波立维在急性冠脉综合征治疗中的应用诸骏仁教授复旦大学中山医院Platelet Activation Mechanism 波立维与阿司匹林联合应用机理波立维背景波立维作用于血小板介导的血栓形成中的关键因素－ADP CAPRIE 研究显示波立维可降低血栓性事件的发生(心肌梗死、脑卒中、血管性死亡) 波立维安全性至少与阿司匹林相当，胃肠道安全性明显优于阿司匹林研究资料支持在包括阿司匹林的标准治疗基础上，使用波立维可获得更大的益处CLASSICS 研究显示介入治疗时时波立维可替代噻氯匹定，安全性优于噻氯匹定Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events 入选条件必须符合下列所有条件：1.	疑有急性冠脉综合征( ACS) 而ST 段抬高<1 mm ( 不稳定性心绞痛或NQMI ) 2. 	 最近一次发作的起病24小时内就诊3.	临床病史中具有典型缺血性胸痛，新起病或病情恶化，即静息时或轻微活动时胸痛(持续超过5分钟或需舌下含服硝酸甘油片以缓解胸痛) 4. 	心电图变化符合缺血性*，如：ST 段压低( 2个相邻导联为1 mm ) T 波倒置(2个相邻导联为2 mm ) 超急性高尖的T波			 或	心肌酶学或心脏肌钙蛋白I 或T >2 倍正常值上限* 最初，即使没有新的心电图改变，只要年龄>60岁且具有缺血的客观证据的患者均为合格的入选研究对象。但是，在最初3000例患者入选后，所有患者均需同时具备心电图变化或心肌标志物的升高。排除标准具有下列任一情况：年龄<21 岁既往中风致残(严重的脑缺陷，如患者卧床不能活动或痴呆) 既往颅内出血或出血性中风严重的合并疾病状态，以致预期生存<12个月严重心力衰竭( NYHA IV 级) 未经控制的高血压正在使用口服抗凝药、非研究的抗血小板药物(包括噻氯匹定或波立维) 或长期使用NSAIDs 患者同时正在参加其它任何药物或医疗设备的研究CURE－研究设计CURE －主要终点下列一组事件中的任一事件首次发生: 心血管死亡心肌梗死中风(缺血性，出血性，或类型不能确定) 下列一组事件中的任一事件首次发生: 心血管死亡心肌梗死中风(缺血性，出血性，或类型不能确定) 顽固性缺血CURE－基线特征CURE--- 随机化分组后的合并用药CURE --- 主要疗效结果主要终点(1) CURE --- 主要疗效结果主要终点(2) CURE --- 主要疗效结果主要终点(3) 重要亚组的主要转归PCI-CURE –研究设计PCI-CURE –30 天结果PCI-CURE –安全性出血并发症ACC / AHA 不稳定心绞痛及非Q 波心肌梗死治疗指南(Class I) 小结对动脉粥样硬化性疾病的二级预防除控制危险因素外，他汀类药物应用及抗血小板治疗是另一治疗学上的进展在非ST 段抬高的急性冠脉综合征患者，无论是否介入治疗，阿司匹林+波立维治疗应视为标准治疗在高危患者的二级预防中，波立维+阿司匹林意义更大对PCI 患者，波立维可作为噻氯匹定的替代治疗，具有更好的安全性Slide 19 	Inclusion Criteria Patients are eligible for CURE if they are admitted to hospital with symptoms suggestive of ACS without ST-segment elevation greater than 1 mm (unstable angina or non-Q-wave MI), and within 24 hours of the most recent symptoms. All patients are required to have either ECG changes compatible with new ischemia or elevated cardiac enzymes or elevated troponin-I or -T (>2 x upper limit of normal). Initially patients over 60 years were eligible without ECG changes or biochemical markers if they had objective evidence of coronary atherosclerosis. However after the first 3000 patients were enrolled, the Steering Committee recommended that only patients with either ECG changes or elevated cardiac markers should be included. Reference CURE Study Investigators. Eur Heart J 2000;21:2033–2041. Slide 20 	Exclusion Criteria Typical exclusion criteria were applied, based mainly on safety considerations, or the presence of other clinical conditions. Reference CURE Study Investigators. Eur Heart J 2000;21:2033–2041. Slide 18 	CURE –Design (cont’d) Patients are eligible for CURE if they are admitted to hospital within 24 hours of an episode of chest pain suggestive of unstable angina or non-Q-wave MI. Patients are randomized to one of the treatments and receive a loading dose of clopidogrel 300 mg or matching placebo on Day 1. Treatment continues with either clopidogrel 75 mg or matching placebo for up to 1 year. Follow-up assessments take place at 1 and 3 months for all patients and at 6, 9 and 12 months for patients randomized early in the study. Reference CURE Study Investigators. Eur Heart J 2000;21:2033–2041. Slide 22 	CURE –Primary Endpoints The co-primary outcomes of CURE are: the composite of cardiovascular death, MI or stroke the composite of cardiovascular death, MI, stroke or refractory ischemia. The primary analysis will be based on intention to treat. Only the first event is counted. Refractory ischemia is defined as either recurrent chest pain with ECG changes indicative of myocardial ischemia while on optimal medical therapy and leading to additional intervention or rehospitalization for unstable angina and ECG changes consistent with acute myocardial ischemia. Reference CURE Study Investigators. Eur Heart J 2000;21:2033–2041. Slide 8 	CURE –Concomitant Medications After Randomization Patients in CURE were receiving optimal medical management based on current guidelines. During the initial hospitalization, 99% of patients received ASA, ~92% of patients received heparin/LMWH, ~84% beta-blockers, ~49% calcium channel blockers, ~62% ACE inhibitors and ~64% lipid-lowering drugs. No clinically relevant adverse interactions were reported between clopidogrel and these concomitant medications. Reference Sanofi-Synthelabo. Data on file. 		 Slide 9 	CURE –Main Efficacy Results 		Primary endpoint (1) A 20% relative risk reduction (RRR) in the primary composite endpoint of cardiovascular death, MI, or stroke was observed with clopidogrel on top of standard therapy (including ASA) versus standard therapy alone (p=0.00009). The Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months. Clopidogrel on top of standard therapy (including ASA) demonstrates an early effect (within hours) and sustained long-term benefit throughout the entire trial period of 12 months. References The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with non ST elevation acute coronary syndromes. N Eng J Med August 2001. Sanofi-Synthelabo. Data on file. Slide 10 	CURE –Main Efficacy Results 		Primary endpoint (2) A 20% relative risk reduction (RRR) in the primary composite endpoint of cardiovascular death, MI, or stroke was observed with clopidogrel on top of standard therapy (including ASA) versus standard therapy alone (p=0.00009). The Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months. Clopidogrel on top of standard therapy (including ASA) demonstrates an early effect (within hours) and sustained long-term benefit throughout the entire trial period of 12 months. References The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with non ST elevation acute coronary syndromes. N Eng J Med August 2001. Sanofi-Synthelabo. Data on file. Slide 11 	CURE –Main Efficacy Results 		Primary endpoint (3) A 20% relative risk reduction (RRR) in the primary composite endpoint of first occurrence of cardiovascular death, MI or stroke was observed with clopidogrel on top of standard therapy (including ASA) versus standard therapy alone (p=0.00009). Although the trial was not powered to detect differences between the two groups in the incidence of the individual endpoints of cardiovascular death, MI, or stroke alone, the risk reduction for each of the individual endpoints was consistent with that observed for the composite. References The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with non ST elevation acute coronary syndromes. New Eng J Med August 2001. Sanofi-Synthelabo. Data on file. * Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level * Pathogenesis of Acute Coronary Syndromes Adapted from Davies MJ. Circulation. 1990; 82 (suplII): 3046. Plaque rupture Platelet adhesion Platelet activation Partially occlusive arterial thrombosis & unstable angina Microembolization & non-ST elevation MI Totally occlusive arterial thrombosis & ST elevation MI Non-ST Elevation Acute Coronary Syndromes Results from cross-linking of platelets by fibrinogen at platelet receptors GP IIb-llla at site of plaque rupture platelet fibrinogen Ruptured plaque GP IIb-llla Generally caused by a partially occlusive, platelet-rich thrombus in a coronary artery Unobstructed lumen thrombus Artery wall 急性冠状动脉综合征非持续性ST- 段抬