Inhaled corticosteroids in COPD

C hronic obstructive pulmonary disease (COPD) is arguably the most common chronic disease of the lungs at present and, by 2020, it will be the third leading cause of death worldwide. COPD is associated with a relentless decline in forced expiratory volume in 1 second (FEV1) and, in the later stages, the condition progresses to pulmonary hypertension and hypoxic respiratory failure. Few interventions have been shown to affect the outcome of COPD. The Lung Health Study-1 (LHS-1) showed that smoking cessation decreases the accelerated decline in FEV1 characteristic of this disease and, more recently, that smoking cessation is associated with decreases in cardiovascular and lung cancer mortality in patients with COPD. Furthermore, two randomised controlled studies of long term oxygen therapy (LTOT) showed that LTOT improves mortality in patients with COPD complicated by hypoxic respiratory failure. 5 Because so few interventions have been shown to affect mortality and FEV1 decline in COPD, two further outcomes have been studied arising from the observed close association between exacerbation frequency and health related quality of life. In the ISOLDE study (Inhaled corticosteroids in Obstructive Lung Disease in Europe), inhaled corticosteroids were shown to slow the decline in health status over time and also to decrease exacerbation frequency. Further statistical modelling has shown that the effect of inhaled corticosteroids on quality of life is largely due to their effect on exacerbation frequency. Recent studies have closed the loop between exacerbation frequency, mortality, and lung function decline by showing that patients with a history of frequent exacerbations have an accelerated decline in FEV1 9 10 and increased mortality from COPD. From these data one would therefore expect that interventions that reduce COPD exacerbations would also reduce COPD mortality. In this issue of Thorax we publish a study by Sin and colleagues who show, for the first time, that inhaled corticosteroids are associated with a reduction in all-cause mortality in patients with COPD. This study is important for several reasons. Firstly, it represents a major collaboration between academia and industry that allowed a pooled analysis of the original data from all seven longer term randomised controlled studies of the effects of inhaled corticosteroids in COPD. 13–18 This is a major strength of this study. Secondly, it is one of the few studies to report an intervention that affects all-cause mortality in COPD. Thirdly, this study shows that COPD mortality may be affected before developing end stage disease in COPD. A previous systematic review found no significant effect of inhaled corticosteroids on mortality but confirmed the beneficial effects of inhaled corticosteroids on exacerbation frequency. A recent meta-analysis of eight studies of inhaled corticosteroids (four of which are included in the current report) showed that inhaled corticosteroids decreased the decline in FEV1, 20 perhaps through their effect on exacerbations. Thus, before the report of Sin and colleagues, the major effect of inhaled corticosteroids in COPD was considered to be on reduction in exacerbations with no clear effect on mortality. The authors obtained the original anonymised data from each of the seven randomised placebo controlled trials of inhaled corticosteroids of at least 12 months duration. 13–18 The data were then pooled to form a dataset of 5085 patients with allowance for source effect. The study design is unique, and the authors should be commended for their contribution and effort in this regard. Sin and colleagues showed that inhaled corticosteroids reduced allcause mortality by 27%, and the effects were more pronounced in women, former smokers, and patients with moderate or severe disease. Sex differences in the natural history of COPD have been recognised for some time, with women showing a faster decline in FEV1. 21 However, as Sin and colleagues point out in the discussion to the paper, women with COPD have greater bronchial hyperreactivity than men and this factor may be associated with the observation that the effects of inhaled corticosteroids on mortality are more pronounced in women. Further studies are required to confirm these sex differences and to investigate the mechanisms associated with these observations. As with all post hoc analyses of this type, there are limitations. Firstly, only two of the studies (ISOLDE and LHS-2) included mortality on an intention to treat basis, while in the other five studies mortality data were only available for those who completed the study. 13 These two studies contributed 37% of the patients to the analysis and were also the two longest studies (34 and 42 months, respectively). The effect of ISOLDE and LHS-2 are therefore likely to influence the results more than the other included studies. The contribution of each study to the overall death rate is not shown in the report and the authors refer to this possible source of bias in their discussion. There are also differences in the pre-intervention treatment of patients between the different studies. For example, in the EUROSCOP study there was a 6 month run-in with no treatment but the ISOLDE study and the study by Calverley and colleagues 17 included a run-in period during which patients were treated with oral corticosteroids. Furthermore, the size of the included studies varied because they were each powered to detect different parameters. For example, four of the seven studies were powered to detect a difference in the decline in FEV1 of 12– 20 ml/year between inhaled corticosteroids and placebo controlled groups 13–15 and all failed to detect a difference, but the meta-analysis by Sutherland et al showed that this difference was in fact much smaller—of the order of 7.7 ml/ year. Finally, in all the included studies the difficulty in finding an effect on mortality hitherto has been because of the effect of dropouts. In a further analysis from the ISOLDE study, Calverley and colleagues showed that dropouts were greater in the placebo arm and were associated with a faster decline in FEV1, thus implying that mortality was probably greater in the placebo arm, which has now been supported by Sin et al. Currently, for patients with COPD, it may no longer be relevant to ask whether inhaled corticosteroids have a role, but the question still remains—which COPD patients should be given inhaled corticosteroids? The ISOLDE study showed that the effects of inhaled corticosteroids on exacerbation frequency were greatest EDITORIAL 977