CI后抗血小板治疗(TCC)

介入术后抗血小板治疗,一抗血小板药物作用机制和阿司匹林抵抗,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,TXA2,ADP,双嘧达莫,磷酸二酯酶,ADP,GpIIb/IIIa,激活,COX,盐酸噻氯匹定,ADP=adenosinediphosphate,TXA2=thromboxaneA2,COX=cyclooxygenase.SchaferAI.AmJMed.1996;101:199209.,Category%ORAcuteMIAcutestrokePriorMIPriorstroke/TIAOtherhighriskCoronaryarterydisease(unstableangina,heartfailure)Peripheralarterialdisease(intermittentclaudication)222%Highriskofembolism(atrialfibrillation)Other(diabetesmellitus)Alltrials,1.0,0.5,0.0,1.5,2.0,ControlBetter,AntiplateletBetter,AntithromboticTrialistsCollaboration(ATC):EfficacyofAntiplateletTherapyonVascularEvents*,*Vascularevents=MI,stroke,orvasculardeath.OR,oddsreduction;MI,myocardialinfarction;TIA,tranientischemicattack.AntithromboticTrialistsCollaboration.BMJ.2002;324:71-86.(withpermission),AspirinResistance:MoreThanJustaLaboratoryCuriosity?,BhattDL.JAmCollCardiol.2004;43:1127-1129.,GeneticPolymorphismsCOX-1GPIIIareceptorCollagenreceptorvWFreceptor,CellularFactorsInsufficientsuppressionofCOX-1OverexpressionofCOX-2mRNAErythrocyte-inducedplateletactivationIncreasednorepinephrineGenerationof8-iso-PGF2,ClinicalFactorsFailuretoprescribeNoncomplianceNonabsorptionInteractionwithibuprofenInteractionwithnaproxen,AspirinResistance,AspirinResistanceandtheRiskofCardiovacularEventsinHighRiskPatients,5529ptsfromHOPEstudywithbaselineurinesamples,Case(n=488)PtswithCVeventsafterrandomization,Controls(n=488)PtswithoutCVeventsafterrandomization,Urinary11-dehydroThromboxaneB2(ng/mmolcreatinine),33.8,1.0,1.3,1.4,1.8,MI,strokeorCVdeath(P=.01),OddRatio,Hypothesis:IncompleteinhibitionofthromboxaneB2increasesriskofcardiovascularevent,AdaptedfromEikelboomJW,etal.Circulation.2002;105:1650-1655.,VerifyNowASA,ASA/clopidogrel(n=464),26.9%ASAresistant,Aspirin-resistant,Aspirin-sensitive,n=125,P=0.007,n=339,CVDeathMICVA/TIAHospUA,Cumulativeincidenceofcompositeendpoint(%),Follow-uptime(days),ASAResponseandLong-TermCVEvents,二、氯吡格雷的早期和长期应用什么时间用？用多长时间？,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;Dec6epub,p=0.02,p=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,47.2,37,63.2,52.7,90分钟,180分钟,试验,PCI后至30天的心血管死亡或心梗,Sabatine,etal.JAMA.2005;294:1224-1232,PCI预处理(300mg负荷量)事件,1.0,0.25,2.0,0.5,预处理更优,不预处理更优,OR(95%CI),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,200228824112420,JACC2006;47:939-943,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300mg,PCI前氯吡格雷预处理的益处,引自:SzukTetal.AmHeartJ2007;153:289295.,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,0.813.13)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,0.05,0.04,0.03,0.02,0.01,0.00,0,5,10,15,20,25,30,死亡、心梗或反复TVR的累积风险,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(%),SpontaneousSTR,p=0.045,p=94,p=0.33,p=0.96,p=0.70,206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;98:14351438,PCI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,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(%),p0.001,*,*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,20.8,8.5,2,28.1,9.4,5.8,1.9,15.6,0,5,10,15,20,25,30,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,ACOSRegistry-AntiplateletTherapyand1-YearMortalityinST-elevationMI,Mortality(%),ASAaloneASA+Clopidogrel,*P12个月(n=252):DES+氯吡格雷12个月(n=276),0%,-3.5%P=0.004,3.5%,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）,EisensteinEL,etal.JAMA.2007;297(2):159-168,*DES=1501例,BMS=3165例,无论置入何种支架，氯吡格雷应用越久，获益越多,JAmCollCardiol2008;51:22207,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,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=5,400,RDESn=12,196BMSn=4,320,30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,TCTOct15,2008,三、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,RelationofPlateletInhibitiontoPeriproceduralNecrosisandMACE,DUALRESISTANCEStudy(N=150),%PatientswithCK-MBElevation,MyocardiolinfarctPlateletInhibitionMajorAdverseCardiacEvents,Levetal.JAmCollCardiol.2006.Chenetal.JAmCollCardiol.2004.,ASAresistant,ASAsensitive,Clopidogrelresistant,Clopidogrelsensitive,Dualresistant,Dualsensitive,RelationofPlateletInhibitiontoPeriproceduralNecrosisandMACE,ASPIRINMyonecrosisStudy(n=151),%PatientswithCK-MBandtroponinIelevation,MagnitudeofCK-MBelevation,MyocardiolinfarctPlateletInhibitionMajorAdverseCardiacEvents,P=0.006,P=0.012,Levetal.JAmCollCardiol.2006.Chenetal.JAmCollCardiol.2004.,ISAR-CHOICE(300,600,900mg),vonBeckerathetal.Circulation.2005.,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,0,Montalescotetal.JACC2006;48:931-8,0,50,10,20,30,40,1,2,3,4,5,6,时间(小时),5mol/LADP,*p0.03g/LLog-Rankp=0.02,Troponin0.03g/LLog-Rankp=0.98,JAMA2006;295:1531-38,%,0,2,4,6,8,10,12,Follow-upduration(months),%,No.atrisk,Log-Rank,P=0.0192,0,1,2,3,4,5,0.8%,0.1%,Triplegroup965957953Dualgroup965948942,TheDECREASERegistryCumulativeincidenceofstentthrombosis,Dualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965),0,2,4,6,8,10,12,Follow-upduration(months),%,No.atrisk,Log-Rank,P=0.0744,0,1,2,3,4,5,2.6%,1.4%,Triplegroup965955950Dualgroup965948940,CumulativeincidenceofDeathorMI,Dualantiplatelettherapy(n=965)Tripleantiplatelettherapy(n=965),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-D3075100mg,ASA高剂量组第1天至少300mg;D2-D30300mg325mg,ASA高剂量组第1天至少300mg;D2-D30300mg325mg,ASA低剂量组第1天至少300mg;D2-D3075100mg,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,四、新型抗血小板药物的研究,JUMBO-TIMI26threedosesofprasugrelvsclopidogrelinelectiveorurgentPCI(safetyevaluation),Circulation2005;11:3366-73,1.7,1.2,%,7.2,9.4,%,Significantnon-CABGBleedingat30daysP=0.77,MACEat30daysHR0.76P=0.26,PRINCIPLETIMI44(PlannedElectivePCI)PRIMARYEPAcutePhase:IPA20uMADP,Prasugrel60mg,P0.0001foreach,IPA(%;20mMADP),Hours,Circulation2007;116:2923-32,Prasugrel10mg,Prasugrel10mg,DifferenceBetweenTreatments:14.995%CI10.619.3,P0.0001,IPA(%;20mMADP),Days,Circulation2007;116:2923-32,PRINCIPLETIMI44,PRIMARYEPChronicPhase:IPA20uMADP,Days,PrimaryEndpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,HR0.77P=0.0001,HR0.80P=0.0003,12.1(781),9.9(643),HR0.81(0.73-0.90)P=0.0004NNT=46,ITT=13,608LTFU=14(0.1%),TRITONTIMI-38ACS(STEMIorUANSTEMI)357:2001-15,ARD0.6HR1.32P=0.03NNH=167,ARD0.5HR1.52P=0.01,ARD0.2P=0.23,ARD0.3P=0.002,ARD0%P=0.74,TRITONTIMI-38BleedingEventsSafetyCohort(n=13,457),ICHinPtswPriorStroke/TIA(N=518)Clop0(0)%Pras6(2.3)%(P=0.02),NEnglJMed2007;357:2001-15,Days,Endpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,12.1,9.9,TRITONTIMI38BalanceofEfficacyandSafety,CVDeath/MI/Stroke,2.4,1.8,TIMIMajorNonCABGBleeds,138eventsHR0.81(0.73-0.90)P=0.0004NNT=46,35eventsHR1.32(1.03-1.68)P=0.03NNH=167,NEnglJMed2007;357:2001-15,OptimizationofPrasugrelmaintenancedosinginaminorityofpatientsmayhelpimprovethebenefit:riskbalance,SafetySignificantincreaseinseriousbleeding(32%increase)AvoidinptswithpriorCVA/TIA,Efficaency1.Asignificantreductionin:CVDeath/MI/Stroke19%StentThrombosis52%uTVR34%MI24%2.Anearlyandsustainedbenefit3.AcrossACSspectrum,NetclinicalbenefitsignificantfavoredPrasugrel,TRITONTIM