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那些病人能从 GP IIb/IIIa Inhibitors 获益

那些病人能从 GP IIb/IIIa Inhibitors 获益. 中国医学科学院　北京协和医学院 心血管病研究所　阜外心血管病医院 袁晋青. 主要内容. Characteristics of GP IIb/IIIa Inhibitors GP IIb/IIIa Inhibitors in ACS GP IIb/IIIa Inhibitors in STEMI GPIIb/IIIa Inhibitors and PCI. 一、 Characteristics of GP IIb/IIIa Inhibitors. GPIIb/IIIa Inhibitors.

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那些病人能从 GP IIb/IIIa Inhibitors 获益

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  1. 那些病人能从GP IIb/IIIa Inhibitors获益 中国医学科学院　北京协和医学院 心血管病研究所　阜外心血管病医院 袁晋青

  2. 主要内容 • Characteristics of GP IIb/IIIa Inhibitors • GP IIb/IIIa Inhibitors in ACS • GP IIb/IIIa Inhibitors in STEMI • GPIIb/IIIa Inhibitors and PCI

  3. 一、Characteristics of GP IIb/IIIa Inhibitors

  4. GPIIb/IIIa Inhibitors Abciximab Eptifibatide Tirofiban

  5. NH NH H2N O HN–SO2–C4H9 O COOH O OH H N HN O HN N H HN O O O S N O S N H N H H2N O 三种静脉GPⅡb/Ⅲa受体抑制剂的比较 Abciximab Tirofiban Eptifibatide Fab fragment of a chimeric monoclonal antibody MW  50,000 D Nonpeptide tyrosine derivativeMW  500 D Cyclic heptapeptideMW  800 D 合成非肽类 鼠源性单克隆抗体 合成肽类 Topol E, et al. Lancet. 1999;353:227-231.

  6. GP IIb/IIIa 受体拮抗剂作用机制 Plaque rupture and platelet adhesion Platelet activation Prevention of platelet aggregation Resting platelet GP IIb/IIIa expression Fibrinogen Agonists released GP IIb/IIIa inhibitor vWF vWF vWF Vessel Wall White HD. Am J Cardiol. 1997;80(4A):2B-10B.

  7. 三种静脉GPⅡb/Ⅲa受体抑制剂的比较

  8. 二、GP IIb/IIIa Inhibitors in ACS

  9. 20% 20% PRISM-PLUS (n=1,570) PURSUIT (n=9,461) 15.7% 15% 15% Heparin 11.9% 14.2% Heparin 10% 10% Eptifibatide + heparin 8.7% 5% 5% Tirofiban + heparin 0% 0% 0 10 20 30 0 10 20 30 Days Days GP IIb/IIIa Inhibitors in ACS - Death or MI at 30 days - OR 0.70 [0.51, 0.96] P=0.03 OR 0.90 [0.75, 0.98] P=0.04 The Prism-Plus Investigators. NEJM 1998;338:1488-97 The PURSUIT Investigators. NEJM 1998;339:436-43

  10. 42% 23% 31% 6% PCI <72h No early PCI PCI <72h No early PCI (n=287) (n=1283) (n=1228) (n=8233) Impact of Early PCI on 30 Day Death/MI PRISM Plus PURSUIT Heparin Tirofiban + Heparin Heparin Eptifibatide+Heparin 15% 20% 16.7% 15.6% 14.5% 10.2% 15% 10.1% 10% 11.6% 7.8% 10% 5.9% 5% 5% 0% 0%

  11. GPIIb/IIIa Inhibitors in ACS 30-Day mortality results of a Meta-analysis* 10% GPIIb/IIIa Inhibitor Placebo P=0.007 6.2% P=NS 5% 4.6% 3.0% 3.0% n= 6,458 n= 23,072 Non-DM DM * PRISM, PRISM-PLUS, PARAGON A & B, PURSUIT, GUSTO-IV Circulation 2001;104:2767-71

  12. GPIIb/IIIa Inhibitors in Diabetic Patients with ACS 30-Day Mortalityof a Meta-analysis* 10% GPIIb/IIIa Inhibitor Placebo P=0.1 6.7% P=0.002 5.5% 5% 4.0% 1.2% n= 5,179 n= 1,279 No PCI PCI * PRISM, PRISM-PLUS, PARAGON A & B, PURSUIT, GUSTO-IV Circulation 2001;104:2767-2771

  13. GUSTO-IV Study Design Non ST-segment elevation ACS Medical rx only planned (no angio or PCI) (n=7800) 2598 ASA+UFH or LMUH +placebo 2590 ASA+UFH + Abciximab 24h 2612 ASA+UFH + Abciximab 48h 2598 2590 2612 Lancet 2001; 357: 1915-24

  14. GUSTO-IV30-Day outcomes 9.1% 10% 8.2% 8.0% 8% 5.9% 5.6% 5.1% 6% 4.3% 3.9% 3.4% 4% 2% P = 0.235 P = 0.190 P = 0.664 0% Death, MI Death MI placebo Abciximab 24h Abciximab 48h Lancet 2001; 357: 1915-24

  15. GUSTO-IVsafety outcomes * p < 0.05,vs placebo * * * * * < 50,000 per µL < 100,000 per µL Lancet 2001; 357: 1915-24

  16. Benefits of GP IIb/IIIa Inhibitors by Troponin Status in Clinical Trials TnT-Positive TnT-Negative PARAGON-B PRISM CAPTURE Combined 0.125 0.5 1 2 0.125 0.5 1 2 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse Circulation 2001;103:2891-96

  17. 20 15 10 5 0 ISAR-REACT 2 Death, MI, or urgent TVR in Subsets With and Without Elevated Troponin Levels (>0.03 µg/L) Placebo Group (N=1010) Abciximab Group (N=1012) % Troponin >0.03 µg/L Log-Rank p = 0.02 Troponin <0.03 µg/L Log-Rank p = 0.98 0 5 10 15 20 25 30 Days After Randomization JAMA 2006; 295:1531-38

  18. 早期应用有效降低住院死亡率NRMI注册研究 N=60770 NSTEMI患者 住 院 死 亡 率 % NRMI-NSTEMI Risk Score NRMI=National Registry of Myocardial Infarction. Peterson E, et al. J Am Coll Cardiol. 2003;42:45-53

  19. (n=2522) (n=2041) (n=3803) (n=1105) 3.0  2.8% 2.3% 2.5 2.0 1.7% 1.5 1.0 0.5 0% 0.0 <6 hours 6–12 hours 12–24 hours >24 hours 越早用药 绝对获益越大 PURSUIT研究： GPIIb/IIIa VS 安慰剂 30天死亡 /心梗绝对下降(%) 1.7%  2.3%  用 药 距 离 发 病 的 时 间 JAMA. 2000; 284:1549-1558

  20. I IIa IIb III UA/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Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂 STEMI行PCI的患者，可尽早应用血小板糖蛋白Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂，但应充分权衡出血与获益风险 A B B B 2009年中国PCI治疗指南 GPⅡb/Ⅲa受体拮抗剂推荐

  21. 三、 GP IIb/IIIa Inhibitors in STEMI

  22. GP IIb/IIIa Inhibitors in STEMI Abciximab and PCI in STEMI Trials 30 Day Endpoint (D, Re-MI, u-TVR) % p<0.05 p=0.005 p=0.038 p=0.023 p=0.01 PTCA N = 483 Stent N = 401 Stent N = 301 PTCA or Stent N = 2082 Stent N = 400

  23. RAPPORTAbciximab in primary PTCA for STEMI 7-day Outcome P=0.003 9.9% p=0.098 P=0.01 5.0% 5.4% 3.3% 2.1% 1.2% Circulation 1998;98;734-741

  24. RAPPORT 30 – Day follow-up P=0.03 11.2% P=0.006 P=0.52 6.6% 5.8% 5.8% 4.6% 1.7% Circulation. 1998; 98: 734-741

  25. RAPPORT6 month follow-up P=0.9 28.1% 28.2% P=0.048 17.8% P=0.36 11.6% 11.2% 8.7% Circulation. 1998; 98: 734-741

  26. CADILLAC AMI <12 h, cardiogenic shock excluded N = 2082 76 centers in N.A. S.A. and Europe randomization Primary PTCA (n=518) MultiLink stent + Abciximab (n=524) Primary PTCA + Abciximab (n=528) MultiLink stent (n=512) N Engl J Med 2002; 346: 957-966

  27. CADILLAC Kaplan-Meier Estimates of the Clinical Outcomes at 30 Days and 6 Months N Engl J Med 2002; 346: 957-966

  28. CADILLAC30 day acute thrombosis P=0.05 P=0.03 N Engl J Med 2002; 346: 957-966

  29. CADILLAC thrombocytopenia and bleeding evnts PTCA PTCA/Abcx Stent Stent/Abcx p Bleeding - sever 0.6% 0.2% 0.4% 0.8% 0.58 - moderate 2.5% 2.3% 4.3% 2.5% 0.18 - intrcranial 0% 0% 0% 0.2% 0.99 thrombocytopenia 1.4% 4.0% 2.6% 4.0% 0.02 Blood-product intrafusion 3.7% 5.1% 4.1% 5.0% 0.62 N Engl J Med 2002; 346: 957-966

  30. 在救护车或急诊室开始用药 在导管室或CCU开始用药 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 P=NS P=NS P<0.05 P<0.05 Circulation 2001; 103:2328-2335

  31. PRISM-PLUS Angiographic Substudy: Tirofiban Increased Perfusion Status P=0.002 for trend by proportional odds model Zhao X-Q, et al. Circulation. 1999;100:1609-1615.

  32. 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) • 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

  33. I IIa IIb III UA/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Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂 STEMI行PCI的患者，可尽早应用血小板糖蛋白Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂，但应充分权衡出血与获益风险 A B B B 2009年中国PCI治疗指南 GPⅡb/Ⅲa受体拮抗剂推荐

  34. 四、 GPIIb/IIIa Inhibitors and PCI

  35. GPIIb/IIIa Inhibitors and PCImeta-Analysis 0.62 (0.55, 0.71) p < 0.000000001 16,770 8.8% 5.6% 0 0.5 1 1.5 2 30-day MI/death GPI better Placebo better

  36. EPISTENT1-year results in diabetes † P<0.546 * P<0.035 † P<0.290 † P<0.389 * P<0.005 * P<0.022 † P<0.440 * P<0.11 †stent+placebo VS angiolpasy+abciximab * stent+placebo VS stent+abciximab Lancet 1999; 354: 2019-24

  37. EPISTENT 1-year mortality 2.4% stent+placebo stent+Abciximab 2.1% angioplasty+Abciximab 1.0% p = 0.037 (days) 0 30 60 90 120 150 180 210 240 270 300 330 360 Follow-up Lancet 1999; 354: 2019-24

  38. EPISTENT1-year results in non-diabetes † P<0.014 * P<0.369 † P<0.084 † P<0.062 * P<0.001 * P<0.002 † P<0.852 * P<0.156 †stent+placebo VS angiolpasy+abciximab * stent+placebo VS stent+abciximab Lancet 1999; 354: 2019-24

  39. TARGETTirofiban vs Abciximab in PCI30-day results 1.26 1.21 2.80 1.27 1.26 1.26 2.43 0.0 0.5 1.0 1.5 2.0 Tirofiban better Abciximab better N Engl J Med 2001; 344: 1888-94

  40. TARGETTirofiban vs Abciximab in PCI 6-month follow-up N Engl J Med 2001; 344: 1888-94

  41. ISAR-REACT abciximab in elective PCI exclude recent MI, ACS, diabetes % abciximab 5 placebo ALL= NS 4 3.3 3.3 3 2 0.9 0.7 1 0.5 0.4 0.3 0.3 0 Death Q-MI NQ-MI Urgent TVR J Am Coll Cardiol 2004; 44: 2133-36

  42. ISAR-REACT abciximab in elective PCIsafety outcomes % abciximab placebo 5 P=0.37 P=0.38 P=0.002 P=0.007 4 2.5 3 2.4 1.9 2 1.1 0.9 0.9 0.7 1 0 0 thrombocytopenia major bleeding minor bleeding transfusion J Am Coll Cardiol 2004; 44: 2133-36

  43. ESPRIT ASA, clopidogrel, randomization in cath lab Eptifibatide 180+180 μg/kg bolus (boluses 10 min apart) 2.0 μg/kg-min infusion×18-24o + Heparin 60 U/mg bolus (ACT 200-300sec) Placebo+ Heparin 60U/kg bolus (ACT 200-300 sec) VS. Elective PCI 48 hour, 30day, 6 month, 1 year follow-up Lancet 2000; 356: 2037- 44

  44. ESPRITeptifibatide in elective PCI30-Day results Placebo Eptifibatide 12% 10% 10.2% 8% 6% Death or MI (%) 6.4% P = 0.0014 4% RR = 0.62 2% 0% 30 20 10 Days following randomization Lancet 2000; 356: 2037-44

  45. ESPRIT30-Day Stroke and bleeding * * * p<0.03 * * Major bleeding (TIMI) Lancet 2000; 356: 2037-44

  46. Abciximab in PCI: Complex Lesions EPIC and EPILOG : 30 day Events (D, MI, uTVR) % p=.047 p=.001 p=.001 p=.001 p=.078 p=.001 p=.001 p=.001 p=.001 JACC 1998; 32:1619-23

  47. EPISTENTAbciximab for Complex Lesions 30 day D, MI, uTVR % p=0.17 p<0.001 Lancet 1999; 354: 2019-24

  48. I IIa IIb III UA/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Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂 STEMI行PCI的患者，可尽早应用血小板糖蛋白Ⅱb/Ⅲa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Ⅱb/Ⅲa受体拮抗剂，但应充分权衡出血与获益风险 A B B B 2009年中国PCI治疗指南 GPⅡb/Ⅲa受体拮抗剂推荐

  49. 小 结 • 血小板在ACS发病中起重要作用 • 抗血小板治疗是ACS的关键治疗之一 • GPⅡb/Ⅲa拮抗剂尤其适宜于中高危行介入治疗的ACS患者 • 三重抗血小板治疗在ACS伴TNI升高者中尤为重要

  50. 谢 谢！

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