Prefontaine Eliza, Macdonald John K, Sutherland Lloyd R
Department of Community Health Sciences, University of Calgary, Health Sciences Centre, 3330 Hospital Dr NW, Calgary, Alberta, Canada, T2N 4N1.
Cochrane Database Syst Rev. 2009 Oct 7(4):CD000545. doi: 10.1002/14651858.CD000545.pub2.
The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.
To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.
Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.
Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.
Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.
Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment > 17 weeks increased the OR to 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.
AUTHORS' CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The OR of response increases after > 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on active therapy.
关于硫唑嘌呤和6-巯基嘌呤治疗活动性克罗恩病疗效的对照临床试验结果存在冲突且有争议。进行了一项荟萃分析以评估这些药物诱导活动性克罗恩病缓解的有效性。
确定硫唑嘌呤和6-巯基嘌呤诱导活动性克罗恩病缓解的有效性。
使用MEDLINE数据库（1966年至2009年7月）、主要胃肠病学会议的摘要以及已发表文章和综述中的参考文献来选择研究。还检索了Cochrane试验注册库和炎症性肠病综述组试验注册库。使用MEDLINE、EMBASE和国际药学文摘数据库以及Cochrane对照试验注册库和Cochrane IBD/FBD组专门试验注册库对该检索策略进行了更新。
纳入涉及成年患者（>18岁）活动性克罗恩病的口服硫唑嘌呤或6-巯基嘌呤的随机、双盲、安慰剂对照试验。
由三名独立观察者根据意向性治疗原则提取数据。根据预定标准为每项研究给出质量评分。提取的数据转换为2×2表格（缓解与未缓解以及抗代谢物与安慰剂），然后使用Cochran、Mantel和Haenszel描述的合并比值比和95%置信区间将其综合为汇总检验统计量。
确定了八项关于硫唑嘌呤和6-巯基嘌呤治疗成年患者的随机安慰剂对照试验：五项涉及活动性疾病，三项有多个治疗组。在活动性克罗恩病中，与安慰剂相比，硫唑嘌呤或6-巯基嘌呤治疗缓解的比值比（OR）为2.43（95%CI 1.62至3.64）。这相当于约5名患者中需要治疗1名才能观察到治疗效果的治疗人数（NNT）。当在分析中排除两项使用6-巯基嘌呤治疗活动性疾病的试验时，OR为2.06（95%CI 1.25至3.39）。治疗>17周时，OR增加至2.61（95%CI 1.69至4.03）。观察到激素节省效应，OR为3.69（95%CI 2.12 - 6.42），相当于约3名患者中需要治疗1名才能观察到激素节省效应的NNT。因主要为过敏、白细胞减少、胰腺炎和恶心等不良事件而退出试验的情况在积极治疗组中增加，比值比为3.44（95%CI 1.52至7.77）。在接受硫唑嘌呤或6-巯基嘌呤治疗的患者中，观察到1例不良事件的NNT为14。
硫唑嘌呤和6-巯基嘌呤是诱导活动性克罗恩病缓解的有效疗法。治疗>17周后缓解的OR增加，表明硫唑嘌呤或6-巯基嘌呤治疗试验有一个最短时间长度。不良事件在积极治疗的患者中更常见。
