Tcheng J E, Ellis S G, George B S, Kereiakes D J, Kleiman N S, Talley J D, Wang A L, Weisman H F, Califf R M, Topol E J
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Circulation. 1994 Oct;90(4):1757-64. doi: 10.1161/01.cir.90.4.1757.
Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent.
The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug.
The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.
血栓形成被认为是冠状动脉血管成形术（PTCA）临床并发症的核心因素。嵌合单克隆7E3 Fab（c7E3 Fab）是一类针对血小板糖蛋白IIb/IIIa整合素的新型抗血小板药物中的首个药物。进行本研究以确定PTCA期间给予c7E3 Fab的药效学，并获得使用这种新型药物的初步临床经验。
本研究是一项分两个阶段进行的多中心、开放标签、剂量递增研究。纳入了56例计划进行择期PTCA的患者，这些患者被估计发生缺血性并发症的风险为中度至高度。所有患者均给予阿司匹林和肝素。研究药物在PTCA前至少10分钟给予。在第1阶段，对15例患者给予递增剂量的c7E3 Fab推注；发现0.25 mg/kg的推注剂量可导致>80%的受体被阻断，与基线相比血小板聚集减少至<20%，确定该剂量为充分抑制血小板活性所需的剂量。在第2阶段，对32例患者通过持续输注给予额外的c7E3 Fab，输注时间逐渐延长（最长24小时），以确认延长药物输注可维持血小板抑制作用。此外，9例符合入选标准的患者给予安慰剂。接受c7E3 Fab的患者中未发生血栓事件。各组之间总体手术和临床成功率、并发症发生率以及出血率在统计学上相似。然而，使用活性药物时轻微出血更为常见。
新型抗血小板药物c7E3 Fab可在PTCA期间与阿司匹林和肝素联合使用。血小板活性的抑制呈剂量依赖性，并且可维持长达24小时。需要进一步评估以确定缺血性并发症和再狭窄率的改善程度，并进一步了解这种强效单克隆血小板抗体的安全性。
