Research in context
Evidence before this study
We searched PubMed for articles published from database inception until April 4, 2019, using the search term “drug therapy, combination’ [MeSH terms] OR triple AND asthma AND trial NOT theophylline NOT montelukast, with no restrictions. Of the 1068 hits, eight articles presented data from clinical trials that assessed the efficacy of triple therapy comprising an inhaled corticosteroid plus a long-acting β2 agonist plus a long-acting muscarinic antagonist. Of these articles, six reported data in adults (the other two reported data in children or adolescents), of which one article was a short-term (4-week) study, one reported pooled safety data, and one reported subgroup analyses of studies presented in another manuscript. The remaining three articles reported data from studies in which the long-acting muscarinic antagonist tiotropium was added as a free combination to any inhaled corticosteroid and long-acting β2 agonist. The first of these articles presented data from two 48-week studies, in which the addition of tiotropium to high-dose inhaled corticosteroid plus a long-acting β2 agonist delayed the time to first asthma exacerbation and reduced the overall risk of these events, with improvements in lung function. The second article focused on the long-term (52-week) safety profile of the addition of tiotropium to inhaled corticosteroid plus a long-acting β2 agonist, which was similar to inhaled corticosteroid plus a long-acting β2 agonist alone. In the third article, the addition of tiotropium improved airflow and reduced airway wall thickness after 48 weeks. All three studies assessed the effect of tiotropium plus inhaled corticosteroid plus long-acting β2-agonist therapy in patients with spirometrically assessed persistent airflow limitation (ie, ratio of forced expiratory volume in 1 s to forced vital capacity <0·7).
Added value of this study
TRIMARAN and TRIGGER are the first studies to assess the efficacy and safety of single-inhaler triple therapy compared with inhaled corticosteroid plus a long-acting β2 agonist in adults with asthma. Additionally, these are the first long-term studies undertaken in patients who had no requirement to show persistent airflow limitation after short-acting β2 agonist use.
Implications of all the available evidence
The combination of a long-acting muscarinic antagonist with an inhaled corticosteroid plus long-acting β2-agonist therapy in adults with uncontrolled asthma results in improved lung function. In large, long-term studies, triple therapy has a positive effect on severe exacerbations.