吡非尼酮治疗特发性肺间质纤维化安全性Meta分析

Safety of pirfenidone in treatment of idiopathic pulmonary fibrosis：a Meta-analysis

目的：评价吡非尼酮治疗特发性肺间质纤维化（ IPF）的安全性。方法以“吡非尼酮”“特发性肺间质纤维化”“pirfenidone”“idiopathic pulmonary fibrosis”“IPF”为关键词，检索PubMed、Cochrane图书馆、EMbase、中国知网、万方数据库（1999年1月至2015年1月），筛选吡非尼酮治疗IPF的随机对照试验（ RCT）。试验组单独口服吡非尼酮，对照组口服安慰剂。结局指标主要终点事件是吡非尼酮不良反应发生率。使用RevMan 5.2软件进行Meta分析。结果最终纳入4篇文献，包括5项RCT，试验组945例，对照组766例。试验组多种不良反应发生率明显高于对照组，包括胃肠不适[12.6%（101/804）比5.2%（40/766），RR=2.31，95%CI为1.63~3.29，P〈0.01]、恶心[34.6%（241/695）比15.0%（99/659），RR=2.373，95%CI为1.92~2.92，P〈0.01]、呕吐[13.3%（83/623）比6.3%（39/624），RR=2.13，95%CI为1.48~3.06，P〈0.01]、腹泻[25.8%（161/623）比20.4%（127/624），RR=1.27，95%CI 为1.03~1.56，P =0.02]、厌食[15.2%（122/804）比4.7%（36/766），RR=3.10，95%CI 为2.16~4.46，P 〈0.01]、肝功能异常[6.0%（49/804）比1.7%（13/766），RR=2.48，95%CI为1.46~4.23，P〈0.01]、皮疹[30.4%（189/623）比10.3%（64/624） RR=2.95，95%CI为2.27~3.83，P 〈0.01，]、光敏性反应[24.7%（129/526）比6.1%（30/489）， RR=5.54，95%CI为1.78~17.30，P〈0.01]、失眠[10.4%（65/623）比6.6%（41/624），RR=1.59，95%CI为1.09~2.31，P〈0.01]、头晕[16.4%（120/732）比9.8%（72/731），RR=1.67，95%CI为1.27~2.19，P〈0.01]、疲劳[25.6%（178/695）比16.3%（108/659），RR=1.60，95%CI 为1.29~1.98，P〈0.01]和体重下降[10.1%（63/623）比5.4%（34/624），RR=1.85，95%CI为1.24~2.77， P=0.03]。而吡非尼酮治疗相关严重不良反应差异无统计学意义[26.5%（165/623）比26.4%（165/624），RR=1.00，95%CI为0.83~1.20，P=0.94]。与对照组比较，试验组停药发生率较高，差异有统计学意义[14.6%（117/804）比9.0%（69/766），RR=1.62，95%CI为1.22~2.15，P〈0.01]。结论吡非尼酮以胃肠道、皮肤、神经系统损伤，以及疲劳和体重下降等常见。不良反应轻微，多可恢复，无明显后遗症。吡非尼酮安全性及耐受性相对良好。

Objective To evaluate the safety of pirfenidone in treatment of idiopathic pulmonary fibrosis（ IPF）. Methods PubMed,the Cochrane library,EMbase,CNKI,and WanFang database were searched using the keywords pirfenidone,idiopathic pulmonary fibrosis,and IPF from January 1999 to January 2015. Randomized controlled trials（ RCTs）of pirfenidone in treatment of IPF were selected. The patients in the trial group were given pirfenidone alone while the patients in the control group were given oral placebo. The primary end point event of the outcome was the incidence of pirfenidone′s adverse events. The Meta-analysis was performed using RevMan 5. 2. Results A total of 4 articles including 5 RCTs were enrolled. There were 945 patients in the trial group and 766 patients in the control group. The incidents of many kinds of adverse events in the trial group were markedly higher than those in the control group, including gastrointestinal discomfort[12. 6%（101/804）vs. 5. 2%（40/766）,RR = 2. 31,95% CI：63-3. 29,P〈 0. 01],nausea[34. 6%（241/695）vs. 15. 0%（99/659）,RR = 2. 373,95% CI：1. 92-2. 92,P〈 0. 01]and vomiting[13. 3%（83/623）vs. 6. 3%（39/624）,RR= 2. 13,95% CI：1. 48-3. 06,P〈 0. 01],diarrhea[25. 8%（161/623）vs. 20. 4%（127/624）,RR= 1. 27,95% CI：1. 03-1. 56,P=0. 02],anorexia[15. 2%（122/804）vs. 4. 7%（36/766）,RR= 3. 10,95% CI：2. 16-4. 46,P〈0. 01],abnormal liver function[6. 0%（49/804）vs. 1. 7%（13/766）,RR= 2. 48,95% CI：1. 46-4. 23,P〈0. 01],rash[30. 4%（189/623）vs. 10. 3%（64/624）,RR= 2. 95,95% CI：2. 27-3. 83,P〈0. 01],photosensitivity reaction[24. 7%（129/526）vs. 6. 1%（30/489）,RR= 5. 54,95%CI：1. 78-17. 30,P〈0. 01],insomnia[10. 4%（65/623）vs. 6. 6%（41/624）,RR=1. 59,95% CI：1. 09-2. 31,P= 0. 02],dizziness[16. 4%（120/732）vs. 9. 8%（72/731）,RR=1. 67,95% CI：1. 27-2. 19,P〈0. 01],fatigue[25. 6%（178/695）vs. 16. 3%（108/659）,RR = 1. 60,95% CI：1. 29-1. 98,P〈 0. 01],and weight loss[10. 1%（63/623）vs. 5. 4%（34/624）,RR= 1. 85,95% CI：1. 24-2. 77,P = 0. 03]. However,there was no statistically significant difference in treatment-related serious events[26. 5%（165/623）vs. 26. 4%（165/624）,RR = 1. 00,95% CI：0. 83-1. 20,P = 0. 94]. Compared with the control group,there was a statistical significance in the rate of drug withdrawal in the trial group[14. 6%（ 117/804 ） vs. 9. 0%（ 69/766 ）,RR = 1. 62,95% CI：1. 22-2. 15,P 〈0. 01 ）. Conclusion The common adverse events of pirfenidone are gastrointestinal,skin,and neurological system damage and fatigue and loss of weight. The adverse events are mild and mostly recoverable without obvious sequelae. The pirfenidone is safe and well-tolerated.