title: Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk.
  
  
  METHODS
  In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40-80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676.
  
  
  RESULTS
  Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1-15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1-14]), but not vilanterol (difference -2 mL per year [95% CI -8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75-1·14]) with similar findings for fluticasone furoate (0·90 [0·72-1·11]) and vilanterol (0·99 [0·80-1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups.
  
  
  CONCLUSIONS
  In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Centre for Respiratory Medicine and Allergy, Manchester Academic Health Sciences Centre, The University of Manchester and South Manchester University Hospital NHS Foundation Trust, Manchester, UK. Electronic address: jorgen.vestbo@manchester.ac.uk.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Research & Development, GlaxoSmithKline, Stockley Park, Middlesex, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Anderson
authors.affiliation: University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
authors.affiliation: University of Liverpool, Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
authors.affiliation: Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Bartolome R
authors.initials: BR
authors.lastname: Celli
authors.affiliation: Research & Development, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Crim
authors.affiliation: University of Michigan Health System, Ann Arbor, MI, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Research & Development, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Yates
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001592:Benzyl Alcohols / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002722:Chlorobenzenes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone / Q000627:therapeutic use*; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; C550468:vilanterol; D000068298:Fluticasone