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.
Keywords: COPD Exacerbations; COPD Pharmacology.
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