Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial
Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial
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DOI：
10.1016/s0140-6736(20)30611-5
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发表时间：
2020-04-11
期刊：
影响因子：
168.9
通讯作者：
Silbergleit, Robert
中科院分区：
文献类型：
--
作者：
Chamberlain, James M.;Kapur, Jaideep;Silbergleit, Robert
背景：苯二氮卓类难治性或已确立的癫痫持续状态被认为在儿童和成人中具有相似的病理生理，但潜在病因和药效学的差异可能会不同地影响对治疗的反应。在确立的癫痫持续状态治疗试验（ESETT）中，我们比较了左乙拉西坦、磷苯妥英和丙戊酸钠在确立的癫痫持续状态中的疗效和安全性，在这里我们描述了在扩大儿童入组后比较三个年龄组结果的结果。方法在这项多中心、双盲、反应适应、随机对照试验中，我们从美国58家医院急诊科招募了患者。如果患者年龄在2岁或以上，使用足够剂量的苯二氮卓类药物治疗持续时间超过5分钟的全面性惊厥发作，并且在最后一次苯二氮卓类药物后持续持续或复发性惊厥至少5分钟，不超过30分钟，则有资格纳入。采用贝叶斯方法并按年龄组（65岁）分层，以反应适应的方式随机分配患者至左乙拉西坦、磷酸苯妥英或丙戊酸盐组。所有患者、调查人员、研究人员和药剂师都不知道治疗分配情况。主要结局是在药物输注开始后1小时，无明显的临床癫痫发作，意识改善，无额外抗癫痫药物。主要安全结局是危及生命的低血压或心律失常。通过意向治疗分析疗效和安全性结果。本研究已在ClinicalTrials.gov注册，编号NCT01960075。在2015年11月3日至2018年12月29日期间，我们纳入了478名患者和462名特殊患者：225名儿童（65岁）。175例（38%）患者被随机分配到左乙拉西坦组，142例（31%）患者被分配到磷苯妥英组，145例（31%）患者被分配到丙戊酸酯组。各组治疗的基线特征是平衡的。在接受左乙拉西坦治疗的患者中，52%（95%可信区间41-62）的儿童、44%（33-55）的成人和37%（19-59）的老年人达到了主要疗效结果；49%（38-61岁）的儿童、46%（34-59岁）的成人和35%（17-59岁）的老年人患有磷苯妥英；52%（41-63）的儿童、46%（34-58）的成人和47%（25-70）的老年人使用丙戊酸盐。各年龄组药物的疗效或主要安全性结果均无差异。除儿童气管插管外，各年龄组药物的次要安全结局无显著差异。结论：儿童、成人和已确定癫痫持续状态的老年人对左乙拉西坦、磷妥英和丙戊酸盐的反应相似，约半数患者治疗成功。这三种药物中的任何一种都可以被认为是苯二氮卓类难治性癫痫持续状态的潜在首选二线药物。Elsevier Ltd.版权所有版权所有。
Background Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.Methods In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.Findings Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.Interpretation Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. Copyright (c) 2020 Elsevier Ltd. All rights reserved.