Clinical Question

Are long-acting muscarinic antagonists a useful adjunct therapy to inhaled corticosteroids in patients 12 years or older with persistent asthma?

Bottom Line

Long-acting muscarinic antagonists added to inhaled corticosteroids are a superior treatment to placebo for improving asthma control in adults and children 12 years or older. Long-acting muscarinic antagonist add-on therapy is not superior to long-acting beta agonist (LABA) add-on therapy. The addition of long-acting muscarinic antagonists in patients already receiving LABA plus inhaled corticosteroids (triple therapy) does not further improve asthma control. (Level of Evidence = 1a)

Synopsis

Since 2014, a number of long-acting muscarinic antagonists (e.g., tiotropium [Spiriva], umeclidinium [Incruse], aclidinium [Tudorza]) have been marketed for the treatment of asthma. Investigators thoroughly searched multiple sources, including Medline, Embase, the Cochrane databases, clinical trial registries, manufacturers' data, and bibliographic references for studies that compared long-acting muscarinic antagonist therapy with placebo or other controllers as an add-on therapy to inhaled corticosteroids in patients at least 12 years of age with uncontrolled persistent asthma. No language restrictions were applied. Two reviewers independently evaluated potential studies for inclusion and used a standard scoring tool to assess methodologic quality. Disagreements were resolved by consensus discussion with a third reviewer. A total of 15 randomized controlled trials (N = 7,122 patients) met inclusion criteria. Of these, three received a high risk of bias score, with the remaining scoring at low risk of bias.

Adding a long-acting muscarinic antagonist to inhaled corticosteroids compared with adding placebo was significantly associated with a reduced risk of asthma exacerbation requiring systemic corticosteroids (relative risk = 0.67; 95% confidence interval, 0.48 to 0.92). There were no significant differences in rescue medication use or quality-of-life scores between add-on long-acting muscarinic antagonist therapy and add-on placebo. When comparing long-acting muscarinic antagonists to LABA as add-on therapy to inhaled corticosteroids, there was no significant difference in risk of asthma exacerbation requiring systemic corticosteroids, rescue medication use, or quality-of-life scores. Triple therapy with a long-acting muscarinic antagonist, LABA, and inhaled corticosteroids was not superior to LABA plus inhaled corticosteroids. Limiting the analysis to only studies with a low risk of bias did not change the results. A formal analysis for publication bias was not possible because of the small number of studies. Formal testing found minimal evidence of significant heterogeneity of results.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Setting: Various (meta-analysis)

Reference: SobierajDMBakerWLNguyenEet alAssociation of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta-analysis [published correction appears in JAMA. 2018;319(18):1939]. JAMA2018;319(14):1473–1484.