GPIIbIIIa受体拮抗剂欣维宁张

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学术地位GPIIb/IIIa临床应用常见问题内容提要ACS发病机制和治疗策略炎症粥样硬化血栓形成ThrombusQuiescentplaquePlateletsandthrombinPlaquerupture急性冠脉综合征发病机制斑块破裂血小板粘附血小板激活血栓部分堵塞动脉引起不稳定心绞痛微血栓引起NSTEMI血栓完全堵塞动脉引起STEMIACS发病机制AdaptedfromDaviesMJ.Circulation.1990;82(suplII):30-46.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在动脉血栓形成中的作用血小板聚集形成血栓

血流中的正常血小板

血小板粘附于损伤的内皮表面并被激活

血小板内皮细胞内皮下血小板粘附到内皮下血小板血栓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-cardiac

chestpainStable

anginaUANSTEMINegativePositiveST-Twave

changesSTelevationLow

probabilityMedium-highriskThrombolysis

PrimaryPCIAspirin+GPIIb/IIIainhibitorclopidogrel+heparin/LMWH+anti-ischemicRx

EarlyinvasiveRxDischargeNegativeDiagnostic

ruleoutMI/ACSpathwaySTEMI

NegativeAtypical

painLowriskAspirin,heparin/low-molecular-weightheparin(LMWH)+clopidogrel

Anti-ischemicRx

EarlyconservativetherapyOngoingpainDM=diabetesmellitus.Cannon,Braunwald.HeartDisease.2001.Restpain,Post-MI,DM,PriorAspirinExertional

painTheSpectrumofACS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ADP血小板活化TXA2活化的血小板COX环氧化酶抑制剂ADP受体拮抗剂

Gp

IIb/IIIa

受体拮抗剂Gp

IIb/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

GPIIb/IIIa受体拮抗剂临床研究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=.50 IIb/IIIaBetter PlaceboBetter OR=0.740 0.5 1 1.5 226%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-PLUSTirofiban

对不稳定心肌缺血病人治疗研究

一项随机、双盲、安慰剂对照、多中心研究入选对象：n=2141，发病72h内接受PTCA或定向斑块旋切术治疗的UA/AMI者研究终点：各种原因的死亡、MI、PCI或复发性心肌缺血需再行PCI或CABG者由独立盲终点委员评价第2天、第7天、30天内的终点事件RESTORETheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE用药方法UA/AMI<72Hr

n=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ACT<180s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%Circulation1997Sep2;96(5):1445-53RR=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%Circulation1997Sep2;96(5):1445-53RESTORE-出血发生率安慰剂组

(n=1070),n(%)替罗非班组(n=1071),n(%)P大出血40(3.7)57(5.3).096血红蛋白下降>5g/dL19(1.8)25(2.3)输血>2U24(2.2)38(3.5)出血需要外科治疗3(0.3)2(0.2)颅内出血3(0.3)1(0.1)腹膜后出血3(0.3)6(0.6)大出血(TIMI标准)22(2.1)26(2.4).662血小板减少<90000/mm310(0.9)12(1.1)血小板减少<50000/mm31(0.1)2(0.2)TheRESTOREInvestigators.Circulation.1997;96:1445-1453.Circulation1997Sep2;96(5):1445-53RESTORE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-PLUS方法一项随机、双盲、多中心研究1570例12h内有静息心绞痛伴ECG或CK-MB

变化并已接受Asprin治疗的UA/NSTEMI患者研究复合终点事件为死亡、MI、或2天、7天内的难治性缺血事件及30天、6月心脏事件ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.PRISM-PLUSUA/NSTEMI

n=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/MIinDiabetes

4.7%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%

TirofibanIncreasedPerfusionStatusP=0.002fortrendbyproportionaloddsmodelZhaoX-Q,etal.Circulation.1999;100:1609-1615.PRISM-PLUS研究替罗非班显著降低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=0.017061218PRISM-PLUS研究JanuzziJL,etal.AmJCardiol.2000;86:713-717.3.28.5P=0.01624小时平均PRISM-PLUS：出血发生率PRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.n=773n=797P=0.34*主要出血的定义：血红蛋白下降＜4.0g/dl、需输血＞2u、需外科纠正出血、颅内出血、腹膜后出血、任何复合出血情况*ACS患者接受tirofiban

治疗可有效减少不良心脏事件的发生对于所有患者联合终点：死亡/MI

48小时↓66%p=0.01第7天↓

43%p=0.006

第30天↓30%p=0.03

6个月↓22%p=0.06对于行PCI的患者在术前,术中,术后持续滴注第30天死亡/MI

↓44%p=0.03

与肝素合用出血副作用未见明显增加（P=0.34)PRISM-PLUS：结论

国内第一个GPIIb/IIIa

受体拮抗剂

——欣维宁药理作用和临床研究欣维宁®--产品简介替罗非班通用名Tirofiban，由美国默克公司创制,1998年5月18日美国FDA批准在美国上市。欣维宁®是目前国内唯一的血小板IIb/IIIa受体拮抗剂，国家二类新药，

2004年8月批准在中国上市。替罗非班药理学通用名：盐酸替罗非班氯化钠注射液英文名：Tirofibanhydrochloridesodiumchlorideinjection商品名：欣维宁分子式：C22H36N2O5S.HCL.H2O分子量：495.08形状：本品为无色澄明液体药理作用抗血小板聚集作用：

欣维宁对血小板聚集率（%）的影响（X±S）

试验组（n=101）实测值对照组（n=99）实测值给药前54.0±19.357.0±20.4

给药后29.1±21.652.1±19.5

变化率-24.9±23.7-4.9±24.9

实验组给药前后及两组之间的变化均有显著性药理作用抗血栓形成在电损伤引起的冠状动脉左旋支闭塞性血栓模型中，静注10μg/kg/min盐酸替罗非班即可防止3只狗形成闭塞性血栓，使血栓形成时间延长，血栓重量减少，与对照组相比有显著差异。

治疗电损伤引起冠状动脉左旋支闭塞性血栓时，在给予组织型纤维蛋白溶解酶原激活物（t-PA）或链激酶（STK）前15min静注盐酸替罗非班可增加再灌注的发生率，减少连续用药期间急性血栓再闭塞的发生率。主要药代动力学的相关参数半衰期:约为2—3小时达峰时间:静注后5分钟血小板抑制率大于93%

*静注时，替罗非班对离体血小板聚集的抑制剂量和浓度成正比。受体的可逆性停药1.5-4小时，血小板的功能迅速恢复。TopolE,etal.Lancet.1999;353:227-231.AbciximabEptifibatideTirofibanOOOOOOOOOHHNHNSSNHNHNNHHNNHNHH2NH2NH

N–SO2–C4H9OCOOHHNFabfragmentofachimericmonoclonal

antibody

MW50,000DNonpeptidetyrosine

derivative

MW500DCyclic

heptapeptide

MW800D鼠源性单克隆抗体合成非肽类合成肽类三种静脉GPⅡb/Ⅲa受体抑制剂的比较

AciximabEptifibatideTirofiban结构鼠人IgG嵌合体环肽KGD小分子非肽RGD分子量(道尔顿)5000800500GPⅡb/Ⅲa选择性差较强较强化学计量法1.5:1100:1100:1血浆半衰期10-15分钟1.5-2.5小时1.5-2.5小时受体抑制可逆性差(输注血小板)较强(停药)较强(停药)出血发生率多较少较少血小板无力症相对较多少少安全性相对较差相对较好相对较好价格昂贵相对较低相对较低适应症(FDA)PCIACS;PCIACS;PCI三种静脉GPⅡb/Ⅲa受体抑制剂的比较JACC2001药代动力学曲线三种静脉GPⅡb/Ⅲa受体抑制剂的比较对血小板抑制的可逆性%血小板聚集率100806040200061218243036依替巴肽替罗非班阿昔单抗停用药物小时

三种静脉GPⅡb/Ⅲa受体抑制剂的比较ScarboroughRM,etal.Circulation.1999;100:437-444.

欣维宁®（盐酸替罗非班）治疗急性冠状动脉综合症有效性和安全性临床研究欣维宁临床研究协作组：华中科技大学同济医学院附属同济医院华中科技大学同济医学院附属协和医院郑州大学国家药品临床研究基地（郑州大学附属第一医院）华中科技大学同济医学院临床药理研究所方法一项随机、双盲、多中心研究200例24h内伴有反复发作胸痛及典型的ST-T改变或血清酶水平改变已接受Asprin治疗的UA/NSTEMI患者疗效观察指标

：1）任何原因的死亡2）新的MI3）顽固性缺血状态4）血小板聚集率安全性评价：1）不良反应2）对一般生命体征的影响

3）实验室检查欣维宁®验证临床研究欣维宁®验证临床研究

给药方法试验组：

1)欣维宁®0.4ug/kg/min30分钟,随后0.1ug/kg/min，2-5天

2)肝素5000IU,静脉注射,随后1000IU/h静脉点滴（试验中期调整肝素剂量，负荷量和维持量均减半)同时根据APTT值调整肝素剂量，使APTT控制在正常水平的1.5-2倍)3)阿司匹林肠溶片

对照组：

(安慰剂+肝素+ASA):用法用量同上RRR=55%P=0.0964.5DaysRR=52.6%P=0.0130Days13.15.929.313.90102030Heparin(n=99)Tirofiban+Heparin(n=101)死亡/心梗/顽固性缺血患者(%)

55%

52.6%欣维宁®验证临床研究主要终点指标和复合终点指标欣维宁®验证临床研究欣维宁®验证临床研究对血小板聚集率的影响

安全性--出血不良反应欣维宁®验证临床研究实验室检查---对APTT(s)的影响欣维宁®验证临床研究实验室检查---对血小板计数（X109/L）的影响欣维宁®验证临床研究

欣维宁--产品特点国内第一个血小板IIb/IIIa受体拮抗剂PCI术前尽早应用临床获益更多显著降低ACS和PCI患者死亡/心梗等严重不良事件5分钟血小板抑制率93%快速完全抑制血栓形成，方便患者急救可逆性好停药后1.5--4小时血小板功能迅速恢复，

使用安全方便进口包材，严格把关，确保产品品质。欣维宁适应证和用法用量ACS的药物治疗（UA/NSTEMI）欣维宁负荷量0.4ug/kg/min静脉滴注30min

维持量0.1ug/kg/min静脉滴注48-108hACS的介入治疗PCI（UA/NSTEMI/STEMI）欣维宁负荷量10ug/kg3min以上静脉推注；维持量0.15ug/kg/min静脉滴注36h欣维宁--包装价格规格100ml:5mg价格:456元疗程价格:

介入治疗1368-2280元药物治疗1824-3648元血小板GPIIb/IIIa受体拮抗剂

的学术地位

NSTEACS

中、高危患者的早期治疗，在应用阿司匹林及肝素的基础上，加用依替巴肽或替罗非班（1A级）同时应用氯吡格雷的中、高危患者，早期加用依替巴肽或替罗非班（2A级）2004ACCP-7NSTEACS治疗建议Guyatt

等定义:等级1:获益大于风险和花费;等级2:获益风险比不确定,应据患者个体差异来进行不同的选择证据强度按A、B、C依次降低

对于被评价为中高危的NSTEMI/UA病人，建议在PCI之前尽可能开始使用GPIIb/IIIa拮抗剂（依替巴肽或替罗非班）(证据1A)

对于正接受替罗非班治疗的NSTEMI/UA病人，建议PCI应在静脉点滴替罗非班4h后进行(证据2C）2004ACCP-7PCI中抗栓治疗建议非ST抬高ACS抗血小板药物治疗建议ESC2004不伴有ST段抬高的ACS,行PCI治疗,建议围手术期静脉应用GPⅡb/Ⅲa拮抗剂(证据1A)

不伴有ST段抬高的ACS,未行PCI治疗,建议静脉应用替罗非班或依替巴肽(证据2A)等级1:获益大于风险和花费;等级2:获益风险比不确定,应据患者个体差异来进行不同的选择证据水平：A级：来自多个随机或汇翠分析；B级：来自单个随机或非随机试验；C级：来自专家共识

血小板GPIIb/IIIa临床应用常见问题

三联抗血小板药物的效果和安全性GPIIb/IIIa有效改善心肌灌注早期应用更多获益高剂量替罗非班的研究合用抗凝药物的剂量

三联抗血小板药物联合治疗的效果和安全性TheCREDOTrial

Clopidogrel

fortheReductionofEvents

DuringObservation

执行委员会

主席:ProfessorEricJ.Topol

主要研究者

DoctorStevenR.Steinhubl

1年CREDO研究

波立维在PCI患者中的疗效和安全性A组B组n=2116患者PCI28天安慰剂负荷剂量

+ASA325mg安慰剂+ASA81–325mg波立维75mg+ASA81–325mgPCI前3–24小时波立维负荷剂量

300mg

+ASA325mg波立维75mg

+ASA325mg波立维75mg

+ASA325mgSteinhublS,etal.JAMA,November20,2002–Vol288,No19:2411–2420

波立维* 安慰剂* n=900PP n=915PP

GPIIb/IIIa拮抗剂的应用(%) 427（47.4%） 396(43.3%)

预先计划(%) 217(24.1%) 208(22.7%) 临时决定(%) 210(23.3%) 188(20.6%)

*OntopofstandardtherapyincludingASA PP=Per-ProtocolCREDO

研究在进行PCI阶段GPIIb/IIIa拮抗剂的应用SteinhublS,etal.JAMA,November20,2002–Vol288,No19:2411–2420氯吡格雷与安慰剂亚组分析28天主要结果（死亡，心梗或急性TVR）SteinhublS,etal.JAMA,November20,2002–Vol288,No19:2411–2420CREDO研究A：PCI前3-6小时给予研究药物GPIIb/IIIa

抑制剂是 (N=417)

否 (N=476)氯吡格雷较好安慰剂较好RRR%GPIIb/IIIa

抑制剂是 (N=378)

否 (N=473)B：PCI前>6-24小时给予研究药物-3.0-21.845.328.3020-20-404060◆◆◆◆接受GPIIb/IIIa拮抗剂治疗的患者在28天时显示出更多的益处安全性:大出血事件

28天的结果ITT(意向治疗人群)*OntopofstandardtherapyincludingASAITT=Intent-to-treatpopulationPP=PerProtocolpopulation

0.347(1.3%)11(2.3%)>0.999(2.3%)9(2.1%)0.1236(3.4%)50(4.7%)0.374(0.4%)1(0.1%)0.2440(3.8%)51(4.8%)P-value严重出血所有状况未进行介入治疗进行介入治疗应用GPIIb/IIIa是(n=823)否(n=991)波立维负荷剂量(n=1,053)无负荷剂量(n=1,063)CREDO研究安全性:小出血事件

28天的结果ITT(意向治疗人群)*OntopofstandardtherapyincludingASAITT=Intent-to-treatpopulationPP=PerProtocolpopulation

CREDO研究CREDO研究的患者接受了全美最好的标准治疗：

阿司匹林＋氯吡格雷＋GPIIb/IIIa抑制剂（几乎半数患者接受GPIIb/IIIa抑制剂）GPIIb/IIIa和氯吡格雷联合应用，显示出进一步的益处。同时接受GPIIb/IIIa抑制剂的患者并未显著增加严重出血和小量出血，重要的是无致命性出血或颅内出血。CREDO研究TOPSTARTrial

EffectofAdditionalTemporaryGPIIb/IIIaReceptorInhibitiononTroponinReleaseinElectivePercutaneousCoronaryInterventionsAfterPretreatmentWithAspirinandClopidogrelBonzAW,etal.JAmCollCardiol2002;40:662-668TOPSTARDesignSinglecenter,double-blind,randomized,prospectivestudyofELECTIVEPCIpatientsAssessedtheadditivebenefitofadministeringaGPIIb-IIIainhibitortothetreatmentregimenofaspirin,unfractionatedheparin,andclopidogrel.Thisadditivebenefitwasassessedintermsof:Cardiactroponin(TnT)releasepost-electivePCI;andTheincidenceofdeath,MI,andtargetvesselrevascularization(TVR)at9months.

BonzAW,etal.JAmCollCardiol2002;40:662-668TOPSTARTOPSTARBackgroundElevatedcardiactroponinpre-PCIisassociatedwithahigherriskofmortality.TOPSTARassessedtheassociationofpostPCItroponinwiththeadjunctiveuseofGPIIbIIIainhibitorsandclinicaloutcomes.RESTOREdosingregimenofTirofibanwasused[10-μg/kgbolus+0.15-μg/kginfusionfor36hours].BonzAW,etal.JAmCollCardiol2002;40:662-668TOPSTARn=109ElectivePCIPatientsGPIIb-IIIaInhibitionReductionsinTroponin&Long-termDeath/MI/TVRwithAspirin,Heparin&PretreatmentWithClopidogrelP<0.05ASA+UFH+PretreatmentwithClopidogrel(n=46)ASA+UFH+Clopidogrel+GPIIb-IIIaInhibitor(n=50)P<0.05P<0.08P<0.05PositiveTroponinDeath/MI/TVRBonzAW,etal.JAmCollCardiol2002;40:662-668TOPSTARStudyResultsTOPSTARdemonstratesthataspirin,heparin,andpretreatmentwithclopidogrelisassociatedwitha74%rateofturningtroponinpositiveby48hoursafterPCI.TheadditionofaGPIIb-IIIainhibitortopretreatmentwithclopidogrelreducestroponinreleaseandreducestheriskofdeathorMImostlikelybyreducingplateletaggregatesandmicroembolization.BonzAW,etal.JAmCollCardiol2002;40:662-668TOPSTARELISAIITrialPresentedatTheEuropeanSocietyofCardiologyHotLineSession2005PresentedbyDr.Saman

RasoulELISAIITrialDualanti-plateletstrategywithaspirinandhigh-doseclopidogrel(600mgload)n=166ELISAIITrialPresentedatESC2005Tripleanti-plateletstrategywithaspirin,standard-doseclopidogrel(300mgload),andtirofiban(10μg/kgbolusfollowedby0.15μg/kginfusion)

n=162328patientswithnon-STelevationMI;ischemicchestpainatrestwithin24hrs;andeitherpositivebiomarkers(CKMBortroponin)oranabnormalECG(STdepression>0.1mVin>2leadsortransientSTelevation)29%female,meanage63years,meanfollow-up30daysLow-molecularweightheparin,beta-blocker,andstatintherapywereadministeredtoallpatientsPrimaryEndpoint:InfarctsizeasassessedbyLDHQat48hoursandasassessedbypeakCKSecondaryEndpoint:InitialTIMIflowgradeoftheculpritarteryAngiographywithorwithoutrevascularization(24-48hrs)BaselineCharacteristicsMediantimetoangiographyPresentedatESC2005Inthedualtherapygroup,mediantimetoangiographywas26hours.Inthetripletherapygroup,mediantimetoangiographywas30hrs.81%ofenrolledpatientshadapositivetroponinand62%hadSTdepressionPCIwasperformedin~60%ofpatientsELISAIIPrimaryEndpointAnalysisofinfarctsizewhenassessedbyLDHQp=0.36PresentedatESC2005TheprimaryendpointofinfarctsizedidnotdifferbetweenthedualtherapygroupandthetripletherapygroupwhenassessedbyLDHQ(p=0.36)orpeakCK(p=NS)392331ELISAIISecondaryEndpointAnalysisofinitialTIMIgrade3flowatangiography(%)p=0.002PresentedatESC2005ThesecondaryendpointofinitialTIMIgrade3flowatangiographywashigherinthetripletherapygroup(47%vs67%)ELISAIIMIFreeSurvivalat30daysAnalysisofsurvivalfreefrommyocardialinfarctionat30days(%)

p=0.098PresentedatESC2005Atrendtowardhigherratesofsurvivalfreefrommyocardialinfarctionat30dayswereobservedinthetripletherapygroupTheseresultsweredrivenalmostexclusivelybymyocardialinfarction(56%MIrateinthedualtherapygroupvs46%MIrateinthetripletherapygroup)Mortalityrateof1%ineachgroupELISAIIBleedingAnalysisofbleeding(%)PresentedatESC2005NosignificantdifferenceamongbleedingexistedbetweenthetwotreatmentgroupsTherewerenostrokesineitherofthetwotreatmentgroupsp=NSELISAIIAmongpatientswithnon-STelevationMIundergoingangiographywithorwithoutrevascularization,useofatripleanti-plateletregimenofaspirin,300mgclopidogrel,andtirofibanwasnotassociatedwithadifferenceintheprimaryendpointofenzymaticinfarctsizecomparedwithadualanti-plateletregimenofaspirinanda600mgloadingdoseofclopidogrel.ThesecondaryendpointofTIMIgrade3flowwasimprovedamongthetripletherapytreatmentgroup.AfavorabletrendtowardlowerratesofMIthrough30dayswasobservedinthetripletherapygroup.Furtherinvestigationoftheclinicalbenefitoftripletherapyiswarranted(upcomingISAR-REACT2).PresentedatESC2005CONCLUSIONSELISAIIGPIIb/IIIa拮抗剂有效改善心肌微循环灌注CumulativeSurvivalafterPrimaryPTCA

inAMIStratifiedbyInitialTIMIFlowGradesStoneG,etal.Circulation.2001;104:636-641.Log-rankPfortrend=0.0096-monthMortality0.5%2.8%4.4%Survival(%)100%98%96%94%92%90%TIMI3(n=375)TIMI2(n=295)TIMI0/1(n=1657)Months0 1 2 3 4 5 6AMI=acutemyocardialinfarction.PRISM-PLUSAngiographicSubstudy:TirofibanIncreasedPerfusionStatusP=0.002fortrendbyproportionaloddsmodelZhaoX-Q,etal.Circulation.1999;100:1609-1615.TIMI-14TRIALAdjunctiveGPIIb/IIIainhibitorsduringdirectangioplastyCombinationtherapy(withreduced-dosethrombolytics)P=0.0009TIMI-3flowrateat60min62770102030405060708090100t-PA100mgt-PA50mg+AbxPatients(%)P=0.02TIMI-3flowrateat90minTIMI-14trial,Circulation1999EffectsofglycoproteinIIb/IIIainhibitiononmicrovascularflowaftercoronaryreperfusion:

Aquantitativemyocardialcontrastechocardiographystudy.

KunichikaH,Ben-YehudaO,LafitteS,KunichikaN,PetersB,DeMariaA.JAmColl

Cardiol.2004;43:276-TirofibanIncreasesMicrovascularBloodFlowafterRevascularization**Studycompletedincaninemodel.KunichikaH,etal.JAmColl

Cardiol.2004;43(2):276-283.140120100806040200Baseline Occlusion R-30 R-60 R-90 R-100Tirofiban

ControlMyocardialBloodFlow(%ofBaseline)****p<0.05TirofibanIncreaseMyocardialBloodFlowafterRevascularizationKunichikaHetal.JAmColl

Cardiol.2004;43(2):284-286.TirofibanControl1CardiacCycle 3CardiacCycle 5CardiacCycle 8CardiacCycle 11CardiacCycle 14CardiacCycle早期应用GPIIb/IIIa

临床获益更多血小板抑制<95%N=125血小板抑制>95%

N=344

MACE%PCI后早期血小板抑制水平和MACE密切相关

14.4%

55%↓P=0.0066.4%

PCI后10分钟的血小板抑制％theGOLDMulticenterStudy<circulation>2001.103:2572—2578早期应用有效降低住院死亡率

NRMI注册研究NRMI-NSTEMIRiskScoreN=60770NSTEMI患者住院死亡率%NRMI=NationalRegistryofMyocardialInfarction.PetersonE,etal.JAmColl

Cardiol.2003;42:45-5330天死亡/

心梗绝对下降(%)1.7%

2.3%

用药距离发病的时间

(n=2522) (n=2041) (n=3803) (n=1105)

0%

0.00.51.01.52.02.53.0

<6hours6–12hours12–24hours>24hours

1.7%

2.3%

2.8%越早用药绝对获益越大

PURSUIT研究：

GPIIb/IIIa

VS安慰剂JAMA.2000;284:1549-15584.15%5.02%1.65%1.32%0%1%2%3%4%5%6%死亡死亡/心梗导管室使用(n=3642)早期使用(n=2191)患者住院期间严重心脏事件下降

CRUSADE注册研究

5%17%PetersonE.CRUSADEregistrydata.ACCScientificSession;March30-April2,2003;Chicago,Il.ADMIRAL研究300患者，AMI<12小时在急诊支架置入前，随机接受阿昔单抗和安慰剂在救护车或急诊室开始用药在导管室或CCU开始用药P<0.05P=NSP=NSP<0.05

Circulation2001;103:2328-2335RandomizedComparison

UpstrEamStandardDoseTirofiban

VersusDownstrEamHigh-doSe

TirofibanorAbciximabinHigh-riskACSTreated

WithPCI

effectsonepicardialandtissuelevelreperfusion,andpostproceduralbiomarkersreleaseTheEVERESTTrialLeonardoBologneseDepartmentofCardiovascular

DiseasesAziendaOspedaliera8ArezzoPatients

treatedwithupstreamtirofibanregimenwouldhaveabettertissue-levelperfusionandreducedTroponinIreleaseafterinterventionscomparedwithpatientswhoweretreatedwithdownstreamHBDtirofibanandabciximabregimenNosignificantdifferencewouldhavefoundbetweendownstreamHBDtirofibanandabciximabregimen.TheEVERESTTrialHypothesesHigh-riskNSTEMIACSASA–HeparinThyenopiridineTirofiban123IntenttoPTCA/stentbetween24and48hoursIntenttoPTCA/stentbetween24and48hours+HBDTirofibanIntenttoPTCA/stentbetween24and48hours+Abciximab

ASA–HeparinThyenopiridineASA–HeparinThyenopiridineTheEVERESTProtocolSTUDYPROTOCOLHospitalAdmissionRandomizationPTCA(24to48hrs)cTnI6,12,18,and24hrsafterPCI

TIMIflowCTFCTMPGMCETIMIflowCTFCTMPGcTnIevery

6hrsbeforePCI

STUDYPOPULATION161patientsInitially

selected131patients

metInclusion

criteriaandwere

randomized93patientsFinalstudypopulation38pts

excluded:28CABG10nosignificantCADUpstream

Tirofibann=32DownstreamHBDTirofibann=30Downstream

Abiciximabn=31TMPGPre-PCIBlushCoroTMPGPost-PCIMCEBasalEcho-contrast2-chamberEcho

before(A)andafter(B)selective

injectionof2-3mlofhand-agitated

iopamidol.TMPGandMCEPre-PCIPost-PCITMPG0/1(%)Tissue

Level

Perfusion

byTMPGpreandpost-PCIUpstreamTirofibanHBDTirofibanAbciximabp=0.015TMPG0/1(%)UpstreamTirofibanHBDTirofibanAbciximabP=0.0009BologneseLetal.:JACC2005,inpressPatients’

AnalysisUpstreamTirofibanHBDTirofibanAbciximabp=0.04MCESIUpstreamTirofibanHBDTirofibanAbciximabP=0.01272.4Tissue

Level

Perfusion

byMCE%BologneseLetal.:JACC2005,inpressPre-PCIPost-PCIng/mLUpstreamTirofibanHBDTirofibanAbciximabp=nsUpstreamTirofibanHBDTirofibanAbciximabp=0.015p=0.0002PeakcTn-I

Levels

preandpost-PCIBologneseLetal.:JACC2005,inpressMechanicisticandclinicalfindingssuggestthatanearlyinvasivestrategywithupstreamGP

IIb/IIIainhibitorsmayyieldmorefavorable

outcomes.TheEVERESTpilotstudyalsoshowsthathighdosetirofibanorabciximad

administredjustpriorPCIachievedsimilareffectsonangiographicoutcomeandcTnIrelease.Furtherstudiesareneededtoclarifyifthisdoseregimenmayhaveaclinicalimpact.CONCLUSIONS高剂量替罗非班的临床研究TheAdditiveValueofTirofibanAdministeredWiththeHigh-DoseBolusinthePreventionofIschemicComplicationsDuringHigh-RiskCoronaryAngioplastyTheADVANCETrialM.ValgimigliUniversityofFerraraItalyErasmusMC,ThoraxcenterTheNetherlandsDepartmentofCardiologyUniversityofFerraraDrSchneider’sHypothesisBaselineplateletreactivityisnotuniforminpatientsundergoingPCIThehigherthebaselinevalue,theworsetheoutcomeBaselineplateletreactivityisproportionaltotheclinicalstatus,lowerinelectivepts,higherinNSTEACSandhighestinSTEMIptsTirofiban,atRestoreregimen,isjustenough,soonafterthebolus,tocontrolplateletreactivityinelectivepatientsCirc01;104:18;AJC02;90:1421;AJC03;91:334;AJC03;91:872;FrossardCirc04;110AbciximabEptifibatideTirofibanPRISMTirofiban

RESTORE10ug/kgin3’15’P<0,02P<0,02COMPARE,Circulation02050100150%AggregationTheCOMPARETrialOnlyACSpatients

elegibileAIMTo

re-assesstheefficacyofTirofiban

when

givenatSHDBontopofADPreceptor

blockersin:

Elective

patientsNSTE-ACSpatientsAIMTo

re-assesstheefficacyofTirofiban

when

givenatSHDBontopofADPreceptor

blockersinHigh-Risk:

Elective

patientsMultivesseltreatmentDiabetesNSTE-ACSpatientsHigh-risk

features(ESCguidelines)PCIIndicationsACSSASilentIschemiaViabilityNSTE-ACSPopulation(n=111)73%Troponinpositive55%ST>0.5mm

2leads23%Diabetes79%160-325mgASA100