What to use INSTEAD of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) have had an important impact on the management of chronic obstructive pulmonary disease (COPD). When combined with an inhaled long-acting β-agonist (LABA), they improve lung function more than is the case with the LABA alone, improve health status and reduce the number of exacerbations patients experience [1]. There are data to suggest that they modify the decline in lung function and improve survival but these effects remain more controversial [1, 2]. There have always been concerns about the risks of developing osteoporosis or cataracts and even diabetes in COPD patients who use ICS drugs, although randomised controlled studies suggest that the impact of such changes are small in patients with more severe COPD [3]. However, there is now consistent evidence from randomised controlled trials that patients using fluticasone-based corticosteroids are more likely to develop pneumonia [4, 5]. The clinical significance of these events remains less certain [6, 7] as does the generalised ability of these findings to all ICS [8]. Nonetheless, concerns about the balance of the risks and benefits of ICS-based treatments has led to renewed interest in defining patients who could be managed as well with other therapies.

One way to establish whether ICS treatment should be continued is to stop it and see what happens. Early observational studies and randomised control trials suggested that acute withdrawal of ICS from the treatment regimen of COPD patients precipitated an exacerbation and/or increased symptoms [9, 10]. Recently, two relatively large studies have examined the effects of withdrawing ICS in rather different populations of patients who were clinically stable at the time of study entry. The larger of these, the Withdrawal of Inhaled Steroids During Optimised Management (WISDOM) trial, screened 3426 patients, of whom 2488 were randomised [11]. All the patients were given an ICS, a LABA and the long-acting antimuscarinic agent (LAMA) tiotropium for 6 weeks then randomised either to continue these drugs or to reduce slowly the dose of the ICS over 3 months, after which time they were managed on the LABA and LAMA alone. To the surprise of everyone, not least the investigators, there was no difference in the exacerbation rate during the period of ICS withdrawal, nor was there a difference in the overall exacerbation rate for moderate and severe events over the year as a whole. There was a suggestion that the number of severe exacerbations increased transiently, just after the ICS was completely withdrawn, and a difference of ∼50 mL in lung function emerged between the two treatments, in keeping with the known effects if ICS on forced expiratory volume in 1 s (FEV₁) [1]. Neither the prior exacerbation history nor the previous treatment used by the patient influenced these conclusions.

With hindsight, it would have been better to extend the follow-up period of this trial, as the original intent of the investigators was to try and define a corticosteroid-response subgroup of patients, something they were unable to do during the period when patients were not using ICS. Nonetheless, the data suggest that even patients with more severe disease, when clinically stable, can be managed for an extended period on two bronchodilators alone without coming to too much harm.

In this issue of the European Respiratory Journal (ERJ), Rossi et al. [12] report the results of the “Indacaterol: Switching Non-Exacerbating Patients with Moderate COPD from Salmeterol/Fluticasone to Indacaterol” (INSTEAD) trial. In this study, 581 patients with a mean post-bronchodilator FEV₁ of 64% predicted and no prior exacerbation history were recruited. Although current management guidance suggests such patients should not receive ICS treatment, all participants had been using these drugs for ≥3 months before study entry. At randomisation, 249 patients were allowed to continue with their ICS-LABA treatment while 247 received indacaterol, a once-daily LABA. Appropriate blinding was maintained and patients were followed for 6 months with monitoring of lung function, exacerbations and symptom-based end-points. In these patients, there were no significant differences in lung function, whether expressed as trough FEV₁ values or during an extended 24-h lung function monitoring after each dose at weeks 12 and 26. In a subset of patients where inspiratory capacity was measured, there were no differences observed between treatment groups. This suggests that in these COPD patients, a once-daily LABA produces similar changes in lung function to a twice-daily LABA plus ICS. Slightly more people withdrew while taking indacaterol, although the reasons for withdrawal were very similar in the groups and although the percentage of people experiencing an exacerbation was somewhat higher in the indacaterol group, the exacerbations rates were not different once the appropriate statistics were applied. No statistically significant differences at either 12 or 26 weeks were seen in the transition dyspnoea index or in the use of rescue medication, nor were there significant numbers of serious adverse events.

Unlike the WISDOM study, the INSTEAD trial was not formally powered for a noninferiority analysis. However, looking at the data, there are clearly no differences in any of the pre-specified outcomes. Unfortunately, the authors were not able to subdivide their patients by the more recent Global Initiative for Chronic Obstructive Lung Disease classification, which has been reviewed previously in the ERJ [13]. However, it is clear that the chronic use of ICS in patients with a mean FEV₁ >60% predicted is largely unnecessary, at least when the alternative is an effective long-acting inhaled bronchodilator. This study did not address whether other drugs such as LAMA would be as effective, and there are data that suggest that drugs such as tiotropium are better at prevent exacerbations and improving lung functions in COPD patients with more severe disease [14]. Moreover, tiotropium was more effective than indacaterol in preventing exacerbations of COPD in patients with more severe disease than those enrolled in the INSTEAD study [15].

Taken together, the results of the WISDOM and INSTEAD studies tell us that not all patients with COPD need an ICS and, thus, support the recommendations of current management strategies [16]. Should we then abandon ICS use in all severities of COPD? I suspect not, although I do believe we are beginning to define the value of such treatment with greater precision. Data from acute trials of oral corticosteroids in COPD exacerbations suggest that patients with a baseline eosinophil count that is raised by only modest degree are more likely to get benefit from the corticosteroids, whilst those who do not show this feature do not [17]. From the database study of elderly COPD patients a history of asthma was a strong identifying factor for patients who clearly benefitted from an ICS in their treatment regime [18]. Another possibility worth considering is that maximising treatment in patients with a degree of clinical instability and including an ICS in the management regimen is helpful in bringing the disease under control but may not be needed during periods of clinical stability. What is now clear is that the way we use ICS in COPD should change if we are to offer the safest and most effective treatment to our patients. Hopefully, future studies like INSTEAD will show us the best way to do this.

• Received October 1, 2014.
• Accepted October 4, 2014.

• ©ERS 2014