Shaw M D, Vermeulen M, Murray G D, Pickard J D, Bell B A, Teasdale G M
The Walton Centre for Neurology and Neurosurgery, Liverpool, Merseyside, United Kingdom.
J Neurosurg. 2000 Dec;93(6):992-7. doi: 10.3171/jns.2000.93.6.0992.
Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients.
Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups.
The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.
迟发性脑缺血仍是蛛网膜下腔出血（SAH）患者死亡和致残的重要原因。内皮素（ET）对脑动脉和小动脉有强烈的收缩作用，并与血管痉挛有关。作者对患有动脉瘤性SAH的患者给予ET（A/B）受体拮抗剂（TAK-044）。然后评估该药物是否能减少迟发性脑缺血事件的发生，并检查其在该组患者中的安全性。
420例SAH患者被纳入一项多中心、随机、双盲、安慰剂对照、平行组II期试验。主要终点是在首次服用研究药物后3个月内是否发生迟发性缺血事件，次要终点包括确定在首次服用研究药物后10天内是否发生迟发性缺血事件、在首次给药后3个月通过计算机断层扫描或尸检是否显示有新的脑梗死、首次给药后3个月时患者的格拉斯哥预后评分以及不良事件。TAK-044治疗组在3个月时迟发性缺血事件的发生率较低：为29.5%，而接受安慰剂治疗的一组患者为36.6%。估计相对风险为0.8，95%置信区间为0.61至1.06。在次要终点方面，包括安慰剂治疗组和TAK-044治疗组的临床结局，没有显著差异。
SAH患者对TAK-044耐受性良好，尽管出现了与药物血管舒张特性相符的低血压和头痛等副作用。进行一项关于ET受体拮抗剂治疗动脉瘤性SAH的充分有力的III期试验将是有价值的。
