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(Chest. 1999;115:31-37.)
© 1999 American College of Chest Physicians

The Effect of High-Dose Inhaled Beclomethasone Dipropionate in Patients With Stable COPD*

Koichi Nishimura, MD; Hiroshi Koyama, MD; Akihiko Ikeda, MD; Mitsuhiro Tsukino, MD; Takashi Hajiro, MD; Michiaki Mishima, MD and Takateru Izumi, MD, FCCP

* From the Department of Respiratory Medicine, Graduate School of Medicine (formerly the Chest Disease Research Institute), Kyoto University, Sakyo-ku, Kyoto, Japan.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The benefits of inhaled corticosteroids in the management of COPD are less apparent than they are in asthma therapy, and the potential for adverse systemic effects of high-dose inhaled corticosteroids has been recognized recently. It is therefore essential to know the maximal obtainable benefits in order to assess the risk/benefit ratio of this treatment.

Purpose: The aim of this study was to investigate the maximal obtainable benefits of high-dose inhaled corticosteroids, 3 mg/d of beclomethasone dipropionate (BDP), when used in combination with adequate doses of regular bronchodilators in patients with stable COPD.

Study Design: Thirty patients with stable COPD completed a randomized, double-blind, placebo-controlled cross-over trial with either 3 mg/d of BDP or with a matching placebo using a metered-dose inhaler with a spacer device for 4 weeks during each treatment period. All of the patients continued to inhale both 400 µg of salbutamol qid and 80 µg of ipratropium bromide qid.

Results: The mean prebronchodilator FEV1 was 0.97 ± 0.35 L during the placebo period and 1.08 ± 0.38 L during the BDP period (p < 0.001). While on BDP, five patients demonstrated a response in their FEV1 of more than 8.5% of the predicted value, which was above the range that covered 95% of the distribution of the placebo response. The mean absolute improvement in the FEV1 in these 5 objective responders was 0.34 ± 0.10 L, compared to 0.06 ± 0.09 L in the 25 objective nonresponders. Symptom scores for wheezing and dyspnea were significantly better with BDP than with placebo. Hoarseness and sore throat were associated more with BDP treatment.

Conclusion: Although a considerable minority of patients benefited substantially from this treatment, the overall outcome does not seem to justify the widespread use of this treatment in the light of increasing recognition of the potential adverse systemic effects of high-dose inhaled corticosteroids.

Key Words: beclomethasone dipropionate • COPD • corticosteroid


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It has been well established that inhaled corticosteroids are the first line of therapy for chronic asthma. However, their role in the management of COPD is less apparent. Earlier studies have failed to demonstrate any beneficial effects of moderate doses of inhaled corticosteroids, <= 800 µg/d of beclomethasone dipropionate (BDP), in COPD patients.1 ,2 The reported efficacies of higher doses of inhaled corticosteroids are not consistent; Weir et al3 ,4 found that there was a significant improvement with BDP at dosages of 1,500 µg/d and 3,000 µg/d, whereas Auffarth et al5 reported placebo-controlled studies of COPD patients in which no improvement was demonstrated with 1,600 µg of budesonide. In addition, the safety of long-term, high-dose inhaled corticosteroid therapy has not been fully established; and the potential for the systemic adverse effects of high-dose inhaled corticosteroids are now being increasingly recognized.6 ,7 ,8 ,9 ,10 Therefore, it is crucial to estimate the risk/benefit ratio of high-dose inhaled corticosteroids in COPD patients. It would be difficult to determine the precise prevalence and severity of the systemic effects of long-term, high-dose inhaled corticosteroid therapy. However, it is also essential to know the maximal obtainable benefits in order to assess the risk/benefit ratio of the treatment. The aim of this study was to investigate the maximal obtainable benefits of high-dose inhaled corticosteroids, 3 mg/d of BDP, when used in combination with adequate doses of regular bronchodilators in patients with stable COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
Thirty-four patients with stable COPD were recruited from the patients who regularly visited the outpatient clinic at the Chest Disease Research Institute, Kyoto University over several months. Patients that had experienced no acute exacerbation of airflow obstruction within the preceding 3 months were considered to have stable COPD. The patient inclusion criteria for the study were as follows: age over 55 years; a history of cigarette smoking of > 20 pack-years; chest radiographs showing hyperinflation with or without a vascular deficiency pattern suggestive of pulmonary emphysema; a maximum FEV1/FVC ratio of < 0.7 after bronchodilator; and an FEV1 of < 80% of the predicted value. Patients with any history of asthma, heart disease, or any other significant medical condition were excluded. Patients treated with inhaled or systemic steroids during the preceding 3 weeks were also excluded. Education on the inhalation technique using a metered-dose inhaler (MDI) equipped with an InspirEase spacer device (Schering-Plough KK; Osaka, Japan) and the recording of peak expiratory flow rate (PEFR) and symptom scores was provided prior to the study. Compliance was confirmed to be satisfactory by an attending physician. Inhalation of the drugs was performed as follows: the canister was activated into the spacer attached to the MDI held in the mouth, a slow inhalation was made from the functional residual capacity until the total lung capacity was reached, and the breath was held for at least 5 s. Patients with a poor technique were excluded from the study. Written informed consent was obtained from each patient.

Study Design
On the first day of the study, all of the patients performed baseline pulmonary function tests 12 h after the withdrawal of inhaled bronchodilators. The functional residual capacity was determined by body plethysmography (MBR-600; Nihon Kohden; Tokyo, Japan), and the residual volume was calculated as the functional residual capacity minus the expiratory reserve volume measured by spirometric testing. The total lung capacity was determined as the sum of the vital capacity plus the residual volume. Static compliance and airway resistance were also measured by body plethysmography. The diffusing capacity of the lung for carbon monoxide was measured by the single-breath technique (CHESTAC-65; Chest; Tokyo, Japan). The reversibility of the FEV1 to 400 µg of salbutamol was measured after these pulmonary function tests were completed using an InspirEase-equipped MDI. The spirometry was measured before and 15 min after the inhalation. The dose of 3,000 µg of inhaled BDP was administered in 750-µg increments qid, or a matching placebo was administered over a 4-week period in a randomized, double-blind, placebo-controlled cross-over fashion (Fig 1 ). All of the patients continued to inhale 400 µg salbutamol qid and 80 µg ipratropium bromide qid using a MDI throughout the study period. In 11 patients, sustained-release theophylline was also given. All other drugs were withheld for at least 4 weeks prior to and during the study period.



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  		Figure 1. Study design.

 
The patients visited the outpatient clinic at 4-week intervals. Medication inhalation was withheld for at least 12 h before every visit. To ensure that the drugs were administered with deep inhalation, the inhalation technique was carefully observed by the same physician (K.N.) at each visit. The physician also carefully observed all of the spirometric measurements. Blood samples were collected at each visit and were stored until the study was completed. The serum theophylline concentrations were determined by fluorescent polarization immunoassay using an analyzer (TDx; Dainabot; Tokyo, Japan). Compliance was checked by recovery and weighing of all the canisters of the MDI and by monitoring daily records.

Outcome Measures
Acute bronchodilator responses to the inhaled bronchodilators were assessed at every visit to the clinic. Spirometry was performed before, and 15 and 60 min after the inhalation (four puffs) of both 400 µg of salbutamol and 80 µg of ipratropium bromide using an InspirEase-equipped MDI. Three consecutive flow-volume curves were recorded according to the methods described in the American Lung Association 1994 update,11 with the patients standing during the measurements. The spirometer (Autospiro AS-600; Minato Medical Science; Osaka, Japan) was calibrated with a 2.0-L syringe before each measurement. The largest FEV1 and the largest FVC of three acceptable maneuvers were then analyzed. The predicted values of the FEV1 and FVC were those calculated according to the Japan Society of Chest Disease.12 The acute bronchodilator responses of the FEV1 and the changes in the response to BDP or placebo were expressed as a percentage of the predicted values of FEV1.

Daily home measurements of PEFR were obtained four times a day during the entire study period before and 15 min after inhalation of the bronchodilators using a mini-Wright peak flow meter (Clement Clarke International; London, UK). The patients recorded the greatest value from three readings for each recording. Symptoms of cough, sputum, wheezing, and shortness of breath, rated on a scale of one to four (1 = minimum to 4 = severe), were noted in a diary. The presence or absence of adverse side effects such as irritation in the mouth, sore throat, hoarseness, dizziness, and others were also recorded daily during the entire study period. The incidences were compared also on a person-per-day basis between the two treatment periods. To exclude any carryover effects of inhaled BDP, daily PEFR and symptom scores for the last 14 days of each 4-week period were analyzed.13

At the end of the study, all of the patients were asked to compare the two different treatment periods with respect to their clinical well-being. When a patient identified one of the treatment periods as being superior to the other, and the preferred period agreed with the active treatment period, then the patient was defined as a subjective responder. Otherwise the patient was classified as a subjective nonresponder.

Statistical Analysis
All of the data are expressed as the mean (± SD). The significance of differences between the values observed during treatment with BDP and the placebo was analyzed by repeated-measures analysis of variance and the least significant difference test. When appropriate, the means were compared using a two-tailed paired t test. The daily symptom scores were analyzed using a nonparametric analysis of variance and the Wilcoxon signed-rank test. Comparisons of the baseline characteristics between responders and nonresponders were performed by an unpaired Student's t test for normally distributed continuous data, a Mann-Whitney U test for nonparametric data, and an {chi}2 test for categorical data. For all tests, p < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Four of the 34 patients were withdrawn or excluded from the study: one because of a respiratory tract infection during the placebo period, one because of an unrelated pneumothorax during the placebo period, one because of self-withdrawal during the placebo period, and one because of poor compliance as judged by canister weighing. Consequently, 30 patients were evaluated.

The baseline clinical data for the 30 patients are shown in Table 1 . In 16 patients, BDP was administered during the first treatment period, followed by the placebo period; 14 patients received the placebos first. In 11 patients, sustained-release theophylline was given throughout the study periods. The average serum theophylline concentrations in these patients were 15.0 ± 6.3 µg/mL at the end of the placebo period and 15.5 ± 6.1 µg/mL at the end of the BDP period. Theophylline was not detected in the blood at the end of both treatment periods in patients who had not been prescribed the drug.


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  		Table 1. Baseline Clinical Data for 30 Patients Who Completed the Study

 
Lung Functions
The results of the spirometric measurements at the end of each treatment period are shown in Table 2 ; treatment with BDP resulted in a statistically significant improvement in the FEV1 and FVC over the placebo treatment, and the bronchodilator response was well preserved in the BDP treatment period. Both preinhalation and postinhalation values of the daily PEFR were significantly higher in the last 14 days of the BDP period than in the placebo period, respectively: 300 ± 90 L/min vs 320 ± 100 L/min for preinhalation, and 340 ± 100 L/min vs 360 ± 100 L/min for postinhalation (p < 0.01 for both comparisons). No order effects were found between the BDP-first and placebo-first regimens in the measurements of lung functions.


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  		Table 2. FEV1 and FVC Before and After the Inhalation of Bronchodilators*

 
In order to assess the response to the treatment in individual patients, the changes in the prebronchodilator FEV1 in response to the active drug or placebo were calculated for each patient. When compared to the baseline period, five patients (16.7%) demonstrated a response of their FEV1 of more than 8.5% of the predicted FEV1 on BDP, which was above 95% confidence limit of the placebo response. The mean absolute improvement in the FEV1 in these five objective responders was 0.34 ± 0.10 L (range, 0.24 to 0.51), as compared to that of 0.06 ± 0.09 L in the objective nonresponders. Only the peripheral eosinophil counts showed a significant correlation with the FEV1 response to BDP among the baseline characteristics shown in Table 3 , although the correlation was weak (r = 0.38, p < 0.05). The histogram of the changes in the prebronchodilator FEV1 (% predicted) at the end of both treatment periods is shown in Figure 2 . There was a weak positive correlation between the changes in the prebronchodilator FEV1 (% predicted) in response to BDP and those in response to placebo (r = 0.37, p < 0.05). As there was no significant order effect in this correlation, this may be partly explained by a lower-than-usual FEV1 at the baseline spirometric measurements in some of the patients. Whereas one of the five objective responders had a peripheral blood eosinophilia of > 400/mm3, none of the objective nonresponders had eosinophilia (p = 0.055). Seven patients had raised serum Ig E levels of > 400 IU/mL: one of them was an objective responder and six were nonresponders (p = 0.847). Three of the objective responders were on theophylline, while eight of the nonresponders were prescribed the drug (p = 0.236).


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  		Table 3. The Individual Data in Five Objective Responders Contrasting Them With the Mean Results in Nonresponders

 


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  		Figure 2. The distribution of changes in FEV1 in response to BDP or placebo therapy, expressed as a percent of the predicted value. Shaded columns show the response to BDP treatment. Open columns show the response to the placebo.

 
Subjective Response
At the end of the study period, 15 patients were found to be subjective responders. Only one patient preferred the placebo period to the BDP period; the remaining 14 patients recognized no subjective difference between the two treatment periods. None of the baseline clinical characteristics shown in Table 1 were significantly different between the subjective responders and subjective nonresponders. Interestingly, there was no significant association between the changes in the FEV1 on BDP and the subjective response; no statistically significant difference was found in the FEV1 changes in response to BDP between subjective nonresponders and subjective responders, respectively: 3.7 ± 4.2% vs 5.0 ± 6.9% of predicted FEV1 (p = 0.529). In contrast, the FEV1 changes in response to the placebo were significantly greater in the subjective nonresponders than in the subjective responders, and was negative in the latter, respectively: 1.9 ± 3.4% vs -2.0 ± 4.3% of predicted FEV1 (p = 0.010). This suggests that at least some of the subjective responders might have noticed a decline in their lung function while on placebo, rather than an improvement while on BDP. A multiple regression analysis—dependent variables included were the FEV1 response to placebo, the FEV1 response to BDP, the difference in the total incidence of adverse effects expressed on a person-per- day basis between the placebo and BDP periods, and the difference in the total symptom score between the placebo and BDP periods—confirmed that the decline in the FEV1 while on placebo and the improvement in the symptom scores while on BDP, as compared with those on placebo, were the independent predictors of a subjective responder (Table 4 ).


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  		Table 4. Multiple Linear Regression Analysis for the Positive Subjective Response

 
Symptom Scores
The total daily symptom scores were significantly better during the BDP treatment period than during the placebo period, as were the scores for wheezing and dyspnea (Table 5 ).


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  		Table 5. Comparison of Symptom Scores Recorded During the Last 14 Days of Each Treatment Period*

 
Side Effects
Thirteen patients (43%) complained of hoarseness during the BDP period, whereas seven patients (23%) reported similar adverse effects while on placebo (p < 0.01)(Table 6 ). When the incidence of adverse effects was expressed on a person-per-day basis, hoarseness was significantly more associated with the BDP period than with the placebo period, as was sore throat.


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  		Table 6. Incidences of Adverse Side Effects

 
Laboratory Findings
The serum osteocalcin levels during the BDP period of 3.7 ± 2.3 ng/mL were significantly lower than the levels of 5.7 ± 2.7 ng/mL during the placebo period or the baseline measurement of 5.8 ± 2.6 ng/mL. The cortisol levels of 10.5 ± 4.26 µg/dL during the BDP period and 11.7 ± 4.2 µg/dL during the placebo period were both lower than the baseline measurement of 13.6 ± 5.1 µg/dL. These findings point to the effects of high-dose inhaled corticosteroids on the hypothalamic-pituitary-adrenal axis and bone metabolism, though not necessarily indicating the clinically significant consequences. No order effects were found between the placebo-first and BDP-first regimens in these comparisons.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present report describes the first placebo-controlled study that demonstrated the extent of the symptomatic and physiologic improvements conferred by 3 mg of BDP in patients with stable COPD. We examined the additive effects of high-dose inhaled corticosteroids in patients with stable COPD, who had presumably been receiving sufficient doses of inhaled anticholinergic agents and inhaled ß2-agonists.

In order to assess the risk/benefit ratio of a particular treatment, it is essential to know the maximal benefits obtainable from that treatment. Shim and Williams1 reported that 640 µg/d of BDP was less than half as effective as 30 mg/d of prednisolone in the treatment of COPD patients who had been responsive to oral corticosteroids, indicating that the dose of inhaled corticosteroids was insufficient. Engel et al2 also reported no effects of inhaled steroids (800 µg/d of budesonide) on most of the indexes evaluated in patients with a relatively good FEV1. However, Weir et al 3 reported that 1,500 µg/d of BDP had significant effects on FEV1, FVC, and/or PEFR in patients with COPD, though the effect was inferior to 40 mg/d of prednisolone. Thus, high doses of BDP of over 1,500 µg/d appear to be required to obtain a therapeutic effect in COPD patients. In addition, Weir and Burge4 compared the effects of 1,500 µg/d of BDP, 3,000 µg/d of BDP, and 40 mg/d of prednisolone, and reported that no significant difference in the therapeutic effects could be observed among the three groups. This suggests that stable COPD patients receiving 1,600 µg/d of BDP probably experience therapeutic effects near the maximum conferred by these corticosteroids. Therefore, the dose of inhaled corticosteroids employed in this study would have conferred the maximal obtainable effect in most of the patients. Furthermore, 16.7% of the patients in the present study demonstrated a significant response in their FEV1 of more than 8.5% of the predicted value to BDP. Although the definition of a positive response was different, this is within the upper limit of the confidence interval of the response rate to oral corticosteroids reported in a meta-analysis by Callahan et al,14 further supporting the notion that the results we obtained here were probably near the maximal benefits from corticosteroids in patients with stable COPD.

Our results indicated that the improvement in airflow limitation conferred by 3 mg of BDP when used in combination with high doses of bronchodilators was statistically significant but small on average. In fact, although the mean (± SD) absolute improvement in the FEV1 in these five objective responders was as large as 0.340 ± 10 L, it was only 0.06 ± 0.09 L in the remaining 25 objective nonresponders. Recently, Cumming et al9 reported that patients on inhaled corticosteroids, especially those whose lifetime dose was over 2,000 mg, were at a higher risk of posterior subcapsular cataracts. This cumulative dose will be reached within a couple of years if a dose of 3 mg of BDP is continued. Therefore, although the improvements in FEV1 observed in the five objective responders were substantial, the effects on the objective nonresponders were too small to justify continued treatment with this dose of inhaled BDP. In addition, although one half of the patients reported symptomatic benefits with the administration of high-dose BDP, this subjective response did not correlate with any improvement of their FEV1 while on BDP. Instead, it was associated with a decline of their FEV1 while on placebo, rather than an improvement while on BDP, making the validity of this methodology dubious as the assessment of subjective response. Furthermore, a weak positive correlation between the FEV1 response to BDP and to placebo was found; this might be explained by a lower-than-usual FEV1 at the baseline spirometric measurements in some of the patients. This in turn will result in an overestimation of the response to both BDP and the placebo. Of course, the potential long-term beneficial effects on the course of COPD could not be addressed in this study; this type of therapy may reduce the rate of decline in the FEV1 or the frequency of exacerbation.15 ,16

There may well be an argument that high-dose inhaled corticosteroids may be preferable for a therapeutic trial instead of oral prednisolone provided that the effect of inhaled steroids parallel that of oral formulation. Although this study does not directly compare the results of both drugs during the trial, the results of the present study might indirectly support this argument because the outcome of high-dose inhaled corticosteroids seems to be largely equivalent to the effect of oral administration of prednisolone thus far reported. Nevertheless, the same problem remains that is seen in oral corticosteroid trials: how to treat those patients who have responded positively to the therapeutic trial. A clinical trial to specifically address this problem is needed.

The specific type of inhaled corticosteroid used in this study, BDP, is available worldwide. It may be difficult to administer this dose of BDP because this would require well over 30 puffs of the most concentrated preparation currently available in the United States. At the present time, budesonide and fluticasone propionate, which may be more potent inhaled corticosteroids, are available in some parts of the world. It could be erroneous to extrapolate the present observations to those newer formulations; although, to date, there is no convincing evidence that the therapeutic effects of the newer formulations significantly outweigh the adverse effects. Besides, it seems unlikely that those newer formulations produce greater effects on lung function because the effects observed here are similar to those reported in studies using oral corticosteroids.

In conclusion, although a considerable minority of patients benefited substantially from this treatment, the overall outcome does not seem to justify the widespread use of this treatment in light of the increasing recognition of the potential adverse systemic effects of high-dose inhaled corticosteroids. Thus, the benefits must be weighed against the potential systemic adverse effects on an individual basis.


   Acknowledgements
 
ACKNOWLEDGMENT: The authors thank Nippon Glaxo for providing matching placebos. The authors also thank Mr. K. Kawakatsu for measuring the serum theophylline levels.


   Footnotes
 
Supported in part by a research grant from the Smoking Research Foundation of Japan.

Correspondence to: Dr. Koichi Nishimura, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

Abbreviations: BDP = beclomethasone dipropionate; MDI = metered-dose inhaler; PEFR = peak expiratory flow rate

Received for publication December 22, 1997. Accepted for publication June 22, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Shim, CS, Williams, MH (1985) Aerosol beclomethasone in patients with steroid-responsive chronic obstructive pulmonary disease. Am J Med 78,655-658[CrossRef][ISI][Medline]
  2. Engel, T, Heinig, JH, Madsen, O, et al (1989) A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. Eur Respir J 2,935-939[Abstract]
  3. Weir, DC, Gove, RI, Robertson, AS, et al (1990) Corticosteroid trials in non-asthmatic chronic airflow obstruction: a comparison of oral prednisolone and inhaled beclomethasone dipropionate. Thorax 45,112-117[Abstract]
  4. Weir, DC, Burge, PS (1993) Effects of high-dose inhaled beclomethasone dipropionate, 750 µg and 1500 µg twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction. Thorax 48,309-316[Abstract]
  5. Auffarth, B, Postma, DS, de Monte, JGR, et al (1991) Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease. Thorax 46,372-377[Abstract]
  6. Brown, PH, Blundell, G, Greening, AP, et al (1991) Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respir Med 85,501-510[ISI][Medline]
  7. Ip, M, Lam, K, Yam, L, et al (1994) Decreased bone mineral density in premenopausal asthma patients receiving long-term inhaled steroids. Chest 105,1722-1727[Abstract/Free Full Text]
  8. Packe, GE, Douglas, JG, McDonald, AF, et al (1992) Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent systemic corticosteroids. Thorax 47,414-417[Abstract]
  9. Cumming, RG, Mitchell, P, Leeder, SR (1997) Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 337,8-14[Abstract/Free Full Text]
  10. Mak, V, Melchor, R, Spiro, S (1992) Easy bruising as a side-effect of inhaled corticosteroids. Eur Respir J 5,1068-1074[Abstract]
  11. . Medical section of the American Lung Association (1995) Standardization of spirometry - 1994 update. Am J Respir Crit Care Med 152,1107-1136[ISI][Medline]
  12. . Japan Society of Chest Diseases. (1993) Standards of pulmonary function tests for Japanese [in Japanese]. Jpn J Thorac Dis 31,appendix
  13. Weir, DC, Robertson, AS, Gove, RI, et al (1990) Time course of response to oral and inhaled corticosteroids in non-asthmatic chronic airflow obstruction. Thorax 45,118-121[Abstract]
  14. Callahan, CM, Dittus, RS, Katz, BP (1991) Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. Ann Intern Med 114,216-223
  15. Renkemma, TEJ, Schouten, JP, Koëter, GH, et al (1996) Effect of long-term treatment with corticosteroids in COPD. Chest 109,1156-1162[Abstract/Free Full Text]
  16. Paggiaro, PL, Dahle, R, Bakran, I, et al (1998) Multicentre randomized placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 351,773-780[CrossRef][ISI][Medline]



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