Clinical Update
Inhaled corticosteroids and COPD

CMAJ 2000;163(3):326

Background

Although inhaled corticosteroid therapy has been well validated as the mainstay for the pharmacological management of asthma,¹ its role in the treatment of chronic obstructive pulmonary disease (COPD) remains less certain.

Question

What is the effect of long-term inhaled corticosteroid therapy on lung function, frequency of exacerbations and health status in patients with moderate to severe COPD?

Design

In this double-blind clinical trial, conducted in 18 hospitals in the United Kingdom, 751 patients with nonasthmatic COPD were randomly assigned to receive either fluticasone, 500 µg twice daily, or placebo. All subjects were given a 14-day course of prednisolone, 0.6 mg/kg daily, before randomization. Bronchodilator therapy with salbutamol or ipratropium bromide, or both, was continued during the trial, and the use of theophyllines and nasal and ophthalmic corticosteroids was also allowed. Subjects were seen quarterly for 3 years to measure their forced expiratory volume in 1 second (FEV₁) and to record self-reported exacerbations, and every 6 months to measure their health status and serum cortisol levels. Exacerbations were defined as worsening respiratory symptoms requiring orally administered corticosteroids or antibiotics, or both, and health status was measured using the St. George's Respiratory Questionnaire, a disease-specific instrument. Subjects were withdrawn if they reported more than 2 exacerbations in 3 months that required treatment with corticosteroids.

Results

The subjects were predominantly male (74%), and the mean age was 64 years. The mean number of cigarette pack-years was 44 at the time of randomization; about 40% of the subjects smoked throughout the trial. The mean FEV₁ was 1.4 L (50% predicted), in keeping with moderate to severe COPD. Each group demonstrated a slight improvement in FEV₁ (by about 60 mL) after taking prednisolone. In the placebo group, however, the mean FEV₁ fell within 3 months to pre-prednisolone levels and remained at least 70 mL lower than in the fluticasone group at each 3-month interval throughout the study period (p < 0.001). In the fluticasone group, there was no correlation between prednisolone response and subsequent response to inhaled corticosteroid therapy. Over the study period, the rate of FEV₁ decline did not differ between the fluticasone and placebo groups (50 v. 59 mL/yr respectively, p = 0.16). However, patients receiving fluticasone experienced 25% fewer exacerbations (0.99 v. 1.32 per year, p = 0.026) and a significantly slower decline in health status (p = 0.004). Withdrawal rates were high in both groups (fluticasone 43%, placebo 53%), but withdrawals related to respiratory disease (chiefly exacerbations of COPD) were significantly more frequent in the placebo group (25% v. 19%, p = 0.034). Rates of adverse events were comparable, with a slightly higher incidence of hoarseness, throat irritation and oropharyngeal candidiasis in the fluticasone group. Although serum cortisol levels were slightly decreased in that group as compared with the placebo group (p < 0.032), the levels were no more than 5% below the lower limit of normal at any time.

Commentary

Results from this trial were similar to those from 2 previously published studies of long-term use of inhaled corticosteroid therapy for COPD: it showed a modest improvement in FEV₁ but no effect on the rate of FEV₁ decline.^2,3 However, this study differed from the others because, in addition to assessing physiologic end points, it measured exacerbation rates and quality of life. Although the study's chief limitation was the high withdrawal rates in both groups, it is conceivable that the higher rate of withdrawal in the placebo arm may have led to an underestimate of treatment effect.

Practice implications

Although this study confirms that long-term inhaled corticosteroid therapy does not alter the rate of decline of FEV₁ in COPD, it does provide evidence of modest clinical benefit in terms of health status and frequency of exacerbations. These findings add a measure of justification for what is fast becoming widespread practice in the management of patients with this common condition. — Donald Farquhar

The Clinical Update section is edited by Dr. Donald Farquhar, head of the Division of Internal Medicine, Queen's University, Kingston, Ont. The updates are written by members of the division.

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1. Boulet LP, Becker A, Bérube D, Beveridge R, Ernst P, on behalf of the Canadian Asthma Consensus Group. Canadian asthma consensus report, 1999. CMAJ 1999;161(11 Suppl):S24-7. [MEDLINE]
2. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;353:1819-23. [MEDLINE]
3. Pauwels RA, Lofdahl CG, Latinen LA, Schouten JP, Postma DS, Pride NB, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Pulmonary Disease. N Engl J Med 1999;340:1948-53. [MEDLINE]

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