Guidelines and care pathways recommend inhaled corticosteroids (ICSs) over longacting bronchodilators in the treatment of patients with severe chronic obstructive pulmonary disease (COPD).1, 2 A Cochrane review3 about the safety and efficacy of combined ICSs and longacting β2 agonists (LABAs) in one inhaler versus LABAs alone for COPD was published in September, 2012. Although the analysis was based on a large database (14 studies, 11 794 people), the conclusions were unclear about prevention of exacerbations, hospital admission, and mortality. Furthermore, moderate-quality evidence suggested an increased risk of pneumonia with ICS—LABA combinations. The authors concluded that more information about the relative benefits and adverse event rates of ICS—LABA combinations versus LABAs alone would be useful and that head-to-head comparisons are needed.3
Fluticasone furoate is a new ICS and vilanterol a new LABA. Both drugs are given once daily. A single inhaler combination of these drugs improved forced expiratory volume in 1 s (FEV1) after a short duration of treatment.4 In The Lancet Respiratory Medicine, Mark T Dransfield and colleagues5 report the results of the first long-term study comparing fluticasone furoate and vilanterol with vilanterol alone for major outcomes of COPD (ie, moderate or severe exacerbations). Two pooled multinational randomised controlled trials (study 1 and study 2) of 3255 patients with severe COPD ran for 52 weeks. Mean FEV1 after bronchodilators was 44—46% of predicted values. Three doses of fluticasone furoate were tested—50 μg, 100 μg, and 200 μg—all in combination with 25 μg vilanterol. The primary efficacy endpoint was the yearly rate of moderate or severe exacerbations. The authors defined moderate exacerbations as worsening symptoms of COPD (≥2 consecutive days) necessitating treatment with oral corticosteroids or antibiotics, or both; severe exacerbations were similar events that necessitated admission to hospital.
Dransfield and coworkers’ study5 is of great interest because it is, to my knowledge, the first investigating the combination of fluticasone furoate and vilanterol for major outcomes of COPD, and because it attempts to answer the queries that arose from the Cochrane review.3 Pneumonia occurrence was recorded and confirmed with chest radiographs. The study was very carefully done, although an independent expert panel did not assess severe adverse events, which might have led to underestimation of pneumonia risk.
The effect of fluticasone furoate and vilanterol compared with that of vilanterol alone is not large. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group. In study 2 and the prespecified pooled analysis, exacerbation rates were significantly lower in all fluticasone furoate/vilanterol groups than in the vilanterol only group. The frequency of only moderate exacerbations was significantly lower with fluticasone furoate and vilanterol than with vilanterol alone. Hospital admissions were uncommon in the studies and did not differ significantly between treatment groups. Thus, the additive effect of fluticasone furoate could not be shown—results that accord with those of the Cochrane review3 and reinforce the strength of evidence.
The safety of ICSs in COPD is a serious problem, which was underscored by Dransfield and colleagues’ results.5 Pneumonia (confirmed by radiography) and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone in studies 1 and 2 and the pooled analysis. Furthermore, severe cases of pneumonia were more frequent in the fluticasone furoate/vilanterol groups than in the vilanterol group. Eight pneumonia-related deaths were reported during treatment, seven participants taking 200 μg fluticasone furoate and one taking 100 μg fluticasone furoate. One case of fatal pneumonia was reported after treatment in the vilanterol only group. The authors raised concerns about the 200/25 μg dose. However, mortality was not increased in any study group, according with the results of Dong and colleagues.
Patients and clinicians should assess the potential benefits and risks of ICSs in severe COPD. For a practising physician, establishing which patients need ICSs (and which do not) is crucial. Randomised controlled studies published so far cannot answer this question because their results are based on means from large groups of patients. The phenotypic characteristics of patients who benefit from ICSs and those of patients prone to pneumonia would be of interest. Dransfield and coworkers’ study might enable an analysis of practical interest. It shows that the debate about ICSs in patients with severe COPD is not yet over, and suggests that a personalised medicine approach is needed for such patients.