title: Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD).
abstract: Three classes of inhaler medications are used to manage chronic obstructive pulmonary disease (COPD): long-acting beta-agonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS). When two classes of medications are required, LAMA plus LABA (LAMA+LABA) and LABA plus ICS (LABA+ICS) are often selected because these combinations can be administered via a single medication device. The previous Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidance recommended LABA+ICS as the first-line treatment for managing stable COPD in high-risk people of categories C and D. However, the updated GOLD 2017 guidance recommends LAMA+LABA over LABA+ICS.
  
  
  
  To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD.
  
  
  
  We performed an electronic search of the Cochrane Airways Group Specialised Register (2 February 2016), ClinicalTrials.gov (4 June 2016), and the World Health Organization Clinical Trials Search Portal (4 June 2016), followed by a handsearch (5 June 2016). Two review authors screened and scrutinised the selected articles.
  
  
  
  We included individual randomised controlled trials, parallel-group trials, and cross-over trials comparing LAMA+LABA and LABA+ICS for stable COPD. The minimum accepted trial duration was one month and trials should have been conducted in an outpatient setting.
  
  
  
  Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (OR), and continuous data as mean differences (MD), with 95% confidence interval (CI) using Review Manager 5. Exacerbations were measured by counting the number of people experiencing one or more exacerbation.
  
  
  
  We included 11 studies comprising 9839 participants in our quantitative analysis. Most studies included people with moderate to severe COPD, without recent exacerbations. One pharmaceutical sponsored trial that included only people with recent exacerbations was the largest study and accounted for 37% of participants. All but one study were sponsored by pharmaceutical companies, thus we rated them as having a high risk of 'other bias'. The unsponsored study was at high risk of performance and detection bias, and possible selective reporting.Five studies recruited GOLD Category B participants, one study recruited Category D participants, two studies recruited Category A/B participants, and three studies recruited participants regardless of category. Follow-up ranged from 6 to 52 weeks.Compared to the LABA+ICS arm, the results for the pooled primary outcomes for the LAMA+LABA arm were as follows: exacerbations, OR 0.82 (95% CI 0.70 to 0.96, P = 0.01, I2= 17%, low quality evidence); serious adverse events (SAE), OR 0.91 (95% CI 0.79 to 1.05, P = 0.18, I2= 0, moderate quality evidence); St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline, MD -1.22 (95% CI -2.52 to 0.07, P = 0.06, I2= 71%, low quality evidence); and trough forced expiratory volume in one second (FEV1) change from the baseline, MD 0.08 L (95% CI 0.06 to 0.09, P < 0.0001, I2= 50%, moderate quality evidence). Compared to the LABA+ICS arm, the results for the pooled secondary outcomes for the LAMA+LABA arm were as follows: pneumonia, OR 0.57 (95% CI 0.42 to 0.79, P = 0.0006, I2= 0%, low quality evidence); all-cause death, OR 1.01 (95% CI 0.61 to 1.67, P = 0.88, I2= 0%, low quality evidence); and SGRQ total score change from the baseline of 4 points or greater (the minimal clinically important difference for the SGRQ is 4 points), OR 1.25 (95% CI 1.09 to 1.44, P = 0.002, I2= 0%, moderate quality evidence).
  
  
  
  For the treatment of COPD, LAMA+LABA has fewer exacerbations, a larger improvement of FEV1, a lower risk of pneumonia, and more frequent improvement in quality of life as measured by an increase over 4 units or more of the SGRQ. These data were supported by low or moderate quality evidence generated from mainly participants with moderate to severe COPD in heterogeneous trials with an observation period of less than one year. Our findings support the recently updated GOLD guidance.
authors.affiliation: Department of Respiratory Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, Japan, 236-0004.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Horita
authors.affiliation: Metabolic Epidemiology Section, Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan, 104-0045.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Respiratory Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, Japan, 236-0004.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Global Health Nursing, St. Luke's International University, Graduate School of Nursing Sciences, 10-1 Akashi-cho, Chuo-Ku, Tokyo, Japan, 104-0044.
authors.forename: Erika
authors.initials: E
authors.lastname: Ota
authors.affiliation: Department of Respiratory Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, Japan, 236-0004.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Respiratory Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, Japan, 236-0004.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Respiratory Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa, Yokohama, Japan, 236-0004.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D002423:Cause of Death; D018450:Disease Progression; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005541:Forced Expiratory Volume; D006801:Humans; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D011014:Pneumonia / Q000209:etiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D018727:Muscarinic Antagonists