停用LAMA或ICS后3个月内慢阻肺急性加重风险不成比例增加：FLAME试验启示
该研究为FLAME试验的事后分析，纳入3362例中重度且有急性加重史的慢阻肺患者，比较LABA+LAMA与LABA+ICS。停用LAMA与首个季度内中重度急性加重短暂显著增加相关（p=0.001，率比最高2.2，95%CI 1.2-4.1）；停用ICS与严重急性加重早期显著增加相关（p=0.023），且不受基线血嗜酸性粒细胞计数影响。
要点
- 停用LAMA后首个季度中重度急性加重短暂增加，率比最高2.2。
- 停用ICS后严重急性加重早期显著增加（p=0.023）。
- ICS撤药效应与基线血嗜酸性粒细胞计数无关。
核心结论
- 停用LAMA和ICS均可能产生撤药效应，导致慢阻肺急性加重风险短暂增加。
- 临床应重视治疗依从性，并在试验设计中考虑撤药效应。
研究设计与样本
- FLAME试验（52周、双盲）的事后分析，比较LABA+LAMA与LABA+ICS。
- 纳入3362例中重度慢阻肺且有急性加重史的患者。
- 按基线用药分层，比较继续与停用各治疗者在首季度与后续季度的结局。
- 采用多变量混合效应模型评估急性加重率差异。
主要发现
- 停用LAMA后首季度较后续季度中重度急性加重显著增加（p=0.001），在受合并ICS影响最小的亚组中率比最高达2.2（95%CI 1.2-4.1）。
- 停用LAMA与严重急性加重的关系未获证实，可能因事件数少。
- 停用ICS后严重急性加重早期显著增加（p=0.023），中重度事件的差异未达统计学显著。
- ICS撤药效应与基线血嗜酸性粒细胞计数无关。
关键数值与推荐
- 停用LAMA：首季度 vs 后续季度中重度急性加重p=0.001，率比最高2.2（95%CI 1.2-4.1）。
- 停用ICS：严重急性加重早期增加p=0.023。
- 中重度急性加重差异未达统计学显著（停用ICS者）。
- ICS撤药效应与基线血嗜酸性粒细胞计数无关。
临床怎么用
- 应强调慢阻肺患者对LAMA和ICS的治療依从性，避免不必要的停药。
- 停药后首3个月需警惕急性加重风险短暂升高。
- 临床试验设计时应考虑撤药效应的影响。
局限性
- 为事后分析，结果需前瞻性研究验证。
- 严重急性加重事件数少，相关分析受限。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
BACKGROUND: In real-world chronic obstructive pulmonary disease (COPD) care, poor adherence often leads to treatment discontinuations. Discontinuing inhaled corticosteroids (ICS) can trigger withdrawal effects transiently increasing exacerbation risk; but evidence for long-acting muscarinic antagonists (LAMA) withdrawal remains limited. METHODS: We performed a post hoc analysis of the 52-week, double-blind, Effect of Indacaterol Glycopyrronium versus Fluticasone Salmeterol on COPD Exacerbations trial that compared long-acting beta-2 agonist (LABA)+LAMA with LABA+ICS in 3362 patients with moderate-to-severe COPD and exacerbation history. Potential withdrawal effects after discontinuing LAMA or ICS were suggested by monthly exacerbation incidence plots during the first quarter of follow-up. Participants were stratified by their baseline use of these therapies, and outcomes were compared between the first and subsequent quarters among those who continued versus discontinued each treatment. Multivariable mixed-effects models assessed differences in exacerbation rates, with temporal variation in treatment effects interpreted as indicative of withdrawal effects. RESULTS: Discontinuing LAMA was associated with a marked, transient increase in moderate-to-severe exacerbations during the first versus subsequent quarters (p=0.001; rate ratio up to 2.2 (95% CI 1.2 to 4.1) in the subgroup least influenced by concomitant ICS use). This observation was not confirmed for severe exacerbations, likely due to low event count. In contrast, discontinuing ICS was associated with a significant early rise in severe exacerbations (p=0.023), though the difference for moderate-to-severe events did not reach statistical significance. Importantly, ICS withdrawal effects appeared consistent regardless of baseline blood eosinophil count. CONCLUSION: Our findings suggest potent LAMA and ICS treatment withdrawal effects on exacerbations, highlighting the importance of treatment adherence and accounting for withdrawal effects in clinical trials. TRIAL REGISTRATION NUMBER: NCT01782326.
引用
- Mathioudakis, Bate, Chatzimavridou-Grigoriadou, et al. Disproportionate increase in COPD exacerbation risk for 3 months after discontinuing LAMA or ICS: insights from the FLAME trial. Thorax. 2026. PMID: 41402044. doi:10.1136/thorax-2025-223282
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。