GP2b/3a受体拮抗剂 的获益／风险 北京大学第一医院 霍 勇

血小板功能的药物干预 斑块破裂 血小板激活的介导剂 水蛭素 凝血酶 —//— 肝素 血小板粘附 噻氯匹定 血小板聚集抑制剂 ADP —//— TXA2 —//—阿司匹林 凝血酶 —//— 水蛭素 肝素 ADP —//— 噻氯匹定 氯吡格雷 GPⅡb/Ⅲa 拮抗剂 —//— 血小板聚集抑制剂

血小板糖蛋白IIb/IIIa受体拮抗剂作用机制

口服 GP IIb/IIIa 试验 : 有害无益 Sibrafibin, Orbofiban, Xemilofibin 33000 pts 27% increase in the risk of death There were strong trends to increased risk.

氯比格雷和Abciximab联合应用 ISAR REACT 稳定性心绞痛接受介入治疗的患者

ISAR REACT

冠脉内支架和抗栓治疗 – 冠脉治疗的早期快速作用研究2 ISAR – REACT 2* 冠脉内支架和抗栓治疗 – 冠脉治疗的早期快速作用研究2 Intracoronary Stenting and Antithrombotic Regimen – Rapid Early Action for coronary Treatment 2 评估对于使用600mg氯吡格雷预治疗后的行PCI术的有高危因素的ACS患者，阿昔单抗是否有治疗利益 研究设计 多中心，随机，双盲，安慰剂对照研究，入组2022名行PCI术的非ST段抬高的ACS病例(平均年龄66岁） 研究终点 主要终点：30天内的复合终点（死亡，心梗和急性靶血管重建 UTVR) 次要终点：入院期间主要次要出血率 2006年发表在JAMA上的ISAR-REACT2 研究则进一步研究了在行PCI术的有高危因素的非ST段抬高的ACS患者中, 术前600mg氯吡格雷预治疗后的，阿昔单抗是否有治疗利益. 2004年发表的ISAR-REACT的结果显示术前600mg氯吡格雷预治疗后的，术后加用阿昔单抗并不能带来额外的治疗利益,并且会增加出血. 因此, ISAR-REACT2 着重针对高危的NSTE-ACS患者. Pr berger: ISAR React was a pivotal study, in which 2100 patients were enrolled. Patients were randomly assigned to abciximab or placebo. Two important points: all of the patients received 600mg of clopi at least 2 hrs before the procedure. So it was not drectly abciximab vs clopi. Everybody got clopi And the question was: is there added value from abciximab above and beyond pretreatment with clopi? The second important point is,the investigators enrolled lower risk ACS patients … But the important point was that biomarker-positive patients and insulin-taking diabetics were excluded from the study. CONTEXT: No specifically designed studies have addressed the role of the glycoprotein IIb/IIIa inhibitor abciximab in patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg of clopidogrel. OBJECTIVE: To assess whether abciximab is associated with clinical benefit in high-risk patients with ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. DESIGN, SETTING, AND PATIENTS: International, multicenter, randomized, double-blind, placebo-controlled study conducted from March 2003 through December 2005, enrolling 2022 patients (mean age, 66 years) with non-ST-segment elevation ACS undergoing PCI. INTERVENTIONS: Patients were assigned to receive either abciximab (0.25 mg/kg of body weight bolus, followed by a 0.125-microg/kg per minute [maximum, 10 microg/min] infusion for 12 hours, plus heparin, 70 U/kg of body weight) or placebo (placebo bolus and infusion of 12 hours, plus heparin bolus, 140 U/kg). All patients received clopidogrel, 600 mg, at least 2 hours prior to the procedure, as well as 500 mg of oral or intravenous aspirin. MAIN OUTCOME MEASURES: The primary end point was a composite of death, myocardial infarction, or urgent target vessel revascularization occurring within 30 days after randomization; secondary end points were rates of in-hospital major and minor bleeding. RESULTS: Of 2022 patients enrolled, 1012 were assigned to abciximab and 1010 to placebo. The primary end point was reached in 90 patients (8.9%) assigned to abciximab vs 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (relative risk [RR], 0.75; 95% CI, 0.58-0.97; P = .03). Among patients without an elevated troponin level, there was no difference in the incidence of primary end point events between the abciximab group (23/499 patients [4.6%]) and the placebo group (22/474 patients [4.6%]) (RR, 0.99; 95% CI, 0.56-1.76; P = .98), whereas among patients with an elevated troponin level, the incidence of events was significantly lower in the abciximab group (67/513 patients [13.1%]) compared with the placebo group (98/536 patients [18.3%]), which corresponds to an RR of 0.71 (95% CI, 0.54-0.95; P = .02) (P = .07 for interaction). There were no significant differences between the 2 groups regarding the risk of major and minor bleeding as well as need for transfusion. CONCLUSIONS: Abciximab reduces the risk of adverse events in patients with non-ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00133003. * Kastrati A, Mehilli J, Neumann F-J, et al; for the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006;295:1531-1538. JAMA. 2006;295:1531-1538.

ISAR – REACT2: 30天结果 11.5% 8.6% 总的研究结果显示, 阿昔单抗组的临床终点事件减少. 15 安慰剂 阿昔单抗 11.5% 10 8.6% 临床终点发生率 (%) 5 总的研究结果显示, 阿昔单抗组的临床终点事件减少. Pr Bhatt: some have criticized the study for being underpowered. What do you think about that comment Pr berger: I think it is a very valid criticism. The anticipated event rate was in the mid 6% range and what was encountered was in the low 4% range. So the 2100 patients were in fact undersized since we did not know in advance that the event rates would be so low. So yes, it was underpowered, but with event rates in the low 4% range, and with placebo trivially outperforming abciximab, ISAR REACT can be viewed as definitife and has influenced practice patterns aroudn the world Long rank P＝0.03 5 10 15 20 25 30 时间（天） Adnan K, et al. JAMA. April 5， 2006; 1531-1538

ISAR – REACT2: 30天结果 15 安慰剂 阿昔单抗 肌钙蛋白>0.03ug/L Long rank P＝0.02 10 临床终点发生率 (%) 肌钙蛋白<0.03ug/L Long rank P＝0.98 5 具体的亚组分析显示: 肌钙蛋白显著升高的患者亚组的临床获益有显著的统计学意义. 而肌钙蛋白<0.03ug/L 的亚组患者则似乎没有临床获益. Pr Bhatt: some have criticized the study for being underpowered. What do you think about that comment Pr berger: I think it is a very valid criticism. The anticipated event rate was in the mid 6% range and what was encountered was in the low 4% range. So the 2100 patients were in fact undersized since we did not know in advance that the event rates would be so low. So yes, it was underpowered, but with event rates in the low 4% range, and with placebo trivially outperforming abciximab, ISAR REACT can be viewed as definitife and has influenced practice patterns aroudn the world 5 10 15 20 25 30 时间（天） Adnan K, et al. JAMA. April 5， 2006; 1531-1538

PCI抗凝治疗2004 ACCP 指南 UFH LMWH 直接凝血酶抑制剂 用GPIIb/IIIa拮抗剂 不用GPIIb/IIIa拮抗剂 PCI前≤ 8h用过LMWH PCI前 8-12h用过LMWH >12h用过LMWH 等级 1C 2C 1A 是否加用 （＋） 非复杂PCI（－） （—） 药物 肝素 依诺肝素 bivalirudin 剂量 50-70 IU/kg ACT>200 60-100 IU/kg ACT 250-350 0.3 mg/kg 常规抗凝剂量 0.75mg/kg → 1.75 mg/kg/h 未来导管室的抗凝方案将发生变化，LMWH有替代UFH的趋势。目前NSTEMI/UA患者中，有很大一部分需要接受PCI手术治疗， LMWH在这些患者中的应用日益广泛 。 这是今年第7届ACCP会议上提出的有关PCI术中抗栓治疗指南中的抗凝治疗的相关内容。 该指南指出，对于PCI前曾接受LMWH治疗的患者，患者在PCI术中是否需要额外的抗凝治疗取决于末次应用LMWH的时间（证据分级1C）。依诺肝素是最常用的LMWH，因此以它作为标准。若最后一剂依诺肝素的使用时间距PCI≤8小时，则无需追加额外的抗凝治疗（证据等级2C） ；若最后一剂依诺肝素的使用时间距PCI在8－12小时之间，则建议在PCI时静脉追加一剂依诺肝素0.3 mg/kg （证据等级2C） ；若最后一剂依诺肝素的使用时间距PCI>12小时，则在PCI时常规应用抗凝治疗 （证据等级2C） 。 Reference: Popma JJ et al. CHEST 2004; 126:576S–599S Popma JJ. CHEST 2004; 126:576S–599S ACT= activated clotting time

GPIIb/IIIa拮抗剂应用的共识 口服制剂无效 中/高危NSTE-ACS患者获益 PCI患者获益: STE-AMI >> NSTE-ACS 其他抗血小板或/和肝素合并应用的利弊 值得探讨的问题: Facilitated PCI Transfer PCI UPSTREAM USE