Abstract
Background: Combination inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) triple therapy is used in severe asthma. The clinical effect of high-dose (HD) vs medium-dose (MD) ICSs in ICS/LABA/LAMA is unclear.
Research question: What is the clinical effect of HD compared with MD ICSs in ICS/LABA/LAMA treatment of asthma?
Study design and methods: A systematic review and meta-analysis of randomized controlled trials including > 1 ICS dose in ICS/LABA/LAMA inhalers compared the outcomes of HD and MD ICS/LABA/LAMA. The primary outcome was the proportion of participants with ≥ 1 severe asthma exacerbations. Secondary outcomes included FEV1, the Asthma Control Questionnaire, emergency department visits, and hospital admissions. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations domains.
Results: Three randomized controlled trials (N = 3,804) were identified, comparing MD and HD ICS/LABA/LAMA containing fluticasone or mometasone. When comparing HD with MD ICS/LABA/LAMA for at least 1 severe exacerbation, the Peto OR was 0.81 (95% CI, 0.68-0.96; P = .01). This corresponds to a number needed to treat to prevent 1 severe exacerbation of 32.9. HD ICS/LABA/LAMA led to a higher FEV1 (mean difference, 50.8 mL; 95% CI, 29.5-72.2 mL; P < .001) and a lower (improvement) Asthma Control Questionnaire (mean difference, -0.09; 95% CI, -0.15 to -0.04; P < .001) than MD ICS/LABA/LAMA. There was no statistically significant difference in emergency department visits (Peto OR, 0.51; 95% CI, 0.25-1.04; P = .07) or hospitalizations (Peto OR, 0.65; 95% CI, 0.33-1.29; P = .22) between HD and MD ICS/LABA/LAMA.
Interpretation: Our results show that HD compared with MD ICS/LABA/LAMA reduces the odds of a severe exacerbation by about 20%. This absolute risk reduction was modest but may be clinically relevant for patients with high baseline exacerbation rates and those with high type 2 inflammation. At both the individual and population level, the use of HD ICS/LABA/LAMA needs to be considered alongside the potential systemic side effects.
Clinical trial registration: PROSPERO Registry; No.: CRD42025634340; URL: https://www.crd.york.ac.uk/prospero/.