POOR treatment adherence remains a major challenge in real-world chronic obstructive pulmonary disease (COPD) care, often leading to unintended therapy discontinuation. New post hoc findings suggest that COPD treatment withdrawal, particularly of long-acting muscarinic antagonists (LAMA) and inhaled corticosteroids (ICS), may trigger early increases in exacerbation risk, with important implications for both clinical practice and trial design.
The analysis draws on data from a large 52-week, double-blind randomised trial comparing LABA+LAMA with LABA+ICS in patients with moderate-to-severe COPD and a history of exacerbations.
Understanding Withdrawal Effects in COPD Treatment
While withdrawal effects following ICS discontinuation are well recognised, evidence for LAMA withdrawal has been limited. To address this gap, investigators examined monthly exacerbation patterns during the first year of follow-up, focusing on whether early spikes in events suggested a withdrawal phenomenon after stopping either therapy.
Participants were stratified according to baseline LAMA or ICS use, and exacerbation rates during the first quarter were compared with subsequent quarters. Multivariable mixed-effects models were used to explore whether changes over time reflected true withdrawal effects rather than background disease variability.
LAMA Withdrawal and COPD Exacerbations
The analysis revealed a clear and transient increase in moderate-to-severe exacerbations following LAMA discontinuation, particularly during the first 3 months after withdrawal. In some subgroups, exacerbation rates were more than doubled compared with later periods, supporting the presence of a clinically meaningful LAMA withdrawal effect.
Interestingly, this signal was strongest in patients least influenced by concomitant ICS therapy, suggesting that LAMA withdrawal may independently destabilise disease control. Severe exacerbations did not show the same pattern, likely due to lower event numbers.
ICS Withdrawal Shows a Different COPD Risk Profile
In contrast, ICS withdrawal was associated with an early increase in severe exacerbations, while effects on moderate-to-severe events were less pronounced. Notably, this withdrawal effect appeared consistent across blood eosinophil levels, challenging assumptions that eosinophil counts reliably predict ICS withdrawal risk.
Implications for COPD Management and Trials
These findings reinforce the clinical importance of maintaining stable COPD therapy and avoiding abrupt discontinuation whenever possible. For clinicians, they highlight the need to support adherence and carefully plan step-down strategies. For researchers, the results underline the importance of accounting for COPD treatment withdrawal effects when interpreting early trial outcomes.
Reference
Mathioudakis AG et al. Disproportionate increase in COPD exacerbation risk for 3 months after discontinuing LAMA or ICS: insights from the FLAME trial. Thorax. 2025; DOI:10.1136/thorax-2025-223282.
