Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis

Abstract

Importance: Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma.

Objective: To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting β-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma.

Data sources: MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017).

Study selection: Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest.

Data extraction and synthesis: Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers.

Main outcomes and measures: Asthma exacerbations.

Results: Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]).

Conclusions and relevance: In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.

Figure 1.. Flow Diagram of the Literature Search

Figure 2.. Association of LAMA Add-on Therapy With Exacerbations Requiring Systemic Corticosteroid and With ACQ-7 Score

ACQ-7 indicates 7-Item Asthma Control Questionnaire; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; MD, mean difference; RR, risk ratio. Size of the data markers indicates the weight of the study. For continuous outcomes, the mean value represents the mean change from baseline (change score) for each study group and the MD value represents the difference in change scores (change from baseline) between the LAMA and control groups. The I² value indicates the percentage of variability across the pooled estimates attributable to statistical heterogeneity (range, 0%-100%), and the P value is a test of heterogeneity across all studies (P < .10 indicates likely variation across pooled estimates related to statistical heterogeneity). “Events” indicates the number of participants in each group who experienced an event. ACQ-7 (range, 0 [worse] to 6 [better control]) is a patient self-administered tool for assessing overall asthma control. The minimal important difference was 0.5 for the ACQ7 and 0.2 L for the FEV₁.

Figure 3.. Association of LAMA Add-on Therapy With FEV₁ Trough and Rescue Medication Use

FEV₁ indicates forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; MD, mean difference. Size of the data markers indicate the weight of the study. For more information, see Figure 2 footnotes.