The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial.
The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial.
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DOI：
10.1161/strokeaha.108.517656
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发表时间：
2008-12
期刊：
影响因子：
8.3
通讯作者：
CLEAR Trial Investigators
中科院分区：
文献类型：
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作者：
Pancioli AM;Broderick J;Brott T;Tomsick T;Khoury J;Bean J;del Zoppo G;Kleindorfer D;Woo D;Khatri P;Castaldo J;Frey J;Gebel J Jr;Kasner S;Kidwell C;Kwiatkowski T;Libman R;Mackenzie R;Scott P;Starkman S;Thurman RJ;CLEAR Trial Investigators
目前正在研究多种方法以提高急性缺血性卒中的溶栓率。与单独使用纤溶药物相比，联合使用低剂量纤溶药物和糖蛋白（GP）IIb/IIIa受体拮抗剂治疗心肌梗死可提高再通率。使用依替巴肽和重组组织型纤溶酶原激活剂（rt-PA）（CLEAR）的联合溶解方法卒中试验评估了在症状发作3小时内使用该联合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/美国国立神经疾病和中风研究所资助的多中心、双盲、随机、剂量递增和安全性研究。患者以3：1的比例随机分配至低剂量rt-PA（第1层=0.3 mg/kg，第2层=0.45 mg/kg）+依替巴肽（75 μg/kg推注，随后每分钟输注0.75 μg/kg，持续2小时）或标准剂量rt-PA（0.9 mg/kg）。主要安全性终点是36小时内症状性脑出血的发生率。对临床疗效进行了次要分析。入组了94例患者（1级40例，2级54例）。2个剂量层的联合治疗组（n=69）的中位年龄为71岁，中位基线国立卫生研究院卒中量表（NIHSS）评分为14，标准剂量rt-PA组（n=25）的中位年龄为61岁，中位基线NIHSS评分为10（NIHSS评分P=0.01）。联合治疗组52例（75%）和标准治疗组24例（96%）的基线改良兰金量表评分为0（P=0.04）。联合治疗组有1例（1.4%; 95% CI，0%-4.3%）症状性颅内出血，rt-PA单药治疗组有2例（8.0%; 95% CI，0%-19.2%）（P=0.17）。在2级随机化期间，独立数据安全性监查委员会的审查表明，2级剂量联合治疗的安全性特征使得进一步入组在统计学上不太可能表明联合治疗组的安全性不足，这是研究的最终结局。因此，研究被停止。与联合治疗组相比，标准剂量rt-PA的临床疗效有增加的趋势。减少剂量的rt-PA联合依替巴肽的安全性证明了在急性缺血性卒中中进行进一步剂量范围试验的合理性。
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 μg/kg bolus followed by 0.75 μg/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 out-come 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.