Triple therapy vs dual inhaler therapy for moderate-to-severe asthma: An updated systematic review and meta-analysis.

Background: Long-acting muscarinic antagonists are typically added to inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) for asthma management.

Objective: To systematically synthesize the benefits and harms of triple therapy (ICS/LABA/long-acting muscarinic antagonists) compared with dual therapy (ICS/LABA) for asthma management across key subpopulations as part of developing linked American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology guidelines.

Methods: We searched MEDLINE, EMBASE, the Cochrane Controlled Register of Trials, and the International Clinical Trials Registry Platform from January 1, 2020 to February 1, 2025, for randomized trials comparing inhaled triple therapy to dual therapy for asthma to update our previous systematic review. Paired reviewers independently screened citations, extracted data, and assessed the risk of bias. Random effects meta-analyses assessed asthma control (asthma control questionnaire-7; 0-6), asthma-related quality of life (asthma quality of life questionnaire; 1-7), prebronchodilator forced expiratory volume in 1 second, severe exacerbations, and serious adverse events. The Grading of Recommendations, Assessment, Development, and Evaluation approach informed the certainty of evidence. Open Science Framework Registration (https://osf.io/u8t4q/).

Results: A total of 26 trials randomized 12,431 participants. Compared with dual therapy, triple therapy reduces severe exacerbations in patients at high risk for future exacerbation (relative risk 0.83, 95% CI 0.76-0.90; risk difference 5.3% fewer; high certainty), with trivial improvement in asthma control (mean difference [MD] -0.04, 95% CI -0.07 to 0.00, moderate certainty; lower better), quality of life (MD 0.05, 95% CI -0.03 to 0.14, moderate certainty; higher better), and prebronchodilator forced expiratory volume in 1 second (MD 0.07, 95% CI 0.05-0.09; high certainty), without increase in serious adverse events (moderate certainty). The effects were consistent across age, body mass index, and exacerbation history.

Conclusion: In patients with moderate-to-severe asthma, triple therapy, compared with dual therapy, reduces severe exacerbations in patients at high risk for future exacerbation with minimal harm.