PCI后抗血小板治疗

PCI后抗血小板治疗第1页/共58页不同的抗血小板药物作用机制

胶原

凝血酶

TXA2阿司匹林ADP(纤维蛋白原受体）氯吡格雷TXA2ADP双嘧达莫磷酸二酯酶ADPGpIIb/IIIa激活COX盐酸噻氯匹定ADP=adenosinediphosphate,TXA2=thromboxaneA2,COX=cyclooxygenase.SchaferAI.AmJMed.1996;101:199–209.第2页/共58页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页/共58页AspirinResistance:

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

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

ClinicalFactorsFailuretoprescribeNoncomplianceNonabsorptionInteractionwithibuprofenInteractionwithnaproxen

AspirinResistance第4页/共58页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页/共58页VerifyNow™ASA,ASA/clopidogrel(n=464),26.9%ASAresistantAspirin-resistantAspirin-sensitiven=125P=0.007n=339CVDeathMICVA/TIAHospUA

Cumulativeincidenceofcompositeendpoint(%)Follow-uptime(days)ASAResponseandLong-TermCVEvents第6页/共58页二、氯吡格雷的早期和长期应用

－什么时间用？用多长时间？第7页/共58页CLARITY急救亚组研究:住院前氯吡格雷对比安慰剂(加溶栓治疗)ECG显示ST段恢复的患者(%)在救护车上给予氯吡格雷的患者伴ST段恢复VerheugtFetal.JThrombThrombolysis2006;Dec6[epub]p=0.02p=0.05给予负荷剂量后的时间3,491名<76岁的STEMI患者，接受溶栓治疗，

随机分组接受氯吡格雷或安慰剂，在救护车或入院时给药STEMI,ST段抬高型心肌梗死;ECG,心电图47.23763.252.790分钟180分钟第8页/共58页试验

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

预处理(300mg负荷量)事件1.00.252.00.5预处理更优不预处理更优OR(95%CI)PCI-CURE PCI-CLARITYCREDO 合计 p=0.0025第9页/共58页PCI前3-24小时氯吡格雷300mg预处理给予负荷剂量的时间越早，受益越大UTVR:紧急目标血管血运重建SteinhublS,etal.JAMA,20022882411–2420,JACC2006;47:939-943第10页/共58页氯吡格雷预处理对PCI显著有益4,160名计划行PCI的患者接受氯吡格雷300mgPCI前氯吡格雷预处理的益处引自:SzukTetal.AmHeartJ2007;153:289–295.ARR,绝地风险降低;TVR,目标血管血运重建;PCI,经皮冠脉介入术;CI,可信区间;MI,心肌梗死ARR:1.97

(95%CI,0.81–3.13)p=0.02重大不良事件发生的时间

(天)负荷量预处理p=0.001植入支架后给予负荷量0.050.040.030.020.010.00051015202530死亡、心梗或反复TVR的累积风险第11页/共58页早期使用氯吡格雷表现为使STR增多血管造影前接受治疗的患者

(%)SpontaneousSTRp=0.045p=94p=0.33p=0.96p=0.70206名因STEMI入院的连续患者，在PCI前，18%的患者ST段自动恢复(STR)JabarenMetal.AmJCardiol2006;98:1435–1438PCI术前早期使用氯吡格雷PCI,经皮冠脉介入术;STEMI,ST段抬高型心肌梗死第12页/共58页氯吡格雷可降低NSTEMI患者1年严重心脑血管不良事件发生率1年事件率(%)p<0.001**MACCE=重大心脑血管不良事件(死亡、非致命性再梗、脑卒中)ZeymerUetal:私人沟通20.88.5228.19.45.81.915.6051015202530死亡再梗脑卒中MACCE阿司匹林阿司匹林+氯吡格雷NSTEMI后给予氯吡格雷ACOS登记研究第13页/共58页ACOSRegistry-AntiplateletTherapyand1-YearMortalityinST-elevationMIMortality(%)ASAaloneASA+Clopidogrel*P<0.0001vsASAalone.Zeymeretal.EurHeartJ.2006October16;[Epubaheadofprint].第14页/共58页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页/共58页荟萃分析表明：DES与BMS相比，迟发性血栓有升高的趋势12个月后：5比012个月后：9比2手术开始后的时间（月）手术开始后的时间（月）Stoneetal,NEnglJMed2007;56:998-1008,Feb132007,epub第16页/共58页迟发性支架内血栓风险比P提前终止抗血小板治疗57.13<0.001分叉病变8.110.001左室射血分数每降低10%1.060.03Iakovou.JAMA2005;293:2126DES术后迟发性支架内血栓的独立危险因素提前终止抗血小板治疗是主要原因之一支架内血栓的死亡率为

45%

第17页/共58页停用氯吡格雷后患者心源性死亡／心梗的发生率明显升高

且大多数事件由血栓引起BASKET-LATE

研究

第18页/共58页Eisenstein,JAMA.2007;297:(doi:10.1001/jama.297.2.joc60179)药物支架后应用氯吡格雷的长期临床效益DES+氯吡格雷>12个月(n=252):DES+氯吡格雷<12个月(n=276)0%-3.5%P=0.0043.5%第19页/共58页DES术后氯吡格雷治疗长期疗效

DukeRegistry*Endpoint(%)校正的死亡和心梗发生率（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页/共58页无论置入何种支架，

氯吡格雷应用越久，获益越多

JAmCollCardiol2008;51:2220–7第21页/共58页未来－双联抗血小板治疗更长的疗程？DualAntiplateletTherapyTrial

(DAPT):30个月vs12个月双重抗血小板在支架患者中的疗效8个厂家出资10亿美元，入组2万例患者FDATownhallMeeting,TCTOct15,2008第22页/共58页开放DAPT治疗DAPT研究设计双盲安慰剂随机对照(RCT):12个月时明确符合入组条件12个月和30个月DAPT组的患者联合主要终点：支架血栓和MACCE；次要终点：严重出血33个月的随访包括3个月“反弹期”BMS组12个月vs30个月同期进行研究参与者自行决定支架类型和噻氯匹啶药物的选择（氯吡格雷或普扎格雷）DESn=15,245BMSn=5,400RDESn=12,196BMSn=4,32030个月DAPT组观察期12个月DAPT组观察期初步阶段：入组随机化：所有符合入组条件的患者0月6个月12个月15个月30个月治疗结束随访结束33个月有MACCE*或严重出血的患者随访至12个月，但是不符12个月时入组的入组条件MACCE*:MajorAdverseCardiacandCerebrovascularevent严重心脑血管不良反应FDATownhallMeeting,TCTOct15,2008第23页/共58页三、氯吡格雷负荷量及相关问题

－用什么样的剂量及三联抗血小板第24页/共58页第25页/共58页RelationofPlateletInhibitiontoPeriproceduralNecrosisandMACE

DUALRESISTANCEStudy(N=150)%PatientswithCK-MBElevation

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

MyocardiolinfarctPlateletInhibitionMajorAdverseCardiacEventsP=0.006P=0.012Levetal.JAmCollCardiol.2006.Chenetal.JAmCollCardiol.2004.第27页/共58页ISAR-CHOICE(300,600,900mg)vonBeckerathetal.Circulation.2005.第28页/共58页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(%)更高剂量的负荷量伴更快速的抑制103名非ST段抬高的ACS患者随机分配接受

300、600或900mg氯吡格雷0Montalescotetal.JACC2006;48:931-805010203040123456时间(小时)5μmol/LADP*p<0.05与300mg相比900mg600mg300mg600mg300mg***900mg***第29页/共58页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页/共58页600mg的氯吡格雷负荷剂量可降低后续事件的发生率292名接受300或600mg氯吡格雷负荷剂量的支架植入的NSTEACS连续患者ST=支架血栓形成

Cuissetetal.JAmCollCardiol2006;48:1339–45无心血管事件生存(%)100809095p<0.0024300mg600mg事件(%)心血管事件012.52.57.510.0脑卒中300mg600mg302010085时间(天)ACS

事件ST心血管

死亡5.0氯吡格雷600Mg与300Mg负荷剂量第31页/共58页高负荷量氯吡格雷显著减少

急诊PCI后的紧急血运重建30天时出现的死亡、心梗、

紧急血运重建或脑卒中(%)600mg负荷量可能比

300mg负荷量更有效165名行急诊PCI的STEMI患者Jungetal.

AmJCardiol2006;Oct22-27(TCTAbstracts)014861012600mg负荷量300mg负荷量n=98n=673%11%42按紧急血运重建的差异驱动的主要终点p=0.021第32页/共58页G.BIONDI-ZOCCAI,SCAI200710项临床研究Meta分析：600mg优于300mg死亡/MI@30d第33页/共58页ISAR-REACT-2

Abciximabinnon-STEACSundergoingPCIpretreatedwith600mgLDclopidogrelJAMA2006;2951531-388.911.9%1.41.4%Death,MI,orurgentTVRby30daysRR0.75P=0.03TIMIMajorBleedIn-hospitalP=NS第34页/共58页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页/共58页024681012Follow-upduration(months)%No.atriskLog-Rank,P=0.01920123450.8%0.1%Triplegroup965957953Dualgroup965948942TheDECREASERegistryCumulativeincidenceofstentthrombosisDualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965)第36页/共58页024681012Follow-upduration(months)%No.atriskLog-Rank,P=0.07440123452.6%1.4%Triplegroup965955950Dualgroup965948940CumulativeincidenceofDeathorMIDualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965)第37页/共58页第38页/共58页第39页/共58页研究设计氯吡格雷高剂量组氯吡格雷600mg负荷剂量第1天，

接第2-7天150mg;

第8-30天75mg氯吡格雷标准剂量组氯吡格雷300mg(+安慰剂)第1天，

接第2-7天75mg(+安慰剂);

第8-30天75mg随机分组随机分组ASA低剂量组第1天至少300mg;D2-D3075–100mg

ASA高剂量组第1天至少300mg;D2-D30300mg–325mg

ASA高剂量组第1天至少300mg;D2-D30300mg–325mgASA低剂量组第1天至少300mg;D2-D3075–100mg计划早期介入治疗的UA/NSTEMI患者，

即有意在24小时内尽早行PCI的患者随机分组PCI:经皮冠脉介入术UA/NSTEMI:不稳定心绞痛/非ST段抬高型心梗CURRENT第40页/共58页四、新型抗血小板药物的研究第41页/共58页第42页/共58页第43页/共58页第44页/共58页JUMBO-TIMI26

threedosesofprasugrelvsclopidogrelinelectiveorurgentPCI

(safetyevaluation)Circulation2005;11:3366-731.71.2%7.29.4%Significantnon-CABGBleedingat30daysP=0.77MACEat30daysHR0.76P=0.26第45页/共58页PRINCIPLETIMI44(PlannedElectivePCI)PRIMARYEPAcutePhase:IPA20uMADPPrasugrel60mgP<0.0001foreachIPA(%;20mMADP)HoursCirculation2007;116:2923-32第46页/共58页Prasugrel10mgPrasugrel10mgDifferenceBetweenTreatments:14.9[95%CI10.6–19.3],P<0.0001IPA(%;20mMADP)DaysCirculation2007;116:2923-32PRINCIPLETIMI44PRIMARYEPChronicPhase:IPA20uMADP第47页/共58页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页/共58页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页/共58页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页/共58页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页/共58页