87(39.7)48(21.9)67(30.6)15(6.8)63(28.7)142(64.8)88(40.2)131(59.9)201(91.7)72(32.9)43739152(23.7)83(37.9)39 31

NoRPR*(n 464)

68(29–94)376(81.0)103(22.2)142(30.6)306(65.9)233(50.2)163(35.1)84(18.1)107(23.1)54(11.6)128(27.5)302(65.1)183(39.4)279(60.1)434(93.5)133(28.6)

87776369(14.8)165(35.5)37 29

P 0.005 0.005 0.005NSNSNSNSNS 0.005NSNSNSNSNSNSNS NSNSNS

-Blockers,n(%)Statins,n(%)Pumpinhibitors,n(%)GlycoproteinIIb/IIIa,n(%)No.oflesionstreatedNo.ofvesselstreatedDrug-elutingstent,n(%)Bifurcationlesion,n(%)Totalstentlength,mm

BMIindicatesbodymassindex;CAD,coronaryarterydisease;LVEF,leftventricularejectionfraction;andSTEMI,ST-elevationMI.*RPRasdefinedbyPRUabovetheoptimalcutoffpointbyreceiveroperatingcharacteristiccurveanalysis(PRU 240);renalinsufficiencywasdefinedbycreatininelevels 2.0mg/dL. RPRvsnoRPR.

likelytobediabetic,andmorelikelytohavereducedleftventricularejectionfractionthanpatientswithoutRPR(Table1).Theevent-freesurvivalcurvesforcardiovasculardeathandnonfatalMIaccordingtothepresenceofRPRareshowninFigures2and3.OnunivariateCoxregressionanalysis,RPRmeasuredbyVerifyNow(cutoff 240PRU)wasassociatedwithasignificantlyhigherriskofbothcardiovasculardeath(hazardratio[HR]2.38,95%CI1.15to5.20,P 0.031)andnonfatalMI(HR2.73,95%CI1.54to5.01,P 0.006),whereasnosignificantassociationwasdetectedwithtarget-vesselrevascularization(HR1.48,95%CI0.78to2.78,P 0.225).Theseresultswereconfirmedafteradjustmentforcardiovascularriskfactors,renalfailure,reducedejectionfraction,multivesseldisease,totalstentlength,bifurcationlesions,numberoflesionstreated,typeofstentused,anduseofglycoproteinIIb/IIIainhibitors(cardiovasculardeath:HR2.55,95%CI1.08to6.07,P 0.034;nonfatalMI:HR3.36,95%CI1.49to7.58,P 0.004).

Table2.

ClinicalOutcomeat12-MonthFollow-Up

OverallGroup(n 683)

CardiovasculardeathandnonfatalMI,n(%)Cardiovasculardeath,n(%)NonfatalMI,n(%)

Target-lesionrevascularization,n(%)*RPRasdefinedbyPRU 240.

44(6.4%)24(3.5)27(3.9)40(5.8)

TheHRforcardiovasculardeathandnonfatalMIwasalsoanalyzedwithrespecttoPRUquartiles(Figure4).Thehighestquartile,whichcorrespondedtoPRUvalues 258,wasassociatedwithasignificantlyincreasedriskforische-micrecurrences(HR3.6,95%CI1.5to9.09,Pfortrend0.005).

WealsotestedtheassociationbetweenRPRand12-monthfollow-upcardiovasculareventsusingthecutoffpreviouslycalculatedinthestudybyPriceetal8(PRUvalues 235).Twohundredthirty-onepatients(33.8%)hadPRUvalues 235;onunivariateCoxregressionanalysis,PRU 235wasassociatedwithanincreasedriskofbothcardiovasculardeath(HR2.37,95%CI1.06to5.30,P 0.035)andnonfatalMI(HR2.94,95%CI1.37to6.34,P 0.006).Theseresultswereconfirmedafteradjustmentforclassicandproceduralcardio-vascularriskfactors(HR2.41,95%CI1.01to5.72,P 0.046andHR3.12,95%CI1.38to7.02,P 0.006,respectively,forcardiovasculardeathandnonfatalMI).

RPR*(n 219)27(12.3)13(5.9)16(7.3)16(7.3)

NoRPR(n 464)

17(3.6)11(2.4)11(2.4)24(5.2)

HR(95%CI)2.52(1.30–5.13)2.38(1.15–5.20)2.73(1.54–5.01)1.48(0.78–2.78)

P0.0110.0310.0060.225

240

1.0

CirculationJanuary20,2009

No RPR (PRU <240)

1.00

RPR (PRU ≥240)

0.8

CV death-freeSurvival

0.98

SENSITIVITY

0.5

0.96

0.94

0.3

log-rank test p=0.02

0.92

2

4

6

8

10

12

0.0

0.0

0.3

0.5 0.8

1.0

Time (months)

1-SPECIFICITY

Figure1.Receiver-operatingcharacteristiccurvefortheVeri-fyNowP2Y12assay.

Figure2.Survivalfreefromcardiovascular(CV)deathinpatientswithandwithoutPRU 240.

Discussion

Inthisprospectivestudyofalargenumberofpatientsundergoingdual-antiplatelettherapy,wefoundthatRPRtoADPmeasuredbyapoint-of-careassaywasanindependentpredictorofcardiovasculardeathandnonfatalMIat12-monthfollow-upinpatientswithACSwhounderwentPCI.Thecutoffvaluefortheidentificationofpatientsathigherriskforischemiceventswas240PRU.Thisvalueisconsis-tentwiththatrevealedbythestudyofPriceetal,basedon380patients,8andbytheARMYDA-PRO(Antiplateletther-apyforReductionofMYocardialDamageduringAngioplasty-PlateletReactivityPredictsOutcome)study,10publishedduringtherevisionofthisreportandbasedon160patients.Thehighnegativepredictivevalue(96%)suggeststhatpatientswithPRUvalues 240canbelabeledasbeingatlowriskofrecurrences,whereasbecauseofthelowpositivepredictivevalue(12%),PRUvalues 240includepatientswhowillnotexperienceanischemicevent.

Inthepresentstudy,aswellasinthestudybyPriceetal,8thepredictiveaccuracyoftheVerifyNowassayintheidentificationofhigh-riskpatientswasmoderate(69%).

Table3.AreaUndertheReceiverOperatingCharacteristicCurveofDifferentRegressionModelsfortheDetectionofCardiovascularDeathandNonfatalMIat12-MonthFollow-Up

AUC(95%CI)

Model1:Classiccardiovascularriskfactors*Model2:Model1 proceduralriskfactors Model3:Model2 residualplateletreactivity

0.67(0.58–0.77)0.71(0.62–0.80)0.79(0.72–0.86)

TheadditionofRPRaccordingtoVerifyNowP2Y12totheclassicandproceduralcardiovascularriskfactorsmoderatelybutsignificantlyenhancedthepredictiveabilitytodefinetheriskofrecurrences.Inarecentstudy,11ahigher(95%)predictiveaccuracyofaplateletaggregationtestforischemiceventswasobtainedwhenplateletfunctionwasassessedbyarachidonicacidandcollageninadditiontoADPstimulation,whichemphasizesthatasinglepathwayassessmentdoesnotencompassthecomplexityoftheplateletroleinthromboticevents.Currently,anumberofassaysforplateletreactivitybydifferentmethodsandagonistsareunderlaboratoryandclinicalevaluation.12,13Amongthese,aflow-cytometricvasodilator-stimulatedphosphoproteinphosphorylationassaywasabletodetectareducedresponsetoclopidogrel14,15andtosuccessfullydrivetheantiplatelettherapyin162patientsundergoingPCI.16

WeareawarethatplateletreactivityatthetimeofACSmaybeinfluencedbyanumberofclinicalandlaboratory

No RPR (PRU <240)RPR (PRU ≥240)

1.00

Non-fatalMI-freeSurvival

0.98

0.96

0.94

log-rank test p=0.01

0.92

2

4

6

8

10

12

AUCindicatesareaunderthecurve.

P 0.004,model3vsmodel1;P 0.021,model3vsmodel2.

*Age,sex,hypertension,diabetes,dyslipidemia,smokinghabit,andrenalfailure.

Typeofstent,bifurcationlesion,totallengthofstent,No.ofvesselstreated,No.ofstentsimplanted,useofglycoproteinIIb/IIIainhibitors.

Time (months)

Figure3.SurvivalfreefromnonfatalMIinpatientswithandwithoutPRU 240.

MarcuccietalPlateletReactivityandIschemicEvents241

3.

4.

5.

6.

Figure4.HRsforcardiovascular(CV)deathandnonfatalMIbyquartilesofPRUvalues.Qindicatesquartile.

7.

parameters,includingthehighleveloftheinflammatorystate17–19andtheincreasedplateletturnover.20–23Conse-quently,apercentageofpatientswithRPRintheacutephaseofdiseasemightsubsequentlyreturntoanadequateplateletinhibitionlevelafterastandarddoseofclopidogrel.There-fore,thepresentresultsstrengthentheevidencethatanimpairedandreducedinhibitionofplateletfunctionbyclopidogrelintheacutephaseofthediseaseisassociatedwithsubsequentworseclinicalfollow-up,whichunderscorestheimportanceofoptimalplateletinhibitionintheacutephaseofthedisease.Thisparadigmmirrorstheclinicalrelevanceoftheoptimizationofanticoagulationtherapyintheacutephaseofdeepvenousthrombosistotheriskofclinicalrecurrence,ie,thebettertheanticoagulationtherapyintheacutephase,thelowertheriskofclinicalrecurrence.However,theavailabilityofasimpletestfortheassessmentofthisbiologicalentity(persistentinvitroplatelethyperre-activitywiththerapy)inthepanelofclinical,laboratory,andproceduralriskfactorsmayallowbetterriskstratificationandidentificationofpatientsinwhoman“aggressive”bloodislikelytoplayakeyroleinmakingthepatienta“vulnerable”patient.

Inconclusion,theresultsofthepresentstudyindicatethatplatelethyperreactivity,measuredbythepoint-of-careassayVerifyNowP2Y12,isabletoidentifyACSpatientsathigherriskof12-monthadverseclinicaleventsandthatthecutoffvalueof240PRUcanbeusedforclinicalandinterventiontrials.

8.

9.

10.

11.

12.

13.

14.

15.

16.

SourcesofFunding

ThisstudywassupportedinpartbyagranttotheFiorGenFoundationbyEnteCassadiRisparmioFlorence,Italy.

17.

Disclosures

None.

References

1.BertrandME,RupprechtHJ,UrbanP,GershlickAH.Double-blindstudyofthesafetyofclopidogrelwithandwithoutaloadingdoseincombi-nationwithaspirincomparedwithticlopidineincombinationwithaspirinaftercoronarystenting:theClopidogrelAspirinStentInternationalCoop-erativeStudy(CLASSICS).Circulation.2000;102:624–629.

2.MehtaSR,YusufS,PetersRJ,BertrandME,LewisBS,NatarajanMK,MalmbergK,RupprechtH,ZhaoF,ChrolaviciusS,CoplandI,FoxKA.Effectsofpretreatmentwithclopidogrelandaspirinfollowedby

18.

19.

long-termtherapyinpatientsundergoingpercutaneouscoronaryinter-vention:ncet.2001;358:527–533.

KrasopoulosG,BristerSJ,BeattieWS,BuchananMR.Aspirin“resistance”andriskofcardiovascularmorbidity:systematicreviewandmeta-analysis.BMJ.2008;336:195–198.

SofiF,MarcucciR,GoriAM,AbbateR,GensiniGF.Residualplateletreactivityonaspirintherapyandrecurrentcardiovascularevents:ameta-analysis.IntJCardiol.2008;128:166–171.

SnoepJD,HovensMM,EikenboomJC,vanderBomJG,HuismanMV.Associationoflaboratory-definedaspirinresistancewithahigherriskofrecurrentcardiovascularevents:asystematicreviewandmeta-analysis.ArchInternMed.2007;167:1593–1599.

SnoepJD,HovensMM,EikenboomJC,vanderBomJG,JukemaJW,HuismanMV.Clopidogrelnonresponsivenessinpatientsundergoingpercutaneouscoronaryinterventionwithstenting:asystematicreviewandmeta-analysis.AmHeartJ.2007;154:221–231.

BuonamiciPG,MarcucciR,MiglioriniA,GensiniGF,SantiniA,PanicciaR,MoschiG,GoriAM,AbbateR,AntoniucciD.Impactofplateletreactivityafterclopidogreladministrationondrug-elutingstentthrombosis.JAmCollCardiol.2007;24:2312–2317.

PriceMJ,EndemannS,GollapudiRR,ValenciaR,StinisCT,LevisayJP,ErnstA,SawhneyNS,SchatzRA,TeirsteinPS.Prognosticsignificanceofpost-clopidogrelplateletreactivityassessedbyapoint-of-careassayonthromboticeventsafterdrug-elutingstentimplantation.EurHeartJ.2008;29:992–1000.

PanicciaR,AntonucciE,GoriAM,MarcucciR,GiglioliC,AntoniucciD,GensiniGF,AbbateR,PriscoD.Differentmethodologiesforeval-uatingtheeffectofclopidogrelonplateletfunctioninhigh-riskcoronaryarterydiseasepatients.JThrombHaemost.2007;5:1839–1847.

PattiG,NuscaA,MangiacapraF,GattoL,D’AmbrosioA,DiSciascioG.Point-of-caremeasurementofclopidogrelresponsivenesspredictsclinicaloutcomeinpatientsundergoingpercutaneouscoronaryintervention.JAmCollCardiol.2008;52:1128–1133.

GoriAM,MarcucciR,MiglioriniA,ValentiR,MoschiG,PanicciaR,BuonamiciP,GensiniGF,VergaraR,AbbateR,AntoniucciD.IncidenceandclinicalImpactofdualnonresponsivenesstoaspirinandclopidogrelinpatientswithdrugelutingstents.JAmCollCardiol.2008;52:734–739.GurbelPA,BeckerRC,MannKG,SteinhublSR,MichelsonAD.Plateletfunctionmonitoringinpatientswithcoronaryarterydisease.JAmCollCardiol.2007;50:1822–1834.

SibbingD,BraunS,JawanskyS,VogtW,MehilliJ,SchömigA,KastratiA,vonBeckerathN.AssessmentofADP-inducedplateletaggregationwithlighttransmissionaggregometryandmultipleelectrodeplateletaggregometrybeforeandafterclopidogreltreatment.ThrombHaemost.2008;99:121–126.

AleilB,RavanatC,CazenaveJP,RochouxG,HeitzA,GachetC.FlowcytometricanalysisofintraplateletVASPphosphorylationforthedetectionofclopidogrelresistanceinpatientswithischemiccardiovas-culardiseases.JThrombHaemost.2005;3:85–92.

FrereC,CuissetT,QuiliciJ,CamoinL,CarvajalJ,MorangePE,LambertM,Juhan-VagueI,BonnetJL,AlessiMC.ADP-inducedplateletaggre-gationandplateletreactivityindexVASParegoodpredictivemarkersforclinicaloutcomesinnon-STelevationacutecoronarysyndrome.ThrombHaemost.2007;98:838–843.

BonelloL,Camoin-JauL,ArquesS,BoyerC,PanagidesD,WittenbergO,SimeoniMC,BarraganP,Dignat-GeorgeF,PaganelliF.Adjustedclopidogrelloadingdosesaccordingtovasodilator-stimulatedphospho-proteinphosphorylationindexdecreaserateofmajoradversecardiovas-culareventsinpatientswithclopidogrelresistance:amulticenterran-domizedprospectivestudy.JAmCollCardiol.2008;51:1404–1411.FuchsI,FrossardM,SpielA,RiedmüllerE,LaggnerAN,JilmaB.Plateletfunctioninpatientswithacutecoronarysyndrome(ACS)predictsrecurrentACS.JThrombHaemost.2006;4:2547–2552.

MarcucciR,GoriAM,PanicciaR,GiglioliC,BuonamiciP,AntoniucciD,GensiniGF,AbbateR.ResidualplateletreactivityisassociatedwithclinicalandlaboratorycharacteristicsinpatientswithischemicheartdiseaseundergoingPCIondualantiplatelettherapy.Atherosclerosis.2007;195:217–223.

GoriAM,CesariF,MarcucciR,GiustiB,PanicciaR,AntonucciE,GensiniGF,AbbateR.Thebalancebetweenpro-andanti-inflammatorycytokinesisassociatedwithplateletaggregabilityinacutecoronarysyndromepatients.Atherosclerosis.April11,2008.doi:10.1016/j.

atherosclerosis.2008.04.001.

242CirculationJanuary20,2009

22.TschoepeD,RoesenP,KauffmannL,SchauseilS,KehrelB,Ostermann

H,GriesFA.Evidenceforabnormalplateletglycoproteinexpressionindiabetesmellitus.EurJClinInvest.1990;20:166–170.

23.CesariF,MarcucciR,CaporaleR,PanicciaR,RomanoE,GensiniGF,

AbbateR,GoriAM.Relationshipbetweenhighplateletturnoverandplateletfunctioninhigh-riskpatientswithcoronaryarterydiseaseondualantiplatelettherapy.ThrombHaemost.2008;99:930–935.

20.JakubowskiJA,ThompsonCB,VaillancourtR,ValeriCR,DeykinD.

Arachidonicacidmetabolismbyplateletsofdifferingsize.BrJHaematol.1983;53:503–511.

21.MartinJF,TrowbridgeEA,SalmonGL,PlumbJ.Thebiologicalsignif-icanceofplateletvolume:itsrelationshiptobleedingtime,plateletthromboxaneB2productionandmegakaryocytenuclearDNAconcen-tration.ThrombRes.1983;32:443–460.

CLINICALPERSPECTIVE

Agrowingbodyofevidenceshowsthataninvitroresidualplateletreactivity(RPR)inpatientsundergoingdual-antiplatelet(aspirinplusclopidogrel)treatmentisassociatedwithanincreasedriskofadversecardiovasculareventsinhigh-riskvascularpatients.Lighttransmittanceaggregometryisconsideredthestandardmethodforassessmentofplateletfunction,butlogisticproblemsmakeitsroutineusedifficult.Inrecentyears,point-of-careassaysofplateletfunctionhavebecomeavailable,includingtheVerifyNowP2Y12system,whichprovidesvaluesofRPRafterADPstimuluscorrelatedwiththosefoundbylighttransmittanceaggregometryinducedbyADP.In683patientswithacutecoronarysyndrometreatedbypercutaneouscoronaryintervention,wesoughttoverifywhethertheVerifyNowP2Y12assayisabletopredictclinicalrecurrences,andwefoundthatRPRtoADPmeasuredbyapoint-of-careassayisanindependentpredictorofcardiovasculardeathandnonfatalmyocardialinfarctionat12-monthfollow-up.Theavailabilityofasimpletestforassessmentofthisbiologicalentity(persistentinvitroplatelethyperreactivitywiththerapy)inthepanelofclinical,laboratory,andproceduralriskfactorsmayallowforbetterriskstratificationandidentificationofpatientsinwhomanaggressivebloodislikelytoplayakeyroleinmakingthepatientavulnerablepatient.

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