那些病人能从GPIIbIIIaInhibitors获益

1、主要内容Characteristics of GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors in ACSGP IIb/IIIa Inhibitors in STEMIGPIIb/IIIa Inhibitors and PCI一、Characteristics of GP IIb/IIIa InhibitorsGPIIb/IIIa InhibitorsAbciximabEptifibatideTirofibanTopol E, et al. Lancet. 1999;353:227-231.AbciximabEptifibatideTirofibanO

2、OOOOOOOOHHNHNSSNHNHNNHHNNHNHH2NH2NHNSO2C4H9OCOOHHNFab fragment of a chimeric monoclonal antibodyMW 50,000 DNonpeptide tyrosine derivative MW 500 DCyclic heptapeptide MW 800 D鼠源性单克隆抗体合成非肽类合成肽类三种静脉GPb/a受体抑制剂的比较White HD. Am J Cardiol. 1997;80(4A):2B-10B.GP IIb/IIIa 受体拮抗剂作用机制RestingplateletPlaquerupture

3、 andplateletadhesionPlateletactivationPrevention of plateletaggregationGP IIb/IIIaexpressionFibrinogenGP IIb/IIIainhibitorvWFvWFvWFAgonistsreleasedVessel WallAciximabEptifibatideTirofiban结构鼠人IgG嵌合体环肽KGD小分子非肽RGD分子量(道尔顿)5000800500GPb/a选择性较强较强较强化学计量法1.5:1100:1100:1血浆半衰期10-15分钟1.5-2.5小时1.5-2.5小时受体抑制可逆性差

4、(输注血小板)较强(停药)较强(停药)出血发生率多较少较少血小板减少症相对较多少少安全性相对较差相对较好相对较好价格昂贵相对较低相对较低适应症(FDA)PCIACS;PCIACS;PCI三种静脉GPb/a受体抑制剂的比较二、GP IIb/IIIa Inhibitors in ACS20%15%10%5%0%1020300DaysPRISM-PLUS (n=1,570)GP IIb/IIIa Inhibitors in ACSThe Prism-Plus Investigators. NEJM 1998;338:1488-97- Death or MI at 30 days -Heparin11

5、.9%Tirofiban+ heparin8.7%OR 0.700.51, 0.96P=0.0320%15%10%5%0%1020300DaysPURSUIT(n=9,461)The PURSUIT Investigators. NEJM 1998;339:436-43Heparin15.7%Eptifibatide+ heparin14.2%OR 0.900.75, 0.98P=0.0416.7%15.6%14.5%11.6%0%5%10%15%20%PCI 72h (n=1228)No early PCI(n=8233)HeparinEptifibatide+HeparinImpact o

6、f Early PCI on 30 Day Death/MI10.2%10.1%7.8%5.9%0%5%10%15%PCI 72h (n=287) No early PCI(n=1283)HeparinTirofiban + HeparinPRISM PlusPURSUIT31%6%42%23%DMNon-DM5%10%6.2%PlaceboGPIIb/IIIa Inhibitor4.6%P=0.0073.0%3.0%P=NSGPIIb/IIIa Inhibitors in ACS30-Day mortality results of a Meta-analysis*Circulation 2

7、001;104:2767-71 * PRISM, PRISM-PLUS, PARAGON A & B, PURSUIT, GUSTO-IVn= 6,458n= 23,072PCINo PCI5%10%4.0%PlaceboGPIIb/IIIa Inhibitor1.2%P=0.0026.7%5.5%P=0.1GPIIb/IIIa Inhibitors in Diabetic Patients with ACS Circulation 2001;104:2767-2771 30-Day Mortalityof a Meta-analysis*n= 1,279n= 5,179* PRISM, PR

8、ISM-PLUS, PARAGON A & B, PURSUIT, GUSTO-IVGUSTO-IV Study DesignNon ST-segment elevation ACSMedical rx only planned (no angio or PCI)(n=7800)2590 ASA+UFH + Abciximab24h2598ASA+UFH or LMUH +placebo2612 ASA+UFH + Abciximab48h2598 2590 2612 Lancet 2001; 357: 1915-24 P = 0.664P = 0.235P = 0.190GUSTO-IV30

9、-Day outcomesLancet 2001; 357: 1915-243.9%5.1%8.0%8.2%5.6%3.4%4.3%5.9%9.1%0%2%4%6%8%10%DeathMIplaceboAbciximab 24hAbciximab 48hDeath, MI* p 0.05,vs placebo* 100,000 per L0.03 g/L)20151050051015202530Days After RandomizationPlacebo Group (N=1010)Abciximab Group (N=1012)Troponin 0.03 g/LLog-Rank p = 0

10、.02Troponin 0.03 g/LLog-Rank p = 0.98JAMA 2006; 295:1531-38%早期应用有效降低住院死亡率NRMI注册研究NRMI-NSTEMI Risk ScoreN=60770NSTEMI患者住 院 死 亡 率 %NRMI=National Registry of Myocardial Infarction.Peterson E, et al. J Am Coll Cardiol. 2003;42:45-5330天死亡/ 心梗绝对下降 (%)1.7% 2.3% 用 药 距 离 发 病 的 时 间(n=2522)(n=2041)(n=3803)(n=1

11、105) 0% 0.00.51.01.52.02.53.0 24 hours 1.7% 2.3% 2.8% 越早用药 绝对获益越大 PURSUIT研究： GPIIb/IIIa VS 安慰剂JAMA. 2000; 284:1549-15582009年中国PCI治疗指南GPb/a受体拮抗剂推荐I IIa IIb IIIUA/NSTEMI行PCI的患者，如未服用氯吡格雷，应给予一种血小板糖蛋白b/a受体拮抗剂，在实施诊断性CAG前或PCI术前即刻给药均可UA/NSTEMI行PCI的患者，如已服用氯吡格雷，可同时给予一种血小板糖蛋白b/a受体拮抗剂STEMI行PCI的患者，可尽早应用血小板糖蛋白b/a

12、受体拮抗剂接受择期PCI并置入支架的高危患者或高危病变（如ACS、近期MI、桥血管狭窄、冠状动脉慢性闭塞病变及CAG可见的血栓病变等），可应用血小板糖蛋白b/a受体拮抗剂，但应充分权衡出血与获益风险BABB三、 GP IIb/IIIa Inhibitors in STEMI %GP IIb/IIIa Inhibitors in STEMIAbciximab and PCI in STEMI Trials30 Day Endpoint (D, Re-MI, u-TVR)p=0.023p0.05p=0.005PTCA N = 483Stent N = 401Stent N = 301PTCA or

13、 Stent N = 2082Stent N = 400p=0.038p=0.01RAPPORTAbciximab in primary PTCA for STEMI 9.9%3.3%5.0%2.1%5.4%1.2%P=0.003p=0.098P=0.01Circulation 1998;98;734-7417-day Outcome RAPPORT11.2%5.8%5.8%4.6%6.6%1.7%P=0.03P=0.52P=0.00630 Day follow-upCirculation. 1998; 98: 734-74128.1%28.2%17.8%11.6%11.2%8.7%P=0.9

14、P=0.048P=0.36Circulation. 1998; 98: 734-741 RAPPORT6 month follow-upPrimary PTCA(n=518)MultiLink stent+ Abciximab(n=524)Primary PTCA+ Abciximab(n=528)MultiLink stent(n=512)randomizationCADILLACAMI 12 h, cardiogenic shock excluded N = 208276 centers in N.A. S.A. and EuropeN Engl J Med 2002; 346: 957-

15、966OUTCOMEPTCA(N=518)PTCA PLUS ABCIXIMAB(N=528)STENTING(N=512)STENTING PLUSABCIMAB(N=524)P VALUEPERCENTAt 30 daysDeath2.51.12.22.70.31Reinfarction0.80.81.00.80.97Disabling stroke0.20.00.20.20.79Revascularization of ischemic target vessel5.63.43.21.60.004Composite end point8.34.85.74.40.02Other adver

16、se enents Target-vessel revascularization for any reason6.03.63.41.60.002 Subacute thrombosis1.90.81.00.00.01 Hemorrhagic complication Severe0.60.40.20.80.58 Moderate2.52.34.32.50.18 Intracrantial hemorrhage0.00.00.00.20.99 Throbocytopenia(100,000 cells/mm3)1.44.02.64.00.02 Blood-product transfusion

17、 3.75.14.15.00.62At 6 months(cumulative)Death4.52.53.04.20.23Reinfarction1.82.71.62.20.64Disabling stroke0.20.20.40.40.88Revascularization of ischemic target vessel15.713.88.35.20.001Composite end point20.016.511.510.20.001Target-vessel revascularization for any reason16.914.88.95.70.001CADILLACKapl

18、an-Meier Estimates of the Clinical Outcomes at 30 Days and 6 MonthsN Engl J Med 2002; 346: 957-966CADILLAC30 day acute thrombosisP=0.05P=0.03N Engl J Med 2002; 346: 957-966CADILLAC thrombocytopenia and bleeding evntsPTCAPTCA/AbcxStentStent/AbcxpBleeding - sever0.6%0.2%0.4%0.8%0.58 - moderate2.5%2.3%

19、4.3%2.5%0.18 - intrcranial0%0%0%0.2%0.99thrombocytopenia1.4%4.0%2.6%4.0%0.02Blood-product intrafusion3.7%5.1%4.1%5.0%0.62 N Engl J Med 2002; 346: 957-966 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，并与安慰剂比较 在救护车或急诊室开始用药在导管室或CCU开始用药P0.05P=NSP=NSP0.05 Circulation 2001; 103:2328-2335PRISM-PLUS Angiograp

20、hic Substudy: Tirofiban Increased Perfusion StatusP=0.002 for trend by proportional odds modelZhao X-Q, et al. Circulation. 1999;100:1609-1615.GPIIb/IIIa受体拮抗剂治疗建议中高危NSTE-ACS患者(尤其TnT、ST或糖尿病)，可在氯吡格雷+ ASA基础上，加用GPIIb/IIIa拮抗剂不建议STEMI患者溶栓时联合应用GPIIb/IIIa受体拮抗剂，尤其是年龄大于75岁的患者GPIIb/IIIa拮抗剂应在抗凝治疗基础上应用(UFH或LMWH)

21、出血危险较高患者慎用或禁忌；若应用GPIIb/IIIa受体拮抗剂，应监测血红蛋白和血小板计数2009年中国PCI治疗指南GPb/a受体拮抗剂推荐I IIa IIb IIIUA/NSTEMI行PCI的患者，如未服用氯吡格雷，应给予一种血小板糖蛋白b/a受体拮抗剂，在实施诊断性CAG前或PCI术前即刻给药均可UA/NSTEMI行PCI的患者，如已服用氯吡格雷，可同时给予一种血小板糖蛋白b/a受体拮抗剂STEMI行PCI的患者，可尽早应用血小板糖蛋白b/a受体拮抗剂接受择期PCI并置入支架的高危患者或高危病变（如ACS、近期MI、桥血管狭窄、冠状动脉慢性闭塞病变及CAG可见的血栓病变等），可应用血小

22、板糖蛋白b/a受体拮抗剂，但应充分权衡出血与获益风险BABB四、 GPIIb/IIIa Inhibitors and PCI trialsCasesOdds ratio & 95% CIplaceboGPIEPIC2,0999.6%6.6%IMPACT-II4,0108.5%7.0%EPILOG2,7929.1%4.0%CAPTURE1,2659.0%4.8%RESTORE2,1416.3%5.1%EPISTENT2,39910.2%5.2%ESPRIT2,06410.2%6.3%Placebo betterGPI better00.511.520.62 (0.55, 0.71)p 0.000

23、00000116,7708.8%5.6%GPIIb/IIIa Inhibitors and PCImeta-Analysis30-day MI/deathEPISTENT1-year results in diabetes* P0.11* P0.005* P0.022* P0.035 P0.440 P0.290 P0.389 P0.546 stent+placebo VS angiolpasy+abciximab * stent+placebo VS stent+abciximabLancet 1999; 354: 2019-24EPISTENTLancet 1999; 354: 2019-2

24、4 1-year mortality0306090120150180210240270300330360p = 0.0371.0%2.4%2.1%stent+placebostent+Abciximabangioplasty+Abciximab(days)Follow-upLancet 1999; 354: 2019-24* P0.156* P0.001* P0.002* P0.369 P0.852 P0.084 P0.062 P0.014EPISTENT1-year results in non-diabetes stent+placebo VS angiolpasy+abciximab *

25、 stent+placebo VS stent+abciximabP-valueOdds-ratioTirofibanAbciximabcomposite end point0.0387.6%6.0%Death0.660.5%0.4%non-fatal MI0.046.9%5.4%death or MI0.047.2%5.7%urgent TVR0.490.8%0.7%N Engl J Med 2001; 344: 1888-94TARGET Tirofiban vs Abciximab in PCI30-day results0.00.51.01.52.01.262.431.261.271.

26、211.262.80Tirofiban betterAbciximab betterTARGET Tirofiban vs Abciximab in PCI 6-month follow-upAbciximabTirofibanP-valueMACE13.8%14.4%0.5death1.0%1.1%0.9MI6.6%8.0%0.07TVR8.0%7.5%0.5N Engl J Med 2001; 344: 1888-94ISAR-REACT abciximab in elective PCI%0.30.43.30.90.30.53.30.7012345DeathQ-MINQ-MIUrgent

27、 TVRJ Am Coll Cardiol 2004; 44: 2133-36 exclude recent MI, ACS, diabetesALL= NSabciximabplacebo%P=0.38P=0.007P=0.002P=0.371.12.50.92.40.71.900.9012345major bleedingminor bleedingtransfusionJ Am Coll Cardiol 2004; 44: 2133-36abciximabplacebothrombocytopeniaISAR-REACT abciximab in elective PCIsafety outcomesASA, clopidogrel, randomization in cath labPlacebo+Heparin 60U/kg bolus(ACT 200-300 sec)Eptifibatide180+180 g/kg bolus(boluses 10 min apart)2.0 g/kg-min infusion18-24o+Heparin 60 U/mg bolus(ACT 200-300sec)48 hour, 30day, 6 month, 1 year follow-upElective PCIVS.Lancet 2000