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Denver, CO
Dr. Sutherland is Assistant Professor of Medicine, National Jewish Medical and Research Center.
Correspondence to: E. Rand Sutherland, MD, MPH, FCCP, Assistant Professor of Medicine, National Jewish Medical & Research Center, 1400 Jackson St, J220, Denver, CO 80206; e-mail: sutherlande{at}njc.org
International guidelines1 recommend the addition of inhaled corticosteroids to inhaled bronchodilators for the treatment of patients with COPD who have a FEV1 < 50% of predicted normal and who experience exacerbations at least once per year. This recommendation has driven aggressive use of inhaled steroids in COPD, with published series suggesting that upwards of 50% of patients with COPD receive at least one prescription for inhaled corticosteroids, independent of FEV1 or exacerbation frequency. While the widespread use of these drugs would suggest that a clear understanding of their benefit exists, unresolved questions remain for the clinician trying to understand the most appropriate clinical outcomes for assessing response in treated patients, as well as the mechanisms by which any beneficial effects might occur.
With regard to defining appropriate outcomes, a robust primary data set of large, placebo-controlled trials evaluating change in FEV1 in response to inhaled corticosteroids for 
12 months suggests that these agents have minimal impact on the rate of decline in lung function in COPD over the long term, when combined with short-acting bronchodilators.2345 These findings have been underscored by two independent metaanalyses67 that demonstrated at best a < 10 mL/yr improvement in the rate of FEV1 decline with inhaled corticosteroids. In a further contribution to this literature, Soriano and colleagues8 in this issue of CHEST (see page 682) now report additional findings from the Inhaled Steroid Effects Evaluation in COPD (ISEEC) study,9 using pooled analysis of individual subject data to reaffirm that while a transient beneficial effect of inhaled corticosteroids on FEV1 can be observed in the first 6 months of therapy, over the long term there is no appreciable effect on the rate of lung function decline. Thus, it is reasonable to conclude that numerous primary studies and secondary analyses have identified the inability of inhaled corticosteroids to modify FEV1, the primary defining and descriptive physiologic variable in COPD.1 What, then, should the clinician look for in determining whether his or her patient is benefiting from these drugs?
Many of these same "negative" studies reported beneficial effects of inhaled corticosteroids on nonphysiologic outcomes such as exacerbation frequency, symptoms, quality of life, and other measures of health status. These outcomes are arguably more meaningful to individual patients than is the FEV1 per se, and the fact that inhaled corticosteroids improve many of these outcomes has been used to justify their wide-scale use in COPD. However, these observations of benefit have been made in long-term studies with secondary outcome variables that often have demonstrated large relative but small absolute improvements, leaving residual uncertainty as to how much benefit an individual patient may experience with regard to these patient-centered outcomes as well as how quickly that benefit might be observed. What is also uncertain is the mechanism by which inhaled corticosteroids might have their effect, given reports that the inflammatory process in COPD is not typically corticosteroid responsive, either due to effects of cigarette smoking, the proportionally minor role that eosinophils play in the process, or possibly to disease-specific alterations of molecular pathways that induce steroid insensitivity.10
Additionally, at least three other questions need to be considered when contemplating inhaled corticosteroids for the patient with COPD: first, is the benefit of these drugs most likely to be obtained when used in combination with long-acting bronchodilators; second, do these agents reduce mortality; and third, are they safe? A number of studies utilizing combinations of either budesonide and formoterol or fluticasone and salmeterol have been performed, and a Cochrane systematic review11 of these studies has suggested that while the combination of an inhaled corticosteroid and a long-acting ß-agonist is more effective than placebo, there is heterogeneity between studies as to whether or not combination therapy reduces exacerbations or improves quality of life or lung function when compared to inhaled corticosteroids used alone. With regard to the question of mortality reduction, retrospective studies, including a previously published report9 from the ISEEC study group, have suggested that inhaled corticosteroid monotherapy reduces all-cause mortality in COPD by approximately 25% when compared with placebo. Whether this effect is due to a reduction in exacerbations or is mediated by alterations in systemic inflammation or other factors remains unknown, and the reduction in mortality observed in these secondary analyses remains to be confirmed by prospective studies. When published, the results of the now-completed Towards a Revolution in COPD Health study,12 a 3-year study with > 6,000 participants assessing the effect of placebo, fluticasone, salmeterol, and fluticasone/salmeterol combination on all-cause mortality in COPD, will provide prospectively obtained data on this important outcome. This study12 should also add to our understanding of the long-term safety of both fluticasone and salmeterol, particularly with regard to steroid-related adverse effects such as reduced bone mineral density, and increased fracture and cataract risk.
Important unanswered questions remain as to how best to utilize inhaled corticosteroids in our patients with COPD, although it is clear that the clinician cannot expect these agents to modify the long-term rate of lung function decline. Further studies are warranted to identify the outcomes most responsive to inhaled corticosteroids as well as to define the optimal place of these agents in COPD pharmacotherapy.
Footnotes
Dr. Sutherland has served as an advisor or consultant to Dey, GlaxoSmithKline, Pfizer, Talecris, and Schering-Plough, has received speaking honoraria from IVAX, and has received unrestricted investigator-initiated grant funding from GlaxoSmithKline.
References
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