Knowing when to stop: inhaled corticosteroids and COPD
Authors: Peter Calverley
Journal: European Respiratory Journal (2015)

The past decade has seen enormous efforts to identify better treatments for chronic obstructive pulmonary disease (COPD) and progress has been made [1, 2]. Despite this work controversies remain about which treatment to choose. Nowhere is this uncertainty more evident than in the use of inhaled corticosteroids (ICS). Most regulatory agencies and guidelines accept that ICS reduce exacerbations and improve health status and that combining ICS and long-acting beta-agonist (LABA) drugs produces larger changes in lung function and greater clinical benefits than either alone [3]. The large TORCH trial failed to conclusively show a difference in mortality between ICS-LABA treatment and placebo [4], although more recent database studies suggest that such an effect may be present in a "real-world" population of older patients [5]. Despite this evidence for efficacy some observers remain sceptical, raising doubts about the conduct and interpretation of the large clinical trials that have evaluated these drugs [6]. With hindsight a number of potential weaknesses have been identified but thus far no systematic bias has been shown to invalidate the primary results of these studies. The critics of ICS use fail to recognise that the perfect is the enemy of the possible when recruiting patients to clinical studies. A particular problem for COPD trialists has been the widespread use of the drug class under study which means that active treatment has been discontinued in order to allow randomisation to a study. As this therapy was likely given for a clinical reason initially it is no surprise that more patients randomised to the placebo limb of treatment withdraw [7, 8]. Premature withdrawal is thought to be a weakness in the conduct of these studies but in reality it tells us something of clinical relevance, namely that all things being equal the patients receiving less effective treatment could not continue with the study. As a result of this differential withdrawal the likelihood of finding a difference between the active and comparator groups is reduced, making any estimate of treatment effectiveness a conservative one. This may explain why data on outcomes from database studies such as that by Gershon et al. [5] are more impressive than the clinical trials data might lead us to expect. However there are downsides to the use of ICS in COPD, with the increased incidence of pneumonia the best-documented treatment risk [9]. This is particularly true for drugs containing the fluticasone moiety [10] where studies involving radiological confirmation of the diagnosis of pneumonia have shown a significantly greater number of events with ICS therapy [11]. These findings are seen in both clinical trials and administrative databases but there is a paradox as the risk of dying is not higher in ICS treated patients as might be expected given the more frequent pneumonic events [12]. This may reflect a change in the character of pneumonias associated with ICS use [13], although more data are needed before this issue can be properly resolved. Inhaled corticosteroids may help some patients with COPD, but we need to better define who those patients might be <http://ow.ly/RZGSh>