Long-Term Treatment with Inhaled Budesonide in Persons with Mild COPD who Continue Smoking
Abstract & Commentary
Synopsis: This paper outlines the effect of the inhaled steroid budesonide on patients with mild COPD who continue to smoke. Pauwels and colleagues report that there was a significant early (6 months) difference between patients who received the steroid vs. placebo, which then remained throughout the entire trial (3 years). This difference was more marked for those patients who had less than a 36-pack-year smoking history.
Source: Pauwels RA, et al. N Engl J Med 1999;340: 1948-1953.
Chronic obstructive pulmonary disease (COPD) is a disease with progressive limitation of airflow. COPD occurs almost exclusively in smokers.1 Smoking cessation has been shown to decrease the rate of decline of lung function, but smoking cessation is often unsuccessful.1,2 The decline in lung function in COPD is related to inflammation in the airways and replacement of Clara cells by mucous cells. The loss of Clara cells and their anti-elastase secretion leads to COPD.3 Inhaled corticosteroids have been shown to decrease sputum neutrophil counts in patients with COPD who were still smoking.4 Many small studies have shown varying effects of inhaled corticosteroids on pulmonary function in COPD. Kerstjens et al showed that addition of an inhaled corticosteroid to maintenance beta 2-agonist reduced morbidity, hyperresponsiveness, and airway obstruction in patients with a spectrum of obstructive airway diseases, including asthma and COPD.5 Weir and Burge demonstrated an improvement in objective (FEV1) and subjective measurements after three weeks for COPD in the nonasthmatics.6 However, Keatings et al demonstrated no significant response to inhaled budesonide in patients with COPD with respect to lung function, peak flow, or shortness of breath.7
Pauwels and colleagues performed a parallel-group, double-blind, placebo-controlled, randomized, multicenter trial throughout Europe. The primary outcome variable was change over time of Forced Expiratory Volume in one second (FEV1) after use of a bronchodilator. A total of 1277 current smokers who failed smoking cessation and showed compliance with medications were randomized to receive budesonide (Pulmicort, Astra, Sweden) 400 mg twice daily or placebo for three years. Patients had mild to moderate obstructive lung disease (FEV1/FVC < 70%) with FEV1 between 50-100% of predicted outcome after bronchodilator treatment.
During the first six months the budesonide group had a small increase in FEV1 (17 mL/yr) vs. a decrease in the placebo group (-81 mL/yr). Over the next 2½ years the rates of decline in the two groups had no significant difference, with a decrease of 57 mL/yr in the budesonide group and 69 mL/yr in the placebo group. The median total decline over three years was 140 mL in the budesonide group and 180 mL in the placebo group. Subgroup analysis showed that over three years patients with less than 36 pack years of smoking at enrollment had a 120 mL decrease in FEV1 with budesonide versus a 190 mL decline with placebo (P < 0.001). Patients with greater than 36 pack years of smoking had a 150-mL decline with budesonide and a 160-mL decline with placebo (P = 0.57). The budesonide group had a significantly (P < 0.001) greater percentage of skin bruising (10%) than the placebo group (4%). All other side effects were not significantly different, including fractures, cataracts, myopathy, and diabetes. Decrease in bone densitometry was also not significant between groups except at the femoral trochanter, which, paradoxically, favored the budesonide group.
COMMENT BY DAVID OST, MD
Chronic obstructive pulmonary disease is a progressive disease. Smoking cessation is the only intervention known to reduce the rate of COPD progression. Unfortunately, it is not successful in the majority of cases. This has led investigators to develop medications that reduce the rate of decline in FEV1 in patients who continue to smoke. The Lung Health Study showed that inhaled ipratropium bromide along with smoking cessation teaching improved the FEV1 by 47 mL in patients within the first year, which then declined at a rate of 52 mL/yr in subsequent years.1 Previous studies with inhaled corticosteroids have been of short duration. In the current study, inhaled corticosteroids provided an initial improvement in FEV1 but, after six months, did not affect the rate of decline compared to placebo. This initial significant improvement remained until the end of the study. If one analyzes the subgroup data, it is evident that the improvement is due to the effect on patients with less than 36 pack years of smoking. It would be interesting to see what would happen to pulmonary functions if the budesonide treatment stopped after six months or was given intermittently during the trial. This study shows that inhaled steroids in patients with greater than a 36-pack-year smoking history has little effect but may be useful in those patients with less smoking history. Patients with concurrent asthma and COPD may also benefit from inhaled corticosteroids. At the current time, smoking cessation is still the best way to reduce the progression of COPD.
References
1. Anthonisen NR, et al. JAMA 1994;272:1497-1505.
2. Xu X, et al. Amer Rev Respir Dis 1992;146:1345-1348.
3. Jeffery PK. Thorax 1998;53:129-136.
4. Confalonieri M, et al. Thorax 1998;53:583-585.
5. Kerstjens HAM, et al. N Engl J Med 1992;327: 1413-1419.
6. Weir DC, Burge PS. Thorax 1993;48:309-316.
7. Keatings VM, et al. Am J Respir Crit Care Med 1997; 155:542-548.
The best method of slowing the decline of FEV1 in patients with COPD is:
a. inhaled ipratropium.
b. smoking cessation.
c. inhaled corticosteroids.
d. nothing can slow the rate of decline of FEV1 in COPD.