Bassand J P, Cariou R, Grollier G, Kragten J, Wolf J E, Heyndrickx G R
Centre Hospitalier, Besançon, France.
Semin Thromb Hemost. 1999;25 Suppl 2:69-75.
The safety and tolerability of clopidogrel coadministration to patients with recent acute myocardial infarction (AMI) treated with recombinant tissue plasminogen activator (rt-PA) and heparin were assessed. Patients of either sex who had a recent uncomplicated AMI with ischemic pain lasting at least 20 minutes and ST-segment elevation, and with indication for thrombolysis were included. Treatment was started within 12 hours after the onset of pain. Clopidogrel 75 mg was administered within 3 hours of starting the rt-PA infusion, and was continued at 75 mg once daily over the next 6 days. Heparin was administered as a 5000 IU intravenous bolus followed by a 1000 IU/h infusion for at least 48 hours to maintain an activated partial thromboplastin time at 1.8 to 2.2 times the control value. rt-PA was administered as a 15 mg bolus injection, followed by a 0.75 mg/kg (up to 50 mg) infusion over 30 minutes and a subsequent 0.50 mg/kg (up to 35 mg) infusion over 60 minutes. The patients were hospitalized at least during the 7-day study period, after which they were followed for 10 days. The primary end point of the study was the occurrence of bleeding complications validated by a data monitoring and safety committee as severe (intracerebral or with substantial hemodynamic alteration requiring treatment), moderate (need for transfusion), or minor (other bleeding). Based on the statistical assumption, at alpha = 0.05 of a true probability of severe bleeding < or =0.06, the required minimum number of patients was calculated as 45, 65, or 94 if no, one, or two moderate-to-severe bleeding events occurred, respectively. Efficacy was assessed based on mortality, reinfarction, or need for emergency revascularization procedures. One intracranial hemorrhage occurred among the first 49 patients included, and one after the inclusion of 16 additional patients (total of 65). After further increase in the number of patients to 94, then to 116 in order to secure a number of 94 evaluable patients for safety, there were no additional cases of severe bleeding. Hence, the observed rate of moderate-to-severe bleeding was estimated at 1.7%, with a 95% probability that the underlying rate was below 7.5%. Deaths occurred in 3.6% compared to 6.3% in the GUSTO trial. Recurrent myocardial infarctions occurred in 4.5% and emergency revascularization procedures in 14.5% of the 110 patients deemed evaluable for efficacy, rates which are similar in this study and the GUSTO trial. The results of the study compare favorably with historical data showing a moderate-to-severe bleeding rate of 6% with aspirin given concomitantly with rt-PA and suggest that clopidogrel could be safely given as platelet aggrega
评估了氯吡格雷与重组组织型纤溶酶原激活剂（rt-PA）和肝素联合使用对近期急性心肌梗死（AMI）患者的安全性和耐受性。纳入了近期发生无并发症AMI、缺血性疼痛持续至少20分钟且有ST段抬高、并有溶栓指征的男女患者。在疼痛发作后12小时内开始治疗。在开始rt-PA输注后3小时内给予氯吡格雷75mg，并在接下来的6天内每天继续给予75mg。肝素以5000IU静脉推注给药，随后以1000IU/h输注至少48小时，以维持活化部分凝血活酶时间为对照值的1.8至2.2倍。rt-PA以15mg静脉推注给药，随后在30分钟内以0.75mg/kg（最大50mg）输注，随后在60分钟内以0.50mg/kg（最大35mg）输注。患者至少在7天的研究期间住院，之后随访10天。该研究的主要终点是由数据监测和安全委员会确认为严重（颅内出血或有需要治疗的明显血流动力学改变）、中度（需要输血）或轻度（其他出血）的出血并发症的发生情况。基于统计假设，在严重出血的真实概率α = 0.05且≤0.06的情况下，如果分别没有、发生1例或2例中度至重度出血事件，所需的最小患者数量计算为45、65或94例。根据死亡率、再梗死或紧急血管重建手术的需求评估疗效。在纳入的前49例患者中有1例发生颅内出血，在纳入另外16例患者（共65例）后又有1例。在进一步将患者数量增加到94例，然后增加到116例以确保有94例可评估安全性的患者后，没有再发生严重出血病例。因此，观察到的中度至重度出血率估计为1.7%，有95%的可能性实际发生率低于7.5%。死亡率为3.6%，而GUSTO试验中的死亡率为6.3%。在110例被认为可评估疗效的患者中，4.5%发生了再发性心肌梗死，14.5%需要进行紧急血管重建手术，该研究中的这些发生率与GUSTO试验中的相似。该研究结果与历史数据相比更具优势，历史数据显示与rt-PA同时使用阿司匹林时中度至重度出血率为6%，这表明氯吡格雷作为血小板聚集抑制剂可以安全给药
