鄭煒平　陳鋒　李永坤　林開陽　江蕓

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達(dá)比加群酯對(duì)非瓣膜性房顫導(dǎo)管消融圍術(shù)期抗凝療效和安全性的Meta分析

鄭煒平陳鋒李永坤林開陽江蕓

目的系統(tǒng)評(píng)價(jià)達(dá)比加群酯對(duì)非瓣膜性房顫導(dǎo)管消融圍術(shù)期的抗凝療效和安全性。方法計(jì)算機(jī)檢索PubMed、EMbase、The Cochrane Library(2016年第2期)、CMB、知網(wǎng)、萬方和維普數(shù)據(jù)庫，搜集有關(guān)房顫導(dǎo)管消融圍術(shù)期使用達(dá)比加群酯和華法林抗凝治療的隨機(jī)對(duì)照及非隨機(jī)對(duì)照的研究文獻(xiàn)，由兩位評(píng)價(jià)員獨(dú)立篩選文獻(xiàn)、提取資料和評(píng)價(jià)納入研究的偏倚風(fēng)險(xiǎn)后，采用RevMan 5.3軟件進(jìn)行Meta分析。結(jié)果最終納入23個(gè)研究、共7 673例患者。Meta分析結(jié)果顯示：達(dá)比加群酯組腦卒中或短暫性腦缺血發(fā)生率與華法林組無明顯區(qū)別[OR=1.0，95%CI：0.60～1.68，P=0.99]，大出血事件發(fā)生率無明顯區(qū)別[OR=0.79，95%CI:0.52～1.19，P=0.25]，小出血事件發(fā)生率顯著降低[OR=0.71，95%CI:0.57～0.87，P=0.001]。結(jié)論達(dá)比加群酯在房顫導(dǎo)管消融圍術(shù)期抗凝療效及大出血并發(fā)癥的發(fā)生率上與華法林無明顯區(qū)別，小出血并發(fā)癥的發(fā)生率較華法林降低。

達(dá)比加群酯；華法林；心房顫動(dòng)；導(dǎo)管消融術(shù)；抗凝

房顫是臨床最常見的心律失常，是腦卒中的獨(dú)立危險(xiǎn)因素之一[1]。房顫患者發(fā)生腦卒中的危險(xiǎn)性是正常人群的5～7倍，預(yù)防房顫引起的血栓栓塞事件是房顫治療策略中重要的一環(huán)。我國《心房顫動(dòng)：目前的認(rèn)識(shí)和治療建議—2015》推薦CHA2DS2-VASc評(píng)分≥2分、無特殊禁忌證的房顫者均應(yīng)進(jìn)行口服抗凝治療[2]。華法林是經(jīng)典的口服抗凝藥物，但由于其個(gè)體差異性大，受多種藥物、食物影響，需要頻繁監(jiān)測(cè)國際標(biāo)準(zhǔn)化比率(internation normalized ratio, INR)，其臨床應(yīng)用受到了限制。達(dá)比加群酯是合成的新型直接凝血酶抑制劑，近年多項(xiàng)隨機(jī)對(duì)照臨床研究[3-5]均肯定了其在非瓣膜性房顫抗凝治療中的療效和安全性，已被歐美和我國的相關(guān)指南或?qū)＜夜沧R(shí)推薦使用[2,6-7]。目前，達(dá)比加群酯對(duì)房顫導(dǎo)管射頻消融圍術(shù)期使用的有效性和安全性的臨床對(duì)照研究不多，對(duì)于其是否能作為射頻消融圍術(shù)期抗凝藥物，指南未作出明確的推薦。本研究采用Meta分析的方法，結(jié)合近年國內(nèi)外多項(xiàng)達(dá)比加群酯在房顫導(dǎo)管射頻消融圍術(shù)期臨床對(duì)照研究的結(jié)果，對(duì)其抗凝治療的有效性和安全性進(jìn)行評(píng)估，以期為臨床工作者提供有益的參考依據(jù)。

1　資料與方法

1.1納入與排除標(biāo)準(zhǔn)

1.1.1研究類型非瓣膜性房顫導(dǎo)管消融圍術(shù)期使用達(dá)比加群酯和華法林抗凝治療的隨機(jī)對(duì)照試驗(yàn)(randomized controlled trials,RCT)或非隨機(jī)對(duì)照試驗(yàn)(non-RCT) 。

1.1.2研究對(duì)象年齡≥18歲，診斷為陣發(fā)性或持續(xù)性非瓣膜性房顫患者，擬行導(dǎo)管消融術(shù)復(fù)律治療。

1.1.3干預(yù)措施治療達(dá)比加群酯組圍術(shù)期采用達(dá)比加群酯110 mg或150 mg，2次/d抗凝治療；對(duì)照組采用華法林抗凝治療，維持INR在2～3。

1.1.4結(jié)局指標(biāo) ① 缺血性卒中、短暫性腦缺血發(fā)作(transient ischemic attack,TIA)；② 大出血事件：包括顱內(nèi)出血、需要心包穿刺的心包填塞、需要輸血或住院治療的失血性休克；③ 小出血事件：包括穿刺后腹股溝血腫、皮下出血、少量心包出血等不需要住院治療的出血事件。

1.1.5排除標(biāo)準(zhǔn)① 重復(fù)發(fā)表的文獻(xiàn)；② 無法提取有效數(shù)據(jù)的文獻(xiàn)；③ 無華法林作為對(duì)照組的研究文獻(xiàn)；④ 不以大出血事件、小出血事件及栓塞事件為結(jié)局指標(biāo)的研究；⑤ 針對(duì)瓣膜性房顫的研究。

1.2文獻(xiàn)檢索策略

計(jì)算機(jī)檢索PubMed、EMbase、The Cochrane Library(2016年第2期)、CMB、知網(wǎng)、萬方和維普數(shù)據(jù)庫，搜集房顫導(dǎo)管消融圍術(shù)期使用達(dá)比加群酯和華法林抗凝治療的RCT和non-RCT的研究文獻(xiàn)，檢索時(shí)限均為從建庫至2016年2月。采用主題詞和自由詞相結(jié)合的方式進(jìn)行檢索，中文檢索詞包括達(dá)比加群酯、華法林、房顫、導(dǎo)管射頻消融等;英文檢索詞包括Dabigatran，Warfarin，atrial fibrillation，Ablation Techniques，Hemorrhage，stroke。以PubMed為例，具體檢索策略為，((((((atrial fibrillation[MeSH Terms]) AND Ablation Techniques[MeSH Terms]) AND Dabigatran[MeSH Terms]) AND Warfarin[MeSH Terms])) OR (((((((atrial fibrillation[Title/Abstract]) AND Ablation[Title/Abstract]) AND Warfarin[Title/Abstract]) AND Dabigatran[Title/Abstract]))) AND Hemorrhage[Title/Abstract])) OR (((((atrial fibrillation[Title/Abstract]) AND Ablation[Title/Abstract]) AND Warfarin[Title/Abstract]) AND Dabigatran[Title/Abstract]) AND stroke[Title/Abstract])。

1.3文獻(xiàn)篩選及資料提取

提取內(nèi)容包括: ① 第一作者及論文發(fā)表年份; ② 試驗(yàn)設(shè)計(jì)方法；③ 研究對(duì)象的基本特征(年齡、性別、隨訪時(shí)間、CHADS2評(píng)分); ③ 干預(yù)措施的具體細(xì)節(jié);④ 偏倚風(fēng)險(xiǎn)評(píng)價(jià)的關(guān)鍵要素; ⑤ 所關(guān)注的結(jié)局指標(biāo)和結(jié)果測(cè)量數(shù)據(jù)。由兩位評(píng)價(jià)員獨(dú)立篩選文獻(xiàn)、提取資料，并交叉核對(duì)，如有分歧，則進(jìn)行討論向第三位評(píng)價(jià)員詢問。

1.4納入研究的文獻(xiàn)質(zhì)量評(píng)價(jià)

由兩位評(píng)價(jià)員按照Newcastle-Ottawa scale (NOS)量表評(píng)價(jià)納入研究的偏倚風(fēng)險(xiǎn)。

1.5統(tǒng)計(jì)分析

采用RevMan 5.3軟件進(jìn)行Meta分析。計(jì)量資料采用比值比(odds ratio, OR)作為效應(yīng)指標(biāo)，各效應(yīng)量均給出其點(diǎn)估計(jì)值和95%CI，采用森林圖表示。納入研究結(jié)果間的異質(zhì)性采用χ2檢驗(yàn)進(jìn)行分析(檢驗(yàn)水準(zhǔn)為α=0.1)，同時(shí)結(jié)合I2定量判斷異質(zhì)性的大小。若各研究結(jié)果間無統(tǒng)計(jì)學(xué)異質(zhì)性，則采用固定效應(yīng)模型進(jìn)行Meta分析;若各研究結(jié)果間存在統(tǒng)計(jì)學(xué)異質(zhì)性，則進(jìn)一步分析異質(zhì)性來源，在排除明顯臨床異質(zhì)性的影響后，采用隨機(jī)效應(yīng)模型進(jìn)行Meta分析，必要時(shí)進(jìn)行亞組分析。采用倒漏斗圖評(píng)價(jià)其發(fā)表偏倚。Meta 分析檢驗(yàn)水準(zhǔn)為α=0.05。

2　結(jié)果

2.1文獻(xiàn)檢索結(jié)果

初檢出相關(guān)文獻(xiàn) 173 篇，經(jīng)逐層篩選后，最終納入23 個(gè)研究[8-30]，其中國外研究19項(xiàng)、國內(nèi)研究4項(xiàng)，共7 673例患者。文獻(xiàn)篩選流程及結(jié)果見圖 1。

圖1　文獻(xiàn)篩選流程及結(jié)果

2.2納入研究的基本特征和研究質(zhì)量評(píng)價(jià)

納入的研究除Bassiouny等[10]的研究為隨機(jī)對(duì)照研究外，其余22個(gè)均為回顧性對(duì)照研究，故文獻(xiàn)質(zhì)量采用NOS量表評(píng)分。納入研究的基本特征及文獻(xiàn)質(zhì)量NOS評(píng)分見表1。

2.3Meta分析結(jié)果

2.3.1卒中或TIA事件發(fā)生率固定效應(yīng)模型的Meta分析顯示，達(dá)比加群酯組卒中或TIA事件發(fā)生率與華法林組比較，差異無統(tǒng)計(jì)學(xué)意義[OR=1.0，95%CI：0.60～1.68，P=0.99]。見圖2。漏斗圖基本對(duì)稱，提示無發(fā)表偏倚。見圖3。

2.3.2大出血事件發(fā)生率固定效應(yīng)模型的Meta分析顯示，達(dá)比加群酯組大出血事件發(fā)生率與華法林組比較，差異無統(tǒng)計(jì)學(xué)意義[OR=0.79，95%CI:0.52～1.19，P=0.25]。見圖4。漏斗圖基本對(duì)稱，提示無發(fā)表偏倚。見圖5。

2.3.3小出血事件發(fā)生率固定效應(yīng)模型的Meta分析顯示，達(dá)比加群酯組小出血事件發(fā)生率較華法林組降低，差異有統(tǒng)計(jì)學(xué)意義[OR=0.71，95%CI：0.57～0.87，P=0.001]。見圖6。漏斗圖基本對(duì)稱提示無發(fā)表偏倚。見圖7。

3　討論

達(dá)比加群酯為直接凝血酶抑制劑，其競(jìng)爭性結(jié)合凝血酶與纖維蛋白的結(jié)合位點(diǎn),從而阻斷了凝血瀑布的最后步驟，抑制血栓的形成。與傳統(tǒng)的抗凝藥華法林相比，達(dá)比加群酯個(gè)體差異性小、起效快、不通過細(xì)胞色素P450系統(tǒng)代謝，受其他藥物影響小，不需要頻繁監(jiān)測(cè)凝血指標(biāo)，臨床應(yīng)用依從性較好。RE-LY試驗(yàn)納入18 113例非瓣膜性房顫患者，研究結(jié)果顯示：達(dá)比加群酯150 mg組卒中或TIA風(fēng)險(xiǎn)較華法林組降低34%，大出血發(fā)生率與華法林組比較無明顯區(qū)別；達(dá)比加群酯110 mg組抗凝治療卒中和/或TIA風(fēng)險(xiǎn)與華法林組比較無明顯區(qū)別，大出血事件發(fā)生風(fēng)險(xiǎn)降低20%[5]。同時(shí)，亞組分析顯示，達(dá)比加群酯150 mg組降低卒中或TIA風(fēng)險(xiǎn)的優(yōu)勢(shì)與房顫類型無關(guān)[31]。近年房顫相關(guān)指南[2,6-7]推薦達(dá)比加群酯作為非瓣膜性房顫的新型口服抗凝藥，其療效和安全性已經(jīng)得到臨床的認(rèn)可。

導(dǎo)管射頻消融是房顫復(fù)律的重要治療措施，較傳統(tǒng)的抗心律失常措施有更高的轉(zhuǎn)復(fù)律和更低的復(fù)發(fā)率[32]。由于目前接受導(dǎo)管射頻消融的房顫患者占房顫總?cè)巳旱谋壤云停_(dá)比加群酯在導(dǎo)管射頻消融圍術(shù)期抗凝治療的有效性和安全性尚缺乏大樣本、多中心的RCT研究證據(jù)。本研究納入23項(xiàng)隨機(jī)對(duì)照及非隨機(jī)對(duì)照研究，國外研究19項(xiàng)，國內(nèi)研究4項(xiàng)，總樣本量7 673例，其中達(dá)比加群酯組3 109例，華法林組4 564例。經(jīng)Meta分析顯示，與華法林相比，導(dǎo)管射頻消融圍術(shù)期使用達(dá)比加群酯抗凝，腦卒中或TIA發(fā)生率無明顯區(qū)別，大出血事件發(fā)生率無明顯區(qū)別，小出血事件發(fā)生率顯著降低，顯示達(dá)比加群酯可安全有效地用于房顫導(dǎo)管射頻消融圍術(shù)期的抗凝治療。本研究納入的人群均為腎功能無明顯異常的人群，Blech等[33]研究顯示達(dá)比加群酯不通過細(xì)胞色素P450系統(tǒng)代謝，80%的達(dá)比加群酯以原型形式通過腎臟排泄；腎功能異常的患者，達(dá)比加群酯在體內(nèi)血藥濃度明顯升高。對(duì)于中度腎功能不全房顫患者(CrCl 30～50 mL/min)達(dá)比加群酯的服藥劑量推薦改為110 mg，2次/d；對(duì)于重度腎功能不全患者(CrCl<30 mL/min)，不推薦使用達(dá)比加群酯，改用華法林抗凝或肝素抗凝治療。對(duì)于達(dá)比加群酯用藥方案，僅有Kaseno等[14]與Nin等[20]兩項(xiàng)研究采用單一110 mg劑量，多數(shù)研究根據(jù)CHADS2評(píng)分決定患者的口服劑量，因此尚沒有足夠的樣本量對(duì)不同達(dá)比加群酯劑型與華法林進(jìn)行亞組分析。對(duì)>75歲的老年患者，導(dǎo)管消融圍術(shù)期是否可以進(jìn)一步降低劑量，國外尚無相關(guān)研究，國內(nèi)江云東等[27]采用達(dá)比加群酯55 mg，2次/d的抗凝治療方案，該組與華法林組均未出現(xiàn)大出血事件，腦卒中或TIA以及小出血事件經(jīng)Fisher精確檢驗(yàn)，兩組發(fā)生率差異無統(tǒng)計(jì)學(xué)意義，但由于樣本量較小，尚不能說明對(duì)于高齡老年患者可以進(jìn)一步降低達(dá)比加群酯劑量。

表1　納入研究的基本特征與NOS評(píng)分

a ：卒中風(fēng)險(xiǎn)CHADS2評(píng)分；b：卒中風(fēng)險(xiǎn)CHA2DS2-VASc評(píng)分；—：無該數(shù)據(jù)

圖2　達(dá)比加群酯組與華法林組腦卒中或短暫性腦缺血發(fā)作風(fēng)險(xiǎn)比較的Meta分析

圖3　達(dá)比加群酯組與華法林組腦卒中或短暫性腦缺血發(fā)作事件漏斗圖

圖4　達(dá)比加群酯組與華法林組大出血風(fēng)險(xiǎn)比較的Meta分析

圖5　達(dá)比加群酯組與華法林組大出血事件漏斗圖

圖6　達(dá)比加群酯組與華法林組小出血風(fēng)險(xiǎn)比較的Meta分析

圖7　達(dá)比加群酯組與華法林組小出血事件漏斗圖

局限性：① 由于各項(xiàng)研究房顫導(dǎo)管射頻消融樣本量相對(duì)較少，多數(shù)研究均選擇非隨機(jī)病例對(duì)照的設(shè)計(jì)方案，僅一項(xiàng)研究[10]采用隨機(jī)對(duì)照臨床試驗(yàn)，總體質(zhì)量偏低，結(jié)果的可靠性仍需大型隨機(jī)臨床對(duì)照研究進(jìn)一步證實(shí)；② 各項(xiàng)研究達(dá)比加群酯110 mg、150 mg劑量的臨床數(shù)據(jù)無法提取，無法對(duì)兩個(gè)劑量進(jìn)行亞組分析。

結(jié)論：達(dá)比加群酯對(duì)房顫導(dǎo)管消融圍術(shù)期抗凝療效和大出血并發(fā)癥的發(fā)生率與華法林無明顯區(qū)別，小出血并發(fā)癥的發(fā)生率較華法林降低，可安全有效地用于房顫導(dǎo)管消融圍術(shù)期抗凝治療。然而，達(dá)比加群酯抗凝治療的有效性和安全性有待大型隨機(jī)臨床對(duì)照研究進(jìn)一步證實(shí)。

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Efficacy and safety of dabigatran perioperative anticoagulation for patients undergoing catheter ablation of non-valvular atrial fibrillation: a Meta-analysis

ZhengWei-ping1,ChenFeng1,LiYong-kun2,LinKai-yang1,JiangYun1

(1. Fujian Provincial Emergency Center, Provincial Clinical Medical College of Fujian Medical University; 2. Department of of Neurology, Fujian Provincial Hospital, Fuzhou Fujian 350001, China)

ObjectiveTo systematically evaluate the efficacy and safety of dabigatran perioperative anticoagulation for patients undergoing catheter ablation of non-valvular atrial fibrillation. MethodsWe collected research literature of randomized controlled trials (RCTs) or non-RCTs about perioperative anticoagulation for patients undergoing catheter ablation of non-valvular atrial fibrillation from databases including PubMed, EMbase, The Cochrane Library (Issue 2, 2016), CMB, CNKI, Wanfang and VIP with computer. Two evaluators independently screened literatures, extracted data and assessed the bias risk of included studies, and then performed Meta-analysis by using software of RevMan 5.3. ResultsA total of 23 studies involving 7 673 patients were finally enrolled in Meta-analysis. It showed no statistically significant difference in the incidence of cerebral apoplexy or transient cerebral ischemia between dabigatran and warfarin groups(OR=1.0, 95%CI：0.60-1.68,P=0.99), and so did the incidence of hemorrhoea event(OR=0.79, 95%CI：0.52-1.19,P=0.25). The incidence of minor hemorrhoea event in dabigatran group was significantly decreased than that in warfarin group(OR=0.71, 95%CI：0.57-0.87,P=0.001). ConclusionThere was no significant difference in the efficacy of perioperative anticoagulation for patients undergoing catheter ablation of non-valvular atrial fibrillation and incidence of complication of hemorrhoea between dabigatran and warfarin. For patients taking dabigatran, the incidence of complication of minor hemorrhoea is reduced if compared with those taking warfarin.

dabigatran; warfarin; atrial fibrillation; catheter ablation; anticoagulation

國家臨床重點(diǎn)?？平ㄔO(shè)項(xiàng)目(急診醫(yī)學(xué)2012) ；國家自然科學(xué)基金資助項(xiàng)目(81670455)

350001 福建 福州， 福建醫(yī)科大學(xué)省立臨床醫(yī)學(xué)院，福建省急救中心(鄭煒平， 陳鋒，林開陽，江蕓)； 福建省立醫(yī)院神經(jīng)內(nèi)科(李永坤)

鄭煒平，副主任醫(yī)師，主要從事心血管內(nèi)科及無創(chuàng)電生理檢查。

陳鋒，E-mail：cf9066@126.com；李永坤，E-mail：liyongkun721@vip.sina.com

10.13308/j.issn.2095-9354.2016.05.007

2016-09-18)(本文編輯：郭欣)

R541.7

A

2095-9354(2016)05-0334-08