title: Medically treated exacerbations in COPD by GOLD 1-4: A valid, robust, and seemingly low-biased definition.
abstract: OBJECTIVE
  We hypothesized that medically treated exacerbations in COPD defined as treatments with oral corticosteroids alone or in combination with antibiotics by register linkage with a nationwide prescription registry is a valid, robust and low-biased measure of exacerbations.
  
  
  METHODS
  A total of 13,591 individuals with COPD in the Copenhagen General Population Study (2003-2013) were linked to the Danish prescription registry. Exacerbations were defined as dispensing of oral corticosteroids alone or in combination with antibiotics, dispensed less than four weeks apart during three years of follow-up. Construct validity of this definition of medically treated exacerbations was assessed by studying baseline determinants as well as by studying the association between GOLD 1 through 4 grades and time to first exacerbation during follow-up.
  
  
  RESULTS
  Among individuals with COPD, 964 individuals (7.1%) had at least one exacerbation during follow-up. At baseline, comparing those with versus without exacerbations during follow-up, FEV1, 72% of predicted vs. 85% (p < 0.001), previous exacerbations, 43% vs. 11% (p < 0.001), breathlessness, 33% vs. 14% (p < 0.001), and use of inhaled medications, 54% vs. 14% (p < 0.001) were associated with exacerbations. Compared to individuals with GOLD 1, the multivariable hazard ratio (HR) for exacerbations was HR = 17.4 (12.3-24.5, p < 0.001) for GOLD 4, HR = 4.8 (3.9-5.9, p < 0.001) for GOLD 3, and HR = 2.0 (1.7-2.3, p < 0.001) for GOLD 2. In sensitivity analyses, our definition of exacerbations was robust and without major biases.
  
  
  CONCLUSIONS
  Compared to individuals with GOLD 1, the risk of exacerbations was 17-fold for GOLD 4, 5-fold for GOLD 3, and 2-fold for GOLD 2. Medically treated exacerbations defined by register linkage seem a valid, robust, and low-biased measure of exacerbations in COPD.
authors.affiliation: Department of Respiratory Medicine, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Copenhagen, Denmark.
authors.forename: Truls S
authors.initials: TS
authors.lastname: Ingebrigtsen
authors.affiliation: The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Copenhagen, Denmark.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Marott
authors.affiliation: The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Copenhagen, Denmark; Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, University of Copenhagen, Kettegård Allé 30, 2650 Hvidovre, Copenhagen, Denmark; Department of Social Medicine, Institute of Public Health, University of Copenhagen, Øster Farimagsgade 5, 1014 København K, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Lange
authors.affiliation: Department of Clinical Pharmacology, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Hallas
authors.affiliation: The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Centre for Respiratory Medicine and Allergy, Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, Southmoor Road, M23 9LT Manchester, UK. Electronic address: jorgen.vestbo@manchester.ac.uk.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D003718:Denmark / Q000453:epidemiology; D011307:Drug Prescriptions / Q000706:statistics & numerical data; D004359:Drug Therapy, Combination; D004417:Dyspnea / Q000453:epidemiology; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000453:epidemiology; D018570:Risk Assessment / Q000379:methods; D014797:Vital Capacity / Q000502:physiology
chemical_list: D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents
keywords: Antibiotics; Epidemiology; Moderate exacerbations; Oral corticosteroids