牛 茜，王 蕾，曹 凱，邵 爽，郭秀花*

·論著·

·醫(yī)學(xué)循證·

膽堿酯酶抑制劑改善輕中度阿爾茨海默病患者認(rèn)知療效的Meta分析

牛 茜1,2，王 蕾2，曹 凱1，邵 爽1，郭秀花1*

目的 探討4種膽堿酯酶抑制劑(多奈哌齊、加蘭他敏、石杉?jí)A甲、卡巴拉汀)治療輕中度阿爾茨海默病(AD)患者的療效。方法 計(jì)算機(jī)檢索PubMed、EMBase、Cochrane Library、Web of Science、中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)知識(shí)服務(wù)平臺(tái)、維普網(wǎng)、中國(guó)生物醫(yī)學(xué)網(wǎng)，檢索時(shí)限為1994年1月—2016年3月，納入關(guān)于膽堿酯酶抑制劑治療輕中度AD患者的隨機(jī)雙盲安慰劑對(duì)照試驗(yàn)。對(duì)納入文獻(xiàn)進(jìn)行數(shù)據(jù)提取和質(zhì)量評(píng)價(jià)，提取包括第一作者、發(fā)表時(shí)間、藥物、日給藥劑量、性別、年齡、觀察時(shí)間、基線簡(jiǎn)易精神狀態(tài)評(píng)價(jià)量表(MMSE)評(píng)分、結(jié)局指標(biāo)等資料。采用RevMan 5.3軟件分析多奈哌齊、加蘭他敏、石杉?jí)A甲、卡巴拉汀改善輕中度AD患者阿爾茨海默病評(píng)定量表-認(rèn)知項(xiàng)目(ADAS-cog)和MMSE評(píng)分的效果。結(jié)果 共納入30篇文獻(xiàn)，其中多奈哌齊15篇，加蘭他敏7篇，石杉?jí)A甲4篇，卡巴拉汀4篇。Meta分析結(jié)果顯示，多奈哌齊5 mg組、多奈哌齊10 mg組、加蘭他敏24 mg組、加蘭他敏32 mg組、卡巴拉汀12 mg組ADAS-cog評(píng)分均低于安慰劑組〔加權(quán)均數(shù)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?jí)A甲400 μg組和安慰劑組ADAS-cog評(píng)分比較，差異無(wú)統(tǒng)計(jì)學(xué)意義〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.270〕。多奈哌齊5 mg組、多奈哌齊10 mg組、石杉?jí)A甲400 μg組、卡巴他汀12 mg組MMSE評(píng)分均高于安慰劑組〔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秩相關(guān)檢驗(yàn)、Egger線性回歸分析，ADAS-cog納入文獻(xiàn)P值分別為0.511、0.755；MMSE納入文獻(xiàn)P值分別為0.441、0.212，未觀察到發(fā)表偏倚。結(jié)論 除石杉?jí)A甲外，其他膽堿酯酶抑制劑治療輕中度AD患者認(rèn)知功能減退效果顯著。石杉?jí)A甲治療效果仍有待納入高質(zhì)量文獻(xiàn)進(jìn)一步論證。

阿爾茨海默??；膽堿酯酶抑制劑；Meta分析

牛茜，王蕾，曹凱，等.膽堿酯酶抑制劑改善輕中度阿爾茨海默病患者認(rèn)知療效的Meta分析[J].中國(guó)全科醫(yī)學(xué)，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.

阿爾茨海默病(AD)是一項(xiàng)重大的公共衛(wèi)生問(wèn)題，是引起老年癡呆最常見(jiàn)的神經(jīng)退行性疾病，威脅衛(wèi)生保健系統(tǒng)和國(guó)民經(jīng)濟(jì)[1]。一項(xiàng)發(fā)表于Lancet的流行病學(xué)系統(tǒng)綜述顯示，1990年我國(guó)AD患者為193萬(wàn)，2010年達(dá)568萬(wàn)，居世界第一位[2]。當(dāng)前藥物雖然可以延緩AD患者病情進(jìn)展，但卻不能預(yù)防或治愈AD。膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀已被歐洲國(guó)家證實(shí)具有延緩AD臨床癥狀的作用[3-4]。在我國(guó)除以上3種膽堿酯酶抑制劑外，石杉?jí)A甲也可作為改善AD患者認(rèn)知功能的臨床用藥，其對(duì)真性膽堿酯酶有選擇性抑制作用，具有促進(jìn)記憶再現(xiàn)和記憶保持作用[5]。

目前已有大量文獻(xiàn)系統(tǒng)評(píng)價(jià)3種膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀治療AD患者認(rèn)知損害的療效及安全性，研究方法和側(cè)重點(diǎn)各不相同[4，6-9]。我國(guó)臨床對(duì)于石杉?jí)A甲的廣泛使用及相關(guān)研究[10-11]也為AD治療方案的選擇提供了經(jīng)驗(yàn)和依據(jù)。本研究將石杉?jí)A甲與其他3種膽堿酯酶抑制劑(多奈哌齊、加蘭他敏、卡巴拉汀)同時(shí)進(jìn)行療效評(píng)價(jià)，為臨床選擇膽堿酯酶抑制劑治療AD患者認(rèn)知功能提供綜合證據(jù)。

1 資料與方法

1.1 納入與排除標(biāo)準(zhǔn) 納入標(biāo)準(zhǔn)：選取1994年1月—2016年3月公開(kāi)發(fā)表的關(guān)于膽堿酯酶抑制劑治療輕中度AD患者的隨機(jī)雙盲安慰劑對(duì)照試驗(yàn)，限于英文和中文兩種語(yǔ)言發(fā)表?；颊咝璺螦D診斷標(biāo)準(zhǔn)，簡(jiǎn)易精神狀態(tài)評(píng)價(jià)量表(MMSE)評(píng)分10～26分，觀察時(shí)間包含12～26周，結(jié)局指標(biāo)包括阿爾茨海默病評(píng)定量表-認(rèn)知項(xiàng)目(ADAS-cog)、MMSE。排除標(biāo)準(zhǔn)：動(dòng)物實(shí)驗(yàn)、臨床前試驗(yàn)或生物實(shí)驗(yàn)，描述性綜述、社論、會(huì)議摘要及使用不充足的方法學(xué)報(bào)道的文獻(xiàn)。

1.2 檢索策略 以“Alzheimer′s Disease”“cholinesterase inhibitors”“galantamine”“rivastigmine”“donepezil”“huperzine A”“randomized controlled trial”及“阿爾茨海默病”“老年癡呆”“膽堿酯酶抑制劑”“多奈哌(派)齊”“安理申(Aricept)”“利凡斯的明”“艾斯能(Exelon)”“卡巴拉汀(丁)”“加蘭他敏”“石杉?jí)A甲”“隨機(jī)對(duì)照”“雙盲”等為關(guān)鍵詞檢索PubMed、EMBase、Cochrane Library、Web of Science、中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)知識(shí)服務(wù)平臺(tái)、維普網(wǎng)、中國(guó)生物醫(yī)學(xué)網(wǎng)等電子數(shù)據(jù)庫(kù)，同時(shí)手動(dòng)搜索相關(guān)文獻(xiàn)進(jìn)行補(bǔ)充。

1.3 數(shù)據(jù)提取和質(zhì)量評(píng)價(jià) 由兩位評(píng)論員獨(dú)立提取數(shù)據(jù)，包括第一作者、發(fā)表時(shí)間、藥物、日給藥劑量、性別、年齡、觀察時(shí)間、基線MMSE、結(jié)局指標(biāo)等資料。如有爭(zhēng)議進(jìn)行討論或由第3位評(píng)論員解決。通過(guò)RevMan 5.3軟件對(duì)納入文獻(xiàn)進(jìn)行偏倚風(fēng)險(xiǎn)評(píng)估得偏倚風(fēng)險(xiǎn)圖，對(duì)文獻(xiàn)質(zhì)量進(jìn)行評(píng)價(jià)。

1.4 統(tǒng)計(jì)學(xué)方法 采用RevMan 5.3和Stata 12.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析，計(jì)量資料以加權(quán)均數(shù)差(WMD)及其95%CI表示。采用I2值及χ2檢驗(yàn)探討研究間異質(zhì)性，I2≤50%，P>0.1為無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性存在，采用固定效應(yīng)模型分析；否則采用隨機(jī)效應(yīng)模型分析；采用Begg秩相關(guān)檢驗(yàn)和Egger線性回歸進(jìn)行發(fā)表偏倚分析。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 文獻(xiàn)基本情況 初檢共獲得文獻(xiàn)2 513篇，通過(guò)閱讀標(biāo)題和摘要排除2 398篇，進(jìn)一步根據(jù)納入與排除標(biāo)準(zhǔn)排除85篇，共納入30篇文獻(xiàn)[12-41]，其中多奈哌齊15篇[12-26]，加蘭他敏7篇[27-33]，石杉?jí)A甲4篇[34-37]，卡巴拉汀4篇[38-41]。文獻(xiàn)篩選流程見(jiàn)圖1，納入文獻(xiàn)基本特征見(jiàn)表1。

表1 納入文獻(xiàn)基本特征

注：ADAS-cog=阿爾茨海默病評(píng)定量表-認(rèn)知項(xiàng)目，MMSE=簡(jiǎn)易精神狀態(tài)評(píng)價(jià)量表；-為無(wú)此數(shù)值

注：RCT=隨機(jī)對(duì)照試驗(yàn)，AD=阿爾茨海默病

圖1 文獻(xiàn)篩選流程圖

Figure 1 Flow chart of literature screening

2.2 文獻(xiàn)質(zhì)量評(píng)價(jià) 19篇文獻(xiàn)[12,15,18,20-21,24,26-33,35,37-39,41]詳細(xì)描述了隨機(jī)分配序列的方法，10篇文獻(xiàn)[15，20，28-33，39，41]詳細(xì)描述分配隱藏方案，18篇文獻(xiàn)[12-13,15,20-22,24,26-32,37,39-41]詳細(xì)描述盲法實(shí)施情況，8篇文獻(xiàn)[13,15,17,26-27,30,32,41]具體報(bào)道對(duì)結(jié)局評(píng)估員實(shí)施盲法，25篇文獻(xiàn)[12-16，18,20-31,33,35,37-41]結(jié)局報(bào)告完整(見(jiàn)圖2)。

2.3 Meta分析結(jié)果

2.3.1 以ADAS-cog評(píng)分為結(jié)局指標(biāo)評(píng)估 23篇文獻(xiàn)[12-16,21-22,24-33,35,37-41]以ADAS-cog評(píng)分為結(jié)局指標(biāo)評(píng)估，其中多奈哌齊5 mg 5篇文獻(xiàn)[12-16]，各研究間無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性(I2=0，P=0.63)；多奈哌齊10 mg 8篇文獻(xiàn)[12-14,21-22,24-26]，

注：+=低度偏倚風(fēng)險(xiǎn)，？=偏倚風(fēng)險(xiǎn)不確定，-=高度偏倚風(fēng)險(xiǎn)

圖2 風(fēng)險(xiǎn)偏倚評(píng)估結(jié)果

Figure 2 Assessment result of risk bias

各研究間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=61%，P=0.01)；加蘭他敏24 mg 6篇文獻(xiàn)[27-29,31-33]，各研究間無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性(I2=0，P=0.57)；加蘭他敏32 mg 4篇文獻(xiàn)[27,29-31]，各研究間無(wú)統(tǒng)計(jì)學(xué)意義(I2=49%，P=0.12)；石杉?jí)A甲400 μg 2篇文獻(xiàn)[35,37]，各研究間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=84%，P=0.01)，卡巴拉汀12 mg 4篇文獻(xiàn)[38-41]，各研究間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=72%，P=0.01)。采用隨機(jī)效應(yīng)模型分析，Meta分析結(jié)果顯示，多奈哌齊5 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-2.13，95%CI(-2.69，-1.57)，P<0.001〕；多奈哌齊10 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-2.03，95%CI(-2.80，-1.25)，P<0.001〕；加蘭他敏24 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-3.05，95%CI(-3.54，-2.55)，P<0.001〕；加蘭他敏32 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-2.64，95%CI(-3.55，-1.73)，P<0.001〕；石杉?jí)A甲400 μg組和安慰劑組ADAS-cog評(píng)分比較，差異無(wú)統(tǒng)計(jì)學(xué)意義〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.27〕；卡巴拉汀12 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-2.17，95%CI(-3.30，-1.04)，P<0.001，見(jiàn)圖3〕。

2.3.2 以MMSE評(píng)分為結(jié)局指標(biāo)評(píng)估 17篇文獻(xiàn)[12-13,17-23,25-26,34-37,40-41]以MMSE評(píng)分為結(jié)局指標(biāo)評(píng)估，其中多奈哌齊5 mg 3篇文獻(xiàn)[12-13,23]，各研究間無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性(I2=0，P=0.89)；多奈哌齊10 mg 10篇文獻(xiàn)[12-13,17-22,25-26]，各研究間無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性(I2=0，P=0.63)；石杉?jí)A甲400 μg 4篇文獻(xiàn)[34-37]，各研究間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=75%，P=0.008)；卡巴他汀12 mg 2篇文獻(xiàn)[40-41]，各研究間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=75%，P=0.04)。采用隨機(jī)效應(yīng)模型分析，Meta分析結(jié)果顯示：多奈哌齊5 mg組MMSE評(píng)分高于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=1.07,95%CI(0.55,1.59)，P<0.001〕；多奈哌齊10 mg組MMSE評(píng)分高于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=1.20,95%CI(0.91,1.50)，P<0.001〕；石杉?jí)A甲400 μg組MMSE評(píng)分高于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=2.47,95%CI(1.15,3.78)，P<0.001〕；卡巴他汀12 mg組MMSE評(píng)分高于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=1.23,95%CI(0.35,2.11)，P=0.006，見(jiàn)圖4〕。

2.4 發(fā)表偏倚及敏感性分析 使用Stata 12.0軟件對(duì)ADAS-cog納入文獻(xiàn)進(jìn)行Begg秩相關(guān)檢驗(yàn)得到Z=0.66，P=0.511；進(jìn)行Egger線性回歸分析得到t=0.32，P=0.755(見(jiàn)圖5)；對(duì)MMSE納入文獻(xiàn)進(jìn)行Begg秩相關(guān)檢驗(yàn)得到Z=0.77，P=0.441；進(jìn)行Egger線性回歸分析得到t=1.30，P=0.212(見(jiàn)圖6)，未觀察到發(fā)表偏倚。

圖3 膽堿酯酶抑制劑和安慰劑治療輕中度AD患者ADAS-cog評(píng)分比較的森林圖

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

圖4 膽堿酯酶抑制劑和安慰劑治療輕中度AD患者M(jìn)MSE評(píng)分比較的森林圖

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，以亞組為單位逐一觀察單個(gè)研究對(duì)亞組合并效應(yīng)量的影響，ADAS-cog評(píng)分中，石杉?jí)A甲400 μg張振馨等[35]、RAFII等[37]；卡巴拉汀12 mg COREY-BLOOM等[38]會(huì)對(duì)亞組合并效應(yīng)量產(chǎn)生影響。由于石杉?jí)A甲400 μg僅納入2篇文獻(xiàn)，而2篇文獻(xiàn)均會(huì)直接影響合并效應(yīng)量使結(jié)果發(fā)生轉(zhuǎn)變，說(shuō)明由其得出的結(jié)果證據(jù)不足，需要納入更多文獻(xiàn)，并謹(jǐn)慎分析結(jié)果。剔除COREY-BLOOM等[38]研究后，卡巴拉汀12 mg組ADAS-cog評(píng)分低于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=-1.60,95%CI(-2.30，-0.90)，P<0.001〕，結(jié)果相對(duì)穩(wěn)定。MMSE評(píng)分中，石杉?jí)A甲400 μg RAFII等[37]對(duì)亞組影響較大，將其剔除后，石杉?jí)A甲400 μg MMSE評(píng)分高于安慰劑組，差異有統(tǒng)計(jì)學(xué)意義〔WMD=3.05,95%CI(1.83，4.27)，P<0.001〕，結(jié)果相對(duì)穩(wěn)定。

圖5 ADAS-cog評(píng)分納入文獻(xiàn)發(fā)表偏倚漏斗圖

圖6 MMSE評(píng)分納入文獻(xiàn)發(fā)表偏倚漏斗圖

3 討論

目前，膽堿酯酶抑制劑治療AD具有多年歷史，最初用于治療的他克林由于嚴(yán)重的不良反應(yīng)已經(jīng)停止使用，相繼上市的藥物有多奈哌齊、加蘭他敏、卡巴拉汀。石杉?jí)A甲是中藥提取物，1996年在我國(guó)被批準(zhǔn)用于治療AD[42]。目前針對(duì)膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀治療輕中度AD認(rèn)知療效，許多學(xué)者對(duì)其進(jìn)行了比較研究。英國(guó)NIC研究結(jié)果顯示多奈哌齊和加蘭他敏改善認(rèn)知療效顯著，但結(jié)果受到測(cè)量方法及觀察時(shí)間的限制。長(zhǎng)期觀察結(jié)果顯示多奈哌齊或卡巴拉汀可能成為最有效的治療方法，但受到藥物使用方法的限制[4]。KOBAYASHI等[9]研究證明加蘭他敏24 mg、32 mg，卡巴拉汀12 mg，多奈哌齊5 mg、10 mg對(duì)降低AD患者ADAS-cog評(píng)分具有顯著效果。

本研究以不同膽堿酯酶抑制劑作為亞組，采用Meta分析方法比較4種膽堿酯酶抑制劑治療輕中度AD患者認(rèn)知的療效。以ADAS-cog、MMSE評(píng)分為結(jié)局指標(biāo)，觀察時(shí)間為12～26周進(jìn)行分析，得出多奈哌齊5 mg、多奈哌齊10 mg、加蘭他敏24 mg、加蘭他敏32 mg、卡巴拉汀12 mg均具有治療輕中度AD患者認(rèn)知的療效。石杉?jí)A甲雖納入我國(guó)治療指南，但在其他國(guó)家并未獲準(zhǔn)，故其藥物研究主要來(lái)自國(guó)內(nèi)試驗(yàn)，而國(guó)外研究較少。結(jié)局變量為ADAS-cog評(píng)分的Meta分析中，只有2篇文獻(xiàn)[35，37]納入石杉?jí)A甲組(1篇中文，1篇英文)，研究數(shù)量及樣本量少，且樣本來(lái)自不同國(guó)家，研究間異質(zhì)性較大，因此可能造成假陰性結(jié)果。結(jié)局變量為MMSE評(píng)分的Meta分析中，石杉?jí)A甲亞組納入3篇中文文獻(xiàn)[34-36]，1篇英文文獻(xiàn)[37]，研究間異質(zhì)性大，觀察原始研究偏倚風(fēng)險(xiǎn)圖，中文文獻(xiàn)方法學(xué)質(zhì)量低，其在隨機(jī)、分配隱藏、盲法、結(jié)局完整性均存在較高風(fēng)險(xiǎn)，低質(zhì)量、小樣本試驗(yàn)可能得出較大的干預(yù)措施療效。所以本研究MMSE評(píng)分對(duì)石杉?jí)A甲治療效果的評(píng)價(jià)可能存在過(guò)高估計(jì)。

綜上所述，石杉?jí)A甲療效評(píng)價(jià)由于存在研究間異質(zhì)性及偏倚風(fēng)險(xiǎn)，需待獲得高質(zhì)量、大樣本的文獻(xiàn)進(jìn)一步分析。本研究納入文獻(xiàn)的隨訪時(shí)間較短，對(duì)于藥物遠(yuǎn)期療效需通過(guò)長(zhǎng)期研究分析評(píng)價(jià)。盡管ADAS-cog、MMSE是評(píng)價(jià)認(rèn)知功能的常用量表，但是MMSE仍然受到教育程度的影響，而ADAS-cog識(shí)別不同嚴(yán)重程度AD患者認(rèn)知變化的敏感性也受到爭(zhēng)議。同時(shí)，本研究采用的Meta分析亞組分析為觀察性研究，而非基于隨機(jī)化比較，容易引起假陰性或假陽(yáng)性結(jié)果。因此研究結(jié)果并不能作為確定的結(jié)果被提出，而需結(jié)合臨床實(shí)際對(duì)藥物的有效性進(jìn)行綜合評(píng)價(jià)。

作者貢獻(xiàn)：牛茜進(jìn)行文章的構(gòu)思與設(shè)計(jì)、撰寫論文；牛茜、王蕾進(jìn)行研究的實(shí)施與可行性分析、數(shù)據(jù)收集、數(shù)據(jù)整理；牛茜、曹凱進(jìn)行統(tǒng)計(jì)學(xué)處理；牛茜、邵爽進(jìn)行結(jié)果的分析與解釋、論文修訂；邵爽負(fù)責(zé)文章的質(zhì)量控制及審校；郭秀花對(duì)文章整體負(fù)責(zé)，監(jiān)督管理。

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(本文編輯：賈萌萌)

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，首都醫(yī)科大學(xué)公共衛(wèi)生學(xué)院

2.100081北京市海淀區(qū)北下關(guān)社區(qū)衛(wèi)生服務(wù)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