Fujimura Miki, Joo Jin-Yang, Kim Jong-Soo, Hatta Motonori, Yokoyama Yoshinari, Tominaga Teiji
Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Cerebrovasc Dis. 2017;44(1-2):59-67. doi: 10.1159/000475824. Epub 2017 May 3.
Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH.
The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared.
Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003).
These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.
在全球范围内，已对克拉唑森坦用于预防动脉瘤性蛛网膜下腔出血（aSAH）后脑血管痉挛进行了研究。在以色列、欧洲和北美的一项剂量探索性试验（CONSCIOUS-1）中，克拉唑森坦（1、5和15毫克/小时）显著降低了脑血管痉挛的发生率，但其对日本和韩国患者的疗效尚不清楚。我们进行了一项双盲对照研究，以评估日本和韩国aSAH患者中脑血管痉挛的发生情况。
这项多中心、双盲、随机、安慰剂对照、剂量探索性2期临床试验的目的是评估克拉唑森坦（5和10毫克/小时）对日本和韩国aSAH患者夹闭手术后脑血管痉挛的疗效、药代动力学和安全性。年龄在20至75岁之间的患者在动脉瘤破裂后56小时内及aSAH后第14天内给予研究药物。根据导管血管造影，将主要颅内动脉内径减少≥34%定义为血管痉挛，比较各治疗组之间血管痉挛的发生率。还比较了6周时因血管痉挛导致的脑梗死情况以及3个月时患者的预后。
在181名入组患者中，158名完成了研究并进行了分析。aSAH发病后至第14天血管痉挛的发生率在安慰剂组为80.0%（95%CI 67.0-89.6），在5毫克/小时克拉唑森坦组为38.5%（95%CI 25.3-53.0），在10毫克/小时克拉唑森坦组为35.3%（95%CI 22.4-49.9），表明克拉唑森坦治疗显著降低了血管痉挛的发生率（安慰剂组与5毫克/小时克拉唑森坦组比较，p<0.0001；安慰剂组与10毫克/小时克拉唑森坦组比较，p<0.0001）。因血管痉挛导致的脑梗死发生率在安慰剂组为20.8%（95%CI 10.8-34.1），在5毫克/小时克拉唑森坦组为3.8%（95%CI 0.5-13.2），在10毫克/小时克拉唑森坦组为4.2%（95%CI 0.5-14.3），表明克拉唑森坦显著降低了血管痉挛导致的脑梗死的发生（安慰剂组与5毫克/小时克拉唑森坦组比较，p=0.0151；安慰剂组与10毫克/小时克拉唑森坦组比较，p=0.0165）。与安慰剂组相比，10毫克/小时克拉唑森坦组全因死亡和/或血管痉挛相关发病率/死亡率的总体发生率显著降低（p=0.0003）。
这些结果表明，克拉唑森坦可预防脑血管痉挛及随后的脑梗死，从而改善日本和韩国aSAH患者夹闭手术后的预后。
