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Emerging evidence suggests current smokers show a reduced response to ICS. This post-hoc analysis of the FLAME trial explored the impact of smoking status on the efficacy of long-acting beta-2 agonist (LABA)+ICS versus LABA+long-acting muscarinic antagonist (LAMA) for preventing exacerbations. Our findings indicate that LABA+LAMA is superior to LABA+ICS in preventing moderate to severe exacerbations in current smokers and inferior in ex-smokers with BEC \u2265200\u2009cells\/\u00b5L. 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