Centre for Clinical Epidemiology, Lady Davis Institute-Jewish General Hospital, Montreal, QC, Canada; Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada; Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada.
Centre for Clinical Epidemiology, Lady Davis Institute-Jewish General Hospital, Montreal, QC, Canada.
Lancet Respir Med. 2018 Nov;6(11):855-862. doi: 10.1016/S2213-2600(18)30368-0. Epub 2018 Oct 18.
Long-acting β agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the recommended initial maintenance treatment for chronic obstructive pulmonary disease (COPD), with almost all LABAs dispensed in fixed combination with inhaled corticosteroids (LABA-ICS). We compared the effectiveness and safety of LABA-ICS versus LAMA treatment initiation as a function of blood eosinophilia, a potential biomarker of ICS effectiveness, in a real-world setting.
In this population-based cohort study, we identified a cohort of patients with COPD initiating treatment with a LAMA or LABA-ICS during 2002-15, age 55 years or older, from the UK's Clinical Practice Research Datalink. We excluded patients who initiated treatment with both bronchodilators on the same date. All patients required at least 1 year of medical history and a measure of blood eosinophil concentration before cohort entry, defined by the date of the first cohort-defining bronchodilator prescription. Patients initiating a LAMA were matched on high-dimensional propensity scores with patients initiating a LABA-ICS. They were followed up for 1 year for the occurrence of a moderate or severe COPD exacerbation and for severe pneumonia. Sensitivity analyses included, among others, repeating the analysis among patients with two blood eosinophil concentration measures and stratification by concurrent asthma and previous exacerbations.
The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs. Propensity score analysis resulted in 12 366 initiators of LAMAs (mainly tiotropium) matched to 12 366 initiators of LABA-ICS. The hazard ratio (HR) of COPD exacerbation associated with LABA-ICS initiation, relative to LAMA initiation, was 0·95 (95% CI 0·90-1·01). In patients with blood eosinophil concentrations of less than 2% of white blood cell count, the HR was 1·03 (95% CI 0·93-1·13) and for those with eosinophil concentrations of 2-4%, the HR was 1·00 (0·91-1·10). For patients with eosinophil concentrations of more than 4%, the HR was 0·79 (0·70-0·88). The incidence of pneumonia increased with LABA-ICS initiation (HR 1·37 [95% CI 1·17-1·60]) and was similar across all eosinophil concentrations. Sensitivity analyses were consistent with these findings, but the incidence of exacerbation with LABA-ICS among the 2766 (11%) of all 24 732 patients with two or more COPD exacerbations during the baseline year was marginally lower (HR 0·87 [95% CI 0·79-0·97]).
In this real-world, clinical practice, observational study, initial COPD treatment with LABA-ICS inhalers was only more effective than with LAMAs in patients with high blood eosinophil concentrations (>4%) or counts (>300 cells per μL) and possibly in frequent exacerbators. Because of the increased risk of pneumonia associated with the ICS component, initiation with a LAMA should be preferred in patients with blood eosinophil concentrations of less than 4%.
Canadian Institutes of Health Research, Canadian Foundation for Innovation.
长效β激动剂（LABA）和长效抗胆碱能药物（LAMA）是慢性阻塞性肺疾病（COPD）的初始维持治疗推荐药物，几乎所有 LABA 都与吸入皮质类固醇（LABA-ICS）联合使用。我们在真实环境中比较了 LABA-ICS 与 LAMA 起始治疗作为血液嗜酸性粒细胞（ICS 有效性的潜在生物标志物）功能的有效性和安全性。
在这项基于人群的队列研究中，我们从英国临床实践研究数据链接中确定了 2002-15 年期间开始使用 LAMA 或 LABA-ICS 治疗的 COPD 患者队列，年龄在 55 岁以上，排除了同时开始使用两种支气管扩张剂的患者。所有患者在队列入组前至少有 1 年的病史和血液嗜酸性粒细胞浓度测量值，以首次确定支气管扩张剂处方的日期为定义。用高维倾向评分匹配开始使用 LAMA 的患者和开始使用 LABA-ICS 的患者。随访 1 年，以记录中度或重度 COPD 加重和严重肺炎的发生情况。敏感性分析包括在有两次血液嗜酸性粒细胞浓度测量值的患者中重复分析，并根据同时患有哮喘和既往加重情况进行分层。
基础队列包括 539643 名从 2002 年 1 月 1 日至 2015 年 12 月 31 日开始使用 LABA 或 LAMA 的患者，其中 18500 名开始使用 LABA-ICS，13870 名开始使用 LAMA。倾向评分分析导致 12366 名开始使用 LAMA（主要是噻托溴铵）的患者与 12366 名开始使用 LABA-ICS 的患者相匹配。与开始使用 LAMA 相比，开始使用 LABA-ICS 的 COPD 加重风险比（HR）为 0.95（95%CI 0.90-1.01）。在白细胞计数中嗜酸性粒细胞浓度低于 2%的患者中，HR 为 1.03（95%CI 0.93-1.13），在嗜酸性粒细胞浓度为 2-4%的患者中，HR 为 1.00（0.91-1.10）。对于嗜酸性粒细胞浓度大于 4%的患者，HR 为 0.79（0.70-0.88）。肺炎的发病率随 LABA-ICS 起始而增加（HR 1.37 [95%CI 1.17-1.60]），且在所有嗜酸性粒细胞浓度下均相似。敏感性分析与这些发现一致，但在基线年发生两次或两次以上 COPD 加重的 24732 名患者中（占 11%），LABA-ICS 治疗的加重发生率略低（HR 0.87 [95%CI 0.79-0.97]）。
在这项真实世界、临床实践的观察性研究中，与 LAMA 相比，初始 COPD 治疗中使用 LABA-ICS 吸入器仅在血液嗜酸性粒细胞浓度（>4%）或计数（>300 个细胞/μL）较高的患者和频繁加重的患者中更有效。由于 ICS 成分与肺炎风险增加相关，在嗜酸性粒细胞浓度<4%的患者中，应优先使用 LAMA 起始治疗。
加拿大卫生研究院，加拿大创新基金会。
