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Dean, Faculty of Medicine, University of Manitoba.
Therapeutic trials of corticosteroids in stable COPD have been going on for 40 years,1 and the occasion for this editorial is another such trial in this issue of CHEST (see page 31), a good indication that the role of steroids in COPD is not yet settled. Why is this the case? First, steroids unquestionably work in asthma, and asthma has features in common with COPD, therefore, steroids "ought" to work in COPD. However, one could argue that the only trials that have shown unequivocally positive results were trials that did not exclude asthmatics.2 ,3 Second, many of the trials in patients fulfilling stringent criteria for COPD have shown substantial short-term benefit in some 15 to 30% of subjects;4 ,5 these benefits seemed too large to be accounted for by random variation, and were not predictable on the basis of the usual baseline characteristics, including those thought to relate to asthma. Third and finally, the advent of inhaled steroid preparations has substantially lowered the risk of steroid therapy, so that the size of a practically useful benefit has decreased. Indeed, in many areas of North America at least, the use of inhaled steroids in COPD has become widespread in the absence of clear evidence of benefit.
The study from Kyoto by Nishimura and colleagues in this issue is reminiscent of the short-term, crossover, double-blind trials of the 1980s, the major difference being that high-dose inhaled beclomethasone dipropionate (BDP) was used as opposed to systemic agents. A well-characterized group of 34 stable patients with moderate to severe COPD were studied: the baseline FEV1 ranged from 15 to 66% of predicted normal. BDP was given at a dose of 3 mg/d for 4 weeks and crossed over with placebo in double-blind fashion; there was apparently no washout period between treatments, but the authors sought to avoid carryover effects between treatments by collecting data during only the last 2 weeks of each treatment period. This was successful to the extent that there was no significant order effect observed in the results. The dose of BDP was deliberately set at the upper limits of those usually employed on the argument that the investigators were interested in the "maximum" benefit obtainable with inhaled therapy. This was certainly a very high dose. Outcomes were essentially spirometric measurements and diary data including peak expiratory flow (PEF) and symptom scores. The group as a whole showed better lung function on BDP than on placebo, but mean differences were small: FEV1 differed by about 10% (0.1 L) and PEF by less. There was significantly less wheeze and dyspnea on BDP than on placebo, but not less cough and sputum. Patients preferred BDP to placebo, but this preference was better related to a decline in lung function during the placebo period than an improvement on BDP. The BDP-placebo difference in FEV1 was greatly influenced by five patients who had increases of 0.24 to 0.51 L (mean, 0.34 L) on BDP; these increases were outside the 95% confidence limits of the responses to placebo. Nishimura et al describe these individuals as "steroid responders" and argue that steroid therapy should be limited to such responders. This argument is based upon the high price of inhaled steroids, by a significant association of BDP with adverse side effects including sore throat and hoarseness, and by the evidence of systemic effects of BDP.
How are we to interpret this interesting and carefully done study? It is supportive of current COPD guidelines,6 ,7 which recommend use of steroids only in patients who show objective benefit during a steroid trial. Implicit in this rationale is that there are two kinds of patients with COPD: those who do respond to steroids and those who don't. In other words, steroid response in COPD patients has a bimodal distribution. Some studies5 support this view, but others do not. Indeed, Nishimura and colleagues show their individual responses, and a bimodal distribution is not clearly evident. If steroid response is, in fact, normally distributed among patients with COPD, then "steroid responders" are simply individuals who fall at one end of the normal distribution. One then assumes that the people at the extreme(s) of the distribution are different from the others in the absence of any a priori reason to do so. Under these circumstances, steroid therapy also assumes that these extreme responses are reproducible, something that has not, to my knowledge, been confirmed. Indeed, trials of steroids during exacerbations of COPD8 have yielded more impressive results than in stable disease, suggesting that steroid response in individual patients may vary with time and/or circumstance. On the other hand, one could argue that the most important finding of Nishimura et al is that steroids tended to increase FEV1 slightly in most or all of the patients as compared to placebo. If this is true, then the question is whether the risk-benefit ratio of such a small increase is acceptable; in considering this, we must recognize that the local and systemic side effects observed by Nishimura and colleagues were related to their very high dose of BDP, and that similar benefits might be obtained at lower doses with less side effects.
We presently stand on the threshold of a considerable increase in data, and one hopes, knowledge, concerning inhaled steroids in COPD. A multinational study of the effects of 1 mg/d of inhaled fluticasone in COPD over 6 months has just been published.9 There was a suggestion that the frequency of severe exacerbations was decreased, but this is an extremely difficult end point to ascertain with certainty. There were also small improvements in lung function and decreases in complaints of cough and sputum, though not of dyspnea. Lung function changes were similar to the mean data of Nishimura and colleagues; on steroids, lung function improved some 10%, about what one would expect to see with bronchodilator therapy. The clinical significance and risk-benefit ratio of such a result is not clear to this reviewer. A very large European trial of inhaled steroids in patients with mild COPD (EUROSCOP) has been presented verbally but not published, and has reportedly failed to show a distinct effect on lung function.10 A similar North American study is nearing completion. A recent Canadian study11 ,12 has shown no benefit of inhaled steroids in patients with severe COPD, and a British study of a similar population is about to be completed.13 Together, these results should give us a clear picture of the long-term effects of inhaled steroids in large groups of patients with COPD. It is less clear whether they will provide us road maps as to how to deal with individual patients.
References
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