Role of Inhaled Corticosteroids in Stable Chronic Obstructive Pulmonary Disease
Abstract & Commentary
Synopsis: A meta-analysis of the original data sets of randomized controlled trials in patients with moderately severe COPD showed a beneficial effect on FEV1 during two years of treatment with daily doses of inhaled corticosteroids.
Source: van Grunsven PM, et al. Thorax 1999;54:7-14.
Chronic obstructive pulmonary disease (COPD) is common and there is an increasing worldwide prevalence. It affects an estimated 15 million Americans and is the fourth most common cause of death in the United States. Despite an improved understanding of the disease, treatment has changed little over the past 20-30 years and COPD remains a major health problem worldwide. Smoking is the major risk factor for COPD, accounting for some 90% of cases. There are no available treatments proven to prevent or slow the progression of airflow obstruction in COPD other than smoking cessation. However, improved understanding of the molecular and cellular mechanisms involved has led to the identification of a variety of inflammatory mediators and proteases that contribute to the lung injury in COPD. Whether anti-inflammatory agents could alter the course of COPD by blocking these pathways is not known.
Inhaled corticosteroids are recognized as an effective anti-inflammatory therapy in asthma, and their early introduction is recommended by national and international guidelines. Since asthma and COPD have many features in common, it has been hypothesized that steroids should be effective in COPD. However, the only trials that have shown unequivocally positive results were those that did not exclude asthmatics. Studies of steroid use in COPD that used stringent criteria for the diagnosis of COPD have shown substantial short-term benefit in 15-30% of subjects. Similarly, trials of steroids during exacerbations of COPD have yielded more impressive results than in stable disease, suggesting that steroid response in individual patients may vary with time and/or circumstance. The role of inhaled corticosteroids in the long-term management of COPD is still unclear.
A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form.3-5 The primary question was: "Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?" The secondary questions were: "What is the point in time when inhaled corticosteroids start to have a significant effect on the course of lung function?" "Is there a dose effect relationship?" and "Which clinical characteristics predict the effect?"
van Grunsven and colleagues have carefully described their inclusion criteria that are based on most recent guidelines for COPD and excluded patients with "asthmatic features" from the original data. They addressed some of the shortcomings of the previous studies by including patients who were likely to have unequivocal COPD for reanalysis. Ninety-five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 mcg beclomethasone daily, 6 with 1600 mcg budesonide daily, and 8 with 800 mcg beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated.
No baseline differences were observed (mean age 61 years, mean FEV1 45% predicted). The estimated two years difference in pre-bronchodilator FEV1 was +0.034 1/year (95% confidence interval [CI] 0.005-0.063) in the inhaled corticosteroid group compared with placebo. The post-bronchodilator FEV1 showed a difference of +0.039 1/year (95% CI -0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. In the treatment group, six of the 95 subjects dropped out because of an adverse effect that may have been related to the treatment compared with two of the 88 patients in the placebo group. Worsening of the disease was the reason for dropout in four patients in the treatment group compared with nine in the placebo group.
Comment by Alan M. Fein, MD
The role of steroids in stable COPD is not yet settled. The current COPD guidelines recommend use of steroids only in patients who show objective benefit during a steroid trial.1,2 This rationale implies that there are two kinds of patients with COPD: those who do respond to steroids and those who don’t. The advent of inhaled steroid preparations has substantially lowered the risk of steroid therapy. Faced with a COPD patient in whom the treatment options with clear-cut benefit are limited, the use of inhaled steroids, a treatment that is judged to be safe, has become widespread in the absence of definite evidence of benefit.
Clearly, this interesting study approach has limitations that must be considered when accepting van Grunsven et al’s conclusions. Some of the data points were obtained by interpolation, as measurement intervals during the follow-up in one of the trials were two-monthly rather than three-monthly.4 No effect of smoking status was seen contrary to previous reports, as steroids may not protect the bronchial wall of the host against bacterial colonization, the beneficial effects on FEV1 with inhaled steroids were not accompanied by a lower number of exacerbations, which is thought to be due to bacterial super-infection. Contrary to general opinion, the use of beta-agonists did not have a deleterious effect on the progression of COPD in this study.
Despite its shortcomings, the most important finding of this study is that the use of high-dose inhaled steroids reduced the observed rate of decline in FEV1 by approximately 34 mL/year in patients with moderately severe COPD. The rate of decline in FEV1 in a COPD population is approximately 50-60 mL per year, with most rapid declines exceeding 80 mL per year. Survival in COPD correlates inversely with FEV1, and treatment that slows the accelerated decline in FEV1 might reduce mortality.
Different dosages of inhaled corticosteroids were used, although it is unlikely that this would affect the data as a majority of the patients received high-dose treatment. A large European trial of inhaled steroids in patients with mild COPD (EUROSCOP) has been presented, but not published, and has reportedly failed to show a distinct effect on lung function, which may be due to the low dose of inhaled corticosteroid (800 mcg budesonide). Two large European studies, the Copenhagen City Lung study (800-1200 mcg budesonide in mild COPD) and ISOLIDE (1000 mcg fluticasone in severe COPD) is about to be completed. Together, these results should give us a clear picture of the long-term effects of inhaled steroids in large groups of patients with COPD.
We presently stand on the threshold of a considerable increase in data concerning inhaled steroids in COPD. This study has provided clear evidence that inhaled corticosteroids may reduce the rate of decline in FEV1 in moderately severe COPD, but a number of unanswered issues remain, such as: optimal dose, duration of treatment, time course of action, and long-term side effects.
References
1. American Thoracic Society. Am J Respir Crit Care Med 1995;152:S77-S120.
2. British Thoracic Society. Thorax 1997;52(suppl 5).
3. Kerstjens HAM, et al. N Engl J Med 1992;327: 1413-1419.
4. Renkema TE, et al. Chest 1996;109(5):1156-1162.
5. Derenne JP. Am J Respir Crit Care Med 1995; 151:A463.
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