目的:最近,美国食品和药物管理局(FDA)批准了替他,大麻二酚,和芬氟拉明治疗Dravet综合征(DS)患者。此外,seticlestat被确定为治疗DS的有希望的新药,因为它具有良好的疗效和安全性。然而,这些药物的疗效和安全性尚未在"头对头"试验中进行评估.本研究旨在比较和评估这些辅助抗癫痫药物治疗DS的疗效和安全性。方法:我们在PubMed中搜索,Embase,科克伦图书馆,和WebofScience数据库用于DS患者的随机对照试验(RCTs)和开放标签扩展(OLE)研究。我们对OLE研究进行了随机效应荟萃分析,并对RCT进行了网络荟萃分析,以评估抗癫痫药物治疗DS的有效性和安全性。主要疗效结果定义为与基线相比癫痫发作频率降低≥50%。此外,安全性评价指标定义为治疗期间不良事件(AEs)和严重不良事件(SAEs)的发生率.使用累积排名曲线(SUCRA)概率下的表面评估相对排名。结果:七个RCT涉及四种抗癫痫药物(stiripentol,大麻二酚,芬氟拉明,和seticlestat),总共634例患者被纳入分析。根据SUCRA的结果,与安慰剂组相比,4种药物均显著降低了癫痫发作频率.与基线相比,Soticlestat最有可能将癫痫发作频率降低≥50%[风险比(RR):19.32;95%置信区间(CI):1.20-311.40],其次是stiripentol和fenfluramine。在癫痫发作率相对于基线[RR:12.33;95%CI:1.71-89.17]和任何治疗引起的不良事件[RR:3.73;95%CI:1.65-8.43]和严重不良事件[RR:4.76;95%CI:0.61-37.28]的降低百分比中,Stiripentol排名最高。我们的研究共纳入了10项OLE研究,包含1,121名患者。根据荟萃分析的结果,癫痫发作频率减少≥50%的概率顺序是芬氟拉明(0.715,95%CI:0.621-0.808),stiripentol(0.604,95%CI:0.502-0.706),大麻二酚(0.448,95%CI:0.403-0.493)。AE的发生概率排序为芬氟拉明(0.832,95%CI:0.795-0.869),大麻二酚(0.825,95%CI:0.701-0.950),stiripentol(0.823,95%CI:0.707-0.938),seticlestat(0.688,95%CI:0.413-0.890)。结论:根据疗效和安全性的间接比较结果,大麻二酚在疗效和安全性方面略低于其他三种抗癫痫药物。Soticlestat,芬氟拉明,而曲戊醇在疗效上可能差别不大,但seticlestat和芬氟拉明更安全.Soticlestat可能是最好的辅助抗癫痫药物,其次是芬氟拉明。这一结论与长期疗效和安全性的比较一致。
Purpose: Recently, the U.S. Food and Drug Administration (FDA) approved
stiripentol, cannabidiol, and fenfluramine to treat patients with Dravet syndrome (DS). Moreover, soticlestat was determined as a promising new drug for the treatment of DS as it has good efficacy and safety. However, the efficacy and safety of these drugs have not yet been evaluated in \"head-to-head\" trials. This study aimed to compare and evaluate the efficacy and safety of these adjunctive antiseizure medications in the treatment of DS. Methods: We searched in PubMed, Embase, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs) and open-label extension (OLE) studies in patients with DS. We performed a random-effect meta-analysis of OLE studies and a network meta-analysis for RCTs to evaluate the efficacy and safety of antiseizure medications in the treatment of DS. Primary efficacy outcomes were defined as a ≥50% reduction in seizure frequency compared with baseline. Furthermore, safety evaluation indicators were defined as the incidence of adverse events (AEs) and serious adverse events (SAEs) during treatment. Relative ranking was assessed using the surface under the cumulative ranking curve (SUCRA) probabilities. Results: Seven RCTs involving four antiseizure medications (
stiripentol, cannabidiol, fenfluramine, and soticlestat) and a total of 634 patients were included in the analysis. According to the SUCRA results, all four drugs significantly reduced the frequency of seizures compared with the placebo. Soticlestat was the most likely to reduce seizure frequency by ≥50% compared to the baseline [risk ratio (RR): 19.32; 95% confidence interval (CI): 1.20-311.40], followed by stiripentol and fenfluramine.
Stiripentol was ranked highest for the near percentage reduction in the seizure rate from baseline [RR: 12.33; 95% CI: 1.71-89.17] and the occurrence of any treatment-emergent adverse events [RR: 3.73; 95% CI: 1.65-8.43] and serious adverse events [RR: 4.76; 95% CI: 0.61-37.28]. A total of ten OLE studies containing 1,121 patients were included in our study. According to the results of the meta-analysis, the order of probability of reducing seizure frequency by ≥50% was fenfluramine (0.715, 95% CI: 0.621-0.808),
stiripentol (0.604, 95% CI: 0.502-0.706), cannabidiol (0.448, 95% CI: 0.403-0.493). And the probability of occurrence of AEs is ranked as fenfluramine(0.832, 95% CI: 0.795-0.869), cannabidiol (0.825, 95% CI:0.701-0.950),
stiripentol (0.823, 95% CI: 0.707-0.938), soticlestat (0.688, 95% CI: 0.413-0.890). Conclusion: According to the results of indirect comparison of efficacy and safety, cannabidiol is slightly inferior to the other three antiseizure medications in terms of efficacy and safety. Soticlestat, fenfluramine, and stripentol may have little difference in efficacy, but soticlestat and fenfluramine are safer. Soticlestat is probably the best adjunctive antiseizure medication, followed by fenfluramine. This conclusion is consistent with the comparison of long-term efficacy and safety.