血小板糖蛋白IIbIIIa受体拮抗剂在介入非介入患者中的应用.ppt

血小板糖蛋白IIb/IIIa受体拮抗剂在介入/非介入患者中的应用,浙江大学医学院附属第二医院 心脏中心 王建安,基本原理 分子结构 适应症和循证医学 结论,血小板GPIIb/IIIa受体拮抗剂的作用机理,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,Collagen ADP Thromboxane A2 Platelet Activation platelet aggregation Thrombus formation,GPIIb/IIIa inhibitor,Aspirin,COX,Ticlopidin Clopidogrel,目前的GPIIb/IIIa受体拮抗剂依据化学结构的不同可分为三类,1.单克隆抗体，Abciximab（阿昔单抗），最早应用于临床的GPIIb/IIIa受体拮抗剂，是GPIIb/IIIa受体的单克隆抗体，通过占据受体的位置而阻断血小板聚集反应。 2.肽类抑制剂，Eptifibatide（埃替非巴肽），是一类含有GPIIb/IIIa受体识别序列的低分子多肽。 3.非肽类抑制剂，静脉的Tirofiban（替罗非班），是肽衍生物，其药理性质与埃替非巴肽相似。口服非肽类抑制剂，Xemilofiban、Orbofiban、Rocifiban、Sibrafiban、Lefradafiban、但试验结果均以失败告终。,三类 GPIIb/IIIa受体拮抗剂的化学结构,STEMI,Clinical finding,EKG,Serum markers,Risk assessment,Non-cardiac chest pain,Stable angina,UA,NSTEMI,Negative,Positive,ST-T wave changes,ST elevation,Low probability,Medium-high risk,Thrombolysis Primary PCI,Aspirin + GP IIb/IIIa inhibitor clopidogrel + heparin/ LMWH + anti-ischemic Rx Early invasive Rx,Discharge,Negative,Diagnostic rule out MI/ACS pathway,STEMI,Negative,Atypical pain,Low risk,Aspirin, heparin/low-molecular-weight heparin (LMWH) + clopidogrel Anti-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 (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% 0.80 0.60-1.06 PRISM-PLUS (1915) 12.0% 8.7% 0.70 0.50-0.98 PARAGON-A (2282) 11.7% (l) 10.3% 0.87 0.58-1.29 (h) 12.3% 1.06 0.72-1.55 PURSUIT (10,948) 15.7% 14.2% 0.89 0.79-1.00 PARAGON-B (5225) 11.4% 10.6% 0.92 0.77-1.09 GUSTO-IV (7800) 8.0% (24h) 8.2% 1.02 0.83-1.24 (48h) 9.1% 1.15 0.94-1.39,Odds Ratio,Placebo,IV GP IIb/IIIa,95% CI,*With/without heparin. Without heparin. (l)=low dose. (h)=high-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,ADMIRAL,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 Coll 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%,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 Antagonists for PCI,ACCP-7对NSTE ACS 治疗建议：NSTE ACS的中、高危患者早期治疗，在应用阿司匹林及肝素基础上，加用Eptifibatide 或Tirofiban（1A级）；同时应用氯吡格雷的中、高危患者，早期加用Eptifibatide 或Tirofiban（2A级）。,急性冠状动脉综合征（ACS）中的应用,ACC/AHA 2007年UA/NSTEMI指南,预行PCI的UA/NSTEMI患者，术前可应用GPb/受体拮抗剂（I/A） 对可能行PCI的患者，阿昔单抗是上游GPb/a受体拮抗剂的首选药物，否则依替巴肽或替罗非班是首选的药物（I/B） UA/NSTEMI的高危患者行PCI，应给予静脉内GPIIb/IIIa拮抗剂（ I/A ） 对于选择保守策略的UA/NSTEMI患者，可应用依替巴肽或替罗非班进行抗凝治疗（b/B） 阿昔单抗不应当应用于不准备行PCI的患者（/A）,ESC 2007 年UA/NSTEMI指南,GPb/a受体拮抗剂应该和抗凝药物联合应用（I/A） 在未预先使用GPb/a受体拮抗剂而计划进行PCI的高危患者，建议在CAG后立即使用阿昔单抗（I/A），这种情况下依替巴肽或替罗非班的使用价值较低（a/B） 中高危的UA/NSTEMI患者，建议在使用口服抗血小板药物的基础上，加用依替巴坦或替罗非班治疗（a/A） 在CAG前的初始治疗中使用依替巴肽或替罗非班者，PCI术中和术后应维持应用原来的药物（a/B）,2007年ACC/AHA/SCAI 关于UA/NSTEMI的PCI指南,UA/NSTEMI患者接受PCI术时，应用静脉GPb/a拮抗剂是有效的 (I/C) 如果PCI术时给予氯吡格雷治疗，同时联合应用GPb/a 受体拮抗剂的抗血小板效果更好（IIa/B） 对阿司匹林有绝对禁忌症的患者，应在PCI术前至少6小时给予300600mg负荷剂量的氯吡格雷；和/或PCI时给予GPb/a 受体拮抗剂(IIa/C),GPb/a受体拮抗剂在STEMI溶栓中的应用,全剂量溶栓剂与GP b/a受体拮抗剂合用再灌注率提高，但出血风险明显增加 SPEED和GUSTO- Pilot试验显示，Abciximab与半量t-PA合用，显著提高梗死相关血管开通率，但出血风险仍高于溶栓组,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-2 Neumann et al. (Stent) J Am Coll Cardiol 2000 ADMIRAL Montalescot et al (Stent) N Engl J Med, 2001 CADILLAC Stone et al. (Stent/PTCA) N Engl J Med, 2002 ACE Antoniucci et al. (Stent) J Am Coll Cardiol 2003 Pooled,Abciximab for PCI in AMI,0,0.5,1,1.5,GP IIb/IIIa受体拮抗剂在AMI患者PCI中的应用,ACC/AHA 2007年关于 STEMI的PCI指南,对于已接受抗凝、拟行PCI的患者, 术前使用UFH者，根据手术需要可予以UFH再次静脉bolus,但同时应考虑GPb/a受体拮抗剂的协同抗凝效应 (I/C),GPIIb/IIIa受体拮抗剂在PCI中的早期应用,ELISA I 、EVEREST 、TIGER-PA、ONTIME 研究证明在PCI患者中，早期应用（急诊室、监护室或院前）GPIIb/IIIa受体拮抗剂（tirofiban）效果优于晚期应用（导管室）,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 *,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 Endpoint Residual 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%,0.026,nor