冠心病抗血小板治療的現(xiàn)在和未來-曲鵬

冠心病抗血小板治療的現(xiàn)在和未來曲鵬大連醫(yī)科大學(xué)附屬二院ACS為什么需要抗血小板治療？不穩(wěn)定性動脈粥樣硬化斑塊破裂？保護(hù)性內(nèi)皮細(xì)胞層的破裂？強(qiáng)促血栓內(nèi)皮下層的暴露血小板粘附到損傷的部位血小板活化GPIIb/IIIa受體暴露血小板聚集通過纖維蛋白原（fibrinogen）與GPIIb/IIIa受體結(jié)合纖維蛋白沉積–血小板塊參與到纖維蛋白絲當(dāng)中12345Aspirin(ASA)/NSAIDS不可逆/可逆性阻斷COX心血管死亡/心肌梗死相對危險(xiǎn)性減少35%-50%

(ARR2.5%NNT40)CLOPIDOGREL&TICLOPIDINE不可逆抑制ADP誘導(dǎo)的血小板聚集PLAVIX:不穩(wěn)定性心絞痛,NSTEMI,PVD,AMI/CVA二級預(yù)防阿司匹林過敏/胃腸道不耐受消化不良,皮疹,腹瀉TICLID:中性粒細(xì)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):作用機(jī)制不太明確是一種磷酸二酯酶III(PDEIII)抑制劑血管擴(kuò)張劑和血小板抑制劑起初證實(shí)對間歇性跛行有效適用于最近卒中、心肌梗死或周圍血管病的動脈粥樣硬化的患者，以減少事件發(fā)生（心肌梗死、卒中，和心血管死亡）為什么不用Cilastazol?Aspirin對既往有ACS或卒中者有效，但對間歇性跛行無效Clopidogrel似乎對上述所有病人都有效Cilastazol對上述所有病人都有效Cilastazol的風(fēng)險(xiǎn):引起輕度心率加快(7beats/min)和輕度VPC增加(從1/hto4/h)–

使用cilostazol的病人主訴心悸的較多Cilostazol在動物實(shí)驗(yàn)中抗血小板劑量時有正性肌力作用Milrinone/Amrinone是其同一家族心力衰竭病人禁忌與clopidogrel合用可能增加出血風(fēng)險(xiǎn)未被證實(shí)的抗血小板藥物:Dipyridamole:在ACS患者，單獨(dú)或與aspirin合用尚無證據(jù)Sulphinpyrazone靜脈使用抗血小板藥物GpIIb-IIIa受體抑制劑通過抑制血栓形成的關(guān)鍵步驟,抑制凝血酶原與活化的血小板激活結(jié)合

適應(yīng)癥Substantialbenefit行急診PCI的病人10%-27%RRRModestlybenefit平時不需使用，但進(jìn)行PCI者Questionablebenefit不需進(jìn)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單克隆抗體:免疫原性不易從受體分離在PCI時優(yōu)于Tirofiban和Eptifibatide作用時間持續(xù)10小時或更長Abciximab需應(yīng)用12小時在ACS,18-24小時內(nèi)擬行PCI的患者應(yīng)使用AbciximabEptifibatide人工合成的肽快速受體阻斷、快速分離作用時間:30–45分鐘應(yīng)持續(xù)應(yīng)用18-24小時上游使用優(yōu)于AbciximabTirofiban非肽類PCI中還沒有更大的收益對ACS不行PCI者也有一定的收益Lamifiban:較新的GP2b3a拮抗劑口服的2b3a抑制劑:OROFIBANxemilofiban,lefradafiban,sibrafiban,roxifiban已經(jīng)證實(shí)用于:不穩(wěn)定性心絞痛和急性心肌梗死PCI時使用不穩(wěn)定性心絞痛等待PCI時使用新近用于:梗死后心絞痛，不行PCI者PCI慢血流或無復(fù)流易化溶栓治療今天的抗血小板治療目前氯吡格雷的局限性起作用慢:需要PCI前較長時間應(yīng)用上限效應(yīng)（ceilingeffect）出血(特別是涉及CABG)中等強(qiáng)度的血小板的抑制作用反應(yīng)的變異性大不可逆抑制血小板上的ADP受體（P2Y1和P2Y12）但存在一些缺點(diǎn)：1、上限效應(yīng)（ceilingeffect）：氯吡格雷是一種前體藥,需通過細(xì)胞色素P450(CYP)通路兩步作用（2-stepprocess）產(chǎn)生有活性的代謝產(chǎn)物,而在這一轉(zhuǎn)化過程中大多數(shù)被轉(zhuǎn)化為無活性的代謝產(chǎn)物。因此，氯吡格雷的療效在不同患者或同一患者不同情況下存在很大差異。且在達(dá)到一定劑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，與細(xì)胞色素CYP2C19基因多態(tài)性有關(guān)；3、由于氯吡格雷需要經(jīng)過CYP3A4代謝，因此與很多藥物存在相互作用。有研究發(fā)現(xiàn)同時使用質(zhì)子泵抑制劑（PPI,如奧美拉唑）增加患者心血管事件，因此FDA發(fā)布提示應(yīng)用氯吡格雷時慎用omeprazole；4、氯吡格雷起效慢是其主要缺點(diǎn)，另外作用時間長，在急診需要盡快抑制血小板功能或應(yīng)用氯吡格雷后又需要盡快CABG的患者，氯吡格雷的缺點(diǎn)更加明顯。

目前氯吡格雷的局限性新的ADPP2Y12

受體抑制劑PrasugrelTicagrelorCangrelorElinogrelPrasugrelTicagrelorCangrelorElonogrel新的ADPP2Y12

受體抑制劑Prasugrel與氯吡格雷相比普拉格雷通過細(xì)胞色素P450作用（1-step）產(chǎn)生有活性的代謝產(chǎn)物，效率更高起效更快（1—2個小時即起作用）對血小板抑制作用更加均一和持久此外尚未發(fā)現(xiàn)普拉格雷抵抗現(xiàn)象其效果似乎并不受臨床、生化因素或基因多態(tài)性影響。

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

受體抑制劑Ticagrelor一種non-thienopyridine,inthechemicalclassCPTP(CycloPentylTriazoloPyrimidine)第一個口服可逆性ADPP2Y12

受體拮抗劑直接作用于P2Y12

受體–不需要代謝為活性產(chǎn)物更強(qiáng)的血小板抑制作用（與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-na?vepatientsreceiveda300-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

受體抑制劑CangrelorIntravenousP2Y12InhibitorPlasmahalf-life3-5minutesFullrecoveryofplateletfunction<60minutesNNNNNHSCF3OHOHOOPOOPPOOOClClOOOS4Na+Dataonfile,TheMedicinesCompanyCangrelor(AR-C69931MX)是一種靜脈使用的DirectandReversible可逆性的ADP-P2Y12受體抑制劑，為ATP類似物（MW=800Daltons）其半衰期3—5分鐘，20分鐘后消失，60分鐘內(nèi)血小板功能完全恢復(fù)比

clopidogrel

作用更強(qiáng)，~90%inhibitionofplateletaggregationat1-4mcg/kg/miniv作用迅速，與噻吩吡啶類藥物不同，它直接作用于P2Y12且不依賴與CYP3A4代謝，而是單純通過內(nèi)皮相關(guān)的ectonucleotidases/CD39代謝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

受體抑制劑唯一直接作用(非前體藥物)、競爭性、可逆性P2Y12抑制劑有靜脈和口服兩種劑型，既適合緊急使用，也適合長期使用?？焖購?qiáng)效靜脈給藥立即并可達(dá)到最大血小板抑制作用，其半衰期是12小時不經(jīng)CYP代謝，藥物相互作用小平衡代謝：50%經(jīng)腎臟清除，50%經(jīng)肝臟清除(10%代謝成無活性的代謝產(chǎn)物)。ElinogrelElinogrelPAR-1抑制劑另外一種新的作用機(jī)制的抗血小板藥物——蛋白酶活性受體-1（Proteaseactivatedreceptors1，PAR-1）抑制劑也備受關(guān)注。凝血酶是體內(nèi)最強(qiáng)的血小板激活劑之一，凝血酶介導(dǎo)的血小板激活主要通過激活PAR-1。目前主要有兩種藥物，Atopaxar和Vorapaxar(SCH530348)

。PlateletStimuliGPIIb/IIIaintegrinADPEpinephrineCollagenThrombinPlateletAggregationSerotoninShearrateAATxA2COX-1ThrombinThrombinThrombinTxA2TxA2

Thrombin

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

1996;101:199-209.AtopaxarAtopaxar是一種可逆性PAR-1抑制劑LANCELOT(LessonsfromAntagonizingtheCelluarEffectsofThrombin)-ACS：Atopaxar可快速抑制ACS患者血小板功能，并且不增加嚴(yán)重出血并發(fā)癥LANCELOT-CAD：是有關(guān)Atopaxar不同劑量在冠心病患者中的隊(duì)列研究，同樣證明了Atopaxar具有快速的抗血小板作用，但增加輕微出血的發(fā)生，增加肝酶，延長QTc，并有一定的劑量依賴性。但沒有發(fā)現(xiàn)明顯的臨床后果。VorapaxarVorapaxar的初期研究表明具有明顯的抗血小板作用，降低缺血事件的發(fā)生，且不增加出血發(fā)現(xiàn)。目前為進(jìn)一步驗(yàn)證其療效和安全性，有兩項(xiàng)III期臨床試驗(yàn)正在進(jìn)行中，TRA2P-TIMI-50(TrialtoAssessthe