GPIIbIIIa受體拮抗劑欣維寧[張]

1、n ACS發(fā)病機(jī)制和治療策略發(fā)病機(jī)制和治療策略n 抗血小板藥物的作用機(jī)制抗血小板藥物的作用機(jī)制n GPIIb/IIIa拮抗劑拮抗劑n 欣維寧的藥理作用和臨床研究欣維寧的藥理作用和臨床研究nGPIIb/IIIanGPIIb/IIIaACS發(fā)病機(jī)制和治療策略發(fā)病機(jī)制和治療策略ThrombusQuiescentplaquePlateletsand thrombinPlaque rupture斑塊破裂血小板粘附血小板激活血小板激活血栓部分堵塞動(dòng)脈引起不穩(wěn)定心絞痛微血栓引起NSTEMI血栓完全堵塞動(dòng)脈引起STEMIACS發(fā)病機(jī)制發(fā)病機(jī)制Adapted from Davies MJ. Circulatio

2、n. 1990; 82 (supl II): 30-46.凝血酶生成凝血酶生成組織因子組織因子黏附分子黏附分子血小板激活血小板激活血管壁炎癥反應(yīng)血管壁炎癥反應(yīng)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 （TXA2、ADP、凝血酶）、凝血酶）Ca2+Ca2+Ca2+Ca2+Clinical findingECGSerum markersRisk assessmentNon-cardiacchest painStableanginaUANSTEMINegativePositiveST-T wave changesST elevationLowprobabilityM

3、edium-high riskThrombolysisPrimary PCIAspirin + GP IIb/IIIa inhibitor clopidogrel + heparin/LMWH + anti-ischemic RxEarly invasive RxDischargeNegativeDiagnostic rule out MI/ACS pathwaySTEMI NegativeAtypical painLow riskAspirin, heparin/low-molecular-weight heparin (LMWH) + clopidogrelAnti-ischemic Rx

4、 Early conservative therapyOngoing painDM=diabetes mellitus.Cannon, Braunwald. Heart Disease. 2001.Rest pain, Post-MI, DM, Prior AspirinExertional pain凝血酶凝血酶膠原膠原5-羥色胺羥色胺腎上腺素腎上腺素血小板活化血小板活化活化的血小板活化的血小板 環(huán)氧化酶環(huán)氧化酶 抑制劑抑制劑 ADP受體受體 拮抗劑拮抗劑 Gp IIb/IIIa 受體拮抗劑受體拮抗劑IIb/IIIa 主要抗血小板藥物作用機(jī)制主要抗血小板藥物作用機(jī)制血小板血小板GP IIb/I

5、IIa 受體拮抗劑受體拮抗劑AbciximabEptifibatideTirofibanWhite HD. Am J Cardiol. 1997;80(4A):2B-10B.RestingplateletPlaquerupture andplateletadhesionPlateletactivationPrevention of plateletaggregationGP IIb/IIIaexpressionFibrinogenGP IIb/IIIainhibitorvWFvWFvWFAgonistsreleasedVessel Wall1安慰劑較好安慰劑較好IIb/IIIa 較好較好試驗(yàn)試

6、驗(yàn)安慰劑安慰劑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%IMPACT I1.0%67891.2%IMPACT II0.9%10,799ESPRIT1.0%0.8%17,403ISAR-21.1%0.8%17,804ADMIRAL1.2%0.8%18,104EPISTENT1.1%0.8%15,3391.3%CADILLAC 0.9%20,186OR & 95% CI0.73 (0.55, 0.96)P=0.0

7、2427% P=0.024Kong D, et al. Am J Cardiol. 2003; 92:651-6559%Roffi M, et al. Circulation. 2001;104:2767-2771. (with permission)30天死亡天死亡2163687362167741211576458PURSUITPRISMPRISM-PLUSGUSTO IVPARAGON APARAGON BPooled6.1%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=.93

8、P=.007 Trial N Odds Ratio & 95% Cl Placebo IIb/IIIaBreslow-Day: P=.50IIb/IIIa BetterPlacebo BetterOR=0.7400.511.5226% P=0.007The RESTORE Investigators. Circulation. 1997; 96:1445-1453. The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.一項(xiàng)隨機(jī)、雙盲、安慰劑對(duì)照、多中心研究一項(xiàng)隨機(jī)、雙盲、安慰劑對(duì)照、多中心研究入選對(duì)象

9、：入選對(duì)象： n=2141，發(fā)病，發(fā)病72h內(nèi)接受內(nèi)接受PTCA或定或定 向斑塊旋切術(shù)治療的向斑塊旋切術(shù)治療的UA/AMI者者研究終點(diǎn)：各種原因的死亡、研究終點(diǎn)：各種原因的死亡、MI、PCI或復(fù)發(fā)性或復(fù)發(fā)性 心肌缺血需再行心肌缺血需再行PCI或或CABG者者由獨(dú)立盲終點(diǎn)委員評(píng)價(jià)第由獨(dú)立盲終點(diǎn)委員評(píng)價(jià)第2天、第天、第7天、天、30天內(nèi)的天內(nèi)的 終點(diǎn)事件終點(diǎn)事件The RESTORE Investigators. Circulation. 1997; 96:1445-1453.用藥方法用藥方法UA/AMI72Hr n=2141阿司匹林阿司匹林325mg肝素肝素10000u iv介入導(dǎo)絲通過(guò)冠介入導(dǎo)

10、絲通過(guò)冠脈病變脈病變隨機(jī)分組隨機(jī)分組 tirofiban 10ug/kg iv 3 min 0.15ug.kg-1.min-1 36h安慰劑安慰劑10ug/kg iv 3 min 0.15ug.kg-1.min-1 36hACT 300400Sn=1071n=1070術(shù)后應(yīng)停用肝素，當(dāng)術(shù)后應(yīng)停用肝素，當(dāng)ACT180s時(shí)，拔除動(dòng)靜脈鞘管時(shí)，拔除動(dòng)靜脈鞘管; ;替羅非班持續(xù)輸注替羅非班持續(xù)輸注3636小時(shí)小時(shí) The RESTORE Investigators. Circulation. 1997; 96:1445-1453.Circulation 1997 Sep 2;96(5):1445-53

11、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(duì)下降24%(p=0.052)The RESTORE Investigators. Circulation. 1997; 96:1445-1453.RR=30%RR=40%RR=24%RR=40%P=0.0022 Days7 Days30 Days8.75.29.86.910.58.0/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) 40% 30% 24%The RESTORE Investigators. Circulation. 1997

12、; 96:1445-1453.Circulation 1997 Sep 2;96(5):1445-53 30天發(fā)生天發(fā)生MI的比例的比例:安慰劑組安慰劑組5.7%, tirofiban 組4.2% ,下降26%(p0.113) 即使是在PCI早期發(fā)生了MI, 但停用tirofiban 后未見(jiàn)任何反彈跡象The RESTORE Investigators. Circulation. 1997; 96:1445-1453.5.7%4.2%RR=26%Circulation 1997 Sep 2;96(5):1445-53The RESTORE Investigators. Circulation.

13、 1997; 96:1445-1453.結(jié)論結(jié)論n ACS接受接受PCI患者使用患者使用tirofiban 可有效預(yù)防不良心可有效預(yù)防不良心 臟事件的發(fā)生臟事件的發(fā)生n 聯(lián)合終點(diǎn)：死亡聯(lián)合終點(diǎn)：死亡/MI/ 48小時(shí)小時(shí) 40% p=0.002 第第7天天 30% p=0.016 第第30天天 24% p=0.052n兩組間主要出血并發(fā)癥無(wú)明顯差異（兩組間主要出血并發(fā)癥無(wú)明顯差異（P=0.096)P=0.096)n兩組間嚴(yán)重血小板減少兩組間嚴(yán)重血小板減少(50 000/mm3)均罕見(jiàn)均罕見(jiàn) 替羅非班組替羅非班組0.2% ，安慰劑組，安慰劑組 0.1%; P=1.000方法方法一項(xiàng)隨機(jī)、雙盲、多

14、中心研究一項(xiàng)隨機(jī)、雙盲、多中心研究1570例例12h內(nèi)有靜息心絞痛伴內(nèi)有靜息心絞痛伴ECG或或CK-MB 變化并已接受變化并已接受 Asprin治療的治療的UA/NSTEMI患者患者研究復(fù)合終點(diǎn)事件為死亡、研究復(fù)合終點(diǎn)事件為死亡、MI、或或2天、天、7天內(nèi)天內(nèi) 的難治性缺血事件及的難治性缺血事件及30天、天、6月心臟事件月心臟事件The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.UA/NSTEMI n=1570阿司匹林阿司匹林325mg隨機(jī)隨機(jī) tirofiban 0.4ug/kg/m iv 30 min

15、0.1ug/kg/m iv 48h 肝素肝素1000u/h iv 48h肝素肝素5000u iv1000u/ h iv 48hAptt=2 倍倍n=773n=797PCIn=475tirofiban 0.1ug/kg/m iv 1224h肝素肝素50007500u iv 然后然后1000u/h iv肝素肝素50007500u iv然后然后1000u/ h iv介入介入術(shù)后停用肝素術(shù)后停用肝素 ( 拔除鞘管前最少拔除鞘管前最少2小時(shí)小時(shí))，術(shù)后，術(shù)后Tirofiban持續(xù)應(yīng)用持續(xù)應(yīng)用1224小時(shí)小時(shí)The PRISM-PLUS Study Investigators. N Engl J Med.

16、 1998;338:1488-1497.RR=risk reduction.The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.RR=66%P=0.012 Days7 DaysRR=43%P=0.006RR=30%P=0.0330 Days2.60.98.34.911.98.7051015Heparin (n=797) Tirofiban + Heparin (n=773)死亡死亡/ /心梗患者心?；颊?(%) 66% 43% 30%42PCI214212876301848肝素組替羅非班+肝素組PCI前前 (

17、 N=1570)小時(shí)小時(shí)66% 44%012243612840PCI后后 (N=475)3.02.52.01.51.00. 50天天肝素組替羅非班+肝素組死亡死亡/ /心?；颊咝墓；颊?(%) PCI前輸注前輸注48小時(shí)小時(shí), 術(shù)中及術(shù)后持續(xù)輸注術(shù)中及術(shù)后持續(xù)輸注12-24小時(shí)小時(shí), 平均輸注平均輸注: 71.3+20 小時(shí)小時(shí)The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.44.7%1.2%3.1%Throux P, et al. Circulation. 2000;102:2466-2472. Hep

18、arin (n=193)Tirofiban + Heparin(n=169)Patients (%)9.3%0.0%P=0.0315.5%P=0.00219.2%11.2%P=0.03Day 7Day 30Day 1805015102048 hoursP=0.005 100% 87% 70% 42%P=0.002 for trend by proportional odds modelZhao X-Q, et al. Circulation. 1999;100:1609-1615.Heparin (n=52)Tirofiban + Heparin (n=53)TnI (ng/mL)基線峰值3.

19、11.6P=NS5.215.5P=0.017061218Januzzi JL, et al. Am J Cardiol. 2000;86:713-717.3.28.5P=0.01624小時(shí)平均PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.n=773n=797P=0.34*主要出血的定義：血紅蛋白下降主要出血的定義：血紅蛋白下降4.0g/dl、需輸血、需輸血2u、需外科糾正出血、顱內(nèi)出血、腹膜后出血、需外科糾正出血、顱內(nèi)出血、腹膜后出血、任何復(fù)合出血情況任何復(fù)合出血情況*n ACS患者接受患者接受tirofiba

20、n 治療可有效減少不良心臟事治療可有效減少不良心臟事 件的發(fā)生件的發(fā)生n 對(duì)于所有患者聯(lián)合終點(diǎn)：死亡對(duì)于所有患者聯(lián)合終點(diǎn)：死亡/MI 48小時(shí)小時(shí) 66% p=0.01 第第7天天 43% p=0.006 第第30天天 30% p=0.03 6個(gè)月個(gè)月 22% p=0.06 對(duì)于行對(duì)于行PCI的患者在術(shù)前的患者在術(shù)前,術(shù)中術(shù)中,術(shù)后持續(xù)滴注術(shù)后持續(xù)滴注 第第30天死亡天死亡/MI 44% p=0.03 與肝素合用出血副作用未見(jiàn)明顯增加與肝素合用出血副作用未見(jiàn)明顯增加（P=0.34)P=0.34)欣維寧藥理作用和欣維寧藥理作用和臨床研究臨床研究 欣維寧對(duì)血小板聚集率（%）的影響（X S） 試驗(yàn)組

21、（n =101）實(shí)測(cè)值 對(duì)照組（n=99）實(shí)測(cè)值 給藥前 54.0 19.3 57.0 20.4 給藥后 29.1 21.6 52.1 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Topol E, et al. Lancet. 1999;353:227-231.AbciximabEptifibatideTirofibanOOOOOOOOOHHNHNSSNHNHNNHHNNHNHH2NH2NHNSO2C4H9OCOOHHNFab fragment of a chimeric monoclonal antibodyMW 50,000 DNo

22、npeptide tyrosine derivative MW 500 DCyclic heptapeptide MW 800 D鼠源性單克隆抗體鼠源性單克隆抗體合成非肽類合成非肽類合成肽類合成肽類0204060801000h6-24小時(shí)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(shí)顯示出更多的益處* On top of standard therapy including ASAITT=Intent-to-treat populationPP = Per Protocol population 嚴(yán)重出血所有狀況未進(jìn)行

23、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(wú)負(fù)荷劑量(n=1,063)* On top of standard therapy including ASAITT=Intent-to-treat populationPP = Per Protocol population 所有狀況 32（3.0）23(2.2)0.22未進(jìn)行介入治療 3(0.3)1(0.1)0.37進(jìn)行介入治療29(2.8)22(2.1)0.35應(yīng)用GPIIb/IIIa是 (n=823)12(2.8)4(1.0)0.08否 (n=991)8(1.7)9(1.

24、7)0.99波立維負(fù)荷劑量n=1,053（%）無(wú)負(fù)荷劑n=1,063（%）小出血 P值vCREDO 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）vGPIIb/IIIa和氯吡格雷氯吡格雷聯(lián)合應(yīng)用，顯示出 進(jìn)一步的益處。v同時(shí)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(wú)致命性出血或顱內(nèi)出血。Bonz AW, et al. J Am Coll Cardiol 2002;40:662-668 Bonz AW, et al. J Am Coll Cardiol 2002;40:662-668

25、 Bonz AW, et al. J Am Coll Cardiol 2002;40:662-668 n = 109 Elective PCI PatientsGP IIb-IIIa Inhibition Reductions in Troponin & Long-term Death/MI/TVR with Aspirin, Heparin & Pretreatment With Clopidogrel P 0.05ASA + UFH + Pretreatment with Clopidogrel (n = 46)ASA + UFH + Clopidogrel + GP II

26、b-IIIa Inhibitor (n = 50) P 0.05P 0.08P 0.1 mV in 2 leads or transient ST elevation)29% female, mean age 63 years, mean follow-up 30 daysLow-molecular weight heparin, beta-blocker, and statin therapy were administered to all patientsgPrimary Endpoint: Infarct size as assessed by LDHQ at 48 hours and

27、 as assessed by peak CKgSecondary Endpoint: Initial TIMI flow grade of the culprit arteryAngiography with or without revascularization (24-48 hrs)Median time to angiographyPresented at ESC 2005 In the dual therapy group, median time to angiography was 26 hours. In the triple therapy group, median ti

28、me to angiography was 30 hrs. 81% of enrolled patients had a positive troponin and 62% had ST depression PCI was performed in 60% of patientsAnalysis of infarct size when assessed by LDHQ p=0.36Presented at ESC 2005 The primary endpoint of infarct size did not differ between the dual therapy group a

29、nd the triple therapy group when assessed by LDHQ (p=0.36) or peak CK (p=NS)Analysis of initial TIMI grade 3 flow at angiography (%) p=0.002Presented at ESC 2005 The secondary endpoint of initial TIMI grade 3 flow at angiography was higher in the triple therapy group (47% vs 67%)Analysis of survival

30、 free from myocardial infarction at 30 days (%) p=0.098Presented at ESC 2005Analysis of bleeding (%) Presented at ESC 2005p = NSPresented at ESC 2005拮抗劑拮抗劑有效改善心肌微循環(huán)灌注有效改善心肌微循環(huán)灌注Stone G, et al. Circulation. 2001;104:636-641.Log-rank P for trend=0.0096-month Mortality0.5%2.8%4.4%Survival (%)100%98%96%

31、94%92%90%TIMI 3 (n=375)TIMI 2 (n=295)TIMI 0/1 (n=1657)Months0123456AMI=acute myocardial infarction.112137481982010203040506070800123TIMI Flow GradePercentageHeparinTirofiban + heparinP=0.002 for trend by proportional odds modelZhao X-Q, et al. Circulation. 1999;100:1609-1615.Adjunctive GP IIb/IIIa i

32、nhibitors during direct angioplastyCombination therapy ( with reduced-dose thrombolytics)P=0.0009TIMI-3 flow rate at 60 min62770102030405060708090100t-PA 100 mgt-PA 50 mg + AbxPatients (%)P=0.02 TIMI-3 flow rate at 90 minTIMI-14 trial, Circulation 1999*Study completed in canine model.Kunichika H, et

33、 al. J Am Coll Cardiol. 2004;43(2):276-283.140120100806040200Baseline OcclusionR-30R-60R-90R-100Tirofiban ControlMyocardial Blood Flow (% of Baseline)* p0.05Kunichika H et al. J Am Coll Cardiol. 2004;43(2):284-286.TirofibanControl1 Cardiac Cycle3 Cardiac Cycle 5 Cardiac Cycle8 Cardiac Cycle 11 Cardi

34、ac Cycle 14 Cardiac Cycle血小板抑制血小板抑制95% N=344 MACE %PCI后早期血小板抑制水平和后早期血小板抑制水平和MACE密切相關(guān)密切相關(guān) 14.4% 55%P=0.0066.4% PCI后后10分鐘的血小板抑制分鐘的血小板抑制the GOLD Multicenter Study2001.103:25722578NRMI-NSTEMI Risk ScoreN=60770NSTEMI患者患者住 院 死 亡 率 %NRMI=National Registry of Myocardial Infarction.Peterson E, et al. J Am Co

35、ll Cardiol. 2003;42:45-5330天天死死亡亡/ 心心梗梗絕絕對(duì)對(duì)下下降降 (%)1.7% 2.3% 用用 藥藥 距距 離離 發(fā)發(fā) 病病 的的 時(shí)時(shí) 間間(n=2522)(n=2041)(n=3803)(n=1105) 0% 0.00.51.01.52.02.53.0 24 hours 1.7% 2.3% 2.8% 越早用藥越早用藥 絕對(duì)獲益越大絕對(duì)獲益越大 PURSUIT研究：研究： GPIIb/IIIa VS 安慰劑安慰劑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=

36、3642)早期使用 (n=2191)患者5%17%Peterson E. CRUSADE registry data. ACC Scientific Session; March 30-April 2, 2003; Chicago, Il.21.1%23.7%12.4%13.3%2.5%2.5%8.3%9.2%0%10%20%30%30 天天6 個(gè)月個(gè)月30 天天6 個(gè)月個(gè)月Death, ReMI, Urg TVR安慰劑安慰劑阿昔單抗阿昔單抗P0.05P=NSP=NSP0.05Randomized Comparison UpstrEam Standard Dose Tirofiban Vers

37、us DownstrEam High-doSe Tirofiban or Abciximab in High-risk ACS Treated With PCI effects on epicardial and tissue level reperfusion, and postprocedural biomarkers releaseThe EVEREST TrialLeonardo BologneseDepartment of Cardiovascular DiseasesAzienda Ospedaliera 8 Arezzo Patients treated with upstrea

38、m tirofiban regimen would have a better tissue-level perfusion and reduced Troponin I release after interventions compared with patients who were treated with downstream HBD tirofiban and abciximab regimen No significant difference would have found between downstream HBD tirofiban and abciximab regi

39、men.The EVEREST Trial HypothesesHigh-risk NSTEMIACSASA Heparin ThyenopiridineTirofiban123Intent to PTCA/stentbetween 24 and 48 hoursIntent to PTCA/stentbetween 24 and 48 hours+ HBD TirofibanIntent to PTCA/stentbetween 24 and 48 hours+ Abciximab ASA HeparinThyenopiridineASA Heparin ThyenopiridineThe

40、EVEREST ProtocolcTnI 6, 12, 18, and 24 hrs after PCI cTnI every 6 hrs before PCI STUDY POPULATION161 patientsInitially selected131 patients metInclusion criteria and were randomized93 patientsFinal study population38 pts excluded: 28 CABG 10 no significant CADUpstream Tirofibann=32Downstream HBD Tir

41、ofibann=30Downstream Abiciximabn=31TMPG Pre-PCITMPG Post-PCIMCE2-chamber Echo before (A) and after (B) selective injection of 2-3 ml of hand-agitated iopamidol.TMPG and MCEPre-PCIPost-PCITMPG 0/1 (%)Tissue Level Perfusion by TMPG pre and post-PCIUpstreamTirofibanHBDTirofibanAbciximabp=0.015TMPG 0/1

42、(%)UpstreamTirofibanHBDTirofibanAbciximabP= 0.0009Bolognese L et al.: JACC 2005, in pressPatients AnalysisUpstreamTirofibanHBDTirofibanAbciximabp=0.04MCESI UpstreamTirofibanHBDTirofibanAbciximabP=0.01272.4Tissue Level Perfusion by MCE%Bolognese L et al.: JACC 2005, in pressPre-PCIPost-PCIng/mL Upstr

43、eamTirofibanHBDTirofibanAbciximabp = nsUpstreamTirofibanHBDTirofibanAbciximabp=0.015p=0.0002Peak cTn-I Levels pre and post-PCIBolognese L et al.: JACC 2005, in pressMechanicistic and clinical findings suggest that an early invasive strategy with upstream GP IIb/IIIa inhibitors may yield more favorab

44、le outcomes. The EVEREST pilot study also shows that high dose tirofiban or abciximad administred just prior PCI achieved similar effects on angiographic outcome and cTnI release. Further studies are needed to clarify if this dose regimen may have a clinical impact.CONCLUSIONSM. ValgimigliUniversity of FerraraItalyEras