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1、血小板IIb/IIIa受体拮抗剂在ACS中应用新进展,首都医科大学附属北京朝阳医院心脏中心杨新春,GP IIb/IIIa受体拮抗剂作用于最终的唯一通路，阻止纤维蛋白原等与该 受体的结合，从而快速，完全地抑制血小板聚集,1,30 天死亡,27%P=0.024,GPIIb/IIIa受体拮抗剂在PCI中的应用,Kong D,et al.Am J Cardiol.2003;92:651-655,9%,GPIIb/IIIa受体拮抗剂在ACS中的应用：30天死亡/心梗发生率,新的问题,双重抗血小板治疗，尤其是氯吡格雷600mg负荷量应用的现在，GP IIb/IIIa受体拮抗剂的临床意义如何？新型抗栓药物的
2、问世，尤其是比伐卢定临床研究结果的公布（ACUITY、HORIZONS研究）对GP IIb/IIIa受体拮抗剂的临床地位造成冲击。在新型抗栓药物尚不成熟的情况下，如何用好IIb/IIIa受体拮抗剂仍然非常重要。为进一步提高GP IIb/IIIa受体拮抗剂的临床疗效，近年来国内外对其临床应用的途径，时机和剂量进行了较多的临床试验。,GP IIb/IIIa受体拮抗剂应用新进展,氯吡格雷600mg负荷量后，GP IIb/IIIa受体拮抗剂的临床意义探讨合理用药方法：合理的时机合理的途径小分子GP IIb/IIIa受体拮抗剂在STEMI急诊PCI应用的临床效果再评价,氯吡格雷600mg负荷，IIb/I
3、IIa受体拮抗剂意义仍然存在,30天死亡、心梗、急诊再血管化复合终点事件发生率,TnI 阳性组（n=1049），差异更为明显30天死亡、心梗、急诊再血管化复合终点事件发生率,DEBATER,阿昔单抗组及对照组30天靶血管重建失败（TVF）发生率,阿昔单抗组及对照组1年MACE发生率,GP IIb/IIIa受体拮抗剂应用新进展,氯吡格雷600mg负荷量后，GP IIb/IIIa受体拮抗剂的临床意义探讨合理用药方法：合理的时机合理的途径小分子GP IIb/IIIa受体拮抗剂在STEMI急诊PCI应用的临床效果再评价,血小板抑制 95%N=125,血小板抑制95%N=344,MACE%,PCI后早期
4、血小板抑制水平和MACE密切相关,14.4%,55%P=0.006,6.4%,PCI后10分钟的血小板抑制,the GOLD Multicenter Study 2001.103:25722578,用 药 距 离 发 病 的 时 间,PURSUIT研究：GPIIb/IIIa 疗效和应用时机,JAMA.2000;284:1549-1558,改善近远期临床疗效,早期应用住院期间严重心脏事件下降 CRUSADE 注册研究,Peterson E.CRUSADE registry data.ACC Scientific Session;March 30-April 2,2003;Chicago,Il.,
5、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,P0.05,P=NS,P=NS,P0.05,Circulation 2001;103:2328-2335,早期应用阿昔单抗对STEMI患者近期预后的影响，n=1650,：,TITAN荟萃分析：不同时机应用IIb/IIIa受体拮抗剂对术前TIMI 血流的影响,术前TIMI 2/3级血 流比率,常规使用组N=78导管室推注欣维宁10g/kg，之后静脉持续滴注0.15g/kg/min 36小时。,ASTEMI 年龄80岁 N=158,随机,早期使用组 N=80急诊室推注欣维宁10g/kg，之后持续滴注0.
6、15g/kg/min 36小时,术中鞘管内推注肝素70IU/kg,所有患者均在急诊室顿服阿斯匹林300mg和氯吡格雷600mg。术后常规皮下注射低分子肝素57天,北京朝阳医院：提前应用替罗非班对急性ST段抬高心肌梗死患者急诊介入治疗疗效的影响研究,徐立，杨新春 等.中华心血管病杂志，2006;11,两组术前TIMI血流的比较,徐立，杨新春 等.中华心血管病杂志，2006;11,P=0.032,P=0.662,P=0.04,AMI患者于急救车或基层医院诊断并给予ASA+600 mg 氯吡格雷+静脉肝素,Angiogram,替罗非班*,安慰剂,转运,PCI center,Angiogram,Tir
7、ofibanprovisional,Tirofiban contd,ON-TIME-2 Ongoing-Tirofiban In MyocardialInfarction Evaluation,N=9846/2006-11/2007,PCI,*Bolus:25 g/kg&0.15 g/kg/min infusion,早！+大剂量,PCI术前术后ST段回落情况,Ongoing Tirofiban In Myocardial Infarction Evaluation,14.39.1,12.19.4,5.98.1,4.86.3,14.59.1,10.99.2,4.45.3,3.34.3,0.002
8、,0.022,0.028,p=0.84,mm,随机时,造影前,术后60分钟,术后90分钟,30 天全因死亡率,open label&double-blind,n=1398,30天无事件生存率,Ongoing Tirofiban In Myocardial Infarction Evaluation,P=0.013,74.0%,66.7%,安全性终点:出血事件,Ongoing Tirofiban In Myocardial Infarction Evaluation,0.115,4.0%,1年全因死亡率,RR:0.78(95%CI:0.53-1.14,p=0.157),RR:0.77(95%CI
9、:0.46-1.29,p=0.276),N=984,N=414,Double Blind,Open Label,-36%,-37%,ACC 2009:1年随访结果公布,1 年无事件生存率,P=0.007,open label&double-blind,n=1.155,GP IIb/IIIa受体拮抗剂应用新进展,氯吡格雷600mg负荷量后，GP IIb/IIIa受体拮抗剂的临床意义探讨合理用药方法：合理的时机合理的途径小分子GP IIb/IIIa受体拮抗剂在STEMI急诊PCI应用的临床效果再评价,冠脉内应用GPIIb/IIIa受体拮抗剂,Whrle：局部高浓度的IIb/IIIa受体拮抗剂，有助
10、于药物进入血栓内部，起到减少血栓负荷，减少微循环栓塞的作用。,Circulation.2003;107:1840-1843,STEMI患者急诊PCI中冠脉内应用阿昔单抗可以减少30天临床事件,ESC 2009,STEMI患者急诊PCI中冠脉内应用阿昔单抗不增加出血事件,ESC 2009,急诊室：阿司匹林300mg，氯吡格雷600mg嚼服,治疗组：首先进行CAG,导管室：随机分组,对照组：首先静脉应用替罗非班,冠脉内应用替罗非班,PCI,进行CAG,PCI,10gkg-1推注,0.15gkg-1min-1维持36小时,北京朝阳医院：替罗非班冠脉内应用对急性STEMI急诊介入治疗后心肌组织水平灌注
11、和临床预后的研究,杨新春，张大鹏，等.中华心血管病杂志,2007,35:517-522,MACE事件的风险比校正其它危险因素后，冠脉组MACE发生比静脉组降低了86%,86%！,杨新春，张大鹏，等.中华心血管病杂志,2007,35:517-522,Waiting for:,Waiting for:,GP IIb/IIIa受体拮抗剂应用新进展,氯吡格雷600mg负荷量后，GP IIb/IIIa受体拮抗剂的临床意义探讨合理用药方法：合理的时机合理的途径小分子GP IIb/IIIa受体拮抗剂在STEMI急诊PCI应用的临床效果再评价,常用GPb/a受体抑制剂,GPIIb/IIIa单克隆抗体：阿昔单抗
12、合成小分子GPb/a受体抑制剂：依替巴肽（肽类）替罗非班（非肽类）与阿昔单抗比较，小分子GPb/a受体抑制剂：半衰期短，停药后血小板功能恢复快抗原性弱，血小板减少症发生率低费用明显低,对血小板抑制的可逆性,%血小板聚集率,100,80,60,40,20,0,0,6,12,18,24,30,36,依替巴肽,替罗非班,阿昔单抗,停用药物,小时,三种静脉GPb/a受体抑制剂的比较,Scarborough RM,et al.Circulation.1999;100:437-444.,以往，STEMI患者PCI中应用GP IIb/IIIa受体拮抗剂的研究以阿昔单抗为主，证据最为充分,30 天终点事件(死
13、亡,再梗,急诊再血管化),因此，现有指南对于GP IIb/IIIa受体拮抗剂在STEMI直接PCI中应用的推荐,ESC PCI 指南：推荐对于STEMI，阿昔单抗用于直接PCI（a/A）ACC/AHA/SCAI PCI指南：推荐直接PCI前（无论是否植入支架）尽可能早地开始阿昔单抗（a/B）亦可以考虑应用替罗非班或依替巴肽治疗（b/C）近年来，小分子GP IIb/IIIa受体拮抗剂在STEMI直接PCI中应用的临床研究明显增多,STEMI急诊PCI中阿昔单抗和依替巴肽的比较,术后60分钟ST段回落无差异,6个月临床事件无差异,安全性终点事件无差异,心肌Blush灌注分级无差异,近期临床事件无差
14、异,STEMI All Comers Patients,Aspirin+Clopidogrel+UFHIntent-to-stent,N 730,替罗非班,阿昔单抗,SES,BMS,MULTI-STRATEGYTrial Design,SES,BMS,Universit degli Studi di Ferrara-Cattedra di Cardiologia,1:1,1:1,1:1,Valgimigli M.et al Am Heart J.2007 Jul;154(1):39-45.,初级终点事件：ST回落 50%的比率无差异,8个月随访死亡/心梗无差异,安全性比较：出血事件无差异替罗非
15、班组血小板减少症发生率低,比较小分子GP IIb/IIIa受体拮抗剂和阿昔单抗在STEMI急诊PCI中作用的荟萃分析,荟萃分析结果：6项随机试验(n=2,197)（5项替罗非班，1项使用依替巴肽）,J Am Coll Cardiol.2009;53:1668-1673.,小分子GP IIb/IIIa受体拮抗剂和阿昔单抗在STEMI急诊PCI中作用类似,替罗非班的剂量问题,值得注意的是：上述替罗非班的研究采用的静脉推注剂量均非 RESTORE 研究采用的10g/kg剂量，而是所谓的“大剂量（HDB）”：25g/kg。由于常规推注剂量不能获得满意的早期血小板抑制效果。近年来涉及替罗非班的临床研究（
16、FATA、STRATEGY、MULTISTRATEGY、ADVANCE、ON-TIME 2 等）均采用了所谓的“大剂量”替罗非班，该推注剂量在国外实际上已经成为替罗非班的“标准有效剂量”。,结论,血小板IIb/IIIa受体拮抗剂在ACS中的应用一直具有非常充分的循征医学证据近年来最新的相关临床试验证明：血小板IIb/IIIa受体拮抗剂现阶段仍是临床高危ACS处理和介入治疗中重要的抗血小板药物合理的应用时机、应用途径和应用剂量（主要指替罗非班）可以获得更好的临床效果,长城会2009 急性冠脉综合症论坛主题：ACS 研究：新进展，新理念 从临床试验到临床实践,谢谢！,New Progress in
17、 the Application of Platelet Glycoprotein IIb/IIIa Inhibitors in the Management of ACS,Yang Xinchun Heart Center,Beijing Chaoyang HospitalAffiliate of Capital Medial University,1,30-days death,27%P=0.024,GP IIb/IIIa Inhibitors in PCI,Kong D,et al.Am J Cardiol.2003;92:651-655,9%,New Question,Is clopi
18、dogrel with 600mg sufficient without GPI in ACS?After disclosure of RCTs about new anti-thrombosis drugs(like Bivalirudin),the value of GPI is controversial.Many RCTs about early and intracoronary administration of GPIs have published in the last few years.,New Progress of GPIs in the Management of
19、ACS,Is clopidogrel with 600mg sufficient without GPI in ACS?Early administration of GPIsIntracoronary administration of GPIsBenefits from small molecule GPIs administration as compared with abciximab among patients with STEMI treated with primary PCI,Is Clopidogrel with 600mg Sufficient Without GPI
20、in ACS?,DEBATER,New Progress of GPIs in the Management of ACS,Is clopidogrel with 600mg sufficient without GPI in ACS?Early administration of GPIsIntracoronary administration of GPIsBenefits from small molecule GPIs administration as compared with abciximab among patients with STEMI treated with pri
21、mary PCI,Platelet Inhibition 95%N=125,Platelet Inhibition 95%N=344,MACE%,Early Platelet Inhibition after PCI and MACE,14.4%,55%P=0.006,6.4%,Platelet Inhibition 10 minutes after PCI(),the GOLD Multicenter Study 2001.103:25722578,Time from Onset to Administration,Decrease of 30-days Death/MI(%),2.3%,P
22、URSUIT Study：Time of Application of GPIIb/IIIa and MACE,JAMA.2000;284:1549-1558,Early Administration and Death/MI in Hospital CRUSADE Registry Study,Peterson E.CRUSADE registry data.ACC Scientific Session;March 30-April 2,2003;Chicago,Il.,ADMIRAL Study,N=300，AMI 12 hrs.Stent Implantation,Circulation
23、 2001;103:2328-2335,：,Cath Lab N=78Tirofiban administration in Cath Lab,ASTEMI N=158,Early N=80Tirofiban administration in ER,Effect of Early Usage of Tirofiban in Patients with Acute ST-elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention.Beijing Chaoyang Hospital,徐
24、立，杨新春 等.中华心血管病杂志，2006;11,Bolus:10 g/kg&0.15 g/kg/min infusion300 ASA+600 mg Clopidogrel+UFH(70IU/kg),Pre-PCI TIMI Flow,徐立，杨新春 等.中华心血管病杂志，2006;11,P=0.032,P=0.662,P=0.04,Acute myocardial infarctiondiagnosed in ambulance or referral centerASA+600 mg Clopidogrel+UFH,Angiogram,Tirofiban*,Placebo,Transpor
25、tation,PCI center,Angiogram,Tirofibanprovisional,Tirofiban contd,ON-TIME-2,N=9846/2006-11/2007,PCI,*Bolus:25 g/kg&0.15 g/kg/min infusion,Cumulative ST-Deviation over Time,Ongoing Tirofiban In Myocardial Infarction Evaluation,14.39.1,12.19.4,5.98.1,4.86.3,14.59.1,10.99.2,4.45.3,3.34.3,0.002,0.022,0.0
26、28,p=0.84,mm,30 days Death,open label&double-blind,n=1398,Event-free Survival,Ongoing Tirofiban In Myocardial Infarction Evaluation,P=0.013,Safety Endpoint:Bleeding,Ongoing Tirofiban In Myocardial Infarction Evaluation,0.115,4.0%,1 year Death,RR:0.78(95%CI:0.53-1.14,p=0.157),RR:0.77(95%CI:0.46-1.29,
27、p=0.276),N=984,N=414,Double Blind,Open Label,-36%,-37%,ACC 2009,Event-free Survival:1 year,P=0.007,open label&double-blind,n=1.155,New Progress of GPIs in the Management of ACS,Is clopidogrel with 600mg sufficient without GPI in ACS?Early administration of GPIsIntracoronary administration of GPIsBen
28、efits from small molecule GPIs administration as compared with abciximab among patients with STEMI treated with primary PCI,Intra Coronary Administration of GPIIb/IIIa,ESC 2009,ESC 2009,IC group：CAG,ASTEMI:300 ASA+600 mg Clopidogrel+UFH(70IU/kg),IV group：IV Injection of Tirofiban,IC Injection of Tir
29、ofiban,PCI,CAG,PCI,10gkg-1,0.15gkg-1min-1,杨新春，张大鹏，等.中华心血管病杂志,2007,35:517-522,Effect of Intracoronary Tirofiban Administration in Patients with Acute STEMI Undergoing Primary PCIBeijing Chaoyang Hospital,MACE,86%！,杨新春，张大鹏，等.中华心血管病杂志,2007,35:517-522,IV,IC,Waiting for:,Waiting for:,New Progress of GPIs
30、 in the Management of ACS,Is clopidogrel with 600mg sufficient without GPI in ACS?Early administration of GPIsIntracoronary administration of GPIsBenefits from small molecule GPIs administration as compared with abciximab among patients with STEMI treated with primary PCI,GPb/a Inhibitors,AbciximabS
31、mall molecule GPIs:Tirofiban Eptifibatide,%Platelet Inhibition,100,80,60,40,20,0,0,6,12,18,24,30,36,eptifibatide,Tirofiban,Abciximab,Stop Using,小时,3 GPb/a inhibitors:Platelet Inhibition,Scarborough RM,et al.Circulation.1999;100:437-444.,PCI in STEMI:Abciximab Had the Most Evidence,30-days MACE(death
32、,Re-MI,U-RV),GP IIb/IIIa Inhibitors during PCI in STEMI,Guideline of ESC PCI：Abciximab：a/A Guideline of ACC/AHA/SCAI PCI：Abciximab：a/BTirofiban and eptifibatide:b/C,STEMI All Comers Patients,Aspirin+Clopidogrel+UFHIntent-to-stent,N 730,Tirofiban,Abciximab,SES,BMS,MULTI-STRATEGYTrial Design,SES,BMS,U
33、niversit degli Studi di Ferrara-Cattedra di Cardiologia,1:1,1:1,1:1,Valgimigli M.et al Am Heart J.2007 Jul;154(1):39-45.,A Meta-Analysis:,6 RCTs(n=2,197)（5 for Tirofiban，1 for Eptifibatide）,J Am Coll Cardiol.2009;53:1668-1673.,Dosage of Tirofiban,Dosage of Tirofiban:RETORE Study:10g/kgHigh Dosage Bo
34、lus(HDB):25g/kg To obtain sufficient early platelet inhibition,administration of tirofiban with HDB of was used in all RCTs about tirofiban in the last few years.,Conclusion,There is powerful evidence about application of platelet glycoprotein IIb/IIIa inhibitors in the management of ACSEarly and intracoronary administration of platelet glycoprotein IIb/IIIa inhibitors can obtain better clinical results.,ACS Forum in GW-ICC 2009：-from clinical trials to clinical practice,thanks,
