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Vancouver, BC, Canada
Drs. Sin and Man are affiliated with the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul’s Hospital, and the Department of Medicine (Division of Respirology), The University of British Columbia.
Correspondence to: Don D. Sin, MD, FCCP, James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul’s Hospital, Room 368A, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada; e-mail: dsin{at}mrl.ubc.ca
COPD is a worldwide epidemic, killing nearly 3 million people annually worldwide.1 Since 1965, the age-adjusted mortality rates for COPD have jumped by > 163%, representing the largest increase in mortality rates among all major causes of death in the Western world.2 Sadly, even the most optimistic estimates suggest that COPD mortality rates will increase by 50% over the next 15 years.1 Until now, aside from smoking cessation and supplemental oxygen therapy for hypoxic patients, no pharmacologic therapies have been demonstrated to enhance survival in COPD patients.3
It is now well-accepted that COPD is an inflammatory disorder that is characterized by both airway and systemic inflammation, and that the inflammatory process intensifies with progression of the disease.45 The inflammatory process appears to be harmful, accelerating the decline in lung function,6 increasing the risk of exacerbations,7 compromising health status, and impairing exercise tolerance and activities of daily living.8 These observations have fueled the notion that antiinflammatory therapies such as that with inhaled corticosteroids may improve health status and survival in COPD patients.
The role of inhaled corticosteroids, however, remains unsettled in COPD patients. Earlier, the dogma had been that the pulmonary inflammatory process in COPD is insensitive or perhaps even refractory to treatment with inhaled corticosteroids, and as such do not improve the health status of COPD patients. However, a careful examination of the clinical data suggests otherwise. A recent metaanalysis9 of randomized controlled trials has reported that when patients were treated for > 6 weeks with inhaled corticosteroids there was a reduction in inflammatory cells and proinflammatory cytokine production was suppressed in the sputum of COPD patients. Ozol and colleagues10 have shown that long-term therapy with inhaled corticosteroids suppressed the production of inflammatory cytokines not only in the sputum samples but also in the BAL fluid samples, further strengthening the notion that these drugs can reduce lung inflammation in COPD patients. At least two independent groups have reported811 that therapy with inhaled corticosteroids may also suppress systemic inflammation in stable COPD patients. This latter observation may be of particular clinical relevance as systemic inflammation has been associated with cardiac and vascular complications, including acute coronary syndromes, strokes, and arrhythmias,5 which collectively are the leading causes of hospitalization and the second leading cause of mortality in patients with mild-to-moderate COPD.12 To date, there have been few data generated on whether therapy with inhaled corticosteroids can reduce cardiovascular mortality in COPD patients.
In this issue of CHEST, Macie and colleagues (see page 640)13 conducted a pharmacoepidemiologic study using a large administrative health database and showed that in COPD patients aged 
65 years inhaled corticosteroid therapy following hospitalization was associated with a 25% relative risk reduction of all-cause mortality. In patients < 65 years of age, the survival benefits were even more impressive (53% relative reduction). Adjustments for a variety of confounding factors, the use of a nested-case control design, elimination of the immortal time bias, and exclusion of patients with a previous diagnosis of asthma made little difference to the overall findings, indicating the robustness of the association. These data add to the growing body of evidence indicating the beneficial effects of therapy with inhaled corticosteroids in reducing mortality in COPD patients.14
What made the present study interesting and provocative was that the main "driver" of the improved survival was the impressive 32% reduction in cardiovascular mortality related to therapy with inhaled corticosteroids. In contrast, such therapy had a modest nonsignificant effect in reducing the rate of respiratory deaths (approximately 13%). If true, the "effect" of therapy with inhaled corticosteroids on cardiovascular mortality in this COPD population would be as large, if not larger, than that for statins or angiotensin-converting enzyme inhibitors in the populations of patients with cardiovascular disorders.15
Pharmacoepidemiologic studies, however, are not randomized controlled trials, and contain many methodological limitations and biases that can distort the "truth." The present study by Macie et al13 is no different. While the authors carefully conducted the analysis using sophisticated statistical techniques and avoided many methodological pitfalls, we cannot discount the possibility of residual or external confounding or biases. Furthermore, the present study did not confirm the diagnosis of COPD by lung function measurements and could not stratify (or even document) the severity of the airflow limitation in this population. For these and other reasons, the data from the present study should not be considered definitive.
However, these data should not be easily dismissed. Systemic inflammation plays an important role in the pathogenesis of atherosclerosis and plaque rupture,5 and corticosteroids can cool the "fire" in the lungs and blood vessels of COPD patients.811 Moreover, there are a growing number of publications supporting the findings of the present study. Huiart and coworkers,16 for instance, demonstrated a 32% reduction in the risk for acute myocardial infarction when low-dose inhaled corticosteroids were dispensed to COPD patients, compared with the risk among nonusers of corticosteroids. In a post hoc analysis of a large randomized controlled trial, the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease trial17 investigators showed a 40% reduction in the cardiovascular event rate in patients who were assigned to receive inhaled budesonide compared with those assigned to receive placebo over a 3-year period. Most importantly, the Inhaled Steroid Effects Evaluation in COPD group has shown14 a 27% reduction in all-cause mortality in COPD patients who received inhaled corticosteroids compared with those who received placebo. Collectively, these data raise the tantalizing possibility that therapy with inhaled corticosteroids may be able to reduce mortality, and especially cardiovascular mortality, in COPD patients. Before incorporating this idea into clinical practice, however, more clinical and animal work is needed to better understand the mechanisms by which inhaled corticosteroids may reduce cardiovascular morbidity and mortality in COPD patients, and, more importantly, to identify novel therapeutic targets that can effectively reduce the growing health burden of COPD.
Footnotes
The authors have received honoraria for speaking engagements from GlaxoSmithKline (GSK) and AstraZeneca, and for consultative services from GSK. They have also received research funding from GSK. These two companies make inhaled corticosteroids.
References
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