刘鑫 钟小燕 李梦雅 徐昌静 付礼亚 田冬梅 黄毅岚

摘 要 目的：系統评价4种降钙素基因相关肽（CGRP）单克隆抗体预防性治疗偏头痛的疗效和安全性，为临床治疗提供循证参考。方法：计算机检索Cochrane图书馆、PubMed、Embase、中国期刊全文数据库、维普网和万方数据等，收集4种CGRP单克隆抗体（试验组）对比安慰剂（对照组）预防性治疗偏头痛的随机对照试验（RCT）。筛选文献并提取资料后，采用Cochrane系统评价员手册5.1.0提供的偏倚风险评估工具对纳入文献质量进行评价，采用GeMTC 0.14.3软件和Stata 16.0软件进行贝叶斯网状Meta分析。结果：共纳入19项RCT，共计11 392例患者，涉及Erenumab 70、140 mg/月，Fremanezumab 675 mg/3月、225 mg/月，Galcanezumab 120、240、300 mg/月，Eptinezumab 100、300 mg/3月和安慰剂等10种干预措施。Meta分析结果显示，与对照组比较，4种GGRP单克隆抗体均可显著减少患者每月平均偏头痛天数较基线的变化（MMD）（P<0.05）;各试验组之间，与Galcanezumab 300 mg/月[MD=-1.30，95%CI（-2.59，-0.05），P<0.05]、Eptinezumab 100 mg/3月[MD=-1.18，95%CI（-2.26，-0.03），P<0.05]比较，Fremanezumab 225 mg/月可显著减少患者MMD;网状Meta排序结果为Fremanezumab 225 mg/月>Fremanezumab 675 mg/3月>Galcanezumab 120 mg/月>Erenumab 140 mg/月>Galcanezumab 240 mg/月>Eptinezumab 300 mg/3月>Erenumab 70 mg/月>Eptinezumab 100 mg/3月>Galcanezumab 300 mg/月>安慰剂。与对照组比较，4种GGRP单克隆抗体均可显著增加每月平均偏头痛天数较基线减少≥50%的患者比例（MMD 50）（P<0.05）;各试验组之间，与Eptinezumab 100 mg/3月组比较，Fremanezumab 675 mg/3月[OR=1.51，95%CI（1.02，2.31），P<0.05]、Fremanezumab 225 mg/月[OR=1.58，95%CI（1.05，2.44），P<0.05]组的MMD 50均显著升高;网状Meta排序结果为Fremanezumab 225 mg/月>Fremanezumab 675 mg/3月>Erenumab 140 mg/月>Galcanezumab 120 mg/月>Eptinezumab 300 mg/3月>Galcanezumab 240 mg/月>Erenumab 70 mg/月>Galcanezumab 300 mg/月>Eptinezumab 100 mg/3月>安慰剂。安全性方面，Fremanezumab 675 mg/3月[OR=1.31，95%CI（1.05，1.64），P<0.05]、Galcanezumab 240 mg/月[OR=1.39，95%CI（1.09，1.74），P<0.05]组患者的总不良反应发生率（AE）均显著高于对照组;各试验组之间，与Galcanezumab 240 mg/月组比较，Erenumab 70 mg/月[OR=0.67，95%CI（0.50，0.93），P<0.05]、140 mg/月[OR=0.70，95%CI（0.51，0.98），P<0.05]组患者的AE均显著降低;与Fremanezumab 675 mg/3月组比较，Erenumab 70 mg/月[OR=0.72，95%CI（0.52，0.98），P<0.05]组患者的AE显著降低;网状Meta排序结果为Galcanezumab 240 mg/月>Fremanezumab 675 mg/3月>Galcanezumab 120 mg/月>Galcanezumab 300 mg/月>Eptinezumab 300 mg/3月>Fremanezumab 225 mg/月>Eptinezumab 100 mg/3月>安慰剂>Erenumab 140 mg/月>Erenumab 70 mg/月。结论：4种CGRP单克隆抗体均能预防性治疗偏头痛，其中Fremanezumab 225 mg/月的疗效可能最佳，Erenumab 70 mg/月的安全性可能最高。

关键词 降钙素基因相关肽单克隆抗体;预防性治疗;偏头痛;贝叶斯网状Meta分析;疗效;安全性

中图分类号 R971 文献标志码 A 文章编号 1001-0408（2020）18-2275-08

DOI 10.6039/j.issn.1001-0408.2020.18.18

ABSTRACT   OBJECTIVE： To systematically evaluate the efficacy and safety of 4 kinds of calcitonin gene-related peptide （CGRP） monoclonal antibodies in the preventive treatment of migraine， and to provide evidence-based reference for the clinical treatment of migraine. METHODS： Retrieved from the Cochrane Library， PubMed， Embase， CJFD， VIP and Wanfang database， RCTs about 4 kinds of CGRP monoclonal antibodies （trial group） versus placebo （control group） in the preventive treatment of migraine were collected. After literature screening and data extraction， the quality evaluation of included literature was performed by using the bias risk assessment tool provided by the Cochrane system evaluator manual 5.1.0. Bayesian network Meta-analysis was performed by using GeMTC 0.14.3 software and Stata 16.0 software. RESULTS： A total of 19 RCTs involving 11 392 patients were included， involving 10 interventions， such as Erenumab 70， 140 mg/month; Fremanezumab 675 mg/3 months， 225 mg/month; Galcanezumab 120， 240， 300 mg/month; Eptinezumab 100 mg/3 months， 300 mg/3 months and placebo. Results of Meta-analysis showed that compared with control group， 4 kinds of CGRP monoclonal antibodies significantly reduced the change of mean monthly migraine days （MMD） （P<0.05）. Among trial groups， compared with Galcanezumab 300 mg/month [MD=-1.30， 95%CI（-2.59， -0.05）， P<0.05] and Eptinezumab 100 mg/3 months [MD=-1.18， 95%CI（-2.26， -0.03）， P<0.05]， Fremanezumab 225 mg/month could significantly reduce MMD. Network Meta-analysis ranking showed that Fremanezumab 225 mg/month>Fremanezumab 675 mg/3 months>Galcanezumab 120 mg/month>Erenumab 140 mg/month>Galcanezumab 240 mg/month>Eptinezumab 300 mg/3 months>Erenumab 70 mg/month>Eptinezumab 100 mg/3 months>Galcanezumab 300 mg/month>placebo. Compared with control group， 4 kinds of CGRP monoclonal antibodies were significantly increased of the proportion of patients whose mean monthly migraine days reduction≥50% compared with baseline （MMD 50） （P<0.05）. Among trial groups， compared with Eptinezumab 100 mg/3 months group， MMD 50 of Fremanezumab 675 mg/3 months group [OR=1.51， 95%CI（1.02， 2.31）， P<0.05]， Fremanezumab 225 mg/month group [OR=1.58， 95%CI（1.05， 2.44）， P<0.05] were increased significantly. Network Meta-analysis ranking showed that Fremanezumab 225 mg/month>Fremanezumab 675 mg/3 months>Erenumab 140 mg/month>Galcanezumab 120 mg/month>Eptinezumab 300 mg/3 months>Galcanezumab 240 mg/month>Erenumab 70 mg/month>Galcanezumab 300 mg/month>Eptinezumab 100 mg/3 months>placebo. In terms of safety， incidence of total adverse events （AE） of trial groups receiving Fremanezumab 675 mg/3 months [OR=1.31， 95%CI（1.05， 1.64）， P<0.05]， Galcanezumab 240 mg/month [OR=1.39， 95%CI（1.09， 1.74）， P<0.05] were significantly higher than control group. Among trial groups， compared with Galcanezumab 240 mg/month group， AE of Erenumab 70 mg/month group [OR=0.67， 95%CI（0.50， 0.93）， P<0.05]， Erenumab 140 mg/month group [OR=0.70， 95%CI（0.51， 0.98）， P<0.05] were decreased significantly. Compared with Fremanezumab 675 mg/3 months group， AE of Erenumab 70 mg/month group [OR=0.72， 95%CI（0.52， 0.98）， P<0.05] were decreased significantly. Network Meta-analysis ranking showed that Galcanezumab 240 mg/month> Fremanezumab 675 mg/3 months>Galcanezumab 120 mg/month>Galcanezumab 300 mg/month>Eptinezumab 300 mg/3 months>Fremanezumab 225 mg/month>Eptinezumab 100 mg/3 months>placebo>Erenumab 140 mg/month>Erenumab 70 mg/month. CONCLUSIONS： Four kinds of CGRP monoclonal antibodies are effective in the preventive treatment of migraine， among which Fremanezumab 225 mg/month is most likely to have the best efficacy and Erenumab 70 mg/month is most likely to have the highest safety.

KEYWORDS   Calcitonin gene-related peptide monoclonal antibodies; Preventive treatment;Migraine; Bayesian network Meta-analysis; Efficacy; Safety

偏头痛是一种以反复发作的偏侧搏动性头痛为特征的原发性、致残性神经系统疾病，其在世界范围内的发病率约为14.7%，在我国的发病率约为9.3%，且女性显著高于男性[1-3]。偏头痛的治疗主要分为急性期治疗和预防性治疗，其中预防性治疗的目的是降低偏头痛发作的频率、严重程度，缩短持续时间[1，4]。目前，临床上用于预防性治疗偏头痛的药物主要有β受体阻滞药（如普萘洛尔、美托洛尔）、抗癫痫药（如丙……