PCI抗栓治疗李为民524.ppt

SlidesPresentedforCIT2006,PCI抗栓治疗的最佳策略李为民教授,EvolutionofPCI,Antman.Circulation2001;103:2310.,Balloon,AntiplateletAnticoagulants,Stent,DES,GPIIb/IIIainhibitorUFHLMWH,ASA,Clopidogrel,AngioJet,ThrombusRemovalandDistalEmbolizationProtectionDevices,EmbolizationProtectionDevice,Platelet,抗栓治疗目标,预防急性血栓和梗死AspirinAntiGPIIb/IIIaPretreatmentwiththienopyridineAnticoagulants预防亚急性支架血栓形成Aspirin1232-1263,Fibrinogen,TxA2ADP,PCI后，对早期动脉壁损伤的反应是血小板活化并沉积于损伤的动脉表面形成血栓；,支架置入术比单纯的球囊血管成形术能引起更强的血小板活化,抗血小板药物,药物分类AspirinClopidogrel47(1):37-45,阿司匹林不同剂量的疗效,AdaptedwithpermissionfromAntithromboticTrialistsCollaboration.BMJ.2002;324:71-86.2002,BMJPublishingGroup.,0.5,1.0,1.5,2.0,500-15003419,160-3251926,75-1501232,75313,Anyaspirin6523,AntiplateletBetter,AntiplateletWorse,Aspirin(mgdaily),OddsRatio,0,No.ofTrials,%OddsReduction,TreatmenteffectP.0001,ESCPCI指南,阿司匹林没有长期使用或病史不详者术前3小时口服300-500mg负荷量或术前静脉注射300mg长期应用者没有必要大于100mg/天EurHeartJ2005;26:804-847,术前使用阿司匹林（级）；术后长期治疗，推荐阿司匹林75162/(1级)。对PCI术后长期接受氯吡格雷或华法林等抗栓治疗的患者，推荐使用小剂量阿司匹林75100mg/d(1+级)。对于置入支架的患者，推荐应用阿司匹林和一种噻吩并吡啶衍生物(噻氯匹定或氯吡格雷)联合治疗(1级)。,AspirinResistance,CellularFactorsInsufficientsuppressionofCOX-1Over-expressionofCOX-2mRNAErythrocyte-inducedplateletactivationIncreasednorepinephrineGenerationof8-iso-PGF2,AdaptedwithpermissionfromBhattDL.JAmCollCardiol.2004;43:1127-1129.,AspirinResistance:mechanism,GeneticPolymorphismsCOX-1GPIIIareceptorCollagenreceptorvWFreceptor,ClinicalFactorsFailuretoprescribeNon-complianceNon-absorptionInteractionwithibuprofen,阿司匹林抵抗表现,PCI中单纯阿司匹林治疗不够，应加用其他抗血小板药物,药理学抵抗尿血栓素B2增加功能抵抗持续血小板聚集不能预防血栓并发症不能延长出血时间不能抑制血小板聚集,阻断ADP受体,和阿司匹林有协同作用,氯吡格雷,氯吡格雷药理学,剂量依赖性抑制血小板聚集单次服用400mg二小时起效，持续48小时；最大的抗血小板作用（40抑制）每天服用50mg-100mg第二天，血小板聚集作用被抑制253047天，达到稳态，血小板抑制5060,PCI-CURE,n=2658CREDO(fulleffect),n=473EPISTENT,n=809ESPRIT*,n=1024Pooled,n=4964,PCI中氯吡格雷的预处理和早期风险,Relative30-DayRiskofDeath,MI,Urg.TVR,0,0.5,1,1.5,*1-yearDeath111:2099-2106,预处理剂量-ARMYDA-2STUDY,Theprimaryendpointsoccurredin:4%ofptswith600mgversus12%with300mg,长期治疗的益处,Steinhubletal.,JAMA2002,Days,CumulativeIncidenceofDeath,InfarctionandStroke%,CREDO,ESCPCI指南氯吡格雷,稳定冠心病患者：术前至少6小时口服300mg氯吡格雷（C）术前2.5小时予300mg氯吡格雷可能剂量不足；PCI术前至少应口服600mg的氯吡格雷AMJCardiol2004;94:358,EurHeartJ2004;25:476,JAMA2002;288:2411,JACC2003;42:1188,Circulation2004;110:1916,JACC2004;44:2133,NSTE-ACS患者：应尽早使用氯吡格雷（B）CURE证实，从进入试验的第一个小时开始，应用氯吡格雷者不良事件明显较少；Circulation2002;Circulation2004;Circulation2003；108：1682STEMI-ACS患者：氯吡格雷负荷剂量600mgEurHeartJ2005;26:804-847,ESCPCI指南氯吡格雷,PCI术后氯吡格雷使用ACC/AHA2005,拟行PCI的病人应给予氯吡格雷治疗:,1monthafterbare-metalstent3monthsaftersirolimus-elutingstent6monthsafterpaclitaxel-elutingstentUpto12monthsinabsenceofhighriskforbleeding.,氯吡格雷抵抗,Matetzkyetal.Circ109:31712004,Wiviott+AntmanCirc109:30642004,急诊PCI治疗STEMI，N=60,5mMADP诱导的血小板聚集,6个月时的死亡/ACS/CVA,天数,1,2,3,4,5,6,基线%,反应的四分位数,Q1,Q2,Q3,Q4,氯吡格雷抵抗,40,6.7,0,0,%,P=0.007,Q1,Q2,Q3,Q4,0,0.5,1.0,1.5,2.5,2.0,3.0,TiclopidineplusAspirinbetter,Controlbetter,death,myocardialinfarctionandtargetvesselrevascularization,ISARSTARSMATTISFANTASTICpooled,抗血小板联合治疗,抑制血小板聚集的最后通路;抑制纤维蛋白原结合于GPIIb/IIIa受体,GPIIb-IIIa抑制剂,GPIIb-IIIa抑制剂,Abciximab,Tirofiban,Eptifibatide,ChimericMabMW50,000D,NonpeptideTyrosineDerivativeMW500D,CyclicHeptapeptideMW800D,GPIIb/IIIa抑制剂的益处,AllpatientswithACSPatientswithACS,undergoingPCIwithin5days,BoersmaEetal.Lancet2002,0.5,0.6,0.7,1.1,AntiGPIIb/IIIabetter,0.8,0.9,1.0,Relative30-DayRiskofDeathandMI,Meta-AnalysisofSixMajorTrials(31,402Patients),0,0.5,1,1.5,30Days,6Months,RAPPORT,Breneretal.(PTCA)Circulation1999ISAR-2Neumannetal.(Stent)JAmCollCardiol2000ADMIRALMontalescotetal(Stent)NEnglJMed,2001CADILLACStoneetal.(Stent/PTCA)NEnglJMed,2002ACEAntoniuccietal.(Stent)JAmCollCardiol2003Pooled,AMI病人PCI阿昔单抗的作用,0,0.5,1,1.5,GPIIb/IIIa抑制剂的有效性,PCIStudiesAbciximabEPIC(bolusarm)EPILOGEPISTENTEptifibatideIMPACT-IIESPRITTirofibanRESTOREPCISubgroupsEptifibatidePURSUIT(death21(2):102-7.,TiclopidinEPISTENT(Abciximab),n=794ClopidogrelESPRIT*(Eptifibatid),n=1040TARGET(Abciximab),n=2411TARGET(Tirofiban),n=2398CREDO(Mixed),n=378Pooled,n=7,021,噻吩吡啶类药物和GPIIb/IIIa抑制剂合用,Relative30-DayRiskofDeath,MIHemochron300350秒)在使用血小板IIb/IIIa受体拮抗剂的患者，抗凝治疗所要求的ACT目标值为200秒。根据ACT监测调整肝素用量。,ACC/AHA2005普通肝素,ESC和ACCPVII2005建议,对于ST段抬高的心肌梗死患者行早期PCI治疗，普通肝素是标准治疗。对于所有进行PCI手术的非ST段抬高型心肌梗死患者，推荐应用普通肝素治疗（证据水平1C）。NSTEACS患者前已经应用LMWHs，建议PCI中继续应用LMWHs(Grade2C),ACCPVII：,ESC2005,抗凝血治疗,HeparinLMWHfondaparinuxBivalirudin294(20):2594-600.JAMA.2004Jul7;292(1):45-54.,StudyDesign,Atleast2of3required:Age60ST(transient)or(+)CK-MBorTroponin,Enoxaparin,IVHeparin,Primaryendpoint:DeathorMIat30days,High-RiskACSPatients,Randomize(n=10,000),EarlyinvasivestrategyOthertherapyperAHA/ACCGuidelines(ASA,-blocker,ACE,clopidogrel,GPIIb/IIIa),60U/kg12U/kg/hr(aPTT50-70sec),1mg/kgSCQ12H,PrimaryResults(30Days),EnoxaparinUFHUnadjusted(n=4993)(n=4985)P-valueDeathandMI(%)14.014.50.396Death(%)3.23.10.705MI(%)11.712.70.135,DeathandMIat30Days,30-DayDeath/MI,0.8,0.8,1,1,1.2,1.2,HazardRatio(95%CI),Enoxaparin,Better,UFH,Better,HR0.96(0.86-1.06),1.1,0,5,10,15,20,25,30,0.8,0.85,0.9,0.95,1.0,FreedomfromDeath/MI,DaysfromRandomization,BleedingEvents,EnoxaparinUFHP-value(n=4993)(n=4985)GUSTOsevere%2.92.40.107TIMImajor-clinical:9.17.60.008CABg/L-related6.85.90.081Non-CABg/L-related2.41.70.025H/H*drop-algorithm15.212.50.001AnyRBCtransfusion17.016.00.155ICH1x,Tn3xRef),ASA+IVEptifibatidefor48hrs,UnfractionatedHeparinTargetaPTT1.5-2.5x,Enoxaparin1mg/kgq12h,Baseline48,96hr12-leadECG96hrcontinuous3channelSTsegmentmonitoring30daybleedingandischemicevents,StudyDesignandProtocol,Goodmanetal.FortheINTERACTTrialInvestigatorcirculation2003;107:238-44,0.90,0.92,0.94,0.96,0.98,1.00,0,5,10,15,20,25,30,DaysfromRandomization,Event-freeSurvival,30-DayDeathorMyocardial(re)Infarction,0.909,LogRankp=0.0282,0.954,Eptifibatide+Enoxaparin(n=380),Eptifibatide+Heparin(n=366),MajorNon-CABGBleeding,%ofPatients,48Hours,4.6,1.8,%ofPatients,96Hours,p=0.030,3.8,1.1,0,1,2,3,4,5,p=0.014,Enoxaparin,UFHeparin,PrimarySafetyOutcome,n=366,n=366,n=380,n=380,Enoxaparin,UFHeparin,0,1,2,3,4,5,circulation2003;107:238-44,HighRiskNon-STACSReceivingEarlyGPIIb/IIIaInhibitionandLMWHvsUFH,AdjustedOddsRatio108(suppl):IV-579,N=11,358withpositivecardiacmarkersorischemicSTchanges,(407U.S.hospitals,Jan2002-Jun2003)receivingGPIIb/IIIainhibitor24hrsplusLMWH(39.4%)orUFH(60.6%),ACC/AHAUA/NSTEMIGuideline,ACS延长期抗凝治疗2002年ACC/AHA指南,“ThebenefitsofprolongeddalteparinadministrationwerelimitedtopatientswhoweremanagedmedicallyandtopatientswithelevatedTnTlevelsatbaseline.TheseresultsmaymakeacasefortheprolongeduseofanLMWHinselectedpatientswhoaremanagedmedicallyorinwhomangiographyisdelayed.”FRISCII结果提示，经过选择的内科药物治疗患者或延迟做血管造影的患者，有必要延长使用LMWH的时间。,ACC/AHAUA/NSTEMIGuideline,ACS延长期抗凝治疗2004年ACCP指南,“TheavailableevidencefavorsanearlyinvasivestrategyforpatientswithNSTEACS.AlthoughprolongedLMWHadministrationprovidesanelementofprotectionforhigh-riskpatients,thoseindividualsshouldbetreatedaggressively(andearly)wheneverpossible.Ifcoronaryangiographyandinterventionareplannedbutdelayed,continuedtherapyasa“bridge”torevascularizationshouldbeconsidered”现有证据支持NSTEACS患者早期接受介入治疗。如果拟行冠状动脉造影及介入治疗，但要延迟进行，就应该考虑继续应用LMWH作为与血运重建治疗之间的过渡治疗。,LMWH关于延长期抗凝治疗的临床研究,FRAX.I.S(1998)那屈肝素关于ACS急性期、延长期治疗的研究TIMI11B(1999年)依诺肝素关于ACS延长期治疗研究FRISCII(2000年)法安明关于ACS延长期抗凝治疗的研究,FRAX.I.S研究,目的那屈肝素能否安全有效用于ACS患者，急性期6天和延长期14天。设计前瞻性、随机、双盲、多中心n=3468例入选发病48h内的患者观察终点和出血发生到3个月,FRAX.I.S：研究设计,安慰剂,5000IU普通肝素静脉入壶后1250IU/h静滴，监测APTT值并控制在正常值1.5-2.5倍,静脉BOLUS后那屈肝素87IU/kg/12h皮下注射BID,不稳定性心绞痛，非Q波心梗发病48小时内,急性期6天,延长期14天,安慰剂,N=3468,87IU/kg/12h皮下注射BID,随访3个月,FRAX.I.SStudyGroup.EurHeartJ1999;20:1553-1562,静脉BOLUS后那屈肝素87IU/kg/12h皮下注射BID,FRAXIS：3个月时那屈肝素组心血管事件显著增加,3个月时，速碧林14天组，死亡和心梗/再发心绞痛/紧急血运重建发生率显著增加,死亡和心梗/再发心绞痛/紧急血运重建发生率（）,55,54.4%,58.8%,P=0.03,肝素组,速碧林6天组,速碧林14天组,FRAX.I.SStudyGroup.EurHeartJ1999;20:1553-1562,51,53,55,57,59,FRAXIS：那屈肝素组出血事件显著增多,14天时严重出血事件：那屈肝素14天组显著大于其他两组,P=0.0035,0,1.0,2.0,3.0,4.0,严重出血事件发生率（）,1.5%,1.6%,3.5%,肝素组,那屈肝素6天组,那屈肝素14天组,FRAX.I.SStudyGroup.EurHeartJ1999;20:1553-1562,FRAX.I.S：研究结论,那屈肝素延长使用的剂量和使用时间都需要再探讨,FRAX.I.SStudyGroup.EurHeartJ1999;20:1553-1562,TIMI11B：研究设计,依诺肝素固定剂量65kg40mg60mgq12h,依诺肝素30mgIV+1.0mg/kg/12hSC,普通肝素70U/kgIV+15U/Kg/hIV,不稳定性心绞痛非Q波心梗发病24小时内,急性期最短72h,最长8天,慢性期,固定剂量安慰剂SCq12h,43天,N=3,910,延长35天,AntmanEM,etal.Circulation1999;100:1593-1601,TIMI11B：依诺肝素43天时降低三联终点,RRR=12%P=0.049,19.6%,17.3%,0,4,8,12,16,20,0,8,16,24,32,40,普通肝素安慰剂,依诺肝素,60%,14.5%,12.4%,RRR=15%P=0.048,死亡/心梗/紧急血运重建发生率（）,天数,AntmanEM,etal.Circulation1999;100:1593-1601,AntmanEM,etal.Circulation1999;100:1593-1601,TIMI11B：延长期依诺肝素组大出血危险明显增加,TIMI11B：研究结果（延长期）,ACS延长期依诺肝素延长使用，获益无继续扩大严重出血事件，依诺肝素组显著大于安慰剂组,AntmanEM,etal.Circulation1999;100:1593-1601,FRISCII：研究目的,目的：评价法安明在ACS延长期治疗是否可带来更多的受益，其合适的时限及剂量是多少比较积极血运重建与保守治疗效果的差别前瞻性、随机、双盲、安慰剂对照试验(n=3489),FRISCII：研究设计,在3,489例不稳定心绞痛和非Q波心肌梗死患者应用法安明和安慰剂对照的前瞻、随机、双盲研究,FRISCIIInvestigators.Lancet.1999;354:701-715.,有禁忌症，被分入非介入治疗组（N=1032）,非介入治疗（N1235）,介入治疗（N1222）,法安明组安慰剂组,法安明组安慰剂组,法安明组安慰剂组,90天,57天,1天,延长期法安明5000IU/7500IU/12H,随机分组治疗,无禁忌症，被随机分至：介入治疗非介入治疗,急性期法安明120IU/kg/12H,入院前48h有症状,主要终点,二级终点,FRISCII:45天时未接受血管再通治疗的结果,Hustedetal.,EurHeartJ2002,0.10,0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02,0.01,0.00,0,10,20,30,40,60,80,达肝素,安慰剂,从双盲阶段开始的时间(天),Probabilityofdeath/MI,29%,57%,50,70,90,P=0.0004,P=0.0415,无禁忌症但分入非介入治疗组的患者：仅在必要时性血管再通治疗,FRISCII：法安明延长治疗期的安全性,0.0,0.2,0.4,0.6,0.8,1.0,1.2,615天,1530天,30