1、血小板糖蛋白IIb/IIIa受體拮抗劑在介入/非介入患者中的應用,浙江大學醫(yī)學院附屬第二醫(yī)院 心臟中心 王建安,基本原理 分子結(jié)構(gòu) 適應癥和循證醫(yī)學 結(jié)論,血小板GPIIb/IIIa受體拮抗劑的作用機理,Mechanism Competitive antagonist of the GP receptor on the platelet surface for adhesive proteins such as fibrinogen, VWF maximally inhibit the final common pathway involved in platelet aggregation,

2、Collagen ADP Thromboxane A2 Platelet Activation platelet aggregation Thrombus formation,GPIIb/IIIa inhibitor,Aspirin,COX,Ticlopidin Clopidogrel,目前的GPIIb/IIIa受體拮抗劑依據(jù)化學結(jié)構(gòu)的不同可分為三類,1.單克隆抗體，Abciximab（阿昔單抗），最早應用于臨床的GPIIb/IIIa受體拮抗劑，是GPIIb/IIIa受體的單克隆抗體，通過占據(jù)受體的位置而阻斷血小板聚集反應。 2.肽類抑制劑，Eptifibatide（埃替非巴肽），是一類含有G

3、PIIb/IIIa受體識別序列的低分子多肽。 3.非肽類抑制劑，靜脈的Tirofiban（替羅非班），是肽衍生物，其藥理性質(zhì)與埃替非巴肽相似?？诜请念愐种苿?，Xemilofiban、Orbofiban、Rocifiban、Sibrafiban、Lefradafiban、但試驗結(jié)果均以失敗告終。,三類 GPIIb/IIIa受體拮抗劑的化學結(jié)構(gòu),STEMI,Clinical finding,EKG,Serum markers,Risk assessment,Non-cardiacchest pain,Stableangina,UA,NSTEMI,Negative,Positive,ST-T wa

4、ve changes,ST elevation,Lowprobability,Medium-high risk,ThrombolysisPrimary PCI,Aspirin + GP IIb/IIIa inhibitor clopidogrel + heparin/ LMWH + anti-ischemic RxEarly invasive Rx,Discharge,Negative,Diagnostic rule out MI/ACS pathway,STEMI,Negative,Atypical pain,Low risk,Aspirin, heparin/low-molecular-w

5、eight heparin (LMWH) + clopidogrelAnti-ischemic Rx Early conservative therapy,Ongoing pain,DM=diabetes mellitus. Cannon, Braunwald. Heart Disease. 2001.,Rest pain, Post-MI, DM, Prior Aspirin,Exertional pain,The Spectrum of ACS,Benefit of GP IIb/IIIa Blockade in ACS Meta-Analysis of Six Major Trials

6、(31,402 Patients),All patients with ACS Patients with ACS, undergoing PCI within 5 days,Boersma E et al. Lancet 2002,0.5,0.6,0.7,1.1,Anti GPIIb/IIIa better,0.8,0.9,1.0,Relative 30-Day Risk of Death and MI,PRISM (3232)7.1%5.8% 0.800.60-1.06 PRISM-PLUS (1915)12.0%8.7% 0.700.50-0.98 PARAGON-A (2282) 11

7、.7%(l)10.3% 0.870.58-1.29(h)12.3% 1.060.72-1.55 PURSUIT (10,948)15.7%14.2% 0.890.79-1.00 PARAGON-B (5225)11.4%10.6% 0.920.77-1.09 GUSTO-IV (7800)8.0%(24h)8.2% 1.020.83-1.24 (48h)9.1% 1.150.94-1.39,Odds Ratio,Placebo,IV GP IIb/IIIa,95% CI,*With/without heparin. Without heparin. (l)=low dose. (h)=high

8、-dose. Adapted from: Boersma E, et al. Lancet. 2002;359:189-198.,Placebo Better,GP IIb/IIIa Better,Odds Ratio (95% CI),0.0,1.0,2.0,Study (n),GP IIb/IIIa Inhibitors in UA/NSTEMI: Death or MI at 30 Days,Favors Control,Favors Treatment,Year,CAPTURE,1997,RESTORE,1998,EPISTENT,1999,1997,CADILLAC-P,2002,A

9、DMIRAL,2001,RAPPORT,1998,Petronio,2002,CADILLAC-S,2002,0.01,0.1,1,10,100,Study,ERASER,1999,ISAR-2,2000,EPIC,Risk Ratio and 95% CI,RR 0.79 Z=-2.27 2P=0.023,EPILOG,1999,ESPRIT,2002,Overall,Tamburino,2002,N,1265,2141,1603,2099,1046,300,483,89,1036,225,401,2792,2064,15,651,107,Karvouni E, et al. J Am Co

10、ll Cardiol. 2003;41:26-32.,Intravenous GP IIb/IIIa Receptor Antagonists Reduce Mortality after PCI,Kong D, et al. Am J Cardiol. 2003; 92:651-655.,Placebo Better,IIb/IIIa Better,Trial,Control,Treatment,N,0.1,1,10,RESTORE,1.1%,0.9%,12,940,EPILOG,1.2%,0.9%,4891,RAPPORT,1.3%,1.0%,5374,CAPTURE,1.3%,1.0%,

11、6639,EPIC,1.7%,1.5%,2099,1.3%,IMPACT I,1.0%,6789,1.2%,IMPACT II,0.9%,10,799,ESPRIT,1.0%,0.8%,17,403,ISAR-2,1.1%,0.8%,17,804,ADMIRAL,1.2%,0.8%,18,104,EPISTENT,1.1%,0.8%,15,339,1.3%,CADILLAC,0.9%,20,186,Odds Ratio and 95% CI,0.73 (0.55, 0.96) P=0.024,Meta-analysis of Survival with Platelet GP IIb/IIIa

12、 Antagonists for PCI,ACCP-7對NSTE ACS 治療建議：NSTE ACS的中、高?；颊咴缙谥委?，在應用阿司匹林及肝素基礎上，加用Eptifibatide 或Tirofiban（1A級）；同時應用氯吡格雷的中、高危患者，早期加用Eptifibatide 或Tirofiban（2A級）。,急性冠狀動脈綜合征（ACS）中的應用,ACC/AHA 2007年UA/NSTEMI指南,預行PCI的UA/NSTEMI患者，術前可應用GPb/受體拮抗劑（I/A） 對可能行PCI的患者，阿昔單抗是上游GPb/a受體拮抗劑的首選藥物，否則依替巴肽或替羅非班是首選的藥物（I/B） UA/N

13、STEMI的高?；颊咝蠵CI，應給予靜脈內(nèi)GPIIb/IIIa拮抗劑（ I/A ） 對于選擇保守策略的UA/NSTEMI患者，可應用依替巴肽或替羅非班進行抗凝治療（b/B） 阿昔單抗不應當應用于不準備行PCI的患者（/A）,ESC 2007 年UA/NSTEMI指南,GPb/a受體拮抗劑應該和抗凝藥物聯(lián)合應用（I/A） 在未預先使用GPb/a受體拮抗劑而計劃進行PCI的高?；颊?，建議在CAG后立即使用阿昔單抗（I/A），這種情況下依替巴肽或替羅非班的使用價值較低（a/B） 中高危的UA/NSTEMI患者，建議在使用口服抗血小板藥物的基礎上，加用依替巴坦或替羅非班治療（a/A） 在CAG前的初始

14、治療中使用依替巴肽或替羅非班者，PCI術中和術后應維持應用原來的藥物（a/B）,2007年ACC/AHA/SCAI 關于UA/NSTEMI的PCI指南,UA/NSTEMI患者接受PCI術時，應用靜脈GPb/a拮抗劑是有效的 (I/C) 如果PCI術時給予氯吡格雷治療，同時聯(lián)合應用GPb/a 受體拮抗劑的抗血小板效果更好（IIa/B） 對阿司匹林有絕對禁忌癥的患者，應在PCI術前至少6小時給予300600mg負荷劑量的氯吡格雷；和/或PCI時給予GPb/a 受體拮抗劑(IIa/C),GPb/a受體拮抗劑在STEMI溶栓中的應用,全劑量溶栓劑與GP b/a受體拮抗劑合用再灌注率提高，但出血風險明顯

15、增加 SPEED和GUSTO- Pilot試驗顯示，Abciximab與半量t-PA合用，顯著提高梗死相關血管開通率，但出血風險仍高于溶栓組,0,0.5,1,1.5,Relative Risk of Death+MI+TVR Abciximab vs Control,30 Days,6 Months,RAPPORT, Brener et al. (PTCA)Circulation 1999 ISAR-2Neumann et al. (Stent)J Am Coll Cardiol 2000 ADMIRALMontalescot et al (Stent) N Engl J Med, 2001

16、CADILLACStone et al. (Stent/PTCA) N Engl J Med, 2002 ACEAntoniucci et al. (Stent) J Am Coll Cardiol 2003 Pooled,Abciximab for PCI in AMI,0,0.5,1,1.5,GP IIb/IIIa受體拮抗劑在AMI患者PCI中的應用,ACC/AHA 2007年關于STEMI的PCI指南,對于已接受抗凝、擬行PCI的患者, 術前使用UFH者，根據(jù)手術需要可予以UFH再次靜脈bolus,但同時應考慮GPb/a受體拮抗劑的協(xié)同抗凝效應 (I/C),GPIIb/IIIa受體拮抗劑

17、在PCI中的早期應用,ELISA I 、EVEREST 、TIGER-PA、ONTIME 研究證明在PCI患者中，早期應用（急診室、監(jiān)護室或院前）GPIIb/IIIa受體拮抗劑（tirofiban）效果優(yōu)于晚期應用（導管室）,ACC 2008：ON-TIME-2：Ongoing-Tirofiban In Myocardial Infarction Evaluation,Acute myocardial infarction diagnosed in ambulance or referral center ASA+600 mg Clopidogrel,Angiogram,Tirofiban *

18、,Placebo,Transportation,PCI centre,Angiogram,Tirofiban provisional,Tirofiban contd,N=984 6/2006-11/2007,PCI,*Bolus: 25 g/kg & 0.15 g/kg/min infusion,Results: Primary EndpointResidual ST deviation at 60 min,mean SD,Placebo,Tirofiban,p- value,Readable ECG,94.1%,95.5%,0.358,Residual,ST - deviation (mm),4.8 6.3,3.3 4.3,0.002, 3 mm ST-deviation,44.3%,36.6