Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials

Background Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting beta(2) agonist is more protective than a once-daily longacting beta(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone. Methods We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of 0.70 or less after bronchodilators (and an FEV1 of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1: 1: 1: 1) on the basis of the Registration and Medication Ordering System to 25 mu g vilanterol alone or 25 mu g vilanterol combined with either 50 mu g, 100 mu g, or 200 mu g fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952). Findings 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 mu g fluticasone furoate/vilanterol group and the vilanterol only group (mean 0.90 events vs 1.05 events per year; ratio 0.9 [95% CI 0.7-1.0]). Because of the statistical hierarchy used, we could not infer significance for the 50 mu g and 100 mu g groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0.0398 for the 50 mu g group, 0.0244 for the 100 mu g group, and 0.0004 for the 200 mu g group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0.0141 for the 50 mu g group, <0.0001 for the 100 mu g group, and 0.0003 for the 200 mu g group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group. Interpretation Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.