胆碱酯酶抑制剂改善轻中度阿尔茨海默病患者认知疗效的Meta分析

牛 茜，王 蕾，曹 凯，邵 爽，郭秀花*

·论著·

·医学循证·

胆碱酯酶抑制剂改善轻中度阿尔茨海默病患者认知疗效的Meta分析

牛 茜1,2，王 蕾2，曹 凯1，邵 爽1，郭秀花1*

目的 探讨4种胆碱酯酶抑制剂(多奈哌齐、加兰他敏、石杉碱甲、卡巴拉汀)治疗轻中度阿尔茨海默病(AD)患者的疗效。方法 计算机检索PubMed、EMBase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网、中国生物医学网，检索时限为1994年1月—2016年3月，纳入关于胆碱酯酶抑制剂治疗轻中度AD患者的随机双盲安慰剂对照试验。对纳入文献进行数据提取和质量评价，提取包括第一作者、发表时间、药物、日给药剂量、性别、年龄、观察时间、基线简易精神状态评价量表(MMSE)评分、结局指标等资料。采用RevMan 5.3软件分析多奈哌齐、加兰他敏、石杉碱甲、卡巴拉汀改善轻中度AD患者阿尔茨海默病评定量表-认知项目(ADAS-cog)和MMSE评分的效果。结果 共纳入30篇文献，其中多奈哌齐15篇，加兰他敏7篇，石杉碱甲4篇，卡巴拉汀4篇。Meta分析结果显示，多奈哌齐5 mg组、多奈哌齐10 mg组、加兰他敏24 mg组、加兰他敏32 mg组、卡巴拉汀12 mg组ADAS-cog评分均低于安慰剂组〔加权均数差(WMD)=-2.13，95%CI(-2.69，-1.57)，P<0.001；WMD=-2.03，95%CI(-2.80，-1.25)，P<0.001；WMD=-3.05，95%CI(-3.54，-2.55)，P<0.001；WMD=-2.64，95%CI(-3.55，-1.73)，P<0.001；WMD=-2.17，95%CI(-3.30，-1.04)，P<0.001〕。石杉碱甲400 μg组和安慰剂组ADAS-cog评分比较，差异无统计学意义〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.270〕。多奈哌齐5 mg组、多奈哌齐10 mg组、石杉碱甲400 μg组、卡巴他汀12 mg组MMSE评分均高于安慰剂组〔WMD=1.07,95%CI(0.55,1.59)，P<0.001；WMD=1.20,95%CI(0.91,1.50)，P<0.001；WMD=2.47,95%CI(1.15,3.78)，P<0.001；WMD=1.23,95%CI(0.35,2.11)，P=0.006〕。Begg秩相关检验、Egger线性回归分析，ADAS-cog纳入文献P值分别为0.511、0.755；MMSE纳入文献P值分别为0.441、0.212，未观察到发表偏倚。结论 除石杉碱甲外，其他胆碱酯酶抑制剂治疗轻中度AD患者认知功能减退效果显著。石杉碱甲治疗效果仍有待纳入高质量文献进一步论证。

阿尔茨海默病；胆碱酯酶抑制剂；Meta分析

牛茜，王蕾，曹凯，等.胆碱酯酶抑制剂改善轻中度阿尔茨海默病患者认知疗效的Meta分析[J].中国全科医学，2017，20(14)：1735-1742.[www.chinagp.net]

NIU Q,WANG L,CAO K,et al.Effect of cholinesterase inhibitorson on cognition of patients with mild to moderate Alzheimer′s disease:a meta-analysis[J].Chinese General Practice，2017，20(14)：1735-1742.

阿尔茨海默病(AD)是一项重大的公共卫生问题，是引起老年痴呆最常见的神经退行性疾病，威胁卫生保健系统和国民经济[1]。一项发表于Lancet的流行病学系统综述显示，1990年我国AD患者为193万，2010年达568万，居世界第一位[2]。当前药物虽然可以延缓AD患者病情进展，但却不能预防或治愈AD。胆碱酯酶抑制剂多奈哌齐、加兰他敏、卡巴拉汀已被欧洲国家证实具有延缓AD临床症状的作用[3-4]。在我国除以上3种胆碱酯酶抑制剂外，石杉碱甲也可作为改善AD患者认知功能的临床用药，其对真性胆碱酯酶有选择性抑制作用，具有促进记忆再现和记忆保持作用[5]。

目前已有大量文献系统评价3种胆碱酯酶抑制剂多奈哌齐、加兰他敏、卡巴拉汀治疗AD患者认知损害的疗效及安全性，研究方法和侧重点各不相同[4，6-9]。我国临床对于石杉碱甲的广泛使用及相关研究[10-11]也为AD治疗方案的选择提供了经验和依据。本研究将石杉碱甲与其他3种胆碱酯酶抑制剂(多奈哌齐、加兰他敏、卡巴拉汀)同时进行疗效评价，为临床选择胆碱酯酶抑制剂治疗AD患者认知功能提供综合证据。

1 资料与方法

1.1 纳入与排除标准 纳入标准：选取1994年1月—2016年3月公开发表的关于胆碱酯酶抑制剂治疗轻中度AD患者的随机双盲安慰剂对照试验，限于英文和中文两种语言发表。患者需符合AD诊断标准，简易精神状态评价量表(MMSE)评分10～26分，观察时间包含12～26周，结局指标包括阿尔茨海默病评定量表-认知项目(ADAS-cog)、MMSE。排除标准：动物实验、临床前试验或生物实验，描述性综述、社论、会议摘要及使用不充足的方法学报道的文献。

1.2 检索策略 以“Alzheimer′s Disease”“cholinesterase inhibitors”“galantamine”“rivastigmine”“donepezil”“huperzine A”“randomized controlled trial”及“阿尔茨海默病”“老年痴呆”“胆碱酯酶抑制剂”“多奈哌(派)齐”“安理申(Aricept)”“利凡斯的明”“艾斯能(Exelon)”“卡巴拉汀(丁)”“加兰他敏”“石杉碱甲”“随机对照”“双盲”等为关键词检索PubMed、EMBase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网、中国生物医学网等电子数据库，同时手动搜索相关文献进行补充。

1.3 数据提取和质量评价 由两位评论员独立提取数据，包括第一作者、发表时间、药物、日给药剂量、性别、年龄、观察时间、基线MMSE、结局指标等资料。如有争议进行讨论或由第3位评论员解决。通过RevMan 5.3软件对纳入文献进行偏倚风险评估得偏倚风险图，对文献质量进行评价。

1.4 统计学方法 采用RevMan 5.3和Stata 12.0软件进行统计学分析，计量资料以加权均数差(WMD)及其95%CI表示。采用I2值及χ2检验探讨研究间异质性，I2≤50%，P>0.1为无统计学异质性存在，采用固定效应模型分析；否则采用随机效应模型分析；采用Begg秩相关检验和Egger线性回归进行发表偏倚分析。以P<0.05为差异有统计学意义。

2 结果

2.1 文献基本情况 初检共获得文献2 513篇，通过阅读标题和摘要排除2 398篇，进一步根据纳入与排除标准排除85篇，共纳入30篇文献[12-41]，其中多奈哌齐15篇[12-26]，加兰他敏7篇[27-33]，石杉碱甲4篇[34-37]，卡巴拉汀4篇[38-41]。文献筛选流程见图1，纳入文献基本特征见表1。

表1 纳入文献基本特征

注：ADAS-cog=阿尔茨海默病评定量表-认知项目，MMSE=简易精神状态评价量表；-为无此数值

注：RCT=随机对照试验，AD=阿尔茨海默病

图1 文献筛选流程图

Figure 1 Flow chart of literature screening

2.2 文献质量评价 19篇文献[12,15,18,20-21,24,26-33,35,37-39,41]详细描述了随机分配序列的方法，10篇文献[15，20，28-33，39，41]详细描述分配隐藏方案，18篇文献[12-13,15,20-22,24,26-32,37,39-41]详细描述盲法实施情况，8篇文献[13,15,17,26-27,30,32,41]具体报道对结局评估员实施盲法，25篇文献[12-16，18,20-31,33,35,37-41]结局报告完整(见图2)。

2.3 Meta分析结果

2.3.1 以ADAS-cog评分为结局指标评估 23篇文献[12-16,21-22,24-33,35,37-41]以ADAS-cog评分为结局指标评估，其中多奈哌齐5 mg 5篇文献[12-16]，各研究间无统计学异质性(I2=0，P=0.63)；多奈哌齐10 mg 8篇文献[12-14,21-22,24-26]，

注：+=低度偏倚风险，？=偏倚风险不确定，-=高度偏倚风险

图2 风险偏倚评估结果

Figure 2 Assessment result of risk bias

各研究间有统计学异质性(I2=61%，P=0.01)；加兰他敏24 mg 6篇文献[27-29,31-33]，各研究间无统计学异质性(I2=0，P=0.57)；加兰他敏32 mg 4篇文献[27,29-31]，各研究间无统计学意义(I2=49%，P=0.12)；石杉碱甲400 μg 2篇文献[35,37]，各研究间有统计学异质性(I2=84%，P=0.01)，卡巴拉汀12 mg 4篇文献[38-41]，各研究间有统计学异质性(I2=72%，P=0.01)。采用随机效应模型分析，Meta分析结果显示，多奈哌齐5 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-2.13，95%CI(-2.69，-1.57)，P<0.001〕；多奈哌齐10 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-2.03，95%CI(-2.80，-1.25)，P<0.001〕；加兰他敏24 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-3.05，95%CI(-3.54，-2.55)，P<0.001〕；加兰他敏32 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-2.64，95%CI(-3.55，-1.73)，P<0.001〕；石杉碱甲400 μg组和安慰剂组ADAS-cog评分比较，差异无统计学意义〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.27〕；卡巴拉汀12 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-2.17，95%CI(-3.30，-1.04)，P<0.001，见图3〕。

2.3.2 以MMSE评分为结局指标评估 17篇文献[12-13,17-23,25-26,34-37,40-41]以MMSE评分为结局指标评估，其中多奈哌齐5 mg 3篇文献[12-13,23]，各研究间无统计学异质性(I2=0，P=0.89)；多奈哌齐10 mg 10篇文献[12-13,17-22,25-26]，各研究间无统计学异质性(I2=0，P=0.63)；石杉碱甲400 μg 4篇文献[34-37]，各研究间有统计学异质性(I2=75%，P=0.008)；卡巴他汀12 mg 2篇文献[40-41]，各研究间有统计学异质性(I2=75%，P=0.04)。采用随机效应模型分析，Meta分析结果显示：多奈哌齐5 mg组MMSE评分高于安慰剂组，差异有统计学意义〔WMD=1.07,95%CI(0.55,1.59)，P<0.001〕；多奈哌齐10 mg组MMSE评分高于安慰剂组，差异有统计学意义〔WMD=1.20,95%CI(0.91,1.50)，P<0.001〕；石杉碱甲400 μg组MMSE评分高于安慰剂组，差异有统计学意义〔WMD=2.47,95%CI(1.15,3.78)，P<0.001〕；卡巴他汀12 mg组MMSE评分高于安慰剂组，差异有统计学意义〔WMD=1.23,95%CI(0.35,2.11)，P=0.006，见图4〕。

2.4 发表偏倚及敏感性分析 使用Stata 12.0软件对ADAS-cog纳入文献进行Begg秩相关检验得到Z=0.66，P=0.511；进行Egger线性回归分析得到t=0.32，P=0.755(见图5)；对MMSE纳入文献进行Begg秩相关检验得到Z=0.77，P=0.441；进行Egger线性回归分析得到t=1.30，P=0.212(见图6)，未观察到发表偏倚。

图3 胆碱酯酶抑制剂和安慰剂治疗轻中度AD患者ADAS-cog评分比较的森林图

Figure 3 Forest plot of the ADAS-cog score between cholinesterase inhibitors and placebo in treating patients with mild to moderate AD

图4 胆碱酯酶抑制剂和安慰剂治疗轻中度AD患者MMSE评分比较的森林图

Figure 4 Forest plot of the MMSE score between cholinesterase inhibitors and placebo in treating patients with mild to moderate AD

敏感性分析，以亚组为单位逐一观察单个研究对亚组合并效应量的影响，ADAS-cog评分中，石杉碱甲400 μg张振馨等[35]、RAFII等[37]；卡巴拉汀12 mg COREY-BLOOM等[38]会对亚组合并效应量产生影响。由于石杉碱甲400 μg仅纳入2篇文献，而2篇文献均会直接影响合并效应量使结果发生转变，说明由其得出的结果证据不足，需要纳入更多文献，并谨慎分析结果。剔除COREY-BLOOM等[38]研究后，卡巴拉汀12 mg组ADAS-cog评分低于安慰剂组，差异有统计学意义〔WMD=-1.60,95%CI(-2.30，-0.90)，P<0.001〕，结果相对稳定。MMSE评分中，石杉碱甲400 μg RAFII等[37]对亚组影响较大，将其剔除后，石杉碱甲400 μg MMSE评分高于安慰剂组，差异有统计学意义〔WMD=3.05,95%CI(1.83，4.27)，P<0.001〕，结果相对稳定。

图5 ADAS-cog评分纳入文献发表偏倚漏斗图

图6 MMSE评分纳入文献发表偏倚漏斗图

3 讨论

目前，胆碱酯酶抑制剂治疗AD具有多年历史，最初用于治疗的他克林由于严重的不良反应已经停止使用，相继上市的药物有多奈哌齐、加兰他敏、卡巴拉汀。石杉碱甲是中药提取物，1996年在我国被批准用于治疗AD[42]。目前针对胆碱酯酶抑制剂多奈哌齐、加兰他敏、卡巴拉汀治疗轻中度AD认知疗效，许多学者对其进行了比较研究。英国NIC研究结果显示多奈哌齐和加兰他敏改善认知疗效显著，但结果受到测量方法及观察时间的限制。长期观察结果显示多奈哌齐或卡巴拉汀可能成为最有效的治疗方法，但受到药物使用方法的限制[4]。KOBAYASHI等[9]研究证明加兰他敏24 mg、32 mg，卡巴拉汀12 mg，多奈哌齐5 mg、10 mg对降低AD患者ADAS-cog评分具有显著效果。

本研究以不同胆碱酯酶抑制剂作为亚组，采用Meta分析方法比较4种胆碱酯酶抑制剂治疗轻中度AD患者认知的疗效。以ADAS-cog、MMSE评分为结局指标，观察时间为12～26周进行分析，得出多奈哌齐5 mg、多奈哌齐10 mg、加兰他敏24 mg、加兰他敏32 mg、卡巴拉汀12 mg均具有治疗轻中度AD患者认知的疗效。石杉碱甲虽纳入我国治疗指南，但在其他国家并未获准，故其药物研究主要来自国内试验，而国外研究较少。结局变量为ADAS-cog评分的Meta分析中，只有2篇文献[35，37]纳入石杉碱甲组(1篇中文，1篇英文)，研究数量及样本量少，且样本来自不同国家，研究间异质性较大，因此可能造成假阴性结果。结局变量为MMSE评分的Meta分析中，石杉碱甲亚组纳入3篇中文文献[34-36]，1篇英文文献[37]，研究间异质性大，观察原始研究偏倚风险图，中文文献方法学质量低，其在随机、分配隐藏、盲法、结局完整性均存在较高风险，低质量、小样本试验可能得出较大的干预措施疗效。所以本研究MMSE评分对石杉碱甲治疗效果的评价可能存在过高估计。

综上所述，石杉碱甲疗效评价由于存在研究间异质性及偏倚风险，需待获得高质量、大样本的文献进一步分析。本研究纳入文献的随访时间较短，对于药物远期疗效需通过长期研究分析评价。尽管ADAS-cog、MMSE是评价认知功能的常用量表，但是MMSE仍然受到教育程度的影响，而ADAS-cog识别不同严重程度AD患者认知变化的敏感性也受到争议。同时，本研究采用的Meta分析亚组分析为观察性研究，而非基于随机化比较，容易引起假阴性或假阳性结果。因此研究结果并不能作为确定的结果被提出，而需结合临床实际对药物的有效性进行综合评价。

作者贡献：牛茜进行文章的构思与设计、撰写论文；牛茜、王蕾进行研究的实施与可行性分析、数据收集、数据整理；牛茜、曹凯进行统计学处理；牛茜、邵爽进行结果的分析与解释、论文修订；邵爽负责文章的质量控制及审校；郭秀花对文章整体负责，监督管理。

本文无利益冲突。

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(本文编辑：贾萌萌)

Effect of Cholinesterase Inhibitorson on Cognition of Patients with Mild to Moderate Alzheimer′s Disease:a Meta-analysis

NIUQian1,2,WANGLei2,CAOKai1,SHAOShuang1,GUOXiu-hua1*

1.SchoolofPublicHealth,CapitalMedicalUniversity,Beijing100069,China2.BeixiaguanCommunityHealthServicesCenter,Beijing100081,China

Objective To discuss the effect of cholinesterase inhibitors (donepezil,galanthamine,huperzine A,rivastigmine) on the treatment of patients with mild to moderate Alzheimer′s Disease (AD).Methods From January 1994 to March 2016,PubMed,EMBase,Cochrane Library,Web of Science,CNKI,Wanfang Data Knowledge Service Platform,VIP Network,and China Biomedical Network was searched by computer retrieval to enroll randomized,double-blind,placebo-controlled trials of cholinesterase inhibitors treating patients with mild to moderate AD.Data extraction and quality evaluation were conducted to the included literatures.The data including the first author,the time of publication,medicine,one-day dose,gender,age,the time of observation,the baseline MMSE and the outcome indicators were extracted.RevMan 5.3 software was used to analyze the effect of donepezil,galanthamine,huperzine A,and rivastigmine on improving the scores of Alzheimer′s Disease Assessment Scale-cognitive Subscale(ADAS-cog) and mini-mental state examination(MMSE) among patients with AD.Results We enrolled 30 literatures totally,of which 15 on donepezil,7 on galanthamine,4 on huperzine A and 4 on rivastigmine.Meta-analysis showed that the ADAS-cog scores of the group of 5 mg donepezil,group of 10 mg donepezil,group of 24 mg galanthamine,group of 32 mg galantamine and group of 12 mg rivastigmine were lower than those of the placebo group〔WMD=-2.13，95%CI(-2.69，-1.57),P<0.001;WMD=-2.03,95%CI(-2.80,-1.25),P<0.001;WMD=-3.05,95%CI(-3.54,-2.55),P<0.001;WMD=-2.64,95%CI(-3.55,-1.73),P<0.001;WMD=-2.17,95%CI(-3.30,-1.04),P<0.001〕.There was no significant difference in the ADAS-cog score between group of 400 μg huperzine A and the placebo group 〔WMD=-2.95,95%CI(-8.19,2.29),P=0.270〕.The MMSE scores of the group of 5 mg donepezil,group of 10 mg donepezil,group of 400 μg huperzine A and group of 12 mg rivastigmine were higher than those of the placebo group〔WMD=1.07,95%CI(0.55,1.59),P<0.001;WMD=1.20,95%CI(0.91,1.50),P<0.001;WMD=2.47,95%CI(1.15,3.78),P<0.001;WMD=1.23,95%CI(0.35,2.11)，P=0.006〕.Begg rank correlation test and Egger linear regression test showed thatPvalue of the literatures included in ADAS-cog scale was 0.511 and 0.755 respectively;Pvalue of the literatures included in MMSE scale was 0.441 and 0.212 respectively.No publication bias was observed.Conclusion Except for huperzine A,other cholinesterase inhibitors have significant effect on the treatment of cognitive decline among patients with mild to moderate AD.The treatment effect of huperzine A needs to be further demonstrated by including high quality literatures.

Alzheimer disease;Cholinesterase inhibitors;Meta-analysis

R 745.7

A

10.3969/j.issn.1007-9572.2017.14.017

2016-07-29；

2017-02-25)

1.100069北京市，首都医科大学公共卫生学院

2.100081北京市海淀区北下关社区卫生服务中心

*通信作者：郭秀花，教授；E-mail：guoxiuh@ccmu.edu.cn

*Correspondingauthor:GUOXiu-hua,Professor;E-mail:guoxiuh@ccmu.edu.cn