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Article(id=1241768182118154697, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.05.13, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1703779200000, receivedDateStr=2023-12-29, revisedDate=null, revisedDateStr=null, acceptedDate=1708876800000, acceptedDateStr=2024-02-26, onlineDate=1773990205554, onlineDateStr=2026-03-20, pubDate=1716566400000, pubDateStr=2024-05-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773990205554, onlineIssueDateStr=2026-03-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773990205554, creator=13701087609, updateTime=1773990205554, updator=13701087609, issue=Issue{id=1241768176522957402, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='5', pageStart='321', pageEnd='400', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773990204220, creator=13701087609, updateTime=1773992176593, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241776449330414547, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241776449330414548, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=387, endPage=393, ext={EN=ArticleExt(id=1241768182583722451, articleId=1241768182118154697, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Efficacy and safety of six drugs for preventing acute attack of hereditary angioedema:a network meta-analysis, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To synthesize the available clinical evidence to evaluate the efficacy and safety of lanadelumab,avoralstat, berotralstat, garadacimab, donidalorsen and plasma-derived C1-esterase inhibitor for preventing the acute attack of hereditary angioedema （HAE） using network meta-analysis.

METHODS

PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, and VIP databases were searched for randomized controlled trials that evaluated the efficacy and safety of these six drugs in the prevention of the acute attack of HAE from the establishment of the library to January 2024. A network meta-analysis （NMA） was performed by Stata 17.0 and R 4.3.2.

RESULTS

A total of 10 randomized controlled trials fulfilling the inclusion criteria were retrieved, including 619 patients. NMA showed that five kinds of drugs were superior to placebo in reducing the number of acute HAE attacks every 4 weeks （P<0.05）. The surface under the cumulative ranking sorting results showed that garadacimab was the most efficacious （MD=2.59, 95%CI: 1.38 to 3.79）. For the comparison between placebo and these drugs, there were no significant differences in the incidence of adverse events and serious adverse events. The SUCRA indicated that lanadelumab had the lowest incidence of adverse events and donidalorsen had the lowest incidence of serious adverse events.

CONCLUSION

Garadacimab is the most effective drug of all these first-line agents used to prevent acute attacks of HAE, while lanadelumab has better safety.

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目的

综合评价拉那利尤单抗（lanadelumab）、阿伏司他（avoralstat）、贝罗司他（berotralstat）、加达西单抗（garadacimab）、多尼达洛森（donidalorsen）和血源性C1酯酶抑制剂（pdC1-INH）6种药物预防遗传性血管性水肿（HAE）急性发作的有效性及安全性。

方法

检索PubMed、Cochrane Library、Embase、Web of Science、中国知网、万方和维普从建库到2024年1月所有关于上述6种药物预防HAE急性发作的文献，在Stata 17.0和R 4.3.2软件中进行网状Meta分析。

结果

共纳入10项随机对照试验，HAE患者619例。网状Meta分析结果显示，在减少患者每4周HAE发作次数方面，有5种药物与安慰剂比较有显著差异（P<0.05），累积排序概率显示加达西单抗疗效最佳（MD=2.59,95%CI: 1.38~3.79）；在不良事件发生率与严重不良事件发生率方面，所有治疗药物与安慰剂相比无显著差异 （P>0.05）；累积排序概率显示拉那利尤单抗不良事件发生率最低，多尼达洛森严重不良事件发生率最低。

结论

预防HAE急性发作的6种药物中，加达西单抗疗效最好，拉那利尤单抗安全性较好。

, correspAuthors=null, authorNote=null, correspAuthorsNote=
胡丹丹
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杨明熹，男，本科在读，主要从事免疫与过敏性疾病的研究，E-mail: 。

胡丹丹，女，主任医师，博士，主要从事儿童保健及儿童神经系统疾病的研究，E-mail:

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A：每4周遗传性血管性水肿发作次数，B：不良事件发生率，C：严重不良事件发生率，a：安慰剂，b：拉那利尤单抗，c：阿伏司他，d：贝罗司他，e：加达西单抗，f：多尼达洛森，g：pdC1-INH。每个端点代表一种干预措施，其直径的大小代表该干预组的总例数；两个端点之间的线段代表此两种干预措施之间存在直接头对头比较，直线的粗细代表两者直接头对头比较研究的数量

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A:每4周遗传性血管性水肿发作次数，B：不良事件发生率，C：严重不良事件发生率

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A：治疗期间每4周遗传性血管性水肿发作次数, B：不良事件发生率, C：严重不良事件发生率，a：安慰剂，b：拉那利尤单抗，c：阿伏司他，d：贝罗司他，e：加达西单抗，f：多尼达洛森，g：pdC1-INH。

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研究分配隐藏测量偏倚随访偏倚其他偏倚
BANERJI 2017［10］UnclearUnclearLowUnclear
BANERJI 2018［11］LowLowLowUnclear
RIEDL 2018［12］UnclearLowLowUnclear
AYGOREN-PURSUN 2018［13］UnclearLowLowUnclear
ZURAW 2021［14］LowUnclearLowUnclear
OHSAWA 2021［15］LowLowLowUnclear
CRAIG 2023［16］LowLowLowUnclear
CRAIG 2022［17］LowUnclearLowUnclear
FIJEN 2022［18］UnclearLowLowUnclear
ZURAW 2010［19］UnclearUnclearUnclearUnclear
), ArticleFig(id=1241768194575237915, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241768182118154697, language=CN, label=表1, caption=

纳入研究的偏倚风险评估结果

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研究分配隐藏测量偏倚随访偏倚其他偏倚
BANERJI 2017［10］UnclearUnclearLowUnclear
BANERJI 2018［11］LowLowLowUnclear
RIEDL 2018［12］UnclearLowLowUnclear
AYGOREN-PURSUN 2018［13］UnclearLowLowUnclear
ZURAW 2021［14］LowUnclearLowUnclear
OHSAWA 2021［15］LowLowLowUnclear
CRAIG 2023［16］LowLowLowUnclear
CRAIG 2022［17］LowUnclearLowUnclear
FIJEN 2022［18］UnclearLowLowUnclear
ZURAW 2010［19］UnclearUnclearUnclearUnclear
), ArticleFig(id=1241768194701067039, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241768182118154697, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
研究组别例数年龄/岁性别（男/女）/例基线发作次数/次·年-1干预措施干预方法疗程/周
BANERJI 2017［10］对照1341.2±13.76/722.7±35.9安慰剂皮下注射18
试验1638.2±13.26/1028.8±33.8拉那利尤单抗皮下注射18
BANERJI 2018［11］对照4140.1±16.87/3448.0±39.6安慰剂皮下注射26
试验8441.1±13.330/5441.6±26.5拉那利尤单抗皮下注射26
RIEDL 2018［12］对照3642.1±12.510/26NA安慰剂口服12
试验7440.8±13.815/59NA阿伏司他口服12
AYGOREN-PURSUN 2018［13］对照2346.6±10.910/1345.2±23.4安慰剂口服4
试验5443.1±13.320/3447.5±20.4贝罗司他口服4
ZURAW 2021［14］对照4044.5±14.113/2734.9±13.4安慰剂口服24
试验8140.2±15.828/5336.2±17.4贝罗司他口服24
OHSAWA 2021［15］对照642.3±13.51/530.0±18.0安慰剂口服24
试验1341.9±12.72/1126.2±14.0贝罗司他口服24
CRAIG 2023［16］对照2537.8±12.811/1437.2±17.2安慰剂皮下注射24
试验3943.3±17.515/2434.4±13.6加达西单抗皮下注射24
CRAIG 2022［17］对照844.0±18.94/4NA安慰剂皮下注射12
试验2438.4±13.510/14NA加达西单抗皮下注射12
FIJEN 2022［18］对照640.0±13.82/425.3±22.9安慰剂皮下注射17
试验1437.8±14.45/923.1±16.2多尼达洛森皮下注射17
ZURAW 2010［19］对照a1134.5±14.80/11NA安慰剂静脉注射12
试验a1141.7±19.32/9NApdC1-INH静脉注射12
), ArticleFig(id=1241768194852061989, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241768182118154697, language=CN, label=表2, caption=

纳入文献基本信息

, figureFileSmall=null, figureFileBig=null, tableContent=
研究组别例数年龄/岁性别（男/女）/例基线发作次数/次·年-1干预措施干预方法疗程/周
BANERJI 2017［10］对照1341.2±13.76/722.7±35.9安慰剂皮下注射18
试验1638.2±13.26/1028.8±33.8拉那利尤单抗皮下注射18
BANERJI 2018［11］对照4140.1±16.87/3448.0±39.6安慰剂皮下注射26
试验8441.1±13.330/5441.6±26.5拉那利尤单抗皮下注射26
RIEDL 2018［12］对照3642.1±12.510/26NA安慰剂口服12
试验7440.8±13.815/59NA阿伏司他口服12
AYGOREN-PURSUN 2018［13］对照2346.6±10.910/1345.2±23.4安慰剂口服4
试验5443.1±13.320/3447.5±20.4贝罗司他口服4
ZURAW 2021［14］对照4044.5±14.113/2734.9±13.4安慰剂口服24
试验8140.2±15.828/5336.2±17.4贝罗司他口服24
OHSAWA 2021［15］对照642.3±13.51/530.0±18.0安慰剂口服24
试验1341.9±12.72/1126.2±14.0贝罗司他口服24
CRAIG 2023［16］对照2537.8±12.811/1437.2±17.2安慰剂皮下注射24
试验3943.3±17.515/2434.4±13.6加达西单抗皮下注射24
CRAIG 2022［17］对照844.0±18.94/4NA安慰剂皮下注射12
试验2438.4±13.510/14NA加达西单抗皮下注射12
FIJEN 2022［18］对照640.0±13.82/425.3±22.9安慰剂皮下注射17
试验1437.8±14.45/923.1±16.2多尼达洛森皮下注射17
ZURAW 2010［19］对照a1134.5±14.80/11NA安慰剂静脉注射12
试验a1141.7±19.32/9NApdC1-INH静脉注射12
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6种药物预防遗传性血管性水肿急性发作有效性及安全性的网状Meta分析
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杨明熹 1 , 陈汝治 2 , 肖子劲 3 , 陈一君 4 , 胡丹丹 3
中国新药与临床杂志 | 论著 2024,43(5): 387-393
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中国新药与临床杂志 | 论著 2024, 43(5): 387-393
6种药物预防遗传性血管性水肿急性发作有效性及安全性的网状Meta分析
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杨明熹1 , 陈汝治2, 肖子劲3, 陈一君4, 胡丹丹3
作者信息
  • 1.广州医科大学第一临床学院，广东　广州　511436
  • 2.广州医科大学第二临床学院，广东　广州　510260
  • 3.广州医科大学附属妇女儿童医疗中心，广东　广州　510620
  • 4.广州医科大学附属第一医院，广东　广州　510120

    • 杨明熹，男，本科在读，主要从事免疫与过敏性疾病的研究，E-mail: 。

    胡丹丹，女，主任医师，博士，主要从事儿童保健及儿童神经系统疾病的研究，E-mail:

通讯作者:

胡丹丹
Efficacy and safety of six drugs for preventing acute attack of hereditary angioedema:a network meta-analysis
Ming-xi YANG1 , Ru-zhi CHEN2, Zi-jin XIAO3, Yi-jun CHEN4, Dan-dan HU3
Affiliations
  • 1.The First Clinical College of Guangzhou Medical University, Guangzhou GUANGDONG 511436, China
  • 2.The Second Clinical College of Guangzhou Medical University, Guangzhou GUANGDONG 510260, China
  • 3.Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou GUANGDONG 510620, China
  • 4.The First Affiliated Hospital of Guangzhou Medical University, Guangzhou GUANGDONG 510120, China
出版时间: 2024-05-25 doi: 10.14109/j.cnki.xyylc.2024.05.13
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摘要
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目的

综合评价拉那利尤单抗（lanadelumab）、阿伏司他（avoralstat）、贝罗司他（berotralstat）、加达西单抗（garadacimab）、多尼达洛森（donidalorsen）和血源性C1酯酶抑制剂（pdC1-INH）6种药物预防遗传性血管性水肿（HAE）急性发作的有效性及安全性。

方法

检索PubMed、Cochrane Library、Embase、Web of Science、中国知网、万方和维普从建库到2024年1月所有关于上述6种药物预防HAE急性发作的文献，在Stata 17.0和R 4.3.2软件中进行网状Meta分析。

结果

共纳入10项随机对照试验，HAE患者619例。网状Meta分析结果显示，在减少患者每4周HAE发作次数方面，有5种药物与安慰剂比较有显著差异（P<0.05），累积排序概率显示加达西单抗疗效最佳（MD=2.59,95%CI: 1.38~3.79）；在不良事件发生率与严重不良事件发生率方面，所有治疗药物与安慰剂相比无显著差异 （P>0.05）；累积排序概率显示拉那利尤单抗不良事件发生率最低，多尼达洛森严重不良事件发生率最低。

结论

预防HAE急性发作的6种药物中，加达西单抗疗效最好，拉那利尤单抗安全性较好。

血管水肿，遗传性  /  药物疗法  /  网状Meta分析
AIM

To synthesize the available clinical evidence to evaluate the efficacy and safety of lanadelumab,avoralstat, berotralstat, garadacimab, donidalorsen and plasma-derived C1-esterase inhibitor for preventing the acute attack of hereditary angioedema （HAE） using network meta-analysis.

METHODS

PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, and VIP databases were searched for randomized controlled trials that evaluated the efficacy and safety of these six drugs in the prevention of the acute attack of HAE from the establishment of the library to January 2024. A network meta-analysis （NMA） was performed by Stata 17.0 and R 4.3.2.

RESULTS

A total of 10 randomized controlled trials fulfilling the inclusion criteria were retrieved, including 619 patients. NMA showed that five kinds of drugs were superior to placebo in reducing the number of acute HAE attacks every 4 weeks （P<0.05）. The surface under the cumulative ranking sorting results showed that garadacimab was the most efficacious （MD=2.59, 95%CI: 1.38 to 3.79）. For the comparison between placebo and these drugs, there were no significant differences in the incidence of adverse events and serious adverse events. The SUCRA indicated that lanadelumab had the lowest incidence of adverse events and donidalorsen had the lowest incidence of serious adverse events.

CONCLUSION

Garadacimab is the most effective drug of all these first-line agents used to prevent acute attacks of HAE, while lanadelumab has better safety.

angioedemas, hereditary  /  drug therapy  /  network meta-analysis
杨明熹, 陈汝治, 肖子劲, 陈一君, 胡丹丹. 6种药物预防遗传性血管性水肿急性发作有效性及安全性的网状Meta分析. 中国新药与临床杂志, 2024 , 43 (5) : 387 -393 . DOI: 10.14109/j.cnki.xyylc.2024.05.13
Ming-xi YANG, Ru-zhi CHEN, Zi-jin XIAO, Yi-jun CHEN, Dan-dan HU. Efficacy and safety of six drugs for preventing acute attack of hereditary angioedema:a network meta-analysis[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (5) : 387 -393 . DOI: 10.14109/j.cnki.xyylc.2024.05.13
正文
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遗传性血管性水肿（hereditary angioedema，HAE）是一种常染色体显性遗传的罕见病，系因SERPING1基因突变导致血浆C1酯酶抑制剂（C1 esterase inhibitor, C1-INH）蛋白缺乏或功能降低引起［1, 2］。HAE临床表现为难以预测且反复发作的皮肤黏膜血管性水肿，累及部位常见于面部、四肢、生殖器、胃肠道及上呼吸道，近30%的HAE患者在其一生中至少会经历一次潜在致命的喉头水肿发作，严重者危及生命。HAE急性发作累及胃肠道黏膜，可表现为剧烈腹痛，伴恶心、呕吐，与急腹症很难鉴别，导致部分患者接受不必要的腹部手术。流行病学调查显示，全球范围内每一万至五万人中会有一人患有HAE，且在这些患者中，未能得到及时诊断和恰当治疗的喉头水肿发作引发窒息的病例死亡率高达30%~50%，因此预防HAE急性发作是降低其死亡率的关键［3-6］。近年随着对HAE分子病理机制的深入研究，新型精准靶向治疗药物接连出现，主要有拉那利尤单抗（lanadelumab）、阿伏司他（avoralstat）、贝罗司他（berotralstat）、加达西单抗（garadacimab）、多尼达洛森（donidalorsen）、血源性C1酯酶抑制剂（pdC1-INH）等，上述药物虽然作用靶点不同，但均对预防HAE急性发作具有较好的临床疗效。本研究拟通过网状Meta分析对上述6种药物预防HAE急性发作的有效性与安全性进行头对头比较，以期遴选出预防性治疗HAE急性发作的最佳药物，为临床治疗决策提供循证医学依据。
资料与方法
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检索策略
首先以遗传性血管性水肿与hereditary angioedema为关键词，检索clinicaltrials.gov、WHO Inter-national Clinical Trials Registry Platform、EU Clinical Trials Register及UpToDate等临床试验注册平台与循证医学数据库并查阅相关指南，确定目前预防性治疗HAE急性发作的药物种类与名称。随后将遗传性血管性水肿、拉那利尤单抗、阿伏司他、贝罗司他、加达西单抗、多尼达洛森、血源性C1-INH、随机对照试验等作为中文检索词；将hereditary angioedema、lanadelumab、avoralstat、berotralstat、garadacimab、donidalorsen、pdC1-INH、randomized controlled trial等作为英文检索词；检索 PubMed、Cochrane Library、Embase、Web of Science、中国知网、万方、维普等数据库以及上述临床试验注册平台，检索时限从建库至2024年1月。
文献纳入及排除标准
1　研究类型
随机对照试验（randomized controlled trial，RCT），语种不限。
2　研究对象
纳入符合HAE诊断标准的患者且受试 者的性别、年龄、国籍、种族、病程不限。
3　干预措施
试验组应用拉那利尤单抗、阿伏司他、贝罗司他、加达西单抗、多尼达洛森、pdC1-INH；对照组应用安慰剂。
4　结局指标
药物有效性结局指标为治疗期间每4周HAE发作次数；药物安全性结局指标为治疗期间不良事件与严重不良事件发生率。
5　排除标准
（1）综述或Meta分析；（2）动物实验；（3）非随机对照试验；（4）治疗HAE急性发作的文献；（5）无法获得数据且联系作者无果的文献。
文献筛选和数据提取
利用EndnoteX9软件查找并删除重复文献，随后由两名研究者独立纳排文献、提取数据及相互核对，若遇分歧则由两人相互讨论、解决。从研究中提取的信息包括： （1）研究的基本信息；（2）患者的基线情况；（3）对照组和试验组的干预措施；（4）主要结局指标。
文献质量评价
根据Cochrane偏倚风险评估工具［7］的各项规则与条目，两位研究者独立评估所有纳入文献的质量，评价内容包括：（1）是否进行了随机化分组；（2）是否在分组时进行了分配隐藏；（3）是否对医患双方实施了盲法；（4）是否对结局评估者实施了盲法；（5）是否存在数据不完整；（6）是否选择性地报告试验数据；（7）是否有其他偏倚。
统计学分析
数据分析基于贝叶斯模型的网状Meta分析方法学，通过R 4.3.2软件的Gemtc程序包调用JAGS软件在一致性模型下完成。治疗期间每4周HAE的发作次数以均数差（mean difference，MD）及95%置信区间（CI）表示，不良事件发生率和严重不良事件发生率以比值比（odds ratio，OR）及95%CI表示。用JAGS软件绘制 Brooks-Gelman-Rubin诊断图判断模型收敛情况。网状Meta结局指标的全局不一致性检验则分别在不一致性模型和一致性模型下计算误差信息准则（DIC）并进行比较。网络关系图和各个结局指标的累积排序概率图下面积值（SUCRA）通过STATA 17.0软件获得。在JAGS软件中计算I2评价模型的异质性并设置I2=50%为临界值，若I2>50%，则表明异质性较大，需通过敏感性分析探究异质性来源。发表偏倚的检验则通过绘制漏斗图进行［8, 9］。
结 果
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文献筛选结果
检索得到相关文献433篇，去重后得到298篇。最后得到10篇符合纳排标准的文献［10-19］。具体检索流程图见图1。
纳入文献的特征与质量评价
纳入的10项研究均为随机双盲试验，其中5项研究报告了分配隐藏的方法，9项研究对失访退出情况进行了说明或进行了意向性分析。各研究随机化、实施偏倚、报告偏倚均为低风险，其他偏倚来源不明。详细的文献偏倚风险结果见表1。
纳入研究的基本信息
在纳入的10项研究中，拉那利尤单抗2项［10,11］，阿伏司他1项［12］，贝罗司他3项［13-15］，加达西单抗2项［16,17］，多尼达洛森1项［18］，pdC1-INH 1项［19］，患者共计619例，10项研究结果发表年份从2010年至2023年。各研究中试验组与对照组的各项基线数据如年龄、性别比例等均衡可比，基本信息见表2。
有效性指标
10项研究均报道了治疗期间每4周HAE发作次数，网状图见图2A，Brooks-Gelman-Rubin诊断图提示模型收敛程度正常。每4周HAE发作次数指标在一致性模型下DIC值为40.04，在不一致性模型下DIC值为40.09。该指标在两种模型中DIC值的差值小于5，提示指标一致性良好，故采用一致性模型进行分析。在一致性模型中检验其异质性，I2为7%，提示异质性较小，故无需进行敏感性分析。
与安慰剂相比，使用加达西单抗（MD=2.59, 95%CI:1.38~3.79）、pdC1-INH（MD=2.13, 95%CI: 0.44~3.82）、多尼达洛森（MD=1.98, 95%CI: 0.13~3.83）、拉那利尤单抗（MD=1.39, 95%CI: 0.39~2.40）以及贝罗司他（MD=1.35, 95%CI: 0.45~2.25）治疗期间均能显著降低每4周HAE发作次数（P<0.05）；各治疗药物之间进行对比，显示加达西单抗与阿伏司他（MD=2.76,95%CI: 0.93~4.58）、pdC1-INH与阿伏司他之间存在显著差异（MD=2.30, 95%CI: 0.12~4.48）；其余各干预措施之间两两比较均无显著差异（P>0.05），见图3A。概率排序结果显示，在降低每4周HAE发病次数方面，疗效从高到低排序（SUCRA值）：加达西单抗（87.2）>pdC1-INH（73.6）>多尼达洛森（69.0）>拉那利尤单抗（51.1）>贝罗司他（49.7）>安慰剂（10.5）>阿伏司他（8.8）。
安全性指标
10项研究均报道了治疗期间不良事件与严重不良事件发生率，网状图见图2B、2C。Brooks-Gelman-Rubin诊断图显示收敛程度满意。不良事件发生率在一致性模型下DIC值为35.73，在不一致性模型下DIC值为35.61；严重不良事件发生率在一致性模型下DIC值为25.27，在不一致性模型下DIC值为25.08。上述2个指标在两种模型中DIC值的差值均小于5，提示一致性良好，故采用一致性模型进行分析。在一致性模型中检验上述2个指标的异质性，I2均小于1%，提示异质性较小，故无需进行敏感性分析。
与安慰剂比较，各治疗药物不良事件发生率无显著差异；各治疗药物之间进行比较，拉那利尤单抗不良事件发生率显著低于贝罗司他（OR=7.03, 95%CI:1.05~47.15），其余各治疗药物之间不良事件发生率无显著差异，见图3B。概率排序结果显示，安全性从高到低排序（SUCRA值）：拉那利尤单抗（81.3）>多尼达洛森（64.1）>加达西单抗（57.8）>pdC1-INH（46.9）>安慰剂（43.8）>阿伏司他（43.0）>贝罗司他（13.2）。
与安慰剂比较，各治疗药物严重不良事件发生率无显著差异；各治疗药物之间进行对比，严重不良事件发生率均无显著差异，见图3C。概率排序结果显示，安全性从高到低排序（SUCRA值）：多尼达洛森（65.4）>阿伏司他（59.2）>安慰剂（52.2）>pdC1-INH（52.1）>加达西单抗（50.0）>拉那利尤单抗（38.4）>贝罗司他（32.7）。
发表偏倚分析
治疗期间每4周HAE发作次数、不良事件发生率及严重不良事件发生率所绘制的漏斗图显示，大部分研究散点位于漏斗图上方且均匀分布于无效线两侧，提示无明显发表偏倚，见图4。
讨 论
收起
HAE的系统性治疗经历了激素治疗、化学药物治疗以及C1-INH替代治疗的转变。近年随着对HAE分子发病机制的深入研究，新型靶向生物制剂以及小分子药物不断研发上市，药物临床试验结果显示这些药物明显改善了HAE患者的预后，大多数HAE患者可实现长期临床缓解的目标。多项RCT发现各类新型靶向生物制剂以及小分子药物在预防HAE急性发作中显示出良好的有效性与安全性，但不同新型靶向生物制剂以及小分子药物之间的疗效及安全性差异仍然缺乏头对头比较。WATT等［20］首次对拉那利尤单抗、贝罗司他及pdC1-INH预防HAE急性发作的有效性展开了Meta分析，结果发现拉那利尤单抗在减少患者每4周HAE发作次数方面较贝罗司他和pdC1-INH有更显著的优势，但是该Meta分析没有对上述3种药物的安全性进行讨论。此外，该研究并未纳入近年来新研发上市的新型小分子药物（如多尼达洛森）以及生物制剂（如加达西单抗）。本研究全面纳入6种预防HAE急性发作的药物，通过网状Meta分析对其有效性及安全性进行比较。
在减少HAE每4周发作次数方面，相比于安慰剂，使用加达西单抗、pdC1-INH、多尼达洛森、拉那利尤单抗以及贝罗司他均能显著降低发作次数且使用加达西单抗效果可能最佳，推测可能因加达西单抗能直接靶向作用于HAE发病机制的上游环节，即抑制激活的凝血因子Ⅻ（FⅫa）的活性有关［21, 22］；而其他药物均作用于发病机制的中下游环节。与加达西单抗和pdC1-INH相比，阿伏司他预防HAE急性发作的疗效较差，推测可能与阿伏司他半衰期较短、口服后体内生物利用度较差且容易受到食物效应的影响有关［12］。
在药物的安全性方面，上述6种药物相较于安慰剂在不良事件发生率上并无显著差异。其中拉那利尤单抗不良事件发生率最低，贝罗司他不良事件发生率最高且两者间存在显著差异。在严重不良事件发生率方面，上述6种药物相较于安慰剂并无显著差异，概率排序结果显示多尼达洛森引发严重不良事件的概率最低，贝罗司他最高。不同药物的安全性具有差异，可能与药物的结构、靶点、药动学、药效学不同有关。例如拉那利尤单抗本质上是一种使用噬菌体展示技术制备的全人源性IgG1单克隆抗体，主要作用靶点为血浆激肽释放酶，其在化学结构上模仿了血浆激肽释放酶天然底物HMWK中存在的P3脯氨酸和P1精氨酸，可能具有较低的抗原性；拉那利尤单抗在动物实验中表现出良好的抑制常数［Ki=（120±5）pmol·L-1］，说明其能较为特异性地抑制血浆激肽释放酶活性而不干扰血浆中其他结构相似的丝氨酸蛋白酶的功能［23, 24］。贝罗司他在安全性方面较差，可能是相较于其他药物，其Ki较大（440 pmol·L-1），提示其在抑制缓激肽活性的同时，可能会抑制结构相近蛋白质的生理功能；此外，临床研究还发现患者的体重对贝罗司他的清除率影响较大［25, 26］。
本研究尚存在局限性：基于HAE罕见病的特点，纳入的RCT较少，样本量较小，导致数据的可靠性减弱；同时由于纳入的文献较少以及原始文献提供的数据有限，未能按年龄、性别、基线发病情况等进行亚组分析。综上所述，结合药物有效性及安全性，本研究的结果支持加达西单抗和拉那利尤单抗为预防HAE急性发作的一线药物，但该结论有待更多的高质量RCT进行证实与评估。
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2024年第43卷第5期
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doi: 10.14109/j.cnki.xyylc.2024.05.13
  • 接收时间：2023-12-29
  • 首发时间：2026-03-20
  • 出版时间：2024-05-25
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  • 收稿日期：2023-12-29
  • 录用日期：2024-02-26
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    1.广州医科大学第一临床学院，广东　广州　511436
    2.广州医科大学第二临床学院，广东　广州　510260
    3.广州医科大学附属妇女儿童医疗中心，广东　广州　510620
    4.广州医科大学附属第一医院，广东　广州　510120

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
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