96血小板GPIIbIIIa受体拮抗剂

血小板GPIIb/IIIa受体拮抗剂的临床应用及进展ACS发病机制和治疗策略抗血小板药物的作用机制GPIIb/IIIa拮抗剂临床研究汇总盐酸替罗非班的临床研究欣维宁的药理作用和临床研究GPIIb/IIIa临床应用常见问题内容提要ACS发病机制和治疗策略非ST段抬高ACS病理生理在斑块破裂处纤维蛋白原通过GPIIb-IIIa受体相互交联血小板纤维蛋白原斑块破裂GPIIb-IIIa富含血小板血栓在冠脉内形成部分堵塞未堵塞管腔血栓动脉壁溶栓无效抗血小板有效ST段抬高MI病理生理在斑块破裂处纤维蛋白网使聚集的血小板稳定血小板红细胞纤维蛋白网GPIIb-IIIa血栓完全堵塞冠脉溶栓有效抗血小板也有效凝血酶生成组织因子黏附分子血小板激活血管壁炎症反应PCI血栓形成主要机制血小板小而无核的血细胞，主要功能是维持止血在循环中的数量约1.5兆，寿命约10天黏附于血管内皮的破裂处与激活物接触后，血小板细胞膜和形状发生改变血小板激活后分泌凝血因子、血管收缩物质和生长因子稳定的血小板激活的血小板血小板粘附和激活激活GPIIb/IIIaGPIb血管内皮vWf因子胶原GPIa/IIa纤维蛋白原或vWf因子GPIIb/IIIa（TXA2、ADP、凝血酶）血小板聚集纤维蛋白原或vWf因子GPIIb/IIIaCa2+Ca2+Ca2+Ca2+血小板在血栓形成中的作用血小板聚集：为血栓形成的前提和核心，凝血系统激活的前提和核心。没有血小板激活，就没有血栓形成抗血小板治疗：是ACS的首要治疗措施之一。STEMIClinicalfindingECGSerummarkersRiskassessmentNon-cardiacchestpainStableanginaUANSTEMINegativePositiveST-TwavechangesSTelevationLowprobabilityMedium-highriskThrombolysisPrimaryPCIAspirin+GPIIb/IIIainhibitorclopidogrel+heparin/LMWH+anti-ischemicRxEarlyinvasiveRxDischargeNegativeDiagnosticruleoutMI/ACSpathwaySTEMINegativeAtypicalpainLowriskAspirin,heparin/low-molecular-weightheparin(LMWH)+clopidogrelAnti-ischemicRxEarlyconservativetherapyOngoingpainDM=diabetesmellitus.Cannon,Braunwald.HeartDisease.2001.Restpain,Post-MI,DM,PriorAspirinExertionalpainTheSpectrumofACS主要抗血小板药物的作用机制凝血酶胶原5-羟色胺肾上腺素血小板活化活化的血小板COX环氧化酶抑制剂ADP受体拮抗剂GpIIb/IIIa受体拮抗剂GpIIb/IIIa受体主要抗血小板药物作用机制血小板GPIIb/IIIa受体拮抗剂AbciximabEptifibatideTirofibanWhiteHD.AmJCardiol.1997;80(4A):2B-10B.GPIIb/IIIa受体拮抗剂作用机制RestingplateletPlaqueruptureandplateletadhesionPlateletactivationPreventionofplateletaggregationGPIIb/IIIaexpressionFibrinogenGPIIb/IIIainhibitorvWFvWFvWFAgonistsreleasedVesselWall大量循证医学研究证实GPIIb/IIIa受体拮抗剂显著改善ACS和PCI患者临床预后1安慰剂较好IIb/IIIa较好试验安慰剂IIb/IIIaN0.110RESTORE1.1%0.9%12,940EPILOG1.2%0.9%4891RAPPORT1.3%1.0%5374CAPTURE1.3%1.0%6639EPIC1.7%1.5%20991.3%IMPACTI1.0%67891.2%IMPACTII0.9%10,799ESPRIT1.0%0.8%17,403ISAR-21.1%0.8%17,804ADMIRAL1.2%0.8%18,104EPISTENT1.1%0.8%15,3391.3%CADILLAC0.9%20,186OR&95%CI0.73(0.55,0.96)P=0.02430天死亡27%P=0.024GPIIb/IIIa受体拮抗剂在PCI中的应用KongD,etal.AmJCardiol.2003;92:651-6559%GPIIb/IIIa受体拮抗剂在ACS中的应用GPIIb/IIIa在糖尿病人中的应用RoffiM,etal.Circulation.2001;104:2767-2771.(withpermission)30天死亡2163687362167741211576458PURSUITPRISMPRISM-PLUSGUSTOIVPARAGONAPARAGONBPooled6.1%4.2%6.7%7.8%6.2%4.8%6.2%5.1%1.8%3.6%5.0%4.6%4.9%4.6%P=.33P=.07P=.17P=.022P=.51P=.93P=.007TrialNOddsRatio&95%ClPlaceboIIb/IIIaBreslow-Day:P=.50IIb/IIIaBetterPlaceboBetterOR=0.7400.511.5226%P=0.007GPIIb/IIIa受体拮抗剂替罗非班的临床研究TheRESTOREInvestigators.Circulation.1997;96:1445-1453.ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.替罗非班的临床研究RESTORETirofiban对高危冠脉介入病人预后和再狭窄疗效的随机试验PRISM-PLUSTirofiban对不稳定心肌缺血病人治疗研究RESTORE用药方法UA/AMI72Hrn=2141阿司匹林325mg肝素10000uiv介入导丝通过冠脉病变随机分组tirofiban10ug/kgiv3min0.15ug.kg-1.min-1×36h安慰剂10ug/kgiv3min0.15ug.kg-1.min-1×36hACT300~400Sn=1071n=1070术后应停用肝素，当ACT180s时，拔除动静脉鞘管;替罗非班持续输注36小时TheRESTOREInvestigators.Circulation.1997;96:1445-1453.联合终点：需紧急血运重建者：30天内安慰剂组为10.5%,tirofiban组8%,相对下降24%(p=0.052)TheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE：联合终点死亡/MI/紧急血运重建RR=30%RR=40%RR=24%RR=40%P=0.0022Days7Days30Days8.75.29.86.910.58.0/紧急血运重建%051015安慰剂替罗非班组RR=24%P=0.052RR=30%P=0.016联合终点RESTORE：联合终点死亡/MI/紧急血运重建40%30%24%TheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE:30天MI发生率30天发生MI的比例:安慰剂组5.7%,tirofiban组4.2%,下降26%(p＝0.113)即使是在PCI早期发生了MI,但停用tirofiban后未见任何反弹迹象TheRESTOREInvestigators.Circulation.1997;96:1445-1453.5.7%4.2%RR=26%RESTORE-出血发生率2(0.2)1(0.1)血小板减少50000/mm312(1.1)10(0.9)血小板减少90000/mm3.66226(2.4)22(2.1)大出血(TIMI标准)6(0.6)3(0.3)腹膜后出血1(0.1)3(0.3)颅内出血2(0.2)3(0.3)出血需要外科治疗38(3.5)24(2.2)输血2U25(2.3)19(1.8)血红蛋白下降5g/dL.09657(5.3)40(3.7)大出血P替罗非班组(n=1071),n(%)安慰剂组(n=1070),n(%)TheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE结论ACS接受PCI患者使用tirofiban可有效预防不良心脏事件的发生联合终点：死亡/MI/紧急血运重建48小时↓40%p=0.002第7天↓30%p=0.016第30天↓24%p=0.052两组间主要出血并发症无明显差异（P=0.096)两组间严重血小板减少(50000/mm3)均罕见替罗非班组0.2%，安慰剂组0.1%;P=1.000PRISM-PLUSUA/NSTEMIn=1570阿司匹林325mg随机tirofiban0.4ug/kg/miv30min0.1ug/kg/miv×48h肝素1000u/hiv×48h肝素5000uiv1000u/hiv×48hAptt=2倍n=773n=797PCIn=475tirofiban0.1ug/kg/miv×12~24h肝素5000~7500uiv然后1000u/hiv肝素5000~7500uiv然后1000u/hiv介入术后停用肝素(拔除鞘管前最少2小时)，术后Tirofiban持续应用12—24小时ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.PRISM-PLUSRR=riskreduction.ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.RR=66%P=0.012Days7DaysRR=43%P=0.006RR=30%P=0.0330Days2.60.98.34.911.98.7051015Heparin(n=797)Tirofiban+Heparin(n=773)死亡/心梗患者(%)66%43%30%42PCI214212876301848肝素组替罗非班+肝素组PCI前(N=1570)小时66%44%012243612840PCI后(N=475)3.02.52.01.51.00.50天肝素组替罗非班+肝素组死亡/心梗患者(%)PCI前输注48小时,术中及术后持续输注12-24小时,平均输注:71.3+20小时PRISM-PLUSThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.4PRISM-PLUS:Death/MIinDiabetes4.7%1.2%3.1%ThérouxP,etal.Circulation.2000;102:2466-2472.Heparin(n=193)Tirofiban+Heparin(n=169)Patients(%)9.3%0.0%P=0.0315.5%P=0.00219.2%11.2%P=0.03Day7Day30Day1805015102048hoursP=0.005100%87%70%42%替罗非班显著降低UA/NSTEMI患者TnI水平Heparin(n=52)Tirofiban+Heparin(n=53)TnI(ng/mL)基线峰值3.11.6P=NS5.215.5P=0.017061