三种不同的联用方案在中到极重度慢性阻塞性肺疾病患者中的有效性和安全性: 系统评价和meta分析

doi:10.5246/jcps.2019.07.048

摘要/Abstract

摘要：

吸入制剂, 包括长效抗胆碱能受体拮抗剂(LAMAs), 长效β2-受体激动剂(LABAs)和吸入糖皮质激素(ICS)是目前COPD患者的主要选择。本研究通过系统评价和meta分析比较三种联合治疗方案(LAMA+LABA+ICS、LAMA+LABA、LABA+ICS)之间的有效性和安全性。通过检索Pubmed, Embase和Cochrane Library电子数据库中的随机对照实验(RCT), 比较联合治疗在COPD患者中的有效性和安全性。使用Review Manager 5.3进行数据分析, 使用Cochrane偏倚风险评估工具评估本研究所纳入RCT的质量。本研究共纳入27篇RCT。LAMA+LABA+ICS组急性加重率显著降低, 当分别和LABA+ICS组(RR = 0.66; 95% CI: 0.59–0.74)及LAMA+LABA组(RR = 0.88; 95% CI: 0.82–0.94)相比。和LABA+ICS组相比, LAMA+LABA组急性加重率显著降低(RR = 0.71; 95% CI: 0.54–0.94)。LAMA+LABA+ICS 组分别与LABA+ICS组及 LAMA+LABA组相比, trough FEV1显著提升了120 mL (MD = 0.12L; 95% CI: 0.09–0.15)和50 mL (MD = 0.05L; 95% CI: 0.04–0.07)。和LABA+ICS组相比, LAMA+LABA组显著提升了trough FEV1 (MD = 0.07L; 95% CI: 0.04–0.09)。LAMA+LABA+ICS 组肺炎的发生率显著高于LABA+ICS组(RR = 1.16; 95% CI: 1.01–1.33)和LAMA+LABA组 (RR = 1.31; 95% CI: 1.06–1.62)。与LABA+ICS 组相比, LAMA+LABA组可以显著降低肺炎的发生率(RR = 0.64; 95% CI: 0.54–0.76)。我们得到的结论是: (1) LAMA+LABA+ICS三联疗法和LAMA+LABA、LABA+ICS两个二联疗法相比时, 表现出更好的安全性(更低的中重度急性加重率, 更好的肺功能和生活质量)和相当的安全性。但是, 三联疗法与两种二联疗法相比, 肺炎发生率显著升高。有肺炎高风险的患者在用三联疗法时需谨慎考虑。此外, 三联疗法的经济性也需考虑。(2) LAMA+LABA二联疗法与LABA+ICS相比, 表现出更好的有效性和更低的肺炎发生率。LAMA+LABA相比LABA+ICS是更好的选择。

关键词: 慢性阻塞性肺疾病, LAMA+LABA+ICS, LAMA+LABA, LABA+ICS, Meta-分析

Abstract:

Inhaled drugs, including long-acting muscarinic antagonists (LAMAs), long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICSs), are the main therapeutic options for patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis to compare the efficacy and safety of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS therapies. The Pubmed, Embase and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing the efficacy (moderate-to-severe exacerbations, lung function and quality of life) and safety (adverse events (AEs), severe adverse events (SAEs), withdrawals due to AEs, deaths and pneumonia) of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS in COPD patients. Two investigators independently searched eligible studies and extracted relevant information. The data were analyzed using the Review Manager software, and the quality of included studies was assessed using the Cochrane risk of bias tool. A total of 27 studies were included, and majority of the studies showed low risk of bias. Moderatetosevere exacerbations were lower after LAMA+LABA+ICS therapy compared with the LABA+ICS (RR = 0.66; 95% CI: 0.59–0.74) and LAMA+LABA therapies (RR = 0.88; 95% CI: 0.82–0.94). Lung function was significantly improved after LAMA+LABA+ICS compared with LAMA+ICS treatment. FEV1, peak FEV1 and trough FEV1 were significantly increased by 100 mL, 150 mL and 120 mL, respectively, in LAMA+LABA+ICS therapy compared with LAMA+ICS. In addition, LAMA+LABA therapy resulted in increased FEV1, peak FEV1 and trough FEV1 by 80 mL, 90 mL and 70 mL, respectively, compared with LAMA+ICS. SGRQ-total score was used to assess quality of life of COPD patients, which indicated that LAMA+LABA+ICS therapy was associated with slightly greater decrease compared with LABA+ICS (MD = –1.33; 95% CI: –2.35 to –0.30). No significant differences were found across all three treatment combinations in term of AEs, SAEs, withdrawals due to AEs and deaths. However, the risk of pneumonia was higher in the triple therapy group than that in the LABA+ICS (RR = 1.16; 95% CI: 1.01–1.33) or LAMA+LABA (RR = 1.31; 95% CI: 1.06–1.62) groups, and significantly lower in the LAMA+LABA group compared with LABA+ICS (RR = 0.64; 95% CI: 0.54–0.76). LAMA+LABA+ICS therapy offered greater efficacy and comparable safety compared with the LAMA+LABAor LABA+ICS therapies. However, triple therapy could increase the risk of pneumonia compared with LAMA+LABA or LABA+ICS therapies. People who have higher risk of pneumonia should carefully consider the use of triple therapy. LAMA+LABA therapy offered greater efficacy and lower risk of pneumonia to LABA+ICS therapy. Collectively, LAMA+LABA therapy might be a better choice than LABA+ICS.

Key words: COPD, LAMA+LABA+ICS, LAMA+LABA, LABA+ICS, Meta-analysis

中图分类号:

Supporting:

FEV1

Appendix figure 1 Forest plot demonstrating FEV1.

Peak FEV1

Appendix figure 2 Forest plot demonstrating peak FEV1.

SGRQ-total score

Appendix figure 3 Forest plot demonstrating SGRQ-total score.

Adverse events (AEs)

Appendix figure 4 Forest plot demonstrating AEs.

Severe adverse events (SAEs)

Appendix figure 5 Forest plot demonstrating SAEs.

Withdrawals due to AEs

Appendix figure 6 Forest plot demonstrating withdrawals due to AEs.

Deaths

Appendix figure 7 Forest plot demonstrating death.

周瑞瑞, 王利群, 孙桐, 吴紫阳, 谢晓慧. 三种不同的联用方案在中到极重度慢性阻塞性肺疾病患者中的有效性和安全性: 系统评价和meta分析[J]. 中国药学(英文版), 2019, 28(7): 502-518.

Ruirui Zhou, Liqun Wang, Tong Sun, Ziyang Wu, Xiaohui Xie. The efficacy and safety of three types of combination therapies in patients with moderate to very severe COPD: a systematic review and meta-analysis[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(7): 502-518.

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