冠心病抗血小板治疗的现在和未来-曲鹏

冠心病抗血小板治疗的现在和未来曲鹏大连医科大学附属二院ACS为什么需要抗血小板治疗？不稳定性动脉粥样硬化斑块破裂？保护性内皮细胞层的破裂？强促血栓内皮下层的暴露血小板粘附到损伤的部位血小板活化GPIIb/IIIa受体暴露血小板聚集通过纤维蛋白原（fibrinogen）与GPIIb/IIIa受体结合纤维蛋白沉积–血小板块参与到纤维蛋白丝当中12345Aspirin(ASA)/NSAIDS不可逆/可逆性阻断COX心血管死亡/心肌梗死相对危险性减少35%-50%

(ARR2.5%NNT40)CLOPIDOGREL&TICLOPIDINE不可逆抑制ADP诱导的血小板聚集PLAVIX:不稳定性心绞痛,NSTEMI,PVD,AMI/CVA二级预防阿司匹林过敏/胃肠道不耐受消化不良,皮疹,腹泻TICLID:中性粒细胞就是,ITP,TTPClopidogrelinACS&PCISTEMINSTEMIElectivePCICLARITY:28daysRx(loadingdosegiven)CURE(upto12monthsmean9months)PCICURECREDO(allgotclopidogrelfor28daysthenrandomisedupto1year)COMMIT28daysRx(noloadingdose)CLARITY-TIMI28(300mgloadingdoseinAMI)

Primaryendpoints:PlaceboClopidogrelp=0.000000361.00.40.60.81.21.6ClopidogrelbetterPlacebobettern=1752n=173936%OddsreductionCVdeath,MI,RIurgentrevascularizationDaysPercentwithendpoint051015051015202530PlaceboClopidogrelOddsratio0.80(95%CI0.65-0.97)p=0.02620%DualAntiplateletRxforPCI

Circ102:624,2000ISARFANTASTICSTARSMATTISCLASSICS%MACE0.91.51.2PT=Pre-treatment*PlusASAandotherstandardtherapiesCombinedEndpointOccurrence(%)DaysFromRandomizationNo-PT-Placebo*PT-Clopidogrel*051007142128Death,MI,UTVR-PPPopulation18.5%RRRP=0.23981432768.3%6.8%SteinhublS,BergerP,TiftMannIIIJetal.JAMA.2002;Vol288,No19:2411-2420.EarlyEffectsofPre-treatmentwithClopidogrel–28DayResultsCREDO:ClopidogrelLoadingDoseTimingandRiskofMACE-6-5-4-3-2051015202530HoursPriortoPCIofStudyDrugLoadingDoseLogOddsofDeath,MIorUTVRat28DaysPlaceboClopidogrelP=0.020fortreatment/timinginteractionSteinhubl,etalCilastazol(Stiloz):作用机制不太明确是一种磷酸二酯酶III(PDEIII)抑制剂血管扩张剂和血小板抑制剂起初证实对间歇性跛行有效适用于最近卒中、心肌梗死或周围血管病的动脉粥样硬化的患者，以减少事件发生（心肌梗死、卒中，和心血管死亡）为什么不用Cilastazol?Aspirin对既往有ACS或卒中者有效，但对间歇性跛行无效Clopidogrel似乎对上述所有病人都有效Cilastazol对上述所有病人都有效Cilastazol的风险:引起轻度心率加快(7beats/min)和轻度VPC增加(从1/hto4/h)–

使用cilostazol的病人主诉心悸的较多Cilostazol在动物实验中抗血小板剂量时有正性肌力作用Milrinone/Amrinone是其同一家族心力衰竭病人禁忌与clopidogrel合用可能增加出血风险未被证实的抗血小板药物:Dipyridamole:在ACS患者，单独或与aspirin合用尚无证据Sulphinpyrazone静脉使用抗血小板药物GpIIb-IIIa受体抑制剂通过抑制血栓形成的关键步骤,抑制凝血酶原与活化的血小板激活结合

适应症Substantialbenefit行急诊PCI的病人10%-27%RRRModestlybenefit平时不需使用，但进行PCI者Questionablebenefit不需进行PCI者REOPRO(Abciximab)INTEGRILIN(Eptifibatide)AGGRASTAT(Tirofiban)

TrialsPRISM-PLUS(Tirofiban–priortoPCI)EPIC(Abciximab–priortoPCI)CAPTURE(Abciximab–priortoPCI)GUSTOIV-ACS(Abciximab–noPCI)PARAGON(Lamifiban–noPCI)PURSUIT(Eptifibatide--noPCI)RESTORE(Tirofiban–noPCI)Abciximab单克隆抗体:免疫原性不易从受体分离在PCI时优于Tirofiban和Eptifibatide作用时间持续10小时或更长Abciximab需应用12小时在ACS,18-24小时内拟行PCI的患者应使用AbciximabEptifibatide人工合成的肽快速受体阻断、快速分离作用时间:30–45分钟应持续应用18-24小时上游使用优于AbciximabTirofiban非肽类PCI中还没有更大的收益对ACS不行PCI者也有一定的收益Lamifiban:较新的GP2b3a拮抗剂口服的2b3a抑制剂:OROFIBANxemilofiban,lefradafiban,sibrafiban,roxifiban已经证实用于:不稳定性心绞痛和急性心肌梗死PCI时使用不稳定性心绞痛等待PCI时使用新近用于:梗死后心绞痛，不行PCI者PCI慢血流或无复流易化溶栓治疗今天的抗血小板治疗目前氯吡格雷的局限性起作用慢:需要PCI前较长时间应用上限效应（ceilingeffect）出血(特别是涉及CABG)中等强度的血小板的抑制作用反应的变异性大不可逆抑制血小板上的ADP受体（P2Y1和P2Y12）但存在一些缺点：1、上限效应（ceilingeffect）：氯吡格雷是一种前体药,需通过细胞色素P450(CYP)通路两步作用（2-stepprocess）产生有活性的代谢产物,而在这一转化过程中大多数被转化为无活性的代谢产物。因此，氯吡格雷的疗效在不同患者或同一患者不同情况下存在很大差异。且在达到一定剂量后其血小板抑制作用不再增加；2、部分患者存在氯吡格雷抵抗，与细胞色素CYP2C19基因多态性有关；3、由于氯吡格雷需要经过CYP3A4代谢，因此与很多药物存在相互作用。有研究发现同时使用质子泵抑制剂（PPI,如奥美拉唑）增加患者心血管事件，因此FDA发布提示应用氯吡格雷时慎用omeprazole；4、氯吡格雷起效慢是其主要缺点，另外作用时间长，在急诊需要尽快抑制血小板功能或应用氯吡格雷后又需要尽快CABG的患者，氯吡格雷的缺点更加明显。

目前氯吡格雷的局限性新的ADPP2Y12

受体抑制剂PrasugrelTicagrelorCangrelorElinogrelPrasugrelTicagrelorCangrelorElonogrel新的ADPP2Y12

受体抑制剂Prasugrel与氯吡格雷相比普拉格雷通过细胞色素P450作用（1-step）产生有活性的代谢产物，效率更高起效更快（1—2个小时即起作用）对血小板抑制作用更加均一和持久此外尚未发现普拉格雷抵抗现象其效果似乎并不受临床、生化因素或基因多态性影响。

Ticlopidine(1stgeneration)NSClClopidogrel(2ndgeneration)NSClOOCH3CPrasugrel(CS-747)(LY640315)(3rdgeneration)NFOSOOCH3TheThienopyridineFamilyActiveMetaboliteFormationHOOC*HSNOFNSOCH3COFActiveMetabolitePrasugrelSankyoAnnReport51:1,1999ClopidogrelPro-drugHepaticMetabolism

CytochromeP450ActiveMetaboliteNSOFOHOOC*HSNOClOCH3SemVascMed3:113,2003Pre-hepaticmetabolism

Esterasesinblood

(?SmallIntestine)O85%InactiveMetabolites

Esterasesinblood

ONSOClOCH3CNSOClOCH3CNSOClOCH3CHealthyvolunteercrossoverstudy

IPA(20

MADP)at24hoursBrandtJetal.AHJ2006–20020406080

100Inhibitionofplateletaggregation(%)Responsetoprasugrel60mgResponsetoclopidogrel300mgN=64

0510150306090180270360450HR0.81

(0.73-0.90)

P=0.0004PrasugrelClopidogrelDaysEndpoint(%)12.19.9HR1.32

(1.03-1.68)

P=0.03PrasugrelClopidogrel1.82.4

138

events35

eventsBalanceof

EfficacyandSafetyCVDeath/MI/StrokeTIMIMajor

NonCABGBleeds

NNT=46

NNH=167WiviottetalNEJM2007StentThrombosis

(ARCDefinite+Probable)

01230306090180270360450HR0.48

P<0.0001PrasugrelClopidogrel2.4

(142)NNT=771.1(68)DaysEndpoint(%)AnyStentatIndexPCI

N=12,844DiabeticSubgroup

0246810121416180306090180270360450HR0.70

P<0.001

DaysEndpoint(%)CVDeath/MI/StrokeTIMIMajor

NonCABGBleeds

NNT=21N=314617.012.2PrasugrelClopidogrelPrasugrelClopidogrel2.62.5WiviottetalNEJM2007NetClinicalBenefit

BleedingRiskSubgroups

OVERALL>=60kg<60kg<75>=75NoYes0.512Prior

Stroke/TIAAgeWgtRisk(%)+54-16-1-16+3-14-13PrasugrelBetterClopidogrelBetterHRPint=0.006Pint=0.18Pint=0.36Post-hocanalysisWiviottetalNEJM2007SafetySignificantincreaseinseriousbleeding

(32%increase)

AvoidinptswithpriorCVA/TIAEfficacy1.Asignificantreductionin:

CVDeath/MI/Stroke 19%

StentThrombosis 52%

uTVR 34%

MI 24%2.Anearlyandsustainedbenefit3.AcrossACSspectrumPrasugrel60mgLD/10mgMDvsClopidogrel300mgLD/75mgMDConclusions

HigherIPAtoSupportPCINetclinicalbenefitsignificantlyfavoredPrasugrelOptimizationofPrasugrelmaintenancedosinginaminorityofpatientsmayhelpimprovethebenefit:riskbalanceComparisonwithHigherDoseClopidogrelP<0.0001foreachIPA(%;20mMADP)Hours14DaysIPA(%;20mMADP)P<0.0001Prasugrel

10mgClopidogrel

150mgWiviottetalCirculation2007.N=201Prasugrel60mgClopidogrel600mgPrasugrelTicagrelorCangrelorElinogrel新的ADPP2Y12

受体抑制剂Ticagrelor一种non-thienopyridine,inthechemicalclassCPTP(CycloPentylTriazoloPyrimidine)第一个口服可逆性ADPP2Y12

受体拮抗剂直接作用于P2Y12

受体–不需要代谢为活性产物更强的血小板抑制作用（与clopidogrel相比）更快的抗血小板作用HOHNHOOHOSFFNNNNNTicagrelorDISPERSE:Faster,GreaterandMoreConsistentIPAwithAZD6140vsclopidogrelTime,hoursTime,hours020406080100AZD6140(100mgbd)812812Inhibition,%24ClopidogrelInhibition,%Day1Day14Day1Day140204060801008128122442424242HustedSEetalEurHeartJ2006;27:1038-1047DISPERSE2StudyDesign

DISPERSE2wasadouble-blind,randomizedstudyofAZD6140comparedwith

clopidogrel,bothonabackgroundofaspirin(75–100mgod)50%ofpatientsineachAZD6140armreceivedaloadingdoseof270mgIntheclopidogrelarm,thienopyridinetreatment-naïvepatientsreceiveda300-mgloadingdoseRandomizationVisit1Day1Visit2Visit3Visit4Follow-upWeek4Week8Week12FinalVisit+7daysAZD614090mgbidAZD6140180mgbidClopidogrel75mgqdNSTE-ACSpatients

withonsetof

chestpain

<48hours

n=334n=329n=327CannonCPetal.JAmCollCardiol2007DISPERSE2AdjudicatedBleedingRates

Week4andOverall0246810Week4TotalBleedingRate(%)0OverallTotalBleedingRate(%)12246810129.6%7.7%8.0%10.2%10.2%9.2%AZD614090mgbidN=334AZD6140180mgbidN=323Clopidogrel75mgqdN=327AZD614090mgbidN=334AZD6140180mgbidN=323Clopidogrel75mgqdN=327Minorbleeding*MajorbleedingAdjudicatedtotalbleedingratesweresimilarforallgroupsNoevidenceofdose-responseformajorbleeds*MinorbleedingwithoutmajorbleedingCannonCPetal.JAmCollCardiol2007DISPERSE-2:Non-bleedingadverseevents024681012141618ClopAZD614090mgAZD6140180mg024681012141618ClopAZD614090mgAZD6140180mg4.4%5.6%9.9%6.4%10.5%15.8%VentricularPauses>2.5SecondsDyspnea%%Discontinuationratesfromnon-bleedingadverseeventswerelowandsimilarbetweengroupsPrimaryendpoint: CVD/MI/strokeSecondaryendpoint: CVD/MI/stroke/revascularizationwithPCI;

CVD/MI/stroke,severerecurrentischemia12-monthmaximumexposure(Min=6mo,Max=12mo,Mean=11mo)(N=18,000)ASA+Clopidogrel300mgld/75mgqd600mgldallowedinPCIASA+AZD6140180mgld/90mgbidModerate-tohigh-riskACSpatients(UA/NSTEMI/STEMI,PCI,medicallymanaged,orCABG)ASA=acetylsalicylicacid;bid=twicedaily;CVD=cardiovasculardisease;ld=loadingdose;MI=myocardialinfarction;NSTEMI=non-ST-segmentelevationMI;qd=oncedaily;STEMI=ST-segmentelevationMI;UA=unstableangina.ClinicalTIdentifier:

NCT00391872PrasugrelTicagrelorCangrelorElinogrel新的ADPP2Y12

受体抑制剂CangrelorIntravenousP2Y12InhibitorPlasmahalf-life3-5minutesFullrecoveryofplateletfunction<60minutesNNNNNHSCF3OHOHOOPOOPPOOOClClOOOS4Na+Dataonfile,TheMedicinesCompanyCangrelor(AR-C69931MX)是一种静脉使用的DirectandReversible可逆性的ADP-P2Y12受体抑制剂，为ATP类似物（MW=800Daltons）其半衰期3—5分钟，20分钟后消失，60分钟内血小板功能完全恢复比

clopidogrel

作用更强，~90%inhibitionofplateletaggregationat1-4mcg/kg/miniv作用迅速，与噻吩吡啶类药物不同，它直接作用于P2Y12且不依赖与CYP3A4代谢，而是单纯通过内皮相关的ectonucleotidases/CD39代谢GproteinTheP2Y12Receptor:

AnEstablishedTherapeuticTargetGproteinReceptorsubtypeMolecularstructureSecondmessengerFunctionalresponseAntagonist

P2X1Intrinsicionchannel[Na+andCa++]

ShapechangeAggregationP2Y1A3P5PGPCR

GQ

PLC/IP

[Ca++]ShapechangeTransientaggregationP2Y12CangreloractivemetaboliteGPCR

G1

AC

CyclicAMPSustainedaggregationPlateletsecretionClopidogrelPrasugrelBhattD,TopolE.NatRevDrugDisc2003;2:15-28.CangrelorPharmacokineticsSteinhubletal.DataonFileTheMedicinesCompanyCangrelorPharmacodynamicsSteinhubletal.DataonFileTheMedicinesCompnayWholeBloodImpedanceAggregometry15µg/kgbolus+2µg/kg/mininfusion30µg/kgbolus+4µg/kg/mininfusionCangrelormetabolismSequentialdephosphorylationtothenucleosideMetabolismnotdependentonrenalorhepaticfunctionMajormetaboliteisnotpharmacologicallyactiveNopotentialforCYP450druginteractionsNNNNNHSCF3OHOHOHOSSC-931-9017andSC-100199.Dataonfile,TheMedicinesCompanyCangrelorwithClopidogrel100806040200012311PretreatmentDaysonclopidogrelMean(+/–SEM)vehicleMean(+/–SEM)Cangrelor500nMinvitro%inhibitionofaggregationresponseinducedbyADP10µMStoreyRF,etal.,ThrombHaemost2002;88:488-94

CangrelorimprovesplateletinhibitioninpatientsreceivingchronicclopidogrelCangrelorAnti-inflammatoryEffects01020304050600.1110100%conjugatesCangrelorcontrolbaselineADP(mM)

StoreyRF,etal.,ThrombHaemost2002;88:488-94

Effectofcangrelorontheformationofplatelet–monocyteconjugatesPhaseIIclinicaldata:ComparedwithAbciximabinPCIDouble-blindrandomizedtrialperformedinUS5.7%5.4%2.1%1.0%Death,MI,revascularizationMajorbleed(TIMIcriteria)Incidenceofeventsupto7-daysAR-C69931MXreportnumberSC931-5129Part2Abciximab(N=94)Cangrelor(N=105)Greenbaumetal.AmHeartJ.2006;151:689.e1-689.e10CHAMPION-PCIPCI

(withorwithoutstent)1:1Doubleblind,doubledummyPlacebo

capsules

(tomatch)Cangrelor

bolus(30µg/kg)&

infusion(4µg/kg/hour)Clopidogrel

capsules

(600mg)Placebo

bolus&infusion

(tomatch)

1ºEndpoint:Death,MI,anduRevascat48hours2ºEndpoints:Death,MI,uRevascat30daysDeathat6monthsand1yearIndexProcedureStudydruginfusion(foratleast2hoursor

thedurationoftheprocedure,whicheverislonger)Clopidogrel

capsules

(600mg)Placebo

capsules

(tomatch)ClopidogrelMaintenance

(atphysiciandiscretion)++Cangrelor(AR-C69931MX)Cangrelor(AR-C69931MX)PrasugrelTicagrelorCangrelorElinogrel新的ADPP2Y12

受体抑制剂唯一直接作用(非前体药物)、竞争性、可逆性P2Y12抑制剂有静脉和口服两种剂型，既适合紧急使用，也适合长期使用。快速强效静脉给药立即并可达到最大血小板抑制作用，其半衰期是12小时不经CYP代谢，药物相互作用小平衡代谢：50%经肾脏清除，50%经肝脏清除(10%代谢成无活性的代谢产物)。ElinogrelElinogrelPAR-1抑制剂另外一种新的作用机制的抗血小板药物——蛋白酶活性受体-1（Proteaseactivatedreceptors1，PAR-1）抑制剂也备受关注。凝血酶是体内最强的血小板激活剂之一，凝血酶介导的血小板激活主要通过激活PAR-1。目前主要有两种药物，Atopaxar和Vorapaxar(SCH530348)

。PlateletStimuliGPIIb/IIIaintegrinADPEpinephrineCollagenThrombinPlateletAggregationSerotoninShearrateAATxA2COX-1ThrombinThrombinThrombinTxA2TxA2

Thrombin

ADPTXA2ADPP2Y12ADP(fibrinogenreceptor)GPIIb/IIIaActivationCOX-1clopidogrelbisulfateaspirincAMPOralAnti-PAR-1receptorsSCH530348E5555adaptedfromSchaferAI.AmJMed.

1996;101:199-209.AtopaxarAtopaxar是一种可逆性PAR-1抑制剂LANCELOT(LessonsfromAntagonizingtheCelluarEffectsofThrombin)-ACS：Atopaxar可快速抑制ACS患者血小板功能，并且不增加严重出血并发症LANCELOT-CAD：是有关Atopaxar不同剂量在冠心病患者中的队列研究，同样证明了Atopaxar具有快速的抗血小板作用，但增加轻微出血的发生，增加肝酶，延长QTc，并有一定的剂量依赖性。但没有发现明显的临床后果。VorapaxarVorapaxar的初期研究表明具有明显的抗血小板作用，降低缺血事件的发生，且不增加出血发现。目前为进一步验证其疗效和安全性，有两项III期临床试验正在进行中，TRA2P-TIMI-50(TrialtoAssessthe