陳超英 張 夢(mèng) 王霄騰 呂 賓

浙江中醫(yī)藥大學(xué)附屬第一醫(yī)院消化內(nèi)科(310006)

序貫療法根除幽門(mén)螺桿菌療效的meta分析*

陳超英 張 夢(mèng) 王霄騰 呂 賓#

浙江中醫(yī)藥大學(xué)附屬第一醫(yī)院消化內(nèi)科(310006)

背景：標(biāo)準(zhǔn)三聯(lián)療法對(duì)幽門(mén)螺桿菌(Hp)的根除療效已顯著下降，甚至低于80%。國(guó)外研究顯示序貫療法的療效明顯高于三聯(lián)療法，國(guó)內(nèi)缺乏大樣本的數(shù)據(jù)分析明確其療效。目的：系統(tǒng)評(píng)價(jià)國(guó)內(nèi)外序貫療法與三聯(lián)療法根除Hp的療效。方法：計(jì)算機(jī)檢索PubMed、Medline、Embase、Cochrane Library、中國(guó)知網(wǎng)、萬(wàn)方、維普、中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)，納入近七年有關(guān)序貫療法與三聯(lián)療法根除Hp的隨機(jī)對(duì)照試驗(yàn)(RCT)。由2名研究者獨(dú)立選擇文獻(xiàn)、提取資料和文獻(xiàn)質(zhì)量評(píng)價(jià)后，采用RevMan 5.3軟件進(jìn)行meta分析。結(jié)果：共納入31項(xiàng)RCT共8 371例患者。Meta分析顯示，序貫療法的Hp根除率顯著高于三聯(lián)療法(83.3%對(duì)74.7%；RR=1.13，95% CI: 1.09～1.16)。16項(xiàng)國(guó)內(nèi)研究顯示序貫療法的Hp根除率顯著高于三聯(lián)療法(88.1%對(duì)78.0%；RR=1.13，95% CI: 1.10～1.16)，15項(xiàng)國(guó)外研究顯示序貫療法的Hp根除率顯著高于三聯(lián)療法(79.0%對(duì)71.8%；RR=1.13，95% CI: 1.06～1.20)。序貫療法的不良反應(yīng)發(fā)生率與三聯(lián)療法無(wú)明顯差異(20.7%對(duì)22.0%；RR=0.94，95% CI: 0.86～1.03)。結(jié)論：序貫療法根除Hp的療效明顯高于三聯(lián)療法，且兩者不良反應(yīng)無(wú)明顯差異。在我國(guó)，序貫療法的Hp根除率明顯高于三聯(lián)療法且根除率>80%，推薦將其作為鉍劑四聯(lián)療法的補(bǔ)充方案。

幽門(mén)螺桿菌； 序貫療法； 三聯(lián)療法； meta分析

流行病學(xué)調(diào)查[1]發(fā)現(xiàn)我國(guó)自然人群幽門(mén)螺桿菌(Hp)的總感染率高達(dá)56.22%。根除Hp對(duì)胃黏膜糜爛、消化性潰瘍、胃黏膜相關(guān)淋巴樣組織淋巴瘤以及早期胃癌等均有重要意義。由質(zhì)子泵抑制劑(PPI)、克拉霉素和阿莫西林組成的三聯(lián)療法是標(biāo)準(zhǔn)的一線Hp根除方案[2]。然而，近年多項(xiàng)研究表明三聯(lián)療法的Hp根除率已顯著下降，甚至低于80%[3]。Maastricht Ⅳ共識(shí)[4]明確提出，在克拉霉素耐藥率>15%～20%的地區(qū)，不再推薦含克拉霉素的三聯(lián)療法，應(yīng)推薦含鉍劑的四聯(lián)療法或序貫療法和非鉍劑四聯(lián)療法作為一線治療方案。國(guó)外一項(xiàng)meta分析[5]表明序貫療法根除Hp的療效明顯高于三聯(lián)療法，甚至在克拉霉素耐藥、非潰瘍性消化不良、吸煙或cagA基因缺失的患者中均具有較為可觀的根除效果。我國(guó)研究亦提示序貫療法的療效明顯高于三聯(lián)療法，但目前尚缺乏大樣本的數(shù)據(jù)分析明確其療效。本研究通過(guò)對(duì)近年國(guó)內(nèi)外有關(guān)序貫療法和三聯(lián)療法根除Hp的隨機(jī)對(duì)照試驗(yàn)(RCT)行meta分析，旨在比較序貫療法根除Hp的療效，從而為臨床Hp根除策略的制定提供一定的理論依據(jù)。

資料與方法

一、文獻(xiàn)檢索

計(jì)算機(jī)檢索PubMed、Medline、Embase、Cochrane Library、中國(guó)知網(wǎng)、萬(wàn)方、維普、中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)近7年(2009年1月—2015年12月)公開(kāi)發(fā)表的臨床RCT。英文檢索詞：Helicobacterpylori, Hp,H.pylori, Sequential therapy, Triple therapy, Clinical randomized controlled trial, RCT；中文檢索詞：幽門(mén)螺桿菌，序貫療法，三聯(lián)療法，臨床隨機(jī)對(duì)照試驗(yàn)。對(duì)所得文獻(xiàn)進(jìn)一步檢索其參考文獻(xiàn)，以補(bǔ)充可能遺漏的研究。

二、文獻(xiàn)納入和排除標(biāo)準(zhǔn)

1. 納入標(biāo)準(zhǔn)：①RCT；②通過(guò)尿素呼氣試驗(yàn)(UBT)、快速尿素酶試驗(yàn)(RUT)或組織學(xué)檢查測(cè)定Hp陽(yáng)性；③包括10 d序貫療法與7 d、10 d或14 d三聯(lián)療法療效的比較；④主要終點(diǎn)為意向性分析(ITT)根除率；⑤Hp根除治療結(jié)束至少4周后行UBT或RUT復(fù)檢。

2. 排除標(biāo)準(zhǔn)：①會(huì)議摘要或綜述類文獻(xiàn)；②重復(fù)發(fā)表的文獻(xiàn)；③非RCT；④7 d或14 d序貫療法；⑤對(duì)照組為非三聯(lián)療法。

三、數(shù)據(jù)提取

繪制資料提取表格，包括第一作者、出版日期、國(guó)家、研究設(shè)計(jì)、Hp診斷方法、研究對(duì)象、Hp根除方案及其根除率。由兩名研究者獨(dú)立納入數(shù)據(jù)，如有分歧，通過(guò)雙方討論解決或由第三者協(xié)助判斷。用Cochrane偏倚風(fēng)險(xiǎn)評(píng)估工具5.1.0版對(duì)納入的文獻(xiàn)行質(zhì)量評(píng)價(jià)，通過(guò)評(píng)估選擇偏倚(包括是否采用正確的隨機(jī)化方法和是否實(shí)施分配隱藏)、實(shí)施偏倚(對(duì)研究對(duì)象和方案實(shí)施者是否采用盲法)、測(cè)量偏倚(對(duì)研究結(jié)果測(cè)量者是否采用盲法)、隨訪偏倚(結(jié)果數(shù)據(jù)報(bào)告是否完整)、報(bào)告偏倚(是否存在選擇性報(bào)告研究結(jié)果)、其他偏倚，作出低度偏倚、高度偏倚和不清楚的判斷。

四、統(tǒng)計(jì)學(xué)分析

采用Cochrane協(xié)作網(wǎng)提供的RevMan 5.3軟件，以相對(duì)危險(xiǎn)度(RR)及其95% CI評(píng)估序貫療法與三聯(lián)療法根除Hp的療效。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。納入研究間異質(zhì)性的分析采用χ2檢驗(yàn)。I2≤50%且P>0.1時(shí)認(rèn)為同質(zhì)性較好，采用固定效應(yīng)模型；否則采用隨機(jī)效應(yīng)模型。運(yùn)用漏斗圖評(píng)估出版偏倚。

結(jié) 果

一、檢索結(jié)果

共檢索到218篇，通過(guò)閱讀文題和摘要排除綜述、評(píng)論、動(dòng)物實(shí)驗(yàn)和非RCT等171篇文獻(xiàn)；進(jìn)一步閱讀全文，根據(jù)納入和排除標(biāo)準(zhǔn)，最終得到31篇文獻(xiàn)，其中亞洲26篇(中國(guó)16篇、韓國(guó)6篇、印度2篇、新加坡1篇、巴勒斯坦1篇)、歐洲1篇、非洲2篇、南美洲2篇。治療對(duì)象均為初次治療患者。所納入文獻(xiàn)的基本特征見(jiàn)表1。

二、納入文獻(xiàn)的質(zhì)量評(píng)價(jià)

31篇文獻(xiàn)均對(duì)患者的基線情況進(jìn)行了報(bào)道，在文中提及隨機(jī)，其中16篇交代了具體的隨機(jī)方法，其中一篇由于研究者在隨機(jī)序列產(chǎn)生過(guò)程中有非隨機(jī)成分的描述為高風(fēng)險(xiǎn)，7篇對(duì)分配隱藏方案進(jìn)行了描述，所有納入研究均數(shù)據(jù)報(bào)告完整。

三、Hp根除率分析

納入的31篇文獻(xiàn)間存在異質(zhì)性(χ2=60.80,P=0.000)， 采用隨機(jī)效應(yīng)模型。 結(jié)果顯示序貫療法的根除率顯著高于三聯(lián)療法(83.3%對(duì)74.7%；RR=1.13，95% CI: 1.09～1.16)。16篇為我國(guó)文獻(xiàn)，各研究間無(wú)異質(zhì)性(χ2=11.54,P=0.710)，采用固定效應(yīng)模型。結(jié)果顯示序貫療法的根除率顯著高于三聯(lián)療法(88.1%對(duì)78.0%；RR=1.13，95% CI: 1.10～1.16)。15篇為國(guó)外文獻(xiàn)，各研究間存在異質(zhì)性(χ2=47.11,P<0.000 1)，采用隨機(jī)效應(yīng)模型。結(jié)果顯示序貫療法的根除率顯著高于三聯(lián)療法(79.0%對(duì)71.8%；RR=1.13，95% CI: 1.06～1.20)。

表1 納入文獻(xiàn)的基本特征

納入文獻(xiàn)的基本特征 續(xù)表1

A：阿莫西林；B：鉍劑；C：克拉霉素；L：蘭索拉唑；M：甲硝唑；O：奧美拉唑；R：雷尼替?。籈：埃索美拉唑；T：替硝唑；P：泮托拉唑；Le：左氧氟沙星；Ra：雷貝拉唑；F：呋喃唑酮

15篇國(guó)外研究根據(jù)不同地區(qū)分為亞洲、歐洲、非洲、南美洲四個(gè)亞組。結(jié)果顯示亞洲(84.1%對(duì)74.1%；RR=1.13，95% CI: 1.11～1.16;P<0.05)、歐洲(76.5%對(duì)64.5%；RR=1.19，95% CI: 1.00～1.41；P<0.05)、非洲(87.7%對(duì)71.5%；RR=1.23，95% CI: 1.13～1.35；P<0.05)的序貫療法根除率顯著高于三聯(lián)療法，南美洲的序貫療法根除率顯著低于三聯(lián)療法(77.4%對(duì)82.5%；RR=0.94，95% CI: 0.88～1.00；P<0.05)。

根據(jù)療程不同，將三聯(lián)療法分為7 d、10 d、14 d亞組。結(jié)果顯示序貫療法的根除率均顯著高于7 d(81.1%對(duì)73.7%；RR=1.10，95% CI: 1.06～1.14；P<0.05)、10 d(84.2%對(duì)73.4%；RR=1.15，95% CI: 1.11～1.19；P<0.05)、14 d(87.2%對(duì)80.7%；RR=1.08，95% CI: 1.03～1.13；P<0.05)三聯(lián)療法。

四、不良反應(yīng)

26項(xiàng)研究報(bào)道了不良反應(yīng)，包括頭暈、頭痛、皮疹、味覺(jué)紊亂、腹痛、惡心、腹瀉、便秘、腹脹等。序貫療法和三聯(lián)療法的不良反應(yīng)發(fā)生率無(wú)明顯差異(20.7%對(duì)22.0%；RR=0.94，95% CI: 0.86～1.03)。

五、敏感性和出版偏倚分析

將納入的31項(xiàng)研究逐一排除后對(duì)剩余的研究行meta分析，其RR值為1.12～1.13，說(shuō)明納入的文獻(xiàn)穩(wěn)定性較好。出版偏倚分析結(jié)果顯示漏斗圖不對(duì)稱，說(shuō)明所納入的研究可能存在出版偏倚。這可能與結(jié)果為陰性的研究未發(fā)表，試驗(yàn)組和對(duì)照組觀察的藥物種類、劑量和療程不同，部分研究樣本量偏小有關(guān)。

討 論

Gatta等[37]的meta分析顯示序貫療法的Hp根除率較高且療效高于三聯(lián)療法。Liu等[38]的一項(xiàng)RCT將357例Hp感染患者隨機(jī)分為兩組，分別給予序貫療法和鉍劑四聯(lián)療法，結(jié)果顯示ITT根除率分別為89.4%和92.7%(P=0.36)，說(shuō)明序貫療法和鉍劑四聯(lián)療法可作為我國(guó)Hp根除的一線方案。張文淵等[39]的meta分析亦發(fā)現(xiàn)，序貫療法的Hp根除率和不良反應(yīng)與鉍劑四聯(lián)療法相當(dāng)，在中國(guó)Hp耐藥率低的地區(qū)可作為鉍劑四聯(lián)療法的有力補(bǔ)充。

本研究結(jié)果顯示序貫療法根除Hp的療效明顯高于三聯(lián)療法(RR=1.13，95% CI: 1.09～1.16)，且兩者的不良反應(yīng)無(wú)明顯差異(RR=0.94，95% CI: 0.86～1.03)。進(jìn)一步分層分析顯示，國(guó)外文獻(xiàn)和國(guó)內(nèi)文獻(xiàn)均發(fā)現(xiàn)序貫療法的Hp根除率明顯高于三聯(lián)療法(RR=1.13，95% CI: 1.10～1.16；RR=1.13，95% CI: 1.06～1.20)。值得注意的是，國(guó)外文獻(xiàn)的序貫療法Hp根除率<80%，因此更有效的Hp根除方法仍有待探究。國(guó)內(nèi)文獻(xiàn)的序貫療法Hp根除率>80%，可推薦作為鉍劑四聯(lián)療法的補(bǔ)充方案。

本研究還發(fā)現(xiàn)，在亞洲和非洲，序貫療法的療效優(yōu)于三聯(lián)療法且Hp根除率>80%，故序貫療法在亞洲和非洲值得推薦作為鉍劑四聯(lián)療法的補(bǔ)充；在歐洲雖然序貫療法療效高于三聯(lián)療法，但Hp根除率<80%，故更有效的根除方案仍需進(jìn)一步研究；而在南美洲，三聯(lián)療法根除Hp的療效優(yōu)于序貫療法。不同洲之間序貫療法的療效不同，這可能是由于Hp的抗菌藥物耐藥性在不同的地理位置的變異所導(dǎo)致。此外，10 d序貫療法的療效亦優(yōu)于7 d、10 d、14 d三聯(lián)療法。本研究雖然納入了31項(xiàng)RCT，但不同地理位置亞組以及不同療程亞組納入的研究數(shù)量仍較少，有待擴(kuò)大樣本量行進(jìn)一步研究。

綜上所述，本研究發(fā)現(xiàn)在亞洲、非洲，序貫療法的Hp根除療效優(yōu)于三聯(lián)療法，且兩者的不良反應(yīng)無(wú)明顯差異，可考慮作為鉍劑四聯(lián)療法的補(bǔ)充方案；在我國(guó)，序貫療法的Hp根除率明顯高于三聯(lián)療法，亦可推薦作為鉍劑四聯(lián)療法的補(bǔ)充方案。

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(2016-05-03收稿；2016-12-23修回)

Efficacy of Sequential Therapy in Eradication ofHelicobacterpylori: A Meta-analysis

CHENChaoying,ZHANGMeng,WANGXiaoteng,LüBin.

DepartmentofGastroenterology,theFirstAffiliatedHospitalofZhejiangChineseMedicalUniversity,Hangzhou(310006)

Lü Bin, Email: lvbin@medmail.com.cn

Helicobacterpylori; Sequential Therapy; Triple Therapy; Meta-Analysis

10.3969/j.issn.1008-7125.2017.03.010

*本課題由國(guó)家自然科學(xué)基金(81470814)資助

#本文通信作者，Email: lvbin@medmail.com.cn

Background: The efficacy of standard triple therapy forHelicobacterpylori(Hp) eradication has been significantly decreased, or even less than 80%. Abroad studies have shown that Hp eradication rate of sequential therapy is significantly higher than that of triple therapy. At home, we lack a large sample of data analysis to clarify the efficacy of sequential therapy. Aims: To systematically review the efficacy of sequential therapy and triple therapy in Hp eradication at home and abroad. Methods: PubMed, Medline, Embase, Cochrane Library, CNKI, Wanfang, VIP and CBMdisc were retrieved to collect the randomized controlled trials (RCT) comparing sequential therapy and triple therapy in the treatment of Hp infection in last 7 years. Article selection, data extraction and quality evaluation were conducted independently by two reviewers. Meta-analysis was conducted by RevMan 5.3 software. Results: A total of 31 RCT involving 8 371 subjects were included. Meta-analysis showed that Hp eradication rate of sequential therapy was significantly higher than that of triple therapy (83.3%vs. 74.7%; RR=1.13, 95% CI: 1.09-1.16). Sixteen domestic studies showed that Hp eradication rate of sequential therapy was significantly higher than that of triple therapy (88.1%vs. 78.0%; RR=1.13, 95% CI: 1.10-1.16), fifteen abroad studies showed that Hp eradication rate of sequential therapy was significantly higher than that of triple therapy (79.0%vs. 71.8%; RR=1.13, 95% CI: 1.06-1.20). No significant difference in incidence of adverse reactions was found between sequential therapy and triple therapy (20.7%vs. 22.0%; RR=0.94, 95% CI: 0.86-1.03). Conclusions: Sequential therapy achieves higher Hp eradication rate than standard triple therapy, and no significant difference in incidence of adverse reactions is found between sequential therapy and triple therapy. Hp eradication rate of sequential therapy is significantly higher than that of triple therapy and is higher than 80% in China, which can be recommended as a Hp eradication supplement of bismuth quadruple therapy.