Abstract

BACKGROUND: Poorly controlled asthma and preventable exacerbations place a significant strain on healthcare, often requiring additional medications, hospital stays or treatment in the emergency department.Long-acting beta2-agonists (LABA) are the preferred add-on treatment for adults with asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS), but have important safety concerns in asthma. Long-acting muscarinic antagonists (LAMA) have confirmed efficacy in chronic obstructive pulmonary disease and are now being considered as an alternative add-on therapy for people with uncontrolled asthma. OBJECTIVES: To assess the efficacy and safety of adding a LAMA to ICS compared with adding a LABA for adults whose asthma is not well controlled on ICS alone. SEARCH METHODS: We searched the Cochrane Airways Group's Specialised Register (CAGR) from inception to April 2015, and imposed no restriction on language of publication. We searched additional resources to pick up unpublished studies, including ClinicalTrials.gov, World Health Organization trials portal, reference lists of primary studies and existing reviews, and manufacturers' trial registries. The most recent search was conducted in April 2015. SELECTION CRITERIA: We searched for parallel and cross-over RCTs in which adults whose asthma was not well controlled with ICS alone were randomised to receive LAMA add-on or LABA add-on for at least 12 weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the electronic and additional searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data, and risk of bias ratings.The pre-specified primary outcomes were exacerbations requiring oral corticosteroids (OCS), quality of life and serious adverse events. MAIN RESULTS: We included eight studies meeting the inclusion criteria, but four double-blind, double-dummy studies of around 2000 people dominated the analyses. These four trials were between 14 and 24 weeks long, all comparing tiotropium (usually Respimat) with salmeterol on top of medium doses of ICS.Studies reporting exacerbations requiring OCS showed no difference between the two add-ons, but our confidence in the effect was low due to inconsistency between studies and because the confidence intervals (CI) included significant benefit of either treatment (odds ratio (OR) 1.05, 95% CI 0.50 to 2.18; 1753 participants; 3 studies); three more people per 1000 might have an exacerbation on LAMA, but the CIs ranged from 29 fewer to 61 more. Imprecision was also an issue for serious adverse events and exacerbations requiring hospital admission, rated low (serious adverse events) and very low quality (exacerbations requiring hospital admission), because there were so few events in the analyses.People taking LAMA scored slightly worse on two scales measuring quality of life (Asthma Quality of Life Questionnaire; AQLQ) and asthma control (Asthma Control Questionnaire; ACQ); the evidence was rated high quality but the effects were small and unlikely to be clinically significant (AQLQ: mean difference (MD) -0.12, 95% CI -0.18 to -0.05; 1745 participants; 1745; 4 studies; ACQ: MD 0.06, 95% CI 0.00 to 0.13; 1483 participants; 3 studies).There was some evidence to support small benefits of LAMA over LABA on lung function, including on our pre-specified preferred measure trough forced expiratory volume in one second (FEV1) (MD 0.05 L, 95% CI 0.01 to 0.09; 1745 participants, 4 studies). However, the effects on other measures varied, and it is not clear whether the magnitude of the differences were clinically significant.More people had adverse events on LAMA but the difference with LABA was not statistically significant. AUTHORS' CONCLUSIONS: Direct evidence of LAMA versus LABA as add-on therapy is currently limited to studies of less than six months comparing tiotropium (Respimat) to salmeterol, and we do not know how they compare in terms of exacerbations and serious adverse events. There was moderate quality evidence that LAMAs show small benefits over LABA on some measures of lung function, and high quality evidence that LABAs are slightly better for quality of life, but the differences were all small. Given the much larger evidence base for LABA versus placebo for people whose asthma is not well controlled on ICS, the current evidence is not strong enough to say that LAMA can be substituted for LABA as add-on therapy.The results of this review, alongside pending results from related reviews assessing the use of LAMA in other clinical scenarios, will help to define the role of these drugs in asthma and it is important that they be updated as results from ongoing and planned trials emerge.