title: LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.
abstract: BACKGROUND
  Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.
  
  
  METHODS
  This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.
  
  
  RESULTS
  Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L,P<0.0001), with patients more likely to achieve clinically important improvements in FEV1of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (bothP<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 andP=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).
  
  
  CONCLUSIONS
  The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.
authors.affiliation: Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Rodrigo
authors.affiliation: Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, UK; Observational and Pragmatic Research Institute, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Price
authors.affiliation: University of Texas Health Science Center; South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Anzueto
authors.affiliation: Medicines Evaluation Unit, National Institute for Health Research Respiratory and Allergy Clinical Research Facility, University Hospital of South Manchester NHS Foundation Trust, University of Manchester, Manchester, England, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Altman
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bader
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Patalano
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fogel
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kostikas
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016009:Chi-Square Distribution; D018450:Disease Progression; D004338:Drug Combinations; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D016017:Odds Ratio; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D020127:Recovery of Function; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004338:Drug Combinations; D018727:Muscarinic Antagonists
keywords: COPD; LABA/ICS; LABA/LAMA combinations; LAMA; meta-analysis