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利福昔明预防自发性细菌性腹膜炎有效性和安全性的Meta分析
DOI: 10.3969/j.issn.1001-5256.2021.02.015
利益冲突声明：本研究不存在研究者利益冲突，特此声明。
作者贡献声明：程书平负责课题设计，资料分析，撰写论文；张庆玉、李明参与收集数据，修改论文；谭诗云负责拟定写作思路，指导撰写文章并最后定稿。
Efficacy and safety of rifaximin in the prevention of spontaneous bacterial peritonitis: A Meta-analysis
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摘要:
目的 评价利福昔明预防自发性细菌性腹膜炎(SBP)的有效性及安全性。 方法 通过计算机检索中国知网、万方数据、中国生物医学数据库、PubMed、Embase、Cochrane图书馆建库至2020年7月5日发表的有关利福昔明预防SBP的随机对照研究(RCT)、队列研究，根据纳入和排除标准对文献进行筛选，并对文献进行提取数据和质量评估，采用RevMan 5.3软件进行Meta分析。 结果 最终纳入13项研究，共2207例患者，其中6项为RCT，7项为队列研究。Meta分析结果显示，与无预防组相比，利福昔明组的SBP发病率(OR=0.36, 95%CI:0.14~0.96, P=0.04)、死亡率(OR=0.59, 95%CI:0.37~0.95, P=0.03)均明显下降；与诺氟沙星组相比，利福昔明组的SBP发病率(OR=0.39, 95%CI:0.25~0.62, P＜0.001)、死亡率(OR=0.55, 95%CI:0.34~0.92, P=0.02)、不良反应(OR=0.36, 95%CI:0.22~0.59, P＜0.001)均明显降低，根据预防类型进行亚组分析，两组在初级预防无显著差异(OR=0.56, 95%CI:0.23~1.35, P=0.20)，二级预防时利福昔明组的SBP发病率(OR=0.18, 95%CI:0.08~0.43, P＜0.001)明显降低。此外，还发现利福昔明可以明显降低肝肾综合征(OR=0.34, 95%CI:0.15~0.77, P=0.01)和肝性脑病(OR=0.55, 95%CI:0.32~0.95, P=0.03)的发生风险。 结论 利福昔明对SBP初级预防和二级预防安全有效，在二级预防时，利福昔明优于诺氟沙星，但仍需高质量多中心RCT进行验证。 -
关键词:
- 肝硬化 /
- 腹膜炎 /
- 利福昔明 /
- 诺氟沙星 /
- Meta分析(主题)
Abstract:Objective To evaluate the efficacy and safety of rifaximin in the prevention of spontaneous bacterial peritonitis (SBP). Methods CNKI, Wanfang Data, CBM, PubMed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) and cohort studies on rifaximin in the prevention of SBP published up to July 5, 2020. The articles were screened according to the inclusion and exclusion criteria, and data extraction and quality assessment were performed. RevMan 5.3 software was used to conduct the meta-analysis. Results A total of 13 studies (with 2207 patients in total) were included, among which there were 6 RCTs and 7 cohort studies. The results of the meta-analysis showed that compared with the non-prevention group, the rifaximin group had significantly lower incidence rate of SBP (odds ratio [OR]=0.36, 95% confidence interval [CI]: 0.14-0.96, P=0.04) and mortality rate (OR=0.59, 95% CI: 0.37-0.95, P=0.03); compared with the norfloxacin group, the rifaximin group had significantly lower incidence rate of SBP (OR=0.39, 95% CI: 0.25-0.62, P < 0.001), mortality rate (OR=0.55, 95% CI: 0.34-0.92, P=0.02), and adverse reactions (OR=0.36, 95% CI: 0.22-0.59, P < 0.001). The subgroup analysis based on the type of prevention showed that there was no significant difference in primary prevention between the two groups (OR=0.56, 95% CI: 0.23-1.35, P=0.20), and in secondary prevention, the rifaximin group had a significantly lower incidence rate of SBP (OR=0.18, 95% CI: 0.08-0.43, P < 0.001). In addition, it was also found that rifaximin significantly reduced the incidence rate of hepatorenal syndrome (OR=0.34, 95% CI: 0.15-0.77, P=0.01) and hepatic encephalopathy (OR=0.55, 95% CI: 0.32-0.95, P=0.03). Conclusion Rifaximin is safe and effective for the primary and secondary prevention of SBP. Rifaximin is superior to norfloxacin in secondary prevention, which still needs to be confirmed by high-quality multicenter RCTs. -
Key words:
- Liver Cirrhosis /
- Peritonitis /
- Rifaximin /
- Norfloxacin /
- Meta-Analysis as Topic
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表 1 纳入文献基本信息
作者、时间及国家 研究类型 预防级别 试验组 对照组 随访时间 结局指标 病因 Child评分或A/B/C 年龄(岁) 例数 干预措施 病因 Child评分或A/B/C 年龄(岁) 例数 干预措施 Elfert 2016[8]埃及 RCT 二级 未提供 0/58/73 53.8±7.5 131 利福昔明1200 mg/d 未提供 0/63/68 54.1±7.1 131 诺氟沙星400 mg/d 6个月 ①②④⑤⑥ Assem 2016[9]埃及 RCT 初级 90%以上为丙型肝炎 10.2±3.1 55±18 82 利福昔明1100 mg/d 90%以上为丙型肝炎 10.1±1.6 58±15 78 诺氟沙星400 mg/d 6个月 ①②③⑤⑦ Mostafa 2015[10]埃及 RCT 二级 丙型肝炎 10.3±1.1 55.8±4.8 40 利福昔明800 mg/d 丙型肝炎 10.7±1.8 56.5±4.1 30 诺氟沙星400 mg/d 6个月 ①⑥⑦ Praharaj(1) 2017[11]印度 RCT 初级 未提供 未提供 38.8±8.8 28 利福昔明1100 mg/d 未提供 未提供 37.7±8.7 30 诺氟沙星400 mg/d 6个月 ① Praharaj(2) 2017[11]印度 二级 未提供 26 未提供 33 ① Shamseya 2015[12]埃及 队列研究 初级和二级 丙型肝炎 11.5±2.1 52.7±8.5 43 利福昔明1200 mg/d 丙型肝炎 11.5±2 50.3±9.0 43 诺氟沙星400 mg/d 12个月 ①②③④⑤⑥ Kumar 2019[13]巴基斯坦 RCT 未知 未提供 未提供 38.8±8.8 122 利福昔明1200 mg/d 未提供 未提供 37.7±8.7 122 诺氟沙星400 mg/d 6个月 ① Flamm 2018[14]美国 RCT 初级和二级 未提供 未提供 55.5 140 利福昔明1100 mg/d 未提供 未提供 56.8 159 安慰剂 6个月 ①②③④ Hanouneh 2012[15]美国 队列研究 初级 未提供 11 55 49 利福昔明1200 mg/d 未提供 10 55 355 无 4.2个月 ①⑤⑥ Lutz 2014[16]德国 队列研究 初级和二级 74%酒精性肝炎，19%病毒性肝炎 未提供 61 27 利福昔明1200 mg/d 57%酒精性肝炎，27%病毒性肝炎 未提供 60 108 无 4周 ①⑥ Vlachogiannakos 2013[17]希腊 队列研究 初级 酒精性肝炎 0/11/12 64.2±9.0 23 利福昔明1200 mg/d 酒精性肝炎 0/22/24 64.1±9.1 46 无 5年 ①②③④⑤ Shokoohi 2013[18]美国 队列研究 初级 未提供 未提供 53.5 79 利福昔明 未提供 未提供 58.2 60 无 20.2个月 ① Dong 2016[19]美国 队列研究 未知 酒精性及丙型肝炎共占60%以上 未提供 59.5 88 利福昔明550 mg/d 酒精性及丙型肝炎共占70%以上 未提供 57.5 88 无 3个月 ①③⑤ Danulescu 2013[20]罗马尼亚 队列研究 未知 未提供 0/0/22 未提供 22 利福昔明 未提供 0/0/24 未提供 24 无 6个月 ① 注：①SBP发生率；②消化道出血；③HRS；④HE；⑤死亡率；⑥腹水细菌培养；⑦不良反应。 
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表 2 RCT文献质量评价
纳入文献 随机方法 分配隐藏 盲法 资料完整 选择报告偏倚 其他偏倚 Jadad评分 Assem 2016 计算机随机序列 不透明的密封信封 不清楚 完整 无 无 5 Mostafa 2015 随机 不清楚 单盲 完整 无 无 5 Elfert 2016 计算机随机序列 不透明的密封信封 不清楚 完整 无 无 5 Praharaj 2017 随机 不清楚 不清楚 完整 无 无 3 Flamm 2018 随机 不清楚 不清楚 完整 无 无 3 Kumar 2019 随机 不清楚 不清楚 完整 无 无 3
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表 3 队列研究文献质量评价
纳入文献 队列的选择 可比性 结果 NOS评分 暴露组代表性 非暴露组代表性 暴露因素确定方法 确定结局指标 基于设计所得队列的可比性 评价是否充分 随访是否充分 随访完整性 Shamseya 2015 1 1 1 1 2 1 1 1 9 Hanouneh 2012 1 1 1 1 1 1 1 1 8 Lutz 2014 1 1 1 1 1 1 0 0 6 Vlachogiannakos 2013 1 1 1 1 2 1 1 1 8 Shokoohi 2013 1 1 1 1 1 1 1 0 7 Dong 2016 1 1 1 1 1 1 1 1 8 Danulescu 2013 0 0 1 1 1 1 1 1 6
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表 4 利福昔明对其他肝硬化并发症Meta分析结果
并发症 预防措施 纳入研究 异质性分析 效应模型 OR 95%CI Z值 P值 I2(%) P值 消化道出血 利福昔明vs无 [14][17] 0 0.33 固定 0.46 0.19~1.13 1.68 0.09 利福昔明vs诺氟沙星 [8][9][12] 0 0.93 固定 0.99 0.49~2.01 0.02 0.99 HRS 利福昔明vs无 [14][17][19] 0 0.77 固定 0.34 0.15~0.77 2.58 0.01 利福昔明vs诺氟沙星 [9][12] 0 0.47 固定 0.40 0.10~1.57 1.31 0.19 HE 利福昔明vs无 [14][17] 0 0.52 固定 0.55 0.32~0.95 2.13 0.03 利福昔明vs诺氟沙星 [8][12] 0 0.70 固定 0.35 0.15~0.82 2.43 0.01
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表 6 利福昔明与对照组SBP腹水细菌培养信息
研究 预防级别 试验组 对照组 SBP 阳性 G+ G- 耐药 SBP 阳性 G+ G- 耐药 Mostafa 2015 二级 0 0 0 0 不清楚 5 5 5 0 不清楚 Elfert 2016 二级 4 2 0 2 2例诺氟沙星 13 8 4 4 8例诺氟
沙星耐药Shamseya 2015 初级和二级 2 0 0 0 不清楚 6 1 0 1 不清楚 Hanouneh 2012 初级 5 0 0 0 不清楚 113 35 18 17 不清楚 Lutz 2014 初级和二级 8 4 0 4 1例三代头孢，1例多重耐药 24 11 4 7 5例三代头孢耐药，1例多重耐药
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J Clin Hepatol, 2018, 34(7): 1551-1554.(in Chinese) DOI: 10.3969/j.issn.1001-5256.2018.07.040吕新月, 李磊. 利福昔明在肝硬化相关并发症中的应用[J]. 临床肝胆病杂志, 2018, 34(7): 1551-1554. DOI: 10.3969/j.issn.1001-5256.2018.07.040 -
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