PCI后抗血小板治療

PCI后抗血小板治療第1頁/共58頁不同的抗血小板藥物作用機(jī)制

膠原

凝血酶

TXA2阿司匹林ADP(纖維蛋白原受體）氯吡格雷TXA2ADP雙嘧達(dá)莫磷酸二酯酶ADPGpIIb/IIIa激活COX鹽酸噻氯匹定ADP=adenosinediphosphate,TXA2=thromboxaneA2,COX=cyclooxygenase.SchaferAI.AmJMed.1996;101:199–209.第2頁/共58頁Category %ORAcuteMI Acutestroke PriorMI Priorstroke/TIA OtherhighriskCoronaryarterydisease

(unstableangina,heartfailure) Peripheralarterialdisease

(intermittentclaudication) 22±2%Highriskofembolism(atrialfibrillation) Other(diabetesmellitus) Alltrials 1.00.50.01.52.0ControlBetterAntiplateletBetterAntithromboticTrialists’Collaboration(ATC):EfficacyofAntiplateletTherapyonVascularEvents** Vascularevents=MI,stroke,orvasculardeath. OR,oddsreduction;MI,myocardialinfarction;TIA,tranientischemicattack. AntithromboticTrialists’Collaboration.BMJ.2002;324:71-86.(withpermission)第3頁/共58頁AspirinResistance:

MoreThanJustaLaboratoryCuriosity?BhattDL.JAmCollCardiol.2004;43:1127-1129.GeneticPolymorphismsCOX-1GPIIIareceptorCollagenreceptorvWFreceptor

CellularFactorsInsufficientsuppressionofCOX-1OverexpressionofCOX-2mRNAErythrocyte-inducedplateletactivationIncreasednorepinephrineGenerationof8-iso-PGF2α

ClinicalFactorsFailuretoprescribeNoncomplianceNonabsorptionInteractionwithibuprofenInteractionwithnaproxen

AspirinResistance第4頁/共58頁AspirinResistanceandtheRiskof

CardiovacularEventsinHighRiskPatients5529ptsfromHOPEstudywithbaselineurinesamplesCase(n=488)PtswithCVeventsafterrandomizationControls(n=488)PtswithoutCVeventsafterrandomizationUrinary11-dehydroThromboxaneB2(ng/mmolcreatinine)<15.115.1-21.821.9-33.8>33.81.01.31.41.8MI,strokeorCVdeath(P=.01)OddRatioHypothesis:IncompleteinhibitionofthromboxaneB2increasesriskofcardiovascularevent AdaptedfromEikelboomJW,etal.Circulation.2002;105:1650-1655.第5頁/共58頁VerifyNow?ASA,ASA/clopidogrel(n=464),26.9%ASAresistantAspirin-resistantAspirin-sensitiven=125P=0.007n=339CVDeathMICVA/TIAHospUA

Cumulativeincidenceofcompositeendpoint(%)Follow-uptime(days)ASAResponseandLong-TermCVEvents第6頁/共58頁二、氯吡格雷的早期和長期應(yīng)用

－什么時(shí)間用？用多長時(shí)間？第7頁/共58頁CLARITY急救亞組研究:住院前氯吡格雷對比安慰劑(加溶栓治療)ECG顯示ST段恢復(fù)的患者(%)在救護(hù)車上給予氯吡格雷的患者伴ST段恢復(fù)VerheugtFetal.JThrombThrombolysis2006;Dec6[epub]p=0.02p=0.05給予負(fù)荷劑量后的時(shí)間3,491名<76歲的STEMI患者，接受溶栓治療，

隨機(jī)分組接受氯吡格雷或安慰劑，在救護(hù)車或入院時(shí)給藥STEMI,ST段抬高型心肌梗死;ECG,心電圖47.23763.252.790分鐘180分鐘第8頁/共58頁試驗(yàn)

PCI后至30天的心血管死亡或心梗Sabatine,etal.JAMA.2005;294:1224-1232PCI

預(yù)處理(300mg負(fù)荷量)事件1.00.252.00.5預(yù)處理更優(yōu)不預(yù)處理更優(yōu)OR(95%CI)PCI-CURE PCI-CLARITYCREDO 合計(jì) p=0.0025第9頁/共58頁P(yáng)CI前3-24小時(shí)氯吡格雷300mg預(yù)處理給予負(fù)荷劑量的時(shí)間越早，受益越大UTVR:緊急目標(biāo)血管血運(yùn)重建SteinhublS,etal.JAMA,20022882411–2420,JACC2006;47:939-943第10頁/共58頁氯吡格雷預(yù)處理對PCI顯著有益4,160名計(jì)劃行PCI的患者接受氯吡格雷300mgPCI前氯吡格雷預(yù)處理的益處引自:SzukTetal.AmHeartJ2007;153:289–295.ARR,絕地風(fēng)險(xiǎn)降低;TVR,目標(biāo)血管血運(yùn)重建;PCI,經(jīng)皮冠脈介入術(shù);CI,可信區(qū)間;MI,心肌梗死ARR:1.97

(95%CI,0.81–3.13)p=0.02重大不良事件發(fā)生的時(shí)間

(天)負(fù)荷量預(yù)處理p=0.001植入支架后給予負(fù)荷量0.050.040.030.020.010.00051015202530死亡、心?；蚍磸?fù)TVR的累積風(fēng)險(xiǎn)第11頁/共58頁早期使用氯吡格雷表現(xiàn)為使STR增多血管造影前接受治療的患者

(%)SpontaneousSTRp=0.045p=94p=0.33p=0.96p=0.70206名因STEMI入院的連續(xù)患者，在PCI前，18%的患者ST段自動(dòng)恢復(fù)(STR)JabarenMetal.AmJCardiol2006;98:1435–1438PCI術(shù)前早期使用氯吡格雷PCI,經(jīng)皮冠脈介入術(shù);STEMI,ST段抬高型心肌梗死第12頁/共58頁氯吡格雷可降低NSTEMI患者1年嚴(yán)重心腦血管不良事件發(fā)生率1年事件率(%)p<0.001**MACCE=重大心腦血管不良事件(死亡、非致命性再梗、腦卒中)ZeymerUetal:私人溝通20.88.5228.19.45.81.915.6051015202530死亡再梗腦卒中MACCE阿司匹林阿司匹林+氯吡格雷NSTEMI后給予氯吡格雷ACOS登記研究第13頁/共58頁ACOSRegistry-AntiplateletTherapyand1-YearMortalityinST-elevationMIMortality(%)ASAaloneASA+Clopidogrel*P<0.0001vsASAalone.Zeymeretal.EurHeartJ.2006October16;[Epubaheadofprint].第14頁/共58頁SteinhublSR,BergerPB,TiftMannIIIJ,etal.JAMA,November20,2002-Vol288,No19:2411-2420.27%RRRp=0.02

ClopidogrelMI,Strokeordeath(%)MonthsofFollow-up0369128.5%11.5%051015CREDO:Long-Term(1Year)BenefitsofClopidogrelinPCIPatients

Placebo第15頁/共58頁薈萃分析表明：DES與BMS相比，遲發(fā)性血栓有升高的趨勢12個(gè)月后：5比012個(gè)月后：9比2手術(shù)開始后的時(shí)間（月）手術(shù)開始后的時(shí)間（月）Stoneetal,NEnglJMed2007;56:998-1008,Feb132007,epub第16頁/共58頁遲發(fā)性支架內(nèi)血栓風(fēng)險(xiǎn)比P提前終止抗血小板治療57.13<0.001分叉病變8.110.001左室射血分?jǐn)?shù)每降低10%1.060.03Iakovou.JAMA2005;293:2126DES術(shù)后遲發(fā)性支架內(nèi)血栓的獨(dú)立危險(xiǎn)因素提前終止抗血小板治療是主要原因之一支架內(nèi)血栓的死亡率為

45%

第17頁/共58頁停用氯吡格雷后患者心源性死亡／心梗的發(fā)生率明顯升高

且大多數(shù)事件由血栓引起B(yǎng)ASKET-LATE

研究

第18頁/共58頁Eisenstein,JAMA.2007;297:(doi:10.1001/jama.297.2.joc60179)藥物支架后應(yīng)用氯吡格雷的長期臨床效益DES+氯吡格雷>12個(gè)月(n=252):DES+氯吡格雷<12個(gè)月(n=276)0%-3.5%P=0.0043.5%第19頁/共58頁DES術(shù)后氯吡格雷治療長期療效

DukeRegistry*Endpoint(%)校正的死亡和心梗發(fā)生率（2年）Difference=-4.1±3.5P=.02Difference=-0.5±2.7P=.70EisensteinEL,etal.JAMA.2007;297(2):159-168*DES=1501例,BMS=3165例第20頁/共58頁無論置入何種支架，

氯吡格雷應(yīng)用越久，獲益越多

JAmCollCardiol2008;51:2220–7第21頁/共58頁未來－雙聯(lián)抗血小板治療更長的療程？DualAntiplateletTherapyTrial

(DAPT):30個(gè)月vs12個(gè)月雙重抗血小板在支架患者中的療效8個(gè)廠家出資10億美元，入組2萬例患者FDATownhallMeeting,TCTOct15,2008第22頁/共58頁開放DAPT治療DAPT研究設(shè)計(jì)雙盲安慰劑隨機(jī)對照(RCT):12個(gè)月時(shí)明確符合入組條件12個(gè)月和30個(gè)月DAPT組的患者聯(lián)合主要終點(diǎn)：支架血栓和MACCE；次要終點(diǎn)：嚴(yán)重出血33個(gè)月的隨訪包括3個(gè)月“反彈期”BMS組12個(gè)月vs30個(gè)月同期進(jìn)行研究參與者自行決定支架類型和噻氯匹啶藥物的選擇（氯吡格雷或普扎格雷）DESn=15,245BMSn=5,400RDESn=12,196BMSn=4,32030個(gè)月DAPT組觀察期12個(gè)月DAPT組觀察期初步階段：入組隨機(jī)化：所有符合入組條件的患者0月6個(gè)月12個(gè)月15個(gè)月30個(gè)月治療結(jié)束隨訪結(jié)束33個(gè)月有MACCE*或嚴(yán)重出血的患者隨訪至12個(gè)月，但是不符12個(gè)月時(shí)入組的入組條件MACCE*:MajorAdverseCardiacandCerebrovascularevent嚴(yán)重心腦血管不良反應(yīng)FDATownhallMeeting,TCTOct15,2008第23頁/共58頁三、氯吡格雷負(fù)荷量及相關(guān)問題

－用什么樣的劑量及三聯(lián)抗血小板第24頁/共58頁第25頁/共58頁RelationofPlateletInhibitiontoPeriproceduralNecrosisandMACE

DUALRESISTANCEStudy(N=150)%PatientswithCK-MBElevation

MyocardiolinfarctPlateletInhibitionMajorAdverseCardiacEventsLevetal.JAmCollCardiol.2006.Chenetal.JAmCollCardiol.2004.ASAresistantASAsensitiveClopidogrelresistantClopidogrelsensitiveDualresistantDualsensitive第26頁/共58頁RelationofPlateletInhibitiontoPeriproceduralNecrosisandMACEASPIRINMyonecrosisStudy(n=151)%PatientswithCK-MBandtroponinIelevationMagnitudeofCK-MBelevation

MyocardiolinfarctPlateletInhibitionMajorAdverseCardiacEventsP=0.006P=0.012Levetal.JAmCollCardiol.2006.Chenetal.JAmCollCardiol.2004.第27頁/共58頁ISAR-CHOICE(300,600,900mg)vonBeckerathetal.Circulation.2005.第28頁/共58頁ALBION:氯吡格雷600Mg可以更迅速地抑制血小板聚集抑制血小板聚集(%)更高劑量的負(fù)荷量伴更快速的抑制103名非ST段抬高的ACS患者隨機(jī)分配接受

300、600或900mg氯吡格雷0Montalescotetal.JACC2006;48:931-805010203040123456時(shí)間(小時(shí))5μmol/LADP*p<0.05與300mg相比900mg600mg300mg600mg300mg***900mg***第29頁/共58頁ARMYDA-2TrialPrimaryEndpoint:death,MI,

orTVRat30days4%0%2%4%6%8%10%12%14%HighDoseStandardDose12%ClopidogrelLoadingDose

600mgPre-PCIClopidogrelLoadingDose300mgPre-PCI255patientswithstableCADorNSTEMIpriortoPCI

13%GPIIb/IIIainhibitors20%DESRandomized4-8hrsPre-PCIp=0.041Circulation2005;111:2099-2106第30頁/共58頁600mg的氯吡格雷負(fù)荷劑量可降低后續(xù)事件的發(fā)生率292名接受300或600mg氯吡格雷負(fù)荷劑量的支架植入的NSTEACS連續(xù)患者ST=支架血栓形成

Cuissetetal.JAmCollCardiol2006;48:1339–45無心血管事件生存(%)100809095p<0.0024300mg600mg事件(%)心血管事件012.52.57.510.0腦卒中300mg600mg302010085時(shí)間(天)ACS

事件ST心血管

死亡5.0氯吡格雷600Mg與300Mg負(fù)荷劑量第31頁/共58頁高負(fù)荷量氯吡格雷顯著減少

急診PCI后的緊急血運(yùn)重建30天時(shí)出現(xiàn)的死亡、心梗、

緊急血運(yùn)重建或腦卒中(%)600mg負(fù)荷量可能比

300mg負(fù)荷量更有效165名行急診PCI的STEMI患者Jungetal.

AmJCardiol2006;Oct22-27(TCTAbstracts)014861012600mg負(fù)荷量300mg負(fù)荷量n=98n=673%11%42按緊急血運(yùn)重建的差異驅(qū)動(dòng)的主要終點(diǎn)p=0.021第32頁/共58頁G.BIONDI-ZOCCAI,SCAI200710項(xiàng)臨床研究Meta分析：600mg優(yōu)于300mg死亡/MI@30d第33頁/共58頁ISAR-REACT-2

Abciximabinnon-STEACSundergoingPCIpretreatedwith600mgLDclopidogrelJAMA2006;2951531-388.911.9%1.41.4%Death,MI,orurgentTVRby30daysRR0.75P=0.03TIMIMajorBleedIn-hospitalP=NS第34頁/共58頁ISAR-REACT2

Death,MI,orurgentTVRinSubsetsWithandWithoutElevatedTroponinLevels(>0.03μg/L)20151050051015202530DaysAfterRandomizationPlaceboGroup(N=1010)AbciximabGroup(N=1012)Troponin>0.03μg/LLog-Rankp=0.02Troponin<0.03μg/LLog-Rankp=0.98JAMA2006;295:1531-38%第35頁/共58頁024681012Follow-upduration(months)%No.atriskLog-Rank,P=0.01920123450.8%0.1%Triplegroup965957953Dualgroup965948942TheDECREASERegistryCumulativeincidenceofstentthrombosisDualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965)第36頁/共58頁024681012Follow-upduration(months)%No.atriskLog-Rank,P=0.07440123452.6%1.4%Triplegroup965955950Dualgroup965948940CumulativeincidenceofDeathorMIDualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965)第37頁/共58頁第38頁/共58頁第39頁/共58頁研究設(shè)計(jì)氯吡格雷高劑量組氯吡格雷600mg負(fù)荷劑量第1天，

接第2-7天150mg;

第8-30天75mg氯吡格雷標(biāo)準(zhǔn)劑量組氯吡格雷300mg(+安慰劑)第1天，

接第2-7天75mg(+安慰劑);

第8-30天75mg隨機(jī)分組隨機(jī)分組ASA低劑量組第1天至少300mg;D2-D3075–100mg

ASA高劑量組第1天至少300mg;D2-D30300mg–325mg

ASA高劑量組第1天至少300mg;D2-D30300mg–325mgASA低劑量組第1天至少300mg;D2-D3075–100mg計(jì)劃早期介入治療的UA/NSTEMI患者，

即有意在24小時(shí)內(nèi)盡早行PCI的患者隨機(jī)分組PCI:經(jīng)皮冠脈介入術(shù)UA/NSTEMI:不穩(wěn)定心絞痛/非ST段抬高型心梗CURRENT第40頁/共58頁四、新型抗血小板藥物的研究第41頁/共58頁第42頁/共58頁第43頁/共58頁第44頁/共58頁JUMBO-TIMI26

threedosesofprasugrelvsclopidogrelinelectiveorurgentPCI

(safetyevaluation)Circulation2005;11:3366-731.71.2%7.29.4%Significantnon-CABGBleedingat30daysP=0.77MACEat30daysHR0.76P=0.26第45頁/共58頁P(yáng)RINCIPLETIMI44(PlannedElectivePCI)PRIMARYEPAcutePhase:IPA20uMADPPrasugrel60mgP<0.0001foreachIPA(%;20mMADP)HoursCirculation2007;116:2923-32第46頁/共58頁P(yáng)rasugrel10mgPrasugrel10mgDifferenceBetweenTreatments:14.9[95%CI10.6–19.3],P<0.0001IPA(%;20mMADP)DaysCirculation2007;116:2923-32PRINCIPLETIMI44PRIMARYEPChronicPhase:IPA20uMADP第47頁/共58頁DaysPrimaryEndpoint(%)100030155PrasugrelClopidogrel6090180270360450HR0.77P=0.0001HR0.80P=0.000312.1(781)9.9(643)HR0.81(0.73-0.90)P=0.0004NNT=46ITT=13,608LTFU=14(0.1%)TRITONTIMI-38ACS(STEMIorUANSTEMI)&PlannedPCI

PrimaryEndpoint:CVDeath,MI,StrokeNEnglJMed

2007;357:2001-15第48頁/共58頁ARD0.6HR1.32P=0.03NNH=167ARD0.5HR1.52P=0.01ARD0.2P=0.23ARD0.3P=0.002ARD0%P=0.74TRITONTIMI-38BleedingEventsSafetyCohort(n=13,457)ICHinPtswPriorStroke/TIA(N=518)Clop0(0)%Pras6(2.3)%(P=0.02)NEnglJMed

2007;357:2001-15第49頁/共58頁DaysEndpoint(%)100030155PrasugrelClopidogrel609018027036045012.19.9TRITONTIMI38BalanceofEfficacyandSafetyCVDeath/MI/Stroke2.41.8TIMIMajorNonCABGBleeds138eventsHR0.81(0.73-0.90)P=0.0004NNT=4635eventsHR1.32(1.03-1.68)P=0.03NNH=167NEnglJMed

2007;357:2001-15第50頁/共58頁OptimizationofPrasugrelmaintenancedosinginaminorityofpatientsmayhelpimprovethebenefit:riskbalanceSafetySignificantincreaseinseriousbleeding(32%increase)AvoidinptswithpriorCVA/TIAEfficaency1.Asignificantreductionin:

CVDeath/MI/Stroke

19%StentThrombosis52%uTVR34%MI24%2.Anearlyandsustainedbenefit3.AcrossACSspectrumNetclinicalbenefitsignificantfavoredPrasugrel

TRITONTIMI-38

HigherIPAtoSupportPCIPrasugrel60mgLD/10mgMDvsClopidogrel300mgLD/75mgLDNEnglJMed

2007;357:2001-15第51頁/共58頁