抑酸药预防术后应激性溃疡出血的系统评价

Systematic Review of Acid-suppressive Drugs Used for the Prophylaxis of Stress Ulcer Bleeding in Postoperative Patients

目的:评价抑酸药[包括质子泵抑制药(PPI)和H2受体阻断药(H2RA)]对比安慰剂(或空白对照)预防术后应激性溃疡出血(SUB)的疗效和安全性,为临床提供循证依据。方法:检索Cochrane图书馆临床对照试验数据库、MEDLINE光盘数据库、EMbase光盘数据库、中国知网中国期刊全文数据库、中国生物医学文献数据库、中国科技期刊全文数据库、万方数字化期刊全文数据库、临床实验注册网站(clinicaltrials.gov,ISRCTN Register和WHO ICTRP),收集抑酸药与安慰剂(或空白对照)比较用于预防术后SUB,以出血发生率、病死率、不良反应发生率、胃液pH和住院天数中任何一项作为研究终点的随机对照试验(RCT)。对纳入研究进行资料提取和偏倚风险评价,采用Stata 12.0软件进行Meta分析,结果以相对危险度(RR)以及95%置信区间(CI)表示,并应用Grade分别评价终点指标的证据质量等级,漏斗图和Eggers test检验判断是否存在发表偏倚。结果:15项RCT(971例)用于Meta分析。Meta分析结果显示抑酸药在预防SUB、显性出血和临床大出血发生率方面均优于安慰剂或空白对照(RR 0.29,95%CI:0.19~0.45;RR 0.25,95%CI:0.10~0.64;RR 0.36,95%CI:0.17~0.77)(中等证据强度),两组在隐性出血、病死率和不良反应发生率方面差异无统计学意义(RR 0.79,95%CI:0.41~1.50;RR 0.49,95%CI:0.17~1.38;RR 0.78,95%CI:0.33~1.85)(极低强度证据)。亚组分析显示预防使用PPI的研究,术后SUB发生率(RR=0.27)低于使用H_2RA的研究(RR=0.33);心脏科手术后SUB发生率(RR=0.20)分别低于普通外科(RR=0.23)和神经外科(RR=0.37)的研究;术前给药的术后SUB发生率(RR=0.31)高于术后给药的研究(RR=0.26)。结论:预防用抑酸药可有效降低术后SUB的发生率,且不增加不良反应发生率和死亡率。但纳入研究方法学质量普遍偏低,部分文献的结局指标不全面,缺乏肺炎、难辨梭菌感染等安全性指标。今后尚需进一步开展高质量、大样本的临床研究验证其临床效果。

Objective： To systematically review the efficacy and safety of acid-suppressive therapy including proton pump inhibitors （PPI） and histamine 2 receptor antagonists （ H2 RA） and compare with those of placebo or blank control in the postoperative patients with stress ulcer bleeding （SUB） to provide evidence-based reference for clinical practice. Methods： The Cochrane library, Medline, Embase, CBM, CNKI, VIP, Wan Fang Data, clinicaltrials, gov, ISRCTN Register and WHO ICTRP were searched. Only randomized controlled trials （RCTs） of acid-suppressive therapy compared with placebo or blank control for postoperative stress ulcer bleeding were selected with bleeding rate, mortality, adverse drug reactions, gastric juice pH and length of stay as the indices. After the quality evaluation and data extraction, Meta-analysis was performed by using Stata 12.0 statistics software. The results were expressed as relative risk（RR） and its corresponding 95% confidence interval（CI）. Funnel plot and Eggers test were used to determine the publication bi- as; and then Grade approach was applied to assess the confidence in the evidence for each outcome. Results： Totally 15 trials enrolling 971 patients were selected, and acid-suppressive therapy was more effective than placebo or blank control in reducing the risk of stress ulcer bleeding, overt upper gastrointestinal bleeding and clinical important bleeding（RR 0.29,95% CI：0. 19-0.45 ;RR 0.25,95% CI： 0.10-0.64 ;RR 0.36,95% CI：0. 17-0.77 ）（ moderate）, however, there was no statistical significance in the incidence of occult bleeding, mortality and adverse drug reactions （RR 0.79,95% CI：0. 41-1.50 ;RR 0.49,95% CI：0. 17-1.38 ;RR 0.78,95% CI：0. 33-1.85, very low confidence）. The subgroup analysis of drug classification, operation types and administration juncture showed that the incidence of SUB using PPI （RR = 0.27） was lower than that using H2 RA （RR = 0.33 ） ; that of heart surgery （ RR = 0.20） was lower than that of general surgery （RR = 0.31 ） and neurosurgery （ RR = 0.37 ） ; that of postoperative administration （RR = 0.26 ） was lower than that of preoperative administration （RR = 0.23）. Conclusion ： Acid-suppressive drugs seem to be more effective than placebo or blank control in reducing the risk of bleeding without significant increase of the risk of mortality or adverse drug reactions. The robustness of the conclusion is limited because of the low quality of the trial methodology, incomplete outcome indicators and lack of safety indices for pneumonia and clostridium diffcile-associated infection. Trials with high-quality and larger sample size are still needed to verify its clinical effects.