Pancioli Arthur M, Broderick Joseph, Brott Thomas, Tomsick Thomas, Khoury Jane, Bean Judy, del Zoppo Gregory, Kleindorfer Dawn, Woo Daniel, Khatri Pooja, Castaldo John, Frey James, Gebel James, Kasner Scott, Kidwell Chelsea, Kwiatkowski Thomas, Libman Richard, Mackenzie Richard, Scott Phillip, Starkman Sidney, Thurman R Jason
Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0769, USA.
Stroke. 2008 Dec;39(12):3268-76. doi: 10.1161/STROKEAHA.108.517656. Epub 2008 Sep 4.
Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination.
The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy.
Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group.
The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.
目前正在研究多种方法以提高急性缺血性卒中的溶栓率。已证实，与单独使用纤溶药物相比，采用低剂量纤溶药物与糖蛋白（GP）IIb/IIIa受体拮抗剂联合治疗心肌梗死可提高血管再通率。利用依替巴肽和重组组织型纤溶酶原激活剂（rt-PA）联合溶栓的CLEAR卒中试验评估了在症状发作3小时内使用该联合方案治疗急性缺血性卒中患者的安全性。
CLEAR试验是一项由美国国立卫生研究院/国立神经疾病与卒中研究所资助的多中心、双盲、随机、剂量递增及安全性研究。患者按3:1随机分为低剂量rt-PA（第1层=0.3mg/kg，第2层=0.45mg/kg）加依替巴肽组（75μg/kg静脉推注，随后以0.75μg/kg每分钟的速度输注2小时）或标准剂量rt-PA（0.9mg/kg）组。主要安全性终点是36小时内症状性颅内出血的发生率。对临床疗效进行了次要分析。
共纳入94例患者（第1层40例，第2层54例）。2个剂量层的联合治疗组（n=69）中位年龄为71岁，国立卫生研究院卒中量表（NIHSS）基线评分中位数为14，标准剂量rt-PA组（n=25）中位年龄为61岁，NIHSS基线评分中位数为10（NIHSS评分P=0.01）。联合治疗组52例（75%）和标准治疗组24例（96%）的改良Rankin量表基线评分为0（P=0.04）。联合治疗组有1例（1.4%；95%CI，0%至4.3%）症状性颅内出血，仅rt-PA组有2例（8.0%；95%CI，0%至19.2%）（P=0.17）。在第2层随机分组期间，独立数据安全监测委员会的审查表明，第2层剂量联合治疗的安全性表明，进一步入组在统计学上不太可能显示联合治疗组安全性不足，这是该研究的最终结果。因此，该研究提前终止。与联合治疗组相比，标准剂量rt-PA的临床疗效有增加趋势。
低剂量rt-PA加依替巴肽联合治疗的安全性为急性缺血性卒中进一步进行剂量范围试验提供了依据。
