当前的指南建议使用更高剂量的吸入性皮质类固醇(ICS)或添加长效毒蕈碱拮抗剂(LAMA),当哮喘无法通过中剂量(MD)ICS/长效β2激动剂(LABA)联合治疗得到控制时。
评估双重疗法(ICS/LABA)和三联疗法(ICS/LABA/LAMA)的有效性和安全性,并比较不同剂量的ICS在青少年和成人未控制哮喘中的作用。
我们在多个数据库中搜索了2008年至2022年2月18日至少12周研究时间的预注册随机对照试验(RCT)。
我们搜索了研究,包括接受过哮喘治疗的青少年和成年人,或者有资格,MD-ICS/LABA,比较双重和三重疗法。我们排除了集群和交叉RCT。
我们根据先前发表的协议进行了系统评价和网络荟萃分析。我们使用Cochrane的Screen4ME工作流程来评估搜索结果和建议评估分级,开发和评估(等级),以评估证据的确定性。主要结果是需要类固醇的哮喘加重和哮喘相关的住院治疗(中度至重度和重度加重)。
我们纳入了17项研究中的17,161例哮喘未控制患者(中位持续时间26周;平均年龄49.1岁;男性40%;白人81%;1秒平均用力呼气量(MEF1)1.9升,预测为61%)。纳入研究的质量总体上是良好的,除了一些研究由于高流失率导致的一些结果。中剂量(MD)和高剂量(HD)三联疗法可减少需要类固醇的哮喘加重(风险比(HR)0.84[95%可信间隔(CrI)0.71至0.99]和0.69[0.58至0.82],分别)(高确定性证据),但不是哮喘相关的住院治疗,与MD-ICS/LABA相比。与MD三联疗法相比,高剂量三联疗法可能会减少需要类固醇的哮喘加重(HR0.83[95%CrI0.69至0.996],[适度的确定性])。亚组分析表明,与三联疗法相关的需要类固醇的恶化减少可能仅适用于前一年有哮喘发作史的患者,而不适用于没有哮喘发作史的患者。大剂量三联疗法,但不是MD三倍,与MD-ICS/LABA相比,全因不良事件(AEs)减少,并可能减少因AEs引起的退出(比值比(OR)0.79[95%CrI0.69至0.90],[高确定性]和0.50[95%CrI0.30至0.84],[适度的确定性],分别)。与双重治疗(高确定性)相比,三重治疗在全因或哮喘相关的严重不良事件(SAE)方面几乎没有差异。证据表明,与双重疗法相比,三联疗法在症状或生活质量方面几乎没有或没有临床上重要的差异,考虑到最小的临床重要差异(MCID)和HD-ICS/LABA相比,与MD-ICS/LABA相比,不太可能产生任何明显的益处或伤害。
中等剂量和HD三联疗法可减少需要类固醇的哮喘加重,但不是哮喘相关的住院治疗,与MD-ICS/LABA相比,尤其是在前一年有哮喘发作史的患者中。在减少需要类固醇的哮喘加重方面,高剂量三联疗法可能优于MD三联疗法。与考虑MCID的双重治疗相比,三重治疗不太可能导致症状或生活质量的临床有意义的改善。大剂量三联疗法,但不是MD三倍,与MD-ICS/LABA相比,导致全因AE减少,并可能减少因AE导致的辍学。与双重疗法相比,三重疗法在全因或哮喘相关的SAE中几乎没有差异。与MD-ICS/LABA相比,HD-ICS/LABA不太可能产生任何重大益处或伤害,尽管考虑到纳入研究的中位持续时间为6个月,更高而非MD-ICS的长期安全性仍有待证明.当MD-ICS/LABA不能控制哮喘时,上述发现可能有助于决定治疗方案。
Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy.
To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma.
We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022.
We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs.
We conducted a systematic
review and network meta-analysis according to the previously published protocol. We used Cochrane\'s Screen4ME workflow to assess search results and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome was steroid-requiring asthma exacerbations and asthma-related hospitalisations (moderate to severe and severe exacerbations).
We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without. High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty). The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA.
Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs. High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD- ICS remains to be demonstrated given the median duration of included studies was six months. The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.