DataSheet1_DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials.docx

Background: DL -3-n-butylphthalide (NBP) is widely used as a neuroprotective drug in stroke patients in China. A systematic review in 2010 suggested NBP to be safe and effective at promoting neurological recovery, but could not conclude whether it decreased risk of long-term death or disability. Since numerous randomized controlled trials (RCTs) have been conducted on NBP since 2010, we performed an updated systematic review and meta-analysis of safety and efficacy data.
Method: We searched electronic databases and reference lists to identify RCTs that compared patients who received NBP or not (including placebo). Methodological quality of RCTs was assessed using the Revised Cochrane Risk of Bias Tool 2.0, and data were meta-analyzed using Review Manager 5.4 software.
Results: Fifty-seven RCTs involving 8,747 participants were included. Twenty trials examined NBP as a capsule, 29 as an injection, and 8 as sequential injection-capsule therapy. Meta-analyses showed that NBP treatment was associated with a reduction in composite outcome of death and dependency (risk ratio 0.59, 95% CI 0.42 to 0.83; 260 participants; 2 studies), death (risk ratio 0.32, 95% CI 0.13 to 0.75; 2,287 participants; 10 studies), modified Rankin Scale score (mean difference -0.80, 95% CI -0.88 to -0.72; 568 participants; 4 studies), and an increase in Barthel Index, which assesses the ability to engage in basic activities of daily living (mean difference 11.08, 95% CI 9.10 to 13.05; 2,968 participants; 22 studies). Meta-analyses found that NBP significantly reduced neurological deficit based on National Institute of Health Stroke Scale (mean difference -3.39, 95% CI -3.76 to -3.03; 7.283 participants; 46 studies) and Chinese Stroke Scale (mean difference -4.16, 95% CI -7.60 to -0.73; 543 participants; 4 studies). Of the adverse events reported in 31 trials, elevated transaminase (incidence, 1.39-17.53%), rash (0-1.96%) and gastrointestinal discomfort (1.09-6.15%) were most frequent and no serious adverse events were reported.
Conclusion: This update review confirms that NBP can help acute ischemic stroke patients regain the ability to perform activities of daily living, reduce their neurological deficit and short-term death rates. However, the available evidence on whether NBP reduces risk of long-term death or dependence after ischemic stroke remains insufficient.

背景：DL-3-正丁基苯酞（DL-3-n-butylphthalide，NBP）在我国被广泛应用于脑卒中患者的神经保护治疗。2010年的一项系统评价指出，NBP在促进神经功能恢复方面安全有效，但无法明确其是否可降低长期死亡或残疾风险。自2010年以来，针对NBP的随机对照试验（randomized controlled trial, RCT）数量众多，因此本研究开展了一项更新版系统评价与荟萃分析，对其安全性及有效性数据进行整合分析。
方法：本研究检索了电子数据库及参考文献列表，以筛选对比接受NBP治疗与未接受NBP治疗（含安慰剂组）患者的随机对照试验。采用修订版Cochrane偏倚风险评估工具2.0（Revised Cochrane Risk of Bias Tool 2.0）评价纳入试验的方法学质量，并使用Review Manager 5.4软件完成荟萃分析。
结果：最终纳入57项随机对照试验，共计8747名受试者。其中20项试验考察了NBP胶囊制剂，29项为注射剂型，8项为序贯注射-胶囊联合治疗方案。荟萃分析结果显示：NBP治疗可降低死亡与功能依赖的复合结局风险（风险比0.59，95%置信区间（Confidence Interval, CI）0.42~0.83；260名受试者，2项试验）、全因死亡风险（风险比0.32，95%CI 0.13~0.75；2287名受试者，10项试验）；同时可改善改良Rankin量表评分（均数差-0.80，95%CI -0.88~-0.72；568名受试者，4项试验），并提升Barthel指数评分——该指数用于评估个体日常基本生活活动能力（均数差11.08，95%CI 9.10~13.05；2968名受试者，22项试验）。此外，荟萃分析表明，基于美国国立卫生研究院卒中量表（National Institute of Health Stroke Scale, NIHSS）与中国卒中量表评分，NBP可显著改善神经功能缺损情况：前者均数差-3.39，95%CI -3.76~-3.03；7283名受试者，46项试验；后者均数差-4.16，95%CI -7.60~-0.73；543名受试者，4项试验。在31项试验报告的不良事件中，转氨酶升高（发生率1.39%~17.53%）、皮疹（0~1.96%）与胃肠道不适（1.09%~6.15%）最为常见，且未报告严重不良事件。
结论：本更新版系统评价证实，NBP可帮助急性缺血性脑卒中患者恢复日常基本生活活动能力，改善神经功能缺损并降低短期死亡率。然而，目前关于NBP能否降低缺血性脑卒中患者长期死亡或残疾风险的证据仍不充分。