Fu W H, Chen P L, Xia J L, Fu L, Shen Y, He W J, Chen Y H, Ren N, Jiang Q, Ma R, Wang T, Wang X N, Zhang N F, Liu C L
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.
Zhonghua Jie He He Hu Xi Za Zhi. 2022 Feb 12;45(2):158-170. doi: 10.3760/cma.j.cn112147-20210707-00473.
To examine the efficacy and safety of endothelin receptor antagonists (ERA) combined with phosphodiesterase 5 inhibitors (PDE5i) in the treatment of pulmonary artery hypertension (PAH). Computer-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 (s) or weighted mean differences (WMDs) and 95% confidence intervals (s) of the results were shown. To help explain s and WMDs, we used the surface under the cumulative ranking curve (SUCRA) to calculate the probability of each intervention. We included 29 trials with 5 949 participants. In network meta-analysis, Bosentan combined with Sildenafil (=53.93, 95%=6.19-101.66) had shown the greatest improvement in 6MWD compared with placebo, followed by Bosentan combined with Tadalafil (=50.84, 95%=7.05-94.62), Ambrisentan combined with Tadalafil (=46.67, 95%=15.88-77.45), Bosentan (=29.44, 95%=5.86-53.02), Ambrisentan (=23.90, 95%=0.31-47.48) and Macitentan (=21.57, 95%=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 (=2.90, 95%=1.04-8.08) was optimal compared with placebo, followed by Bosentan (=2.15, 95%=1.15-4.04), and there was no significant difference in the rest. For clinical worsening, Bosentan combined with Tadalafil (=0.08, 95%=0.01-0.49) performed best compared with placebo, followed by Bosentan (=0.20, 95%=0.11-0.38), Bosentan combined with Sildenafil (=0.21, 95%=0.09-0.46), Ambrisentan combined with Tadalafil (=0.27, 95%=0.15-0.50), Sildenafil (=0.33, 95%=0.17-0.66) and Tadalafil (=0.44, 95%=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 (=0.28, 95%=0.11-0.74) was statistically superior to placebo and there was no statistics difference in the rest. The 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.
探讨内皮素受体拮抗剂（ERA）联合磷酸二酯酶5抑制剂（PDE5i）治疗肺动脉高压（PAH）的疗效和安全性。通过计算机检索PubMed、Cochrane图书馆、中国知网、万方和维普数据库（截至2021年2月12日）。收集关于PAH患者使用内皮素受体拮抗剂（ERAs）或PDE5i的随机对照试验。将12 - 16周内6分钟步行距离（6MWD）变化作为主要结局指标。病死率、临床恶化事件、世界卫生组织功能分级（FC）改善情况、不良事件（AEs）、严重不良事件（SAE）为关键次要结局指标。使用STATA 16.0软件进行网状Meta分析，并展示结果的比值比（s）或加权平均差（WMDs）及95%置信区间（s）的合并估计值。为帮助解释s和WMDs，我们使用累积排名曲线下面积（SUCRA）计算各干预措施的概率。我们纳入了29项试验，共5949名参与者。在网状Meta分析中，与安慰剂相比，波生坦联合西地那非（=53.93，95%=6.19 - 101.66）在6MWD改善方面表现最佳，其次是波生坦联合他达拉非（=50.84，95%=7.05 - 94.62）、安立生坦联合他达拉非（=46.67，95%=15.88 - 77.45）、波生坦（=29.44，95%=5.86 - 53.02）、安立生坦（=23.90，95%=0.31 - 47.48）和马昔腾坦（=21.57，95%=2.45 - 40.69）。根据SUCRA，不同干预措施对改善动脉性肺动脉高压患者6MWD的效果如下：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%）>马昔腾坦（37.3%）>他达拉非（33.0%）>安慰剂（3.3%）。对于世界卫生组织功能分级，与安慰剂相比，西地那非（=2.90，95%=1.04 - 8.08）最佳，其次是波生坦（=2.15，95%=1.15 - 4.04），其余无显著差异。对于临床恶化，与安慰剂相比，波生坦联合他达拉非（=0.08，95%=0.01 - 0.49）表现最佳，其次是波生坦（=0.20，95%=0.11 - 0.38）、波生坦联合西地那非（=0.21，95%=0.09 - 0.46）、安立生坦联合他达拉非（=0.27，95%=0.15 - 0.50）、西地那非（=0.33，95%=0.17 - 0.66）和他达拉非（=0.44，95%=0.21 - 0.90）。在不良事件和严重不良事件发生率方面，所有干预措施与安慰剂之间无统计学差异。对于病死率，安立生坦（=0.28，95%=0.11 - 0.74）在统计学上优于安慰剂，其余无统计学差异。ERA与PDE5i联合治疗在短期改善运动功能方面表现良好。此外，在安全性方面与单药治疗无显著差异。然而，值得强调的是，治疗选择应基于患者的个体情况和患者的需求。
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