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内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压疗效与安全性：网状Meta分析
付文海
陈沛玲
夏嘉俐
富琳
沈毅
何汶俊
陈扬航
任妮
江倩
马冉
王涛
王欣妮
张挪富
刘春丽
作者及单位信息
·
DOI： 10.3760/cma.j.cn112147-20210707-00473
Efficacy and safety of endothelin receptor antagonists combined with phosphodiesterase 5 inhibitor in the treatment of pulmonary arterial hypertension: a network meta-analysis
Fu Wenhai
Chen Peiling
Xia Jiali
Fu Lin
Shen Yi
He Wenjun
Chen Yanghang
Ren Ni
Jiang Qian
Ma Ran
Wang Tao
Wang Xinni
Zhang Nuofu
Liu Chunli
Authors Info & Affiliations
Fu Wenhai
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Chen Peiling
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Xia Jiali
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Fu Lin
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Shen Yi
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
He Wenjun
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Chen Yanghang
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Ren Ni
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Jiang Qian
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Ma Ran
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Wang Tao
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Wang Xinni
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Zhang Nuofu
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
Liu Chunli
The First Affiliated Hospital of Guangzhou Medical University, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510005, China
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DOI： 10.3760/cma.j.cn112147-20210707-00473
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摘要

目的通过网状Meta分析确定内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压（PAH）的有效性和安全性。

方法使用标准检索式［（“Pulmonary Arterial Hypertension”OR“PAH”）AND（“Bosentan”OR“Ambrisentan”OR“Macitentan”OR“Sildenafil”OR“Tadalafil”）］检索PubMed和Cochrane Library数据库；使用检索词“肺动脉高压”“波生坦”“安立生坦”“马西腾坦”“西地那非”“他达拉非”检索中国知网（CNKI）、万方数据和维普等中文数据库。检索时间截至2021年2月12日。阅读所有文献筛选纳入比较3种内皮素受体拮抗剂和2种5型磷酸二酯酶抑制剂以及联合治疗方案治疗动脉性肺动脉高压的随机对照临床试验（RCT）。以随访12~16周6 min步行距离作为主要结果指标，病死率、临床恶化率、WHO心功能提升、不良事件（AE）和严重不良事件（SAE）作为关键的次要结果指标。使用STATA 16.0软件进行网状Meta分析，合并估计结果的优势比（ OR）或加权平均差（ WMD）和95%置信区间（ CI）。使用累积排名曲线下面积（SUCRA）来计算各干预项的概率，帮助解释 OR或 WMD。

结果共纳入29篇文献，包含5 949例PAH患者。网状Meta分析结果显示，在改善6 min步行距离方面，与安慰剂比较，波生坦+西地那非提升最大（ WMD=53.93，95% CI：6.19~101.66），其次为波生坦+他达拉非（ WMD=50.84，95% CI：7.05~94.62），安立生坦+他达拉非（ WMD=46.67，95% CI：15.88~77.45），波生坦（ WMD=29.44，95% CI：5.86~53.02），安立生坦（ WMD=23.90，95% CI：0.31~47.48），马西腾坦（ WMD=21.57，95% CI：2.45~40.69）。不同干预措施对提高动脉性肺动脉高压患者6 min步行距离的效果，根据SUCRA排序依次为：波生坦+西地那非（82.9%）>波生坦+他达拉非（78.4%）>安立生坦+他达拉非（77.1%）>波生坦（49.2%）>西地那非（48.5%）>安立生坦（40.3%）>马西腾坦（37.3%）>他达拉非（33.0%）>安慰剂（3.3%）。在提高WHO心功能分级方面，与安慰剂相比，西地那非最优（ OR=2.90，95% CI：1.04~8.08），其次为波生坦（ OR=2.15，95% CI：1.15-4.04），其余差异均无统计学意义。在降低临床恶化率方面，相较于安慰剂，波生坦+他达拉非最优（ OR=0.08，95% CI：0.01~0.49），其次依次为波生坦（ OR=0.20，95% CI：0.11~0.38），波生坦+西地那非（ OR=0.21，95% CI：0.09~0.46），安立生坦+他达拉非（ OR=0.27，95% CI：0.15~0.50），西地那非（ OR=0.33，95% CI：0.17~0.66），他达拉非（ OR=0.44，95% CI：0.21~0.90）。在不良事件发生率与严重不良事件发生率方面，所有干预措施与安慰剂相比差异均无统计学意义。在病死率方面，安立生坦（ OR=0.28，95% CI：0.11~0.74）在统计学上优于安慰剂，其余差异均无统计学意义。

结论内皮素受体拮抗剂与5型磷酸二酯酶抑制剂联合治疗方案在短期改善运动功能方面均表现较好。并且在安全性方面，与单药治疗并无明显差异。然而，未来在选择治疗方案时，应该根据患者的个体化情况以及患者的需求进行选择。

动脉性肺动脉高压;网状Meta;内皮素受体拮抗剂;5型磷酸二酯酶抑制剂
ABSTRACT

ObjectiveTo examine the efficacy and safety of endothelin receptor antagonists (ERA) combined with phosphodiesterase 5 inhibitors (PDE5i) in the treatment of pulmonary artery hypertension (PAH).

MethodsComputer-based retrieval was performed on PubMed, Cochrane Library, CNKI, Wanfang, and VIP database (up to February 12th, 2021). Randomized controlled trials about endothelin receptor antagonists (ERAs) or PDE5i in patients with PAH were collected. The change of 6-minute walking distance (6MWD) in 12-16 weeks was used as primary outcome index. Case fatality rate, worsening clinical events, WHO functional class (FC) improvement, adverse events (AEs), serious adverse events (SAE) were the key secondary outcomes indicators. STATA 16.0 software was used for network meta-analysis, and the pooled estimates of odds ratios ( ORs) or weighted mean differences (WMDs) and 95% confidence intervals ( CIs) of the results were shown. To help explain ORs and WMDs, we used the surface under the cumulative ranking curve (SUCRA) to calculate the probability of each intervention.

ResultsWe included 29 trials with 5 949 participants. In network meta-analysis, Bosentan combined with Sildenafil ( WMD=53.93, 95% CI=6.19-101.66) had shown the greatest improvement in 6MWD compared with placebo, followed by Bosentan combined with Tadalafil ( WMD=50.84, 95% CI=7.05-94.62), Ambrisentan combined with Tadalafil ( WMD=46.67, 95% CI=15.88-77.45), Bosentan ( WMD=29.44, 95% CI=5.86-53.02), Ambrisentan ( WMD=23.90, 95% CI=0.31-47.48) and Macitentan ( WMD=21.57, 95% CI=2.45-40.69). According to SUCRA, the effects of different intervention measures on improving 6MWD in patients with arterial pulmonary hypertension were as follows: Bosentan+Sildenafil (82.9%)>Bosentan+Tadalafil (78.4%)>Ambrisentan+Tadalafil (77.1%)>Bosentan (49.2%)>Sildenafil (48.5%)>Ambrisentan (40.3%)>Macitentan (37.3%)>Tadalafil (33.0%)>Placebo (3.3%). For the WHO functional class, Sildenafil ( OR=2.90, 95% CI=1.04-8.08) was optimal compared with placebo, followed by Bosentan ( OR=2.15, 95% CI=1.15-4.04), and there was no significant difference in the rest. For clinical worsening, Bosentan combined with Tadalafil ( OR=0.08, 95% CI=0.01-0.49) performed best compared with placebo, followed by Bosentan ( OR=0.20, 95% CI=0.11-0.38), Bosentan combined with Sildenafil ( OR=0.21, 95% CI=0.09-0.46), Ambrisentan combined with Tadalafil ( OR=0.27, 95% CI=0.15-0.50), Sildenafil ( OR=0.33, 95% CI=0.17-0.66) and Tadalafil ( OR=0.44, 95% CI=0.21-0.90). There was no statistical difference between all interventions and placebo in terms of the incidence of adverse events and serious adverse events. For case fatality rate, Ambrisentan ( OR=0.28, 95% CI=0.11-0.74) was statistically superior to placebo and there was no statistics difference in the rest.

ConclusionsThe combination therapy of ERAs and PDE5i performed well in the short-term improvement of motor function. Furthermore, there was no significant difference with monotherapy in terms of safety. However, it is worth emphasizing that the choice of treatment should be based on the patient′s individualized situation and the patient′s requirements.

Pulmonary artery hypertension;Network meta-analysis;Endothelin receptor antagonists;Phosphodiesterase 5 inhibitors
Liu Chunli, Email: nc.defdrabigilnuhc
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引用本文

付文海,陈沛玲,夏嘉俐,等. 内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压疗效与安全性：网状Meta分析[J]. 中华结核和呼吸杂志,2022,45(02)：158-170.

DOI:10.3760/cma.j.cn112147-20210707-00473

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动脉性肺动脉高压（PAH）是一种进展性的，且预后不良的肺血管疾病，其血流动力学定义为肺动脉平均压（mean pulmonary artery pressure，mPAP）≥25 mmHg（1 mmHg=0.133 kPa），同时肺小动脉楔压（pulmonary artery wedge pressure，PAWP）≤15 mmHg 及肺血管阻力>3 Wood单位 ［ 1 ］ ，特征是肺小动脉的血管痉挛、内膜增生和重塑 ［ 2 ］ ，进而使肺血管阻力增加，加重右心负荷，最终导致右心衰竭甚至死亡 ［ 3 ］ 。确诊患者5年生存率为61.2% ［ 4 ］ 。随着靶向药物的上市，越来越多的患者接受靶向治疗。近些年来，多组随机对照试验均证实靶向药物可进一步缓解PAH症状，改善运动功能和血流动力学 ［ 5 , 6 , 7 ］ 。但是对于这种进展性疾病，延迟达标治疗（达到低危状态）可能会影响患者的长期预后。因此建议PAH起始联合治疗 ［ 8 ］ ，尽早达到低危状态。在2015年AMBITION 研究中首次证实了WHO 功能Ⅱ、Ⅲ级的 PAH 患者接受联合治疗的获益更多 ［ 9 ］ 。2018年的第6届世界肺动脉高压大会（WSPH）基于此强调了联合治疗对PAH患者的重要性，并推荐对于血管反应试验阴性的低危/中危/高危的PAH患者应先考虑初始联合内皮素受体拮抗剂（endothelin receptor antagonists，ERA）和5型磷酸二酯酶抑制剂（phosphodiesterase 5 inhibitor，PDE5-I） ［ 10 ］ ，但目前由于缺乏几种联合治疗方案的头对头RCT试验，如何选择最佳的药物组合仍存在争议。因此，本研究旨在通过网状Meta 分析的方法，对国内外已发表的相关临床随机对照试验进行系统定量的综合分析，结合直接及间接证据，评价内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压的有效性和安全性，为临床决策提供一定依据。
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备注信息
A
刘春丽，Email： nc.defdrabigilnuhc
B

付文海、陈沛玲：研究的设计和实施；夏嘉俐、富琳和沈毅负责选取文章并提取数据；何汶俊、陈扬航、任妮：分析数据；江倩、马冉、王涛：起草文章；王欣妮、张挪富、刘春丽：对文章知识性内容进行审查，提供行政、技术和经费支持

C

付文海, 陈沛玲, 夏嘉俐, 等. 内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压疗效与安全性：网状Meta分析[J]. 中华结核和呼吸杂志, 2022, 45(2): 158-170. DOI: 10.3760/cma.j.cn112147-20210707-00473.

D
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E
国家重点研发计划 (2016YFC0901500)
呼吸疾病国家重点实验室自主课题 (SKLRD-MS-201901)
广州医科大学高水平大学临床研究培育项目 (B185004065)
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