Macdonald R Loch, Kassell Neal F, Mayer Stephan, Ruefenacht Daniel, Schmiedek Peter, Weidauer Stephan, Frey Aline, Roux Sebastien, Pasqualin Alberto
St Michael's Hospital, Division of Neurosurgery, Toronto, Ontario, Canada.
Stroke. 2008 Nov;39(11):3015-21. doi: 10.1161/STROKEAHA.108.519942. Epub 2008 Aug 7.
This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage.
Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks.
Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P<0.0001). No significant effects were seen on secondary end points. Post hoc analysis using a centrally assessed morbidity/mortality end point that included death and rescue therapy but only cerebral infarcts and delayed ischemic neurological deficit due to vasospasm on central review showed a trend toward improvement with clazosentan (37%, 28%, and 29% in the 1, 5, and 15 mg/h groups versus 39% in the placebo group, nonsignificant). Clazosentan was associated with increased rates of pulmonary complications, hypotension, and anemia.
Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.
本随机、双盲、安慰剂对照、剂量探索性研究评估了内皮素受体拮抗剂1毫克/小时、5毫克/小时和15毫克/小时静脉注射克拉生坦预防动脉瘤性蛛网膜下腔出血后血管痉挛的疗效和安全性。
413例患者在56小时内被随机分配至安慰剂组或克拉生坦组，并在开始治疗后持续用药14天。主要终点是基于在基线以及蛛网膜下腔出血后7至11天对数字减影血管造影进行中心阅片、盲法评估的中度或重度血管造影血管痉挛。通过局部评估来评价包括全因死亡率、任何原因导致的新发脑梗死、血管痉挛所致的迟发性缺血性神经功能缺损或使用抢救治疗在内的发病/死亡终点。在12周时通过扩展格拉斯哥预后量表评估临床结局。
中度或重度血管痉挛呈剂量依赖性降低，从安慰剂组的66%降至15毫克/小时克拉生坦组的23%（风险降低65%；95%置信区间，47%至78%；P<0.0001）。对次要终点未见显著影响。使用中心评估的发病/死亡终点进行事后分析，该终点包括死亡和抢救治疗，但仅将中心复查时血管痉挛所致的脑梗死和迟发性缺血性神经功能缺损纳入分析，结果显示克拉生坦有改善趋势（1毫克/小时、5毫克/小时和15毫克/小时组分别为37%、28%和29%，而安慰剂组为39%，差异无统计学意义）。克拉生坦与肺部并发症、低血压和贫血发生率增加相关。
克拉生坦以剂量依赖性方式显著降低中度和重度血管痉挛，在进行中心评估时，显示出降低动脉瘤性蛛网膜下腔出血患者血管痉挛相关发病/死亡的趋势。总体而言，不良反应可控，不被视为严重不良反应。
