title: Efficacy of roflumilast in the COPD frequent exacerbator phenotype.
abstract: BACKGROUND
  COPD exacerbations are associated with increased morbidity and mortality and can accelerate disease progression. The best predictor of future exacerbations is a history of previous exacerbations, which helps identify a frequent exacerbator phenotype. This post hoc analysis evaluated the effect of roflumilast, a drug known to reduce the COPD exacerbation rate, on exacerbation status.
  
  
  METHODS
  Pooled data from two 1-year, placebo-controlled, roflumilast (500 μg once daily) studies in patients with symptomatic COPD and severe airflow obstruction were evaluated (studies M2-124 and M2-125, ClinicalTrials.gov identifiers NCT00297102 and NCT00297115). A total of 3,091 patients were included in this analysis (62.5% with GOLD [Global Initiative for Chronic Obstructive Lung Disease] III COPD and 29.2% with GOLD 4 COPD). Based on their exacerbation frequency status in the previous year, patients were classified as frequent (two or more events) or infrequent (fewer than two events) exacerbators. Exacerbation frequency was analyzed at baseline and at year 1.
  
  
  RESULTS
  Among frequent exacerbators treated with roflumilast, 32.0% still had frequent exacerbations at year 1 compared with 40.8% of placebo-treated patients (risk ratio, 0.799; P = .0148). Among infrequent exacerbators, 17.5% of roflumilast-treated patients became frequent exacerbators at year 1 compared with 22.9% of those taking placebo (risk ratio, 0.768; P = .0018). The reduction in severe exacerbations leading to hospitalization/death was similar between subgroups and occurred independently of concomitant long-acting β2-agonists or previous inhaled corticosteroid treatment. When analyzed by severity of airflow limitation, 26.4% of roflumilast-treated frequent exacerbators with GOLD III COPD remained frequent exacerbators at year 1 compared with 38.9% of those taking placebo (P = .0042).
  
  
  CONCLUSIONS
  Treatment with roflumilast shifts patients from the frequent to the more stable infrequent exacerbator state.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00297102 and NCT00297115; URL: www.clinicaltrials.gov.
authors.affiliation: Centre for Respiratory Medicine, University College London, Royal Free Campus, London. Electronic address: j.wedzicha@ucl.ac.uk.
authors.forename: Jadwiga A
authors.initials: JA
authors.lastname: Wedzicha
authors.affiliation: School of Clinical Sciences, University Hospital Aintree, Liverpool, England; University Kiel, Kiel; Krankenhaus Grosshansdorf, Center for Pulmonology and Thoracic Surgery, Grosshansdorf, Konstanz, Germany; Department of Pulmonology C3-P, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Department of Respiratory Medicine, Konstanz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bredenbröker
authors.affiliation: Department of Data Science, Nycomed: a Takeda Company, Konstanz, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Brose
authors.affiliation: Department of Respiratory Medicine, Konstanz, Germany.
authors.forename: Udo-Michael
authors.initials: UM
authors.lastname: Goehring
authors.affiliation: School of Clinical Sciences, University Hospital Aintree, Liverpool, England; University Kiel, Kiel.
authors.forename: Peter M A
authors.initials: PMA
authors.lastname: Calverley
mesh_terms: D000368:Aged; D000631:Aminopyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology; D018450:Disease Progression; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast