張少君，董小林

湖北醫(yī)藥學(xué)院附屬人民醫(yī)院體檢中心，湖北 十堰 442000

PPI聯(lián)合瑞巴派特促進(jìn)內(nèi)鏡黏膜下剝離術(shù)術(shù)后潰瘍愈合的療效分析

張少君，董小林

湖北醫(yī)藥學(xué)院附屬人民醫(yī)院體檢中心，湖北 十堰 442000

目的 系統(tǒng)評(píng)價(jià)質(zhì)子泵抑制劑(proton pump inhibitors, PPI)聯(lián)合瑞巴派特治療內(nèi)鏡黏膜下剝離術(shù)(endoscopic submucosal dissection, ESD)術(shù)后潰瘍的有效性和安全性。方法 計(jì)算機(jī)檢索PubMed、Web of Science、Medline、Embase、Cochrane Central Register of Controlled Trials、CENTRAL、CJFD、CBM、CNKI、VIP及WanFang Data，檢索時(shí)間截至2015年8月1日，查找所有比較PPI聯(lián)合瑞巴派特預(yù)防ESD術(shù)后潰瘍出血作用的隨機(jī)對(duì)照試驗(yàn)(RCTs)。由2名評(píng)價(jià)者按照納入和排除標(biāo)準(zhǔn)獨(dú)立選擇文獻(xiàn)、提取資料、評(píng)價(jià)質(zhì)量，采用RevMan 5.2和Stata 12.0軟件進(jìn)行Meta分析。結(jié)果 共納入6項(xiàng)RCTs，共724例患者。合并結(jié)果顯示：與單用PPI相比，應(yīng)用PPI聯(lián)合瑞巴派特后潰瘍愈合率明顯升高(OR=2.40, 95%CI: 1.68～3.44)；根據(jù)療程長短(4周和8周)進(jìn)行亞組分析顯示：聯(lián)合用藥組潰瘍愈合率均高于單用PPI組(4周：OR=2.22, 95%CI: 1.53～3.24；8周：OR=3.19, 95%CI: 1.22～8.31)。對(duì)于直徑>2 cm潰瘍，聯(lián)合用藥組療效更明顯(OR=4.77, 95%CI: 2.22～10.26)。而對(duì)于潰瘍部位、是否合并H.pylori感染，兩者療效無明顯差異。用藥過程中兩組均無明顯不良反應(yīng)。結(jié)論 PPI聯(lián)合瑞巴派特療效優(yōu)于單用PPI，尤其對(duì)于直徑>2 cm的潰瘍。受納入研究數(shù)量和質(zhì)量限制，需要開展更多高質(zhì)量、大樣本、多中心的RCTs進(jìn)一步論證其安全性。

內(nèi)鏡黏膜下剝離術(shù)；瑞巴派特；質(zhì)子泵抑制劑；Meta分析

目前，內(nèi)鏡黏膜下剝離術(shù)(endoscopic submucosal dissection，ESD)是廣泛應(yīng)用于胃腺瘤和早期胃癌的微創(chuàng)治療，具有創(chuàng)傷小、愈合快的特點(diǎn)。與傳統(tǒng)的內(nèi)鏡黏膜下切除術(shù)(endoscopic mucosal resection，EMR)相比，ESD 更適用于直徑大(>2 cm)、形狀扁平的胃癌，且其腫瘤完全切除率遠(yuǎn)高于EMR，但其所引起的醫(yī)源性潰瘍也更大更深，且ESD術(shù)后出現(xiàn)延遲出血和穿孔風(fēng)險(xiǎn)增加，因此，盡快促進(jìn)ESD術(shù)后潰瘍面的愈合可有效預(yù)防出血和穿孔的并發(fā)癥[1]。質(zhì)子泵抑制劑(proton pump inhibitor, PPI)是治療ESD術(shù)后潰瘍最有效的藥物，然而有報(bào)道[2]稱單用PPI 4周治療ESD術(shù)后潰瘍是不充分的。瑞巴派特是一種胃黏膜保護(hù)劑，廣泛應(yīng)用于亞洲國家[3]。許多臨床試驗(yàn)[4-5]發(fā)現(xiàn)瑞巴派特可加快潰瘍的愈合。目前已有大量研究[6-12]報(bào)道了PPI聯(lián)合瑞巴派特治療ESD術(shù)后潰瘍的有效性和安全性，然而在藥物選擇、治療時(shí)間及最佳治療方案等方面仍未達(dá)成一致意見。我們運(yùn)用循證醫(yī)學(xué)的原理和方法，對(duì)比PPI聯(lián)合瑞巴派特和單用PPI治療ESD術(shù)后潰瘍愈合作用的隨機(jī)對(duì)照試驗(yàn)(randomized controlled trials,RCTs)進(jìn)行系統(tǒng)評(píng)價(jià)，為臨床決策提供最佳證據(jù)。

1 資料與方法

1.1 納入及排除標(biāo)準(zhǔn)

1.1.1 納入標(biāo)準(zhǔn)：(1)比較PPI聯(lián)合瑞巴派特和單用PPI治療ESD術(shù)后潰瘍愈合的研究；(2)RCTs；(3)干預(yù)措施：試驗(yàn)組采用PPI聯(lián)合瑞巴派特，對(duì)照組采用PPI;(4)結(jié)局指標(biāo)：ESD術(shù)后潰瘍愈合率。

1.1.2 排除標(biāo)準(zhǔn)：(1)缺失重要研究數(shù)據(jù)的文獻(xiàn)；(2)重復(fù)發(fā)表且病例數(shù)較少的文獻(xiàn)；(3)有摘要而無全文，且聯(lián)系作者索取未果。

1.2 文獻(xiàn)檢索計(jì)算機(jī)檢索PubMed、Web of Science、Medline、Embase、Cochrane Central Register of Controlled Trials、CENTRAL、CJFD、CBM、CNKI、VIP及WanFang Data，檢索時(shí)間均為建庫至2015年8月1日。文種限中、英文。英文檢索endoscopic submucosal dissection or ESD、proton pump inhibitor or PPI、Rebamipide；中文檢索內(nèi)鏡黏膜下剝離術(shù)(ESD)、質(zhì)子泵抑制劑(PPI)、瑞巴派特，同時(shí)輔以文獻(xiàn)追溯。

1.3 資料提取由2名研究者獨(dú)立進(jìn)行文獻(xiàn)篩選并提取資料，意見不一致時(shí)通過討論解決或由第三名研究者協(xié)助解決。資料提取內(nèi)容包括：作者、發(fā)表年份、國家、年齡、性別、試驗(yàn)組和對(duì)照組樣本量、干預(yù)措施、療程、腫瘤部位、大小、H.pylori感染狀態(tài)及結(jié)局指標(biāo)(達(dá)到S期認(rèn)為潰瘍愈合)。

1.4 文獻(xiàn)質(zhì)量評(píng)價(jià)由2名研究者根據(jù)Jadad量表[13]對(duì)納入研究的方法學(xué)質(zhì)量進(jìn)行評(píng)估，具體內(nèi)容包括隨機(jī)序列產(chǎn)生、盲法、分配隱藏、退出/失訪。分?jǐn)?shù)范圍為1～5分，得分>3分提示文獻(xiàn)質(zhì)量較高。

1.5 統(tǒng)計(jì)學(xué)分析統(tǒng)計(jì)分析采用Cochrane協(xié)作網(wǎng)的RevMan 5.2軟件進(jìn)行。合并效應(yīng)量選用比值比(OR)及其95%CI。對(duì)納入研究進(jìn)行異質(zhì)性檢驗(yàn)(采用Q檢驗(yàn)和I2統(tǒng)計(jì)量)[14]，如P>0.1或I2<50%提示各研究間無異質(zhì)性，采用固定效應(yīng)模型進(jìn)行合并分析[15]，反之則采用隨機(jī)效應(yīng)模型[16]。敏感性分析為依次排除單個(gè)文獻(xiàn)后重新進(jìn)行Meta分析，估計(jì)綜合效應(yīng)大小。發(fā)表偏倚分析應(yīng)用Stata 12.0軟件通過Begg秩相關(guān)法[17]、Egger回歸法[18]進(jìn)行量化檢測(cè)(P<0.05認(rèn)為存在發(fā)表偏倚)。

2 結(jié)果

2.1 文獻(xiàn)檢索結(jié)果根據(jù)檢索策略，初檢出310篇文獻(xiàn)，經(jīng)初步篩查，7篇文獻(xiàn)[6-12]初步納入分析，其中1篇文獻(xiàn)[12]缺少可提取數(shù)據(jù)被排除，最終納入6個(gè)RCTs[6-11]，包括724例患者。納入研究的一般情況如表1所示，其中5項(xiàng)研究來自日本，1項(xiàng)研究來自韓國。Jadad評(píng)分結(jié)果顯示均>3分，提示納入文獻(xiàn)的研究質(zhì)量較好。

表1 納入文獻(xiàn)的基本情況

續(xù)表1

納入文獻(xiàn)年份國家年齡(歲)性別(男/女)例數(shù)干預(yù)措施劑量療程(d)結(jié)局指標(biāo)評(píng)分Kobayashi等[9]2012日本70．8±9．068/1785A奧美拉唑20mg/d，或蘭索拉唑30mg/d28～42(1)潰瘍愈合470．0±9．066/1985BPPI+300mg瑞巴派特，1次/d(2)瑞巴派特對(duì)不同潰瘍大小的作用比較Shin等[10]?2012韓國64．9±10．298/44?129A泮托拉唑40mg/d28(1)潰瘍愈合463．4±10．0101/47126BPPI+100mg瑞巴派特，3次/d(2)潰瘍愈合的質(zhì)量和時(shí)期Takayama等[11]2013日本70．0±7．835/944A蘭索拉唑30mg/d28/56(1)潰瘍愈合467．0±8．031/1445B蘭索拉唑30mg/d，5d；300mg瑞巴派特，3次/d(2)不同切除部位的潰瘍愈合比較

注：A：PPI；B：PPI+瑞巴派特。*指A、B兩組入選例數(shù)分別為142和148，但最終符合條件的例數(shù)分別為129和126。

2.2 Meta分析結(jié)果

2.2.1 潰瘍愈合率：6個(gè)研究[6-11]均報(bào)道了PPI 與瑞巴派特促進(jìn)ESD術(shù)后潰瘍愈合的作用，其中PPI 組和PPI聯(lián)合瑞巴派特組均為362例。各研究結(jié)果間無統(tǒng)計(jì)學(xué)異質(zhì)性(I2=22%，P=0.27)，故采用固定效應(yīng)模型進(jìn)行Meta分析。結(jié)果顯示，PPI聯(lián)合瑞巴派特組促進(jìn)潰瘍愈合的作用優(yōu)于單用PPI組(OR=2.40, 95%CI: 1.68～3.44)(見圖1)；根據(jù)療程進(jìn)行亞組分析顯示，無論用藥4周還是8周，PPI聯(lián)合瑞巴派特組均優(yōu)于單用PPI組(4周：OR=2.22, 95%CI: 1.53～3.24；8周：OR=3.19, 95%CI: 1.22～8.31)(見圖2)。

有2項(xiàng)研究分別報(bào)道了切除部位[7,11]和H.pylori感染狀態(tài)[10-11]的數(shù)據(jù)，結(jié)果顯示在潰瘍愈合率方面，兩組之間無明顯差異；另外，有2項(xiàng)研究[6,8]報(bào)道了潰瘍大小的數(shù)據(jù)，結(jié)果顯示，無論是直徑為2～4 cm還是>4 cm的潰瘍，PPI聯(lián)合瑞巴派特組均優(yōu)于單用PPI組(2～4 cm：OR=3.58, 95%CI: 1.51～8.52；>4 cm：OR=12.66, 95%CI: 2.04～78.70)(見圖3)。

圖3 基于潰瘍大小PPI 和瑞巴派特促進(jìn)ESD 術(shù)后潰瘍愈合作用比較的Meta 分析

2.2.2 不良反應(yīng)：3項(xiàng)研究[7-8,11]報(bào)道了不良反應(yīng)情況，僅有1項(xiàng)研究[7]中單用PPI組出現(xiàn)了術(shù)后出血。

2.3 敏感性和發(fā)表偏倚分析依次單獨(dú)剔除1篇文獻(xiàn)后，合并效應(yīng)量無明顯改變。Begg漏斗圖結(jié)果顯示未見發(fā)表偏倚(見圖4)。Egger回歸法量化檢測(cè)也未見發(fā)表偏倚(P=0.143)。

圖4 Begg漏斗圖分析

3 討論

本文共納入6項(xiàng)RCTs，包括724例患者。合并結(jié)果顯示，與單用PPI相比，應(yīng)用PPI聯(lián)合瑞巴派特后潰瘍愈合率明顯升高；根據(jù)療程長短(4周和8周)進(jìn)行亞組分析同樣顯示：聯(lián)合用藥組潰瘍愈合率均高于單用PPI組。此外，對(duì)于直徑>2 cm潰瘍，聯(lián)合用藥組療效更明顯。而對(duì)于不同部位的潰瘍，兩者療效無明顯差異。雖然H.pylori感染是消化性潰瘍的病因之一，有研究[19]顯示H.pylori感染狀態(tài)對(duì)ESD術(shù)后潰瘍愈合無明顯影響。本文有2篇文獻(xiàn)報(bào)道了H.pylori感染的情況，合并分析結(jié)果提示兩者療效無明顯差異。然而由于納入文獻(xiàn)較少，結(jié)論需進(jìn)一步驗(yàn)證。另外，我們也對(duì)兩組中不良反應(yīng)情況進(jìn)行分析，發(fā)現(xiàn)用藥過程中兩組均無明顯不良反應(yīng)。

雖然PPI是ESD術(shù)后治療潰瘍和出血的標(biāo)準(zhǔn)藥物，F(xiàn)ujiwara等[7]報(bào)道稱在胃酸分泌水平較低的患者(如胃黏膜嚴(yán)重萎縮)中，單獨(dú)給予PPI和胃酸抑制劑作用有限，在這種患者中，單純的抑制胃酸對(duì)于潰瘍愈合已不是主要因素。另外，不同個(gè)體間對(duì)PPI藥物的反應(yīng)性也可影響藥物的療效，如PPI代謝與細(xì)胞色素P450 2C19酶有關(guān)，該酶基因型差異可能會(huì)影響機(jī)體對(duì)PPI藥物的反應(yīng)性。因此，與其他藥物合用是必須的。瑞巴派特是一種新型的黏膜保護(hù)劑，兼有增強(qiáng)防御因子和炎癥抑制兩方面作用。Terano等[4]進(jìn)行的一項(xiàng)研究顯示與安慰劑相比，H.pylori根除治療后，給予7周瑞巴派特治療可促進(jìn)胃潰瘍的愈合。其主要機(jī)制[20-25]可能為；(1)抑制中性粒細(xì)胞引發(fā)的自由基損傷；(2)劑量依賴性地清除氧自由基；(3)減少炎癥因子的產(chǎn)生；(4)升高表皮生長因子(epidermal growth factor, EGF)及其受體的表達(dá)；(5)激活環(huán)氧化酶-2 的基因表達(dá)；(6)促進(jìn)胃黏膜PG 合成；(7)加強(qiáng)上皮屏障作用。

本Meta 分析也存在一定的局限性：(1)納入文獻(xiàn)較少，且文獻(xiàn)質(zhì)量參差不齊；(2)納入文獻(xiàn)均為正式發(fā)表的文獻(xiàn)，不能完全排除發(fā)表偏倚的影響；(3)納入文獻(xiàn)中結(jié)局指標(biāo)不完全一致，影響進(jìn)一步的亞組分析等；(4)納入文獻(xiàn)中PPI選擇存在差異，可能會(huì)對(duì)結(jié)果有所影響。

綜上所述，PPI聯(lián)合瑞巴派特治療ESD術(shù)后潰瘍療效優(yōu)于單用PPI，尤其對(duì)于直徑>2 cm的潰瘍。然而受納入研究數(shù)量和質(zhì)量限制，尚需要開展更多高質(zhì)量、大樣本、多中心的RCTs進(jìn)一步論證其安全性。

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(責(zé)任編輯：李 健)

The efficacy and safety of PPI plus Rebamipide for endoscopic submucosal dissection-induced ulcers: a Meta-analysis

ZHANG Shaojun, DONG Xiaolin

Medical Examination Center, Renmin Hospital Affiliated to Hubei University of Medicine, Shiyan 442000, China

Objective To compare the efficacy and safety of proton pump inhibitors (PPI) plus Rebamipide and PPI alone for the healing of ulcer after endoscopic submucosal dissection (ESD). Methods PubMed, Web of Science, Medline, Embase, Cochrane Central Register of Controlled Trials, CENTRAL, CJFD, CBM, CNKI, VIP and WanFang Data were researched up to the end of Aug. 2015 to identify all randomized controlled trials (RCTs) that reported the effect of PPI plus Rebamipide for the healing of ulcer after ESD. Outcome measures were ulcer healing. Results Six studies involving 724 patients were included. Pooled data suggested a significantly higher ulcer healing rate after endoscopic therapies in PPI plus Rebamipide group than that in the PPI alone group (OR=2.40, 95%CI: 1.68-3.44). Subgroup analysis showed PPI plus Rebamipide was more effective in the healing of ESD-induced ulcer than PPI in both 4-week (OR=2.22, 95%CI: 1.53-3.24) and 8-week duration of medication (OR=3.19, 95%CI: 1.22-8.31). The combination therapy was significantly more effective than the PPI alone for every size of ESD ulcer larger than 2 cm (OR=4.77, 95%CI: 2.22-10.26). There was no significantly difference in ulcer location (low, middle, or upper stomach) andH.pyloriinfection or not between combination therapy and PPI alone groups. No serious adverse events occurred in the two groups. Conclusion PPI plus Rebamipide is superior to PPI alone for the healing of ulcer after ESD, especially for large-sized ulcers. However, more well-designed trials are needed to confirm the findings.

Endoscopic submucosal dissection; Rebamipide; Proton pump inhibitor; Meta-analysis

10.3969/j.issn.1006-5709.2016.06.024

張少君，主治醫(yī)師，研究方向：膽胰疾病的診斷。E-mail: zhangshaojunsy@163.com

董小林，主治醫(yī)師，研究方向：膽胰疾病和消化道腫瘤的防治。E-mail: dongxlmail@163.com

R57

A

1006-5709(2016)06-0686-05

2015-09-06