GPIIbIIIa受體拮抗劑欣維寧張

血小板GPIIb/IIIa受體拮抗劑

的臨床應(yīng)用及進(jìn)展ACS發(fā)病機(jī)制和治療策略抗血小板藥物的作用機(jī)制

GPIIb/IIIa拮抗劑臨床研究匯總鹽酸替羅非班的臨床研究欣維寧的藥理作用和臨床研究GPIIb/IIIa學(xué)術(shù)地位GPIIb/IIIa臨床應(yīng)用常見問題內(nèi)容提要ACS發(fā)病機(jī)制和治療策略炎癥粥樣硬化血栓形成ThrombusQuiescentplaquePlateletsandthrombinPlaquerupture急性冠脈綜合征發(fā)病機(jī)制斑塊破裂血小板粘附血小板激活血栓部分堵塞動脈引起不穩(wěn)定心絞痛微血栓引起NSTEMI血栓完全堵塞動脈引起STEMIACS發(fā)病機(jī)制AdaptedfromDaviesMJ.Circulation.1990;82(suplII):30-46.凝血酶生成組織因子黏附分子血小板激活血管壁炎癥反應(yīng)PCI血栓形成主要機(jī)制血小板在動脈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

血小板粘附于損傷的內(nèi)皮表面并被激活

血小板內(nèi)皮細(xì)胞內(nèi)皮下血小板粘附到內(nèi)皮下血小板血栓血小板小而無核的血細(xì)胞，主要功能是維持止血在循環(huán)中的數(shù)量約1.5兆，壽命約10天黏附于血管內(nèi)皮的破裂處與激活物接觸后，血小板細(xì)胞膜和形狀發(fā)生改變血小板激活后分泌凝血因子、血管收縮物質(zhì)和生長因子穩(wěn)定的血小板激活的血小板血小板粘附和激活激活GPIIb/IIIaGPIb血管內(nèi)皮vWf

因子膠原GPIa/IIa纖維蛋白原或vWf因子GPIIb/IIIa（TXA2、ADP、凝血酶）血小板聚集纖維蛋白原或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：為血栓形成的前提和核心，凝血系統(tǒng)激活的前提和核心。

沒有血小板激活，就沒有血栓形成抗血小板治療：是ACS的首要治療措施之一。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主要抗血小板藥物的作用機(jī)制

凝血酶膠原5-羥色胺腎上腺素ADP血小板活化TXA2活化的血小板COX環(huán)氧化酶抑制劑ADP受體拮抗劑

Gp

IIb/IIIa

受體拮抗劑Gp

IIb/IIIa

受體主要抗血小板藥物作用機(jī)制血小板GPIIb/IIIa

受體拮抗劑AbciximabEptifibatideTirofibanWhiteHD.AmJCardiol.1997;80(4A):2B-10B.GPIIb/IIIa

受體拮抗劑作用機(jī)制RestingplateletPlaqueruptureandplateletadhesionPlateletactivationPreventionofplateletaggregationGPIIb/IIIaexpressionFibrinogenGPIIb/IIIainhibitorvWFvWFvWFAgonistsreleasedVesselWall大量循證醫(yī)學(xué)研究證實(shí)

GPIIb/IIIa受體拮抗劑

顯著改善ACS和PCI患者臨床預(yù)后

GPIIb/IIIa受體拮抗劑臨床研究1安慰劑較好IIb/IIIa

較好試驗(yàn)安慰劑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受體拮抗劑在PCI中的應(yīng)用KongD,etal.AmJCardiol.2003;92:651-6559%GPIIb/IIIa受體拮抗劑在ACS中的應(yīng)用GPIIb/IIIa

在糖尿病人中的應(yīng)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受體拮抗劑

替羅非班的臨床研究TheRESTOREInvestigators.Circulation.1997;96:1445-1453.ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.

替羅非班的臨床研究RESTORE

Tirofiban

對高危冠脈介入病人預(yù)后和再狹窄療效的隨機(jī)試驗(yàn)

PRISM-PLUSTirofiban

對不穩(wěn)定心肌缺血病人治療研究

一項(xiàng)隨機(jī)、雙盲、安慰劑對照、多中心研究入選對象：n=2141，發(fā)病72h內(nèi)接受PTCA或定向斑塊旋切術(shù)治療的UA/AMI者研究終點(diǎn)：各種原因的死亡、MI、PCI或復(fù)發(fā)性心肌缺血需再行PCI或CABG者由獨(dú)立盲終點(diǎn)委員評價第2天、第7天、30天內(nèi)的終點(diǎn)事件RESTORETheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE用藥方法UA/AMI<72Hr

n=2141阿司匹林325mg肝素10000uiv介入導(dǎo)絲通過冠脈病變隨機(jī)分組

tirofiban10ug/kgiv3min0.15ug.kg-1.min-1×36h安慰劑10ug/kgiv3min0.15ug.kg-1.min-1×36hACT300~400Sn=1071n=1070術(shù)后應(yīng)停用肝素，當(dāng)ACT<180s時，拔除動靜脈鞘管;替羅非班持續(xù)輸注36小時

TheRESTOREInvestigators.Circulation.1997;96:1445-1453.聯(lián)合終點(diǎn)：需緊急血運(yùn)重建者：30天內(nèi)安慰劑組為10.5%,tirofiban

組8%,相對下降24%(p=0.052)TheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE：聯(lián)合終點(diǎn)

死亡/MI/緊急血運(yùn)重建RR=30%RR=40%RR=24%Circulation1997Sep2;96(5):1445-53RR=40%P=0.0022Days7Days30Days8.75.29.86.910.58.0/緊急血運(yùn)重建

%051015安慰劑替羅非班組RR=24%P=0.052RR=30%P=0.016聯(lián)合終點(diǎn)RESTORE：聯(lián)合終點(diǎn)

死亡/MI/緊急血運(yùn)重建

40%

30%

24%TheRESTOREInvestigators.Circulation.1997;96:1445-1453.RESTORE:30天MI發(fā)生率30天發(fā)生MI的比例:安慰劑組5.7%,tirofiban

組4.2%,下降26%(p＝0.113)

即使是在PCI早期發(fā)生了MI,但停用tirofiban

后未見任何反彈跡象TheRESTOREInvestigators.Circulation.1997;96:1445-1453.5.7%4.2%RR=26%Circulation1997Sep2;96(5):1445-53RESTORE-出血發(fā)生率安慰劑組

(n=1070),n(%)替羅非班組(n=1071),n(%)P大出血40(3.7)57(5.3).096血紅蛋白下降>5g/dL19(1.8)25(2.3)輸血>2U24(2.2)38(3.5)出血需要外科治療3(0.3)2(0.2)顱內(nèi)出血3(0.3)1(0.1)腹膜后出血3(0.3)6(0.6)大出血(TIMI標(biāo)準(zhǔn))22(2.1)26(2.4).662血小板減少<90000/mm310(0.9)12(1.1)血小板減少<50000/mm31(0.1)2(0.2)TheRESTOREInvestigators.Circulation.1997;96:1445-1453.Circulation1997Sep2;96(5):1445-53RESTORE結(jié)論ACS接受PCI患者使用tirofiban

可有效預(yù)防不良心臟事件的發(fā)生聯(lián)合終點(diǎn)：死亡/MI/緊急血運(yùn)重建

48小時↓40%p=0.002

第7天↓

30%p=0.016第30天↓24%p=0.052兩組間主要出血并發(fā)癥無明顯差異（P=0.096)兩組間嚴(yán)重血小板減少(<50000/mm3)均罕見替羅非班組0.2%

，安慰劑組0.1%;P=1.000PRISM-PLUS方法一項(xiàng)隨機(jī)、雙盲、多中心研究1570例12h內(nèi)有靜息心絞痛伴ECG或CK-MB

變化并已接受Asprin治療的UA/NSTEMI患者研究復(fù)合終點(diǎn)事件為死亡、MI、或2天、7天內(nèi)的難治性缺血事件及30天、6月心臟事件ThePRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.PRISM-PLUSUA/NSTEMI

n=1570阿司匹林325mg隨機(jī)

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介入術(shù)后停用肝素(拔除鞘管前最少2小時)，術(shù)后Tirofiban持續(xù)應(yīng)用12—24小時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?；颊?%)

66%

43%

30%42PCI214212876301848肝素組替羅非班+肝素組PCI前(N=1570)小時66%

44%012243612840PCI后(N=475)3.02.52.01.51.00.50天肝素組替羅非班+肝素組死亡/心?；颊?%)PCI前輸注48小時,術(shù)中及術(shù)后持續(xù)輸注12-24小時,

平均輸注:71.3+20小時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研究替羅非班顯著降低UA/NSTEMI患者TnI水平Heparin(n=52)Tirofiban+Heparin(n=53)TnI

(ng/mL)基線峰值3.11.6P=NS5.215.5P=0.017061218PRISM-PLUS研究JanuzziJL,etal.AmJCardiol.2000;86:713-717.3.28.5P=0.01624小時平均PRISM-PLUS：出血發(fā)生率PRISM-PLUSStudyInvestigators.NEnglJMed.1998;338:1488-1497.n=773n=797P=0.34*主要出血的定義：血紅蛋白下降＜4.0g/dl、需輸血＞2u、需外科糾正出血、顱內(nèi)出血、腹膜后出血、任何復(fù)合出血情況*ACS患者接受tirofiban

治療可有效減少不良心臟事件的發(fā)生對于所有患者聯(lián)合終點(diǎn)：死亡/MI

48小時↓66%p=0.01第7天↓

43%p=0.006

第30天↓30%p=0.03

6個月↓22%p=0.06對于行PCI的患者在術(shù)前,術(shù)中,術(shù)后持續(xù)滴注第30天死亡/MI

↓44%p=0.03

與肝素合用出血副作用未見明顯增加（P=0.34)PRISM-PLUS：結(jié)論

國內(nèi)第一個GPIIb/IIIa

受體拮抗劑

——欣維寧藥理作用和臨床研究欣維寧?--產(chǎn)品簡介替羅非班通用名Tirofiban，由美國默克公司創(chuàng)制,1998年5月18日美國FDA批準(zhǔn)在美國上市。欣維寧?是目前國內(nèi)唯一的血小板IIb/IIIa受體拮抗劑，國家二類新藥，

2004年8月批準(zhǔn)在中國上市。替羅非班藥理學(xué)通用名：鹽酸替羅非班氯化鈉注射液英文名：Tirofibanhydrochloridesodiumchlorideinjection商品名：欣維寧分子式：C22H36N2O5S.HCL.H2O分子量：495.08形狀：本品為無色澄明液體藥理作用抗血小板聚集作用：

欣維寧對血小板聚集率（%）的影響（X±S）

試驗(yàn)組（n=101）實(shí)測值對照組（n=99）實(shí)測值給藥前54.0±19.357.0±20.4

給藥后29.1±21.652.1±19.5

變化率-24.9±23.7-4.9±24.9

實(shí)驗(yàn)組給藥前后及兩組之間的變化均有顯著性藥理作用抗血栓形成在電損傷引起的冠狀動脈左旋支閉塞性血栓模型中，靜注10μg/kg/min鹽酸替羅非班即可防止3只狗形成閉塞性血栓，使血栓形成時間延長，血栓重量減少，與對照組相比有顯著差異。

治療電損傷引起冠狀動脈左旋支閉塞性血栓時，在給予組織型纖維蛋白溶解酶原激活物（t-PA）或鏈激酶（STK）前15min靜注鹽酸替羅非班可增加再灌注的發(fā)生率，減少連續(xù)用藥期間急性血栓再閉塞的發(fā)生率。主要藥代動力學(xué)的相關(guān)參數(shù)半衰期:約為2—3小時達(dá)峰時間:靜注后5分鐘血小板抑制率大于93%

*靜注時，替羅非班對離體血小板聚集的抑制劑量和濃度成正比。受體的可逆性停藥1.5-4小時，血小板的功能迅速恢復(fù)。TopolE,etal.Lancet.1999;353:227-231.AbciximabEptifibatideTirofibanOOOOOOOOOHHNHNSSNHNHNNHHNNHNHH2NH2NH

N–SO2–C4H9OCOOHHNFabfragmentofachimericmonoclonal

antibody

MW50,000DNonpeptidetyrosine

derivative

MW500DCyclic

heptapeptide

MW800D鼠源性單克隆抗體合成非肽類合成肽類三種靜脈GPⅡb/Ⅲa受體抑制劑的比較

AciximabEptifibatideTirofiban結(jié)構(gòu)鼠人IgG嵌合體環(huán)肽KGD小分子非肽RGD分子量(道爾頓)5000800500GPⅡb/Ⅲa選擇性差較強(qiáng)較強(qiáng)化學(xué)計量法1.5:1100:1100:1血漿半衰期10-15分鐘1.5-2.5小時1.5-2.5小時受體抑制可逆性差(輸注血小板)較強(qiáng)(停藥)較強(qiáng)(停藥)出血發(fā)生率多較少較少血小板無力癥相對較多少少安全性相對較差相對較好相對較好價格昂貴相對較低相對較低適應(yīng)癥(FDA)PCIACS;PCIACS;PCI三種靜脈GPⅡb/Ⅲa受體抑制劑的比較JACC2001藥代動力學(xué)曲線三種靜脈GPⅡb/Ⅲa受體抑制劑的比較對血小板抑制的可逆性%血小板聚集率100806040200061218243036依替巴肽替羅非班阿昔單抗停用藥物小時

三種靜脈GPⅡb/Ⅲa受體抑制劑的比較ScarboroughRM,etal.Circulation.1999;100:437-444.

欣維寧?（鹽酸替羅非班）治療急性冠狀動脈綜合癥有效性和安全性臨床研究欣維寧臨床研究協(xié)作組：華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬協(xié)和醫(yī)院鄭州大學(xué)國家藥品臨床研究基地（鄭州大學(xué)附屬第一醫(yī)院）華中科技大學(xué)同濟(jì)醫(yī)學(xué)院臨床藥理研究所方法一項(xiàng)隨機(jī)、雙盲、多中心研究200例24h內(nèi)伴有反復(fù)發(fā)作胸痛及典型的ST-T改變或血清酶水平改變已接受Asprin治療的UA/NSTEMI患者療效觀察指標(biāo)

：1）任何原因的死亡2）新的MI3）頑固性缺血狀態(tài)4）血小板聚集率安全性評價：1）不良反應(yīng)2）對一般生命體征的影響

3）實(shí)驗(yàn)室檢查欣維寧?驗(yàn)證臨床研究欣維寧?驗(yàn)證臨床研究

給藥方法試驗(yàn)組：

1)欣維寧?0.4ug/kg/min30分鐘,隨后0.1ug/kg/min，2-5天

2)肝素5000IU,靜脈注射,隨后1000IU/h靜脈點(diǎn)滴（試驗(yàn)中期調(diào)整肝素劑量，負(fù)荷量和維持量均減半)同時根據(jù)APTT值調(diào)整肝素劑量，使APTT控制在正常水平的1.5-2倍)3)阿司匹林腸溶片

對照組：

(安慰劑+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/頑固性缺血患者(%)

55%

52.6%欣維寧?驗(yàn)證臨床研究主要終點(diǎn)指標(biāo)和復(fù)合終點(diǎn)指標(biāo)欣維寧?驗(yàn)證臨床研究欣維寧?驗(yàn)證臨床研究對血小板聚集率的影響

安全性--出血不良反應(yīng)欣維寧?驗(yàn)證臨床研究實(shí)驗(yàn)室檢查---對APTT(s)的影響欣維寧?驗(yàn)證臨床研究實(shí)驗(yàn)室檢查---對血小板計數(shù)（X109/L）的影響欣維寧?驗(yàn)證臨床研究

欣維寧--產(chǎn)品特點(diǎn)國內(nèi)第一個血小板IIb/IIIa受體拮抗劑PCI術(shù)前盡早應(yīng)用臨床獲益更多顯著降低ACS和PCI患者死亡/心梗等嚴(yán)重不良事件5分鐘血小板抑制率93%快速完全抑制血栓形成，方便患者急救可逆性好停藥后1.5--4小時血小板功能迅速恢復(fù)，

使用安全方便進(jìn)口包材，嚴(yán)格把關(guān)，確保產(chǎn)品品質(zhì)。欣維寧適應(yīng)證和用法用量ACS的藥物治療（UA/NSTEMI）欣維寧負(fù)荷量0.4ug/kg/min靜脈滴注30min

維持量0.1ug/kg/min靜脈滴注48-108hACS的介入治療PCI（UA/NSTEMI/STEMI）欣維寧負(fù)荷量10ug/kg3min以上靜脈推注；維持量0.15ug/kg/min靜脈滴注36h欣維寧--包裝價格規(guī)格100ml:5mg價格:456元療程價格:

介入治療1368-2280元藥物治療1824-3648元血小板GPIIb/IIIa受體拮抗劑

的學(xué)術(shù)地位

NSTEACS

中、高?；颊叩脑缙谥委煟趹?yīng)用阿司匹林及肝素的基礎(chǔ)上，加用依替巴肽或替羅非班（1A級）同時應(yīng)用氯吡格雷的中、高?；颊?，早期加用依替巴肽或替羅非班（2A級）2004ACCP-7NSTEACS治療建議Guyatt

等定義:等級1:獲益大于風(fēng)險和花費(fèi);等級2:獲益風(fēng)險比不確定,應(yīng)據(jù)患者個體差異來進(jìn)行不同的選擇證據(jù)強(qiáng)度按A、B、C依次降低

對于被評價為中高危的NSTEMI/UA病人，建議在PCI之前盡可能開始使用GPIIb/IIIa拮抗劑（依替巴肽或替羅非班）(證據(jù)1A)

對于正接受替羅非班治療的NSTEMI/UA病人，建議PCI應(yīng)在靜脈點(diǎn)滴替羅非班4h后進(jìn)行(證據(jù)2C）2004ACCP-7PCI中抗栓治療建議非ST抬高ACS抗血小板藥物治療建議ESC2004不伴有ST段抬高的ACS,行PCI治療,建議圍手術(shù)期靜脈應(yīng)用GPⅡb/Ⅲa拮抗劑(證據(jù)1A)

不伴有ST段抬高的ACS,未行PCI治療,建議靜脈應(yīng)用替羅非班或依替巴肽(證據(jù)2A)等級1:獲益大于風(fēng)險和花費(fèi);等級2:獲益風(fēng)險比不確定,應(yīng)據(jù)患者個體差異來進(jìn)行不同的選擇證據(jù)水平：A級：來自多個隨機(jī)或匯翠分析；B級：來自單個隨機(jī)或非隨機(jī)試驗(yàn)；C級：來自專家共識

血小板GPIIb/IIIa臨床應(yīng)用常見問題

三聯(lián)抗血小板藥物的效果和安全性GPIIb/IIIa有效改善心肌灌注早期應(yīng)用更多獲益高劑量替羅非班的研究合用抗凝藥物的劑量

三聯(lián)抗血小板藥物聯(lián)合治療的效果和安全性TheCREDOTrial

Clopidogrel

fortheReductionofEvents

DuringObservation

執(zhí)行委員會

主席:ProfessorEricJ.Topol

主要研究者

DoctorStevenR.Steinhubl

1年CREDO研究

波立維在PCI患者中的療效和安全性A組B組n=2116患者PCI28天安慰劑負(fù)荷劑量

+ASA325mg安慰劑+ASA81–325mg波立維75mg+ASA81–325mgPCI前3–24小時波立維負(fù)荷劑量

300mg

+ASA325mg波立維75mg

+ASA325mg波立維75mg

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

波立維* 安慰劑* n=900PP n=915PP

GPIIb/IIIa拮抗劑的應(yīng)用(%) 427（47.4%） 396(43.3%)

預(yù)先計劃(%) 217(24.1%) 208(22.7%) 臨時決定(%) 210(23.3%) 188(20.6%)

*OntopofstandardtherapyincludingASA PP=Per-ProtocolCREDO

研究在進(jìn)行PCI階段GPIIb/IIIa拮抗劑的應(yīng)用SteinhublS,etal.JAMA,November20,2002–Vol288,No19:2411–2420氯吡格雷與安慰劑亞組分析28天主要結(jié)果（死亡，心?；蚣毙訲VR）SteinhublS,etal.JAMA,November20,2002–Vol288,No19:2411–2420CREDO研究A：PCI前3-6小時給予研究藥物GPIIb/IIIa

抑制劑是 (N=417)

否 (N=476)氯吡格雷較好安慰劑較好RRR%GPIIb/IIIa

抑制劑是 (N=378)

否 (N=473)B：PCI前>6-24小時給予研究藥物-3.0-21.845.328.3020-20-404060◆◆◆◆接受GPIIb/IIIa拮抗劑治療的患者在28天時顯示出更多的益處安全性:大出血事件

28天的結(jié)果ITT(意向治療人群)*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嚴(yán)重出血所有狀況未進(jìn)行介入治療進(jìn)行介入治療應(yīng)用GPIIb/IIIa是(n=823)否(n=991)波立維負(fù)荷劑量(n=1,053)無負(fù)荷劑量(n=1,063)CREDO研究安全性:小出血事件

28天的結(jié)果ITT(意向治療人群)*OntopofstandardtherapyincludingASAITT=Intent-to-treatpopulationPP=PerProtocolpopulation

CREDO研究CREDO研究的患者接受了全美最好的標(biāo)準(zhǔn)治療：

阿司匹林＋氯吡格雷＋GPIIb/IIIa抑制劑（幾乎半數(shù)患者接受GPIIb/IIIa抑制劑）GPIIb/IIIa和氯吡格雷聯(lián)合應(yīng)用，顯示出進(jìn)一步的益處。同時接受GPIIb/IIIa抑制劑的患者并未顯著增加嚴(yán)重出血和小量出血，重要的是無致命性出血或顱內(nèi)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拮抗劑有效改善心肌微循環(huán)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早期應(yīng)用GPIIb/IIIa

臨床獲益更多血小板抑制<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密切相關(guān)

14.4%

55%↓P=0.0066.4%

PCI后10分鐘的血小板抑制％theGOLDMulticenterStudy<circulation>2001.103:2572—2578早期應(yīng)用有效降低住院死亡率

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

Cardiol.2003;42:45-5330天死亡/

心梗絕對下降(%)1.7%

2.3%

用藥距離發(fā)病的時間

(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%越早用藥絕對獲益越大

PURSUIT研究：

GPIIb/IIIa

VS安慰劑JAMA.2000;284:1549-15584.15%5.02%1.65%1.32%0%1%2%3%4%5%6%死亡死亡/心梗導(dǎo)管室使用(n=3642)早期使用(n=2191)患者住院期間嚴(yán)重心臟事件下降

CRUSADE注冊研究

5%17%PetersonE.CRUSADEregistrydata.ACCScientificSession;March30-April2,2003;Chicago,Il.ADMIRAL研究300患者，AMI<12小時在急診支架置入前，隨機(jī)接受阿昔單抗和安慰劑在救護(hù)車或急診室開始用藥在導(dǎo)管室或CCU開始用藥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高劑量替羅非班的臨床研究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