title: Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD.
abstract: Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design.
authors.affiliation: Group Practice and Respiratory, Allergy and Sleep Unit, Red Cross Maingau Hospital, Frankfurt, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kardos
authors.affiliation: GSK, Stockley Park, Middlesex.
authors.forename: Sally
authors.initials: S
authors.lastname: Worsley
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Primary Care Respiratory Research Unit, Instituto de Investigación Sanitaria de Palma IdisPa, Palma de Mallorca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Román-Rodríguez
authors.affiliation: BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
authors.affiliation: GSK, Stockley Park, Middlesex.
authors.forename: Hana
authors.initials: H
authors.lastname: Müllerová
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D001592:Benzyl Alcohols / Q000009:adverse effects / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000453:epidemiology*; D002722:Chlorobenzenes / Q000009:adverse effects / Q000627:therapeutic use*; D015897:Comorbidity; D004338:Drug Combinations; D019317:Evidence-Based Medicine / Q000379:methods*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D061214:Patient Safety; D018579:Patient Selection; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D011812:Quinuclidines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D000069447:Tiotropium Bromide / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D004338:Drug Combinations; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol; D000069447:Tiotropium Bromide
keywords: cardiovascular; cerebrovascular; real-world observational study; safety; umeclidinium; vilanterol