Withdrawal Effects of LAMA on COPD Exacerbations: Post-hoc Analysis of FLAME Trial

Background

Poor adherence in COPD frequently results in treatment discontinuation. While withdrawal of inhaled corticosteroids (ICS) is known to increase exacerbation risk, the clinical impact of long-acting muscarinic antagonist (LAMA) withdrawal remains uncertain.

Objective

To evaluate the effects of LAMA withdrawal on COPD exacerbations and re-assess the impact of ICS withdrawal using data from the FLAME trial.

Study Design

• Post-hoc analysis of the 52-week, double-blind, randomized FLAME trial
• Patients: 3,362 COPD patients with:
  • Moderate-to-severe airflow limitation
  • ≥1 exacerbation in the previous year
  • mMRC score ≥2
• Treatment arms:
  • Indacaterol/Glycopyrronium (LABA/LAMA)
  • Salmeterol/Fluticasone (LABA/ICS)

Endpoints

Primary

• Rate of moderate or severe COPD exacerbations

Secondary

• Severe exacerbation rate
• Exacerbations requiring systemic corticosteroids
• Exacerbations requiring antibiotics
• Time to first exacerbation

Key Findings

• Before randomization:
  • 56.3% were receiving ICS
  • 67.1% LABA
  • 60.6% LAMA
• Patients discontinuing LAMA experienced a significant early increase in moderate-to-severe exacerbations during the first 3 months compared with later follow-up.
  • Rate Ratio (RR): 2.2
  • p = 0.001
• Early exacerbation peaks were observed after discontinuation of both LAMA and ICS, suggesting clinically relevant withdrawal effects.
• Among previous LAMA users, patients switched to LABA/ICS had significantly more first-quarter exacerbations than those continuing LABA/LAMA (p < 0.001).
• Evidence for ICS withdrawal was modest for moderate exacerbations but significant for severe exacerbations (p = 0.023).
• Withdrawal effects were more pronounced in patients with lower blood eosinophil counts.

Clinical Take-Home Message

• LAMA withdrawal is associated with a marked increase in COPD exacerbations, particularly during the first three months after discontinuation.
• Both LAMA and ICS withdrawal can adversely affect clinical outcomes.
• Maintaining long-acting bronchodilator therapy is essential, and treatment discontinuation should be avoided unless clinically indicated.
• These findings reinforce the importance of medication adherence and should be considered when interpreting COPD clinical trials.

Reference

Thorax. 2026;81(6):533–540.
DOI: 10.1136/thorax-2025-223282