《血小板GPIIbIIIa受体拮抗剂临床应用新视点.ppt》由会员分享，可在线阅读，更多相关《血小板GPIIbIIIa受体拮抗剂临床应用新视点.ppt（71页珍藏版）》请在三一办公上搜索。
1、1,血小板GP IIb/IIIa受体拮抗剂临床应用新视点,上海交通大学附属胸科医院心内科仇兴标,2,IIb/IIIa受体拮抗剂的作用机制,3,Pharmacologic Intervention in Thrombosis,4,5,三类 GPIIb/IIIa受体拮抗剂的化学结构,6,三类 GP IIb/IIIa受体拮抗剂的特点,7,IIb/IIIa受体拮抗剂的循证依据,8,GP IIb/IIIa Inhibitors,CoronaryInterventionEPICRESTORECAPTUREEPILOGRAPPORTIMPACT IIEPISTENTESPRITCADILLACTARGET,
2、24,141 Patients,Unstable AnginaNon-Q Wave MIPURSUITPRISMPRISM PLUSPARAGON APARAGON BGUSTO-IV,31,056 Patients,Oral IIb/IIIaPCI-ACS EXCITEOPUS1st SYMPHONY2nd SYMPHONY,33,340 Patients,ST-ElevationAcute MI GUSTO-VASSENT-3,22,683 Patients,Completed early Large RCTs,9,IIb/IIIa受体拮抗剂在PCI患者中的应用,10,Kong D,et
3、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
4、.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,11,Favors Control,Favors Treatment,Year,CAPTURE,1997,RESTORE,1998,EPISTENT,1999,1997,CADILLAC-P,
5、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 0.79Z=-2.272P=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 C
6、oll Cardiol.2003;41:26-32.,Intravenous GP IIb/IIIa Receptor Antagonists Reduce Mortality after PCI,12,ISAR-REACT,600 mg Clopidogrel load 2 hours before PCI,Low-risk PCI,30-Day Ischemic and Bleeding Events,European and1 US Center,Placebo,Abciximab,Design,Patients Excluded:IDDMACS or recent MIVein gra
7、ftsThrombotic lesionsLVEF 30%,13,p=NS,p=NS,p=NS,p=NS,NEJM 2004;350:232-8,ISAR-REACT low-risk PCI-30 days outcome,14,p=0.06,p=0.03,p=0.34,p=0.64,JAMA 2006;295:1531-38,ISAR-REACT 2 high-risk PCI-30 days outcome,15,In patients undergoing elective PCI treated with UFH and not pretreated with clopidogrel
8、,it is reasonable to administer a GP IIb/IIIa inhibitor(abciximab,double-bolus eptifibatide,or high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy:SIHD,B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,16,In patients undergoing elective PCI with stent implantation treate
9、d with UFH and adequately pretreated with clopidogrel,it might be reasonable to administer a GP IIb/IIIa inhibitor(abciximab,double-bolus eptifibatide,or high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy:SIHD(cont.),B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,17,
10、IIb/IIIa受体拮抗剂在NSTE-ACS患者中的应用,18,STEMI,Clinical finding,EKG,Serum markers,Risk assessment,Non-cardiacchest pain,Stableangina,UA,NSTEMI,Negative,Positive,ST-T wave changes,ST elevation,Lowprobability,Medium-high risk,ThrombolysisPrimary PCI,Aspirin+GP IIb/IIIa inhibitor clopidogrel+heparin/LMWH+anti-i
11、schemic RxEarly invasive Rx,Discharge,Negative,Diagnostic rule out MI/ACS pathway,STEMI,Negative,Atypical pain,Low risk,Aspirin,heparin/low-molecular-weight heparin(LMWH)+clopidogrelAnti-ischemic Rx Early conservative therapy,Ongoing pain,DM=diabetes mellitus.Cannon,Braunwald.Heart Disease.2001.,Res
12、t pain,Post-MI,DM,Prior Aspirin,Exertional pain,The Spectrum of ACS,19,PRISM(3232)7.1%5.8%PRISM-PLUS(1915)12.0%8.7%0.700.50-0.98 PURSUIT(10,948)15.7%14.2%0.890.79-1.00 PARAGON-B(5225)11.4%10.6%0.920.77-1.09,Odds Ratio,Placebo,IV GP IIb/IIIa,95%CI,*With/without heparin.Without heparin.(l)=low dose.(h
13、)=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,20,Benefit of GP IIb/IIIa Blockade in ACSMeta-Analysis of Six Major Trials(31,402 Patients),All patien
14、ts with ACSPatients 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,21,IIb/IIIa ACS Meta-analysis,30-Day Death or MI,Boersma et al.Lancet 2002;359:189-98,OR=0.95(0.87-1.02),OR=0.77(0.64-0.92),22
15、,IIb/IIIa ACS 30-day Death or MI Early PCI,23,IIb/IIIa ACS 30-day Death or MI No Early PCI,24,ACUITY:Ischemic Composite Endpoint,Stone GW.ACC 2007 presentation,*Death,MI,unplanned revascularization for ischemia,25,26,EARLY-ACS study,27,ACC/AHA 2012年UA/NSTEMI指南,预行PCI的中、高危UA/NSTEMI患者，与阿司匹林联合应用GPb/受体拮抗
16、剂，开始于术前(I/B)或术中(I/A)Bivalirudin作为术中抗凝时可不用GPb/a受体拮抗剂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栓治疗(b/B)预行PCI的高危UA/NSTEMI且非高出血风险患者，与双联抗血小板药联合上游应用GPb/受体拮抗剂(b/B)阿昔单抗不应当应用于不准备行PCI的患者（/A）预行PCI的低危UA/NSTEMI患者或高出血风险患者，不推荐与双联抗血小板药联合上游应用GPb/受体拮抗剂(/B),28,In UA/NSTEMI patients with high-risk features(e.g.,elevated trop
17、onin level)not treated with bivalirudin and not adequately pretreated with clopidogrel,it is useful at the time of PCI to administer a GP IIb/IIIa inhibitor(abciximab,double-bolus eptifibatide,or high-bolus dose tirofiban)in patients treated with UFH.,Intravenous Antiplatelet Therapy:UA/NSTEMI,A,201
18、1 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,29,In UA/NSTEMI patients with high-risk features(e.g.,elevated troponin level)treated with UFH and adequately pretreated with clopidogrel,it is reasonable at the time of PCI to administer a GP IIb/IIIa inhibitor(abciximab,double-bolus
19、eptifibatide,or high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy:UA/NSTEMI(cont.),B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,30,IIb/IIIa受体拮抗剂在AMI患者中的应用,31,早期研究IIb/III受体拮抗剂对AMI直接PCI的作用,32,Relative Risk of Death+MI+TVRAbciximab vs Control,GP IIb/IIIa受体拮抗剂在AMI患者PC
20、I中的应用,33,33,FINESSE:Study design,Ellis et al.N Eng J Med.2008;358:2205-2217.,34,34,Ellis et al.N Eng J Med.2008;358:2205-2217,35,FINESSE 90-Day Endpoints,Ellis S.ESC 2007 Vienna,36,FINESSE 90-Day Bleeding,Ellis S.ESC 2007 Vienna,37,CARESS Abciximab with 1/2 Dose Reteplase,Di Mario C.ESC 2007 Vienna,
21、38,38,OnTIME 2:Study design,Acute myocardial infarctiondiagnosed in ambulance or referral centerASA+600 mg Clopidogrel,Angiogram,Tirofiban*,Placebo,Transportation,PCI centre,Angiogram,Tirofibanprovisional,Tirofiban contd,PCI,vant Hof et al.Lancet 2008;372:537-46.,*Bolus 25 g/kg&0.15 g/kg/min infusio
22、n,39,39,OnTIME 2:endpoints,PrimaryResidual ST segment deviation(3mm)1 hour after PCIKey Clinical SecondaryCombined occurrence of death,recurrent MI,urgent TVR or thrombotic bailout at 30 days follow-upSafety(major bleeding)Death at 1 year follow-up,40,40,On-TIME 2:Results,vant Hof et al.Lancet 2008;
23、372:537-46,Residual ST Deviation after PCI,p=0.003 3.6 4.6mm4.8 6.3mm,41,On-TIME 2:Results Event-free Survival,survival free from death,recurrent myocardial infarction,urgent target vessel revascularisation,or blinded bail-out use of study drug,42,On-TIME 2:Results,vant Hof et al.Lancet 2008;372:537
24、-46.,Event-free Survival at 30 days,Death at 1 yr.in primary PCI group:Tirofiban(2.4%)vs.Placebo(5.5%)(p=0.007,RR=0.44(0.24-0.81),43,In patients undergoing primary PCI treated with UFH,it is reasonable to administer a GP IIb/IIIa inhibitor(abciximab,double-bolus eptifibatide,or high-bolus dose tirof
25、iban),whether or not pretreated with clopidogrel.For GP IIb/IIIa inhibitor administration in patients not pretreated with clopidogrel.For GP IIb/IIIa inhibitor administration in patients who are pretreated with clopidogrel.,Intravenous Antiplatelet Therapy:STEMI,A,2011 ACCF/AHA/SCAI Guideline for Pe
26、rcutaneous Coronary Intervention,44,44,It is reasonable to start treatment with glycoprotein IIb/IIIa receptor antagonists at the time of primary PCI(with or without stenting)in selected patients with STEMI:abciximabtirofiban and eptifibatide,Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEM
27、I,45,45,Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI,The usefulness of glycoprotein IIb/IIIa receptor antagonists(as part of a preparatory pharmacologic strategy for patients with STEMI prior to arrival in the cardiac catheterization laboratory for angiography and PCI)is uncertain.,46,
28、BRAVE 3:Study design,Mehilli et al.Circ.2009;119:1933-1940,TREATMENT:pre-PCI treatment with clopidogrel(600 mg),followed by abciximab vs.placeboINCLUSION:suspected acute MI(ST change or LBBB)within 24 h of symptom onsetEXCLUSION:high risk for bleeding,prior stroke,shock,trauma,thrombolytics,hyperten
29、sion,relevant hematologic deviations1 OUTCOMES:infarct size,death,stroke,urgent revascularization of affected artery,47,Effects of Abciximab,Mehilli et al.Circ.2009;119:1933-1940,No significant difference in infarct size or major bleeding,P=0.47,P=0.40,48,Routine precatheterization laboratory(e.g.,a
30、mbulance or emergency room)administration of GP IIb/IIIa inhibitors as part of an upstream strategy for patients with STEMI undergoing PCI is not beneficial.,Intravenous Antiplatelet Therapy:STEMI(cont.),B,No Benefit,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,49,冠脉内注射IIb/III
31、a受体拮抗剂,50,Meta-Analysis I All ACS+GpIIb/IIIa-Inh.,Friedman et al.Am J Cardiol 2011;108:1244-1251,TIMI-3-Flow after PCI,0.569,1,1.76,Favors IV route,Favors IC route,Risk ratio,DeibeleGuIversenDominguez-RodriguezWuThieleYangBellandiOverall(I-squared=20.1%;p=0.27),1.07(0.89,1.28)8.661.03(0.97,1.10)34.9
32、01.10(0.98,1.24)17.431.29(0.95,1.76)3.271.22(1.01,1.48)7.960.98(0.86,1.12)14.251.27(0.98,1.64)4.601.15(0.96,1.37)8.921.08(1.02,1.15)100.00,Study,RR(95%CI),Weight,51,Meta-Analysis I All ACS+GpIIb/IIIa-Inh.,Friedman et al.Am J Cardiol 2011;108:1244-1251,Short-term Mortality,GuIversenWuThieleYangBellan
33、diOverall(I-squared=0.0%;p=0.772),Study,RR(95%CI),Weight,0.69(0.22,2.16)28.340.20(0.04,0.93)37.420.49(0.05,5.27)8.050.67(0.11,3.68)11.970.19(0.01,3.71)10.331.05(0.07,15.70)3.900.45(0.23,0.90)100.00,0.0936,1,107,Risk ratio,52,Meta-Analysis II STEMI+Abciximab,Navarese et al.Platelets 2011;1-8,53,Picco
34、lo,Thiele et al.Submitted,Individual Patient-based Meta-Analysis III,5 randomized trials(n=1198);individual patient-based meta-analysisIC Abciximab n=611IV Abciximab n=587,Death+Reinfarction,IV Abciximab 587 572 568 552 559 555IC Abciximab 611 603 597 595 594 594,0,0,6,12,18,24,30,0,2,4,6,8,HR 0.54(
35、95%CI 0.30;0.95);p=0.03,Days after Randomization,Probability of deathor reinfarction(%),Patients at risk:,IC Abciximab,IV Abciximab,54,Piccolo,Thiele et al.Submitted,Individual Patient-based Meta-Analysis III,5 randomized trials(n=1198);individual patient-based meta-analysisIC Abciximab n=611IV Abci
36、ximab n=587,Mortality,IV Abciximab 587 577 574 572 570 567IC Abciximab 611 606 603 602 602 602,0,0,6,12,18,24,30,0,2,4,6,8,HR 0.43(95%CI 0.20;0.94);p=0.03,Days after Randomization,Probability of death(%),Patients at risk:,IC Abciximab,IV Abciximab,55,In patients undergoing primary PCI with abciximab
37、,it may be reasonable to administer intracoronary abciximab.,Intravenous Antiplatelet Therapy:STEMI(cont.),B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,56,不同IIb/IIIa受体拮抗剂的比较,57,57,Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI,Grum et al.Small Molecule GP IIb/III
38、a Inhibitors primary PCI.Circ Cardiovas Intervent.2009;2:230-2236.,0.1 0.2 0.5 1 2 5,Favors SM GPI Favors Abciximab,OR and 95%CI of 30-day Mortality,58,High-Dose Bolus Tirofiban vs.Abciximab,Pooled Analysis of 5 Studies,Abciximab Tirofiban Study 0.25 mg/kg bolus 25 g/kg bolus 0.125 g/kg/min infusion
39、0.15 g/kg/min infusionBolognese3130Danzi280274Gunasekara110 109TENACITY194 189Valgimigli88 87Total Subjects:703689,Dawson CB et al.AHA 2006,59,30-Day Adverse Outcomes,TirofibanBetter,AbciximabBetter,Death0.401MI0.827TVR0.500Composite0.458,0,4.0,.5,3.0,2.0,EndpointOdds Ratio&95%CIP-Value,1.0,6.53,Hig
40、h-Dose Bolus Tirofiban vs.Abciximab,N=1,392,Dawson CB et al.AHA 2006,60,不同IIb/IIIa受体拮抗剂的比较,既往由于缺乏相关循证依据以及应用剂量的关系，认为阿昔单抗优于小分子IIb/IIIa受体拮抗剂，尤其在AMI患者目前认为三者之间临床效果差别不大，阿昔单抗应用于STEMI证据级别更强，而小分子IIb/IIIa受体拮抗剂用于non-STEMI ACS证据级别更强阿昔单抗延长应用于ACS保守治疗策略时部分激活IIb3受体，反而激活了血小板(GUSTO IV),61,GPb/a受体拮抗剂在STEMI溶栓中的应用,GP b/
41、a受体拮抗剂合用全剂量或半剂量溶栓剂再灌注率、梗死相关血管开通率提高，但出血风险明显增加，临床净效益不肯定，欧美指南均未给出推荐意见,62,2010 ESC:Antithrombotic treatment options in myocardial revascularization,www.escardio.org/guidelines,63,2010 ESC:Antithrombotic treatment options in myocardial revascularization,www.escardio.org/guidelines,64,2011 ESC Recommendat
42、ions for GP IIb/IIIa receptor inhibitors in NSTE-ACS,www.escardio.org/guidelines,IIb/IIIa inhibitors合用必须权衡心肌缺血及出血风险已用DATP时，IIb/IIIa inhibitors合用于高危PCI者(TnI/T升高或血栓)，或上游用于进行性心肌缺血单用aspirin时IIb/IIIa inhibitors上游合用于高危患者不作常规上游应用不用于保守治疗者,65,2012 ESC Guidelines for the STEMI,2012 ESC Guidelines for the mana
43、gement of acute myocardial infarction in patients presenting with ST-segment elevation,www.escardio.org/guidelines,66,不良反应,主要的不良反应包括出血及血小板减少在EPIC试验中Abciximab引起的大出血比安慰剂要高一倍。但是随后的一些临床试验证实出血的风险能够通过减少肝素的剂量、应用较小血管鞘以及尽早拔除血管鞘来减少Abciximab、Eptifibatide、Tirofiban所导致的血小板减少（血小板100109/L）的发生率分别为2.5%-6.0%、0.4%-1.6
44、%、1.2%-6.8%，预防措施包括用药后4-6小时及24h监测血常规，必要时调整剂量及停药。严重时输注血小板,67,Heparin with Abciximab,N=3,876,Chew DP et al.Circulation 2001;103:961-966,Maximum ACT,250,300,350,400,450,0.20,0.15,0.10,0.05,0.00,Probability of Majoror Minor Bleeding,68,Bleeding events over time,Evolving PCI Practice,EPIC 10,000-12,000 U
45、heparinEPIC:8F to 10F sheathsEPILOG 100 U/kg vs 70 U/kg+abciximabEPILOG:no overnight sheathsEPISTENT:no post procedure heparinEPISTENT:8F to 6-7F cathetersESPRIT:60 U/kg heparinREPLACE-2:bivalirudin,69,TIMI Major Bleeding,PCI Trials,TrialAgentPlacebo(%)Active Drug(%)EPICAbciximab6.612.5IMPACT IIEpti
46、fibatide4.85.1CAPTUREAbciximab2.54.1RESTORETirofiban2.12.4EPILOGAbciximab3.12.8PARAGON ALamifiban3.04.5PRISMTirofiban0.40.4PRISM PLUSTirofiban0.81.4PURSUITEptifibatide1.33.0EPISTENTAbciximab2.21.4PARAGON BLamifiban0.91.3ESPRITEptifibatide0.41.4GUSTO-IVAbciximab0.30.8TARGETAbcix vs Tirofib0.70.9REPLACE-2Bivalirudin vs IIb/IIIa 0.60.9,70,小结,由于新的抗栓治疗以及临床实践的进展，IIb/IIIa受体拮抗剂应用范围较以往缩小、应用时间也较前缩短GP IIb/IIIa拮抗剂在降低缺血事件的同时也会增加出血机会，应权衡血栓及出血风险IIb/IIIa受体拮抗剂在ACS病人中合用于Bivalirudin 时，并不能提供额外的临床得益 适应症强调高危non-STEMI-ACS患者PCI，STEMI以及术中bail-out血栓病变联合阿司匹林，作为第二种抗血小板药物的过渡治疗,71,谢谢！,
