Triple extrafine fixed-dose combination in asthma: from randomized controlled trials to real-world evidence

Small airway dysfunction affects 50-90% of asthmatic patients, leading to airway remodeling, worsening symptoms, and quality of life. Targeting small airway dysfunction with inhaled extrafine formulations, with a mass median aerodynamic diameter < 2 µm, is crucial. Triple extrafine fixed-dose combination with inhaled corticosteroids (ICS), long-acting β₂-agonists (LABA), and long-acting muscarinic antagonists (LAMA) been approved for uncontrolled asthma, supported by TRIMARAN and TRIGGER randomized controlled trials (RCT). However, while RCTs offer valuable efficacy and safety data under controlled conditions, findings need to be combined with real-world evidence (RWE).

This narrative review assessed the impact of triple extrafine fixed-dose combination in asthma, integrating RCTs and RWE findings. Post-hoc analyses of RCTs and preliminary gray literature were also considered.

RCTs and RWE showed significant overlap in outcomes for triple extrafine fixed-dose combination, although differing in some crucial patient characteristics (e.g. smoking status). Triple extrafine fixed-dose combination might be more effective in patients with persistent airflow limitation by targeting small airway dysfunction. However, further RCTs and RWE are needed to address remaining gaps, such as the determinants of response to medium-strength triple extrafine fixed-dose combination vs. high-strength ICS/LABA and to high-strength triple extrafine fixed-dose combination vs. open triple therapy.