title: Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma.
abstract: BACKGROUND
  Maintenance treatment with long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) can relieve asthma symptoms and reduce the frequency of exacerbations, but there are limited treatment options for people who do not gain control on combination LABA/ICS. Long-acting muscarinic antagonists (LAMA) are a class of inhaled drug which have been effective for people with chronic obstructive pulmonary disease and are now becoming available for people with asthma to take alongside their LABA/ICS inhaler.
  
  
  OBJECTIVE
  To assess the effects of adding a long-acting muscarinic antagonist (LAMA) to combination long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) in adults whose asthma is not well controlled by LABA/ICS.
  
  
  METHODS
  We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to January 2016. We also searched ClinicalTrials.gov, the WHO trials portal, and reference lists of other reviews, and we contacted trial authors for additional information.
  
  
  METHODS
  We included parallel randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies met the inclusion criteria if they compared LAMA as an add-on to LABA/ICS versus LABA/ICS alone for adults with asthma. We included studies reported as full text, those published as abstract only, and unpublished data. Primary outcomes were exacerbations requiring oral corticosteroids (OCS), validated measures of asthma control, and serious adverse events (including mortality).
  
  
  METHODS
  Two review authors screened searches and independently extracted details on risk of bias and numerical data. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MD) using a random-effects model. We rated all outcomes using GRADE.
  
  
  RESULTS
  We found four double-blind, double-dummy trials comparing LAMA to placebo, including 1197 people with asthma taking combination LABA/ICS. One of the trials was designed to study glycopyrronium bromide but was withdrawn prior to enrolment, and the other three all studied tiotropium bromide (mostly 5 µg once daily via Respimat) over 48 to 52 weeks. People in the trials had a mean forced expiratory volume in one second (FEV1) of 55% of their predicted value, indicating severe asthma.People randomised to take tiotropium add-on had fewer exacerbations requiring oral corticosteroids than those continuing to take LABA/ICS alone, but the confidence intervals did not rule out no difference (OR 0.76, 95% CI 0.57 to 1.02; moderate quality evidence). Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS would have to take oral corticosteroids for an exacerbation compared with 271 if they took tiotropium as well (95% CI 218 to 333 per 1000). Analyses comparing the number of exacerbations per patient in each group (rate ratio) and the time until first exacerbation (hazard ratio) were in keeping with the main result. Quality of life, as measured by the Asthma Quality of Life Questionnaire (AQLQ) was no better for those taking tiotropium add-on than for those taking LABA/ICS alone when considered in light of the 0.5 minimal clinically important difference on the scale (MD 0.09, 95% CI - 0.03 to 0.20), and evidence for whether tiotropium increased or decreased serious adverse events in this population was inconsistent (OR 0.60, 95% CI 0.24 to 1.47; I(2) = 76%).Within the secondary outcomes, exacerbations requiring hospital admission were too rare to tell whether tiotropium was beneficial over LABA/ICS alone. There was high quality evidence showing benefits to lung function (trough FEV1 and forced vital capacity (FVC)) and potentially small benefits to asthma control. People taking tiotropium add-on were less likely to experience non-serious adverse events.
  
  
  CONCLUSIONS
  Tiotropium add-on may have additional benefits over LABA/ICS alone in reducing the need for rescue oral steroids in people with severe asthma. The effect was imprecise, and there was no evidence for other LAMA preparations. Possible benefits on quality of life were negligible, and evidence for the effect on serious adverse events was inconsistent. There are likely to be small added benefits for tiotropium Respimat 5 µg daily on lung function and asthma control over LABA/ICS alone and fewer non-serious adverse events. The benefit of tiotropium add-on on the frequency of hospital admission is still unknown, despite year-long trials.Ongoing and future trials should clearly describe participants' background medications to help clinicians judge how the findings relate to stepwise care. If studies test LAMAs other than tiotropium Respimat for asthma, they should be at least six months long and use accepted and validated outcomes to allow comparisons of the safety and effectiveness between different preparations.
authors.affiliation: Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, UK, SW17 0RE.
authors.forename: Kayleigh M
authors.initials: KM
authors.lastname: Kew
authors.forename: Karen
authors.initials: K
authors.lastname: Dahri
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy*; D018450:Disease Progression; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D000069447:Tiotropium Bromide / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D018727:Muscarinic Antagonists; D000069447:Tiotropium Bromide