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Keywords:

  • inhaled and oral steroids;
  • stable COPD

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Background. A significant minority of patients with COPD have favourable response to corticosteroid treatment. In addition, the benefit of corticosteroid treatment may be outweighed by the side-effects. Long-term administration of inhaled steroids is a safe means of treatment. However, only a few studies have addressed the role of inhaled steroids in patients with COPD, with conflicting results.

Methods. Forty-four patients with stable COPD were defined as ‘responders to bronchodilators’ (increase in FEV1 > 20% following administration of β2-agonist) (group A), and 124 as ‘non-responders to bronchodilators’ (group B). All patients were randomized to receive a 6-week course of either a daily dose of 800 μg of inhaled budesonide or placebo, separated by 4 weeks when no medication was taken; were randomized again to receive a 6-week course of either 1600 μg day−1 of inhaled budesonide, or 800 μg day−1 of inhaled budesonide plus placebo; and were randomized once again to receive a 6-week course of either 40 mg day−1 of prednisone or placebo. All stages were performed in a double-blind cross-over design.

Results. Following administration of 800 μg day−1 of inhaled budesonide, there was an increase in the mean FEV1 from 1.40 ± 0.20 to 1.92 ± 0.22 L (P < 0.001) and a significant decrease in inhaled β2 agonist consumption in group A. These changes remained almost stable during the increased dose of inhaled budesonide or during prednisone treatment. The mean FEV1 did not change during the placebo period, or in group B in either treatments.

Conclusions. Treatment with inhaled steroids improved spirometry data and inhaled β2-agonist consumption in about one-quarter of patients with stable COPD, and this rate increased to about three-quarters in patients who responded to β2-agonist inhalation. There was no additional benefit in using a higher dose of inhaled budesonide or prednisone.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Although efficacy of the use of corticosteroids in patients with COPD is still controversial [ 1, 2], they continue to be widely used in these patients. However, previous studies performed by us [ 3] and by others [ 4–7] have shown, with objective measurements of improved airflow, rates of response to corticosteroids of about 25% in stable COPD patients. Because of the serious adverse effect of a long course of oral corticosteroid treatment, inhaled steroids became attractive as a means of treatment in asthma [ 8], and more recently also in patients with COPD [ 9–12]. However, most of the studies compared varied aerosolized beclomethasone dipropionate dosages to oral prednisone or prednisolone and reported a greater effect of the oral drugs [ 11]. They also found a significant number of patients responding to one form of therapy only. It is therefore of practical value to assess the number of patients with COPD ('responders' and ‘non-responders’ to bronchodilators, and ‘responders’ and ‘non-responders’ to inhaled steroids) who will benefit from oral treatment with corticosteroids.

It was therefore undertaken, in stable patients with COPD, to determine the rate of response to inhaled β2-agonist, its ability to serve as a criterion for differentiating those who respond to ‘regular’ doses of inhaled steroids (800 μg day−1 of inhaled budesonide) from other patients, and whether a higher dose (1600 μg day−1 of inhaled budesonide) would result in a better improvement in clinical symptoms and pulmonary function. In addition, we tried to determine the number of patients ('responders' and ‘non-responders’ to inhaled steroids) who will benefit from oral treatment with corticosteroids.

Materials and methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

The patients were recruited for the study from our outpatient clinic during the years 1991–95. The subjects from our previous study, with a similar design [ 3], were included in the present study. One hundred and sixty-eight consecutive patients (102 men and 66 women) who had spirometric evidence of chronic airflow limitation, but without evidence of asthma, were recruited for the study. Patients suspected of having asthma by the personal physician or by the pulmonary specialist were excluded from the study. In addition, patients with seasonal or episodic dyspnoea or wheezing, family history of asthma, atopy (history of allergy and positive skinprick test to common antigens), or a more than partial response to inhaled β2-agonist (improvement of FEV1/FVC to more than 70%) were also excluded from the study. Entry criteria included: (1) stable condition; (2) heavy smokers (> 30 packets year−1); (3) FEV1 < 50% of predicted; (4) FEV1/FVC < 60%; and (5) no therapy with oral or inhaled steroids within 3 months of entry to the study. In case of deterioration and an increase in dyspnoea, the patients were instructed to use inhalations of a β2-agonist only. β2-agonist consumption served also as an indirect method of assessment of the frequency and severity of dyspnoea. Their characteristics are summarized in Table 1. There was no significant difference in FEV1, before bronchodilators, between ‘responders’ and ‘non-responders’ to bronchodilators. The study was approved by the institutional committee on human research and inform consent was obtained from all patients.

Table 1.   Characteristics of 168 COPD patients. Data are means ± SEM. BD, bronchodilators Thumbnail image of

Study design

The study design is shown in Fig. 1. The subjects' response to bronchodilators (increase in FEV1 > 20% following inhalation of 5 mg of salbutamol administered by a Devilbiss no. 646 nebulizer) was determined first and they were categorized as: (1) responders to β2-agonist-group A – each patient had at least 20% increase in FEV1 following bronchodilators; (2) non-responders to β2-agonist-group B – no patient had at least 20% increase in FEV1 following bronchodilators.

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Figure 1.  The study design. The ‘responders to bronchodilators’ (an increase in FEV1 > 20%) were separated from the ‘non-responders to bronchodilators’. All patients were then randomized to receive a 6-week course of a twice daily dose (400 μg in the morning and at bedtime) of either inhaled budesonide or placebo, separated by 2 weeks when no medication was taken, and randomized again to receive a 6-week course of a twice daily dose of either inhaled budesonide (800 µg in the morning and at bedtime) or 400 μg of inhaled budesonide and 2 puffs of placebo in the morning and at bedtime; they were then randomized once again to receive a 6-week course of either 40 mg of prednisone or placebo, separated by 2 weeks when no medication was taken. R, responders; NR, non-responders; BD, bronchodilators; B, budesonide; IS, inhaled steroids; P, prednisone; OS, oral steroids.

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Spirometry was performed, with the patient sitting erect, at least three times before and after bronchodilator inhalation on a computerized spirometer (Compact, Vitalograph, Buckingham, England) and the best of these was used in the analysis.

All subjects were then randomized to receive a 6-week course of a twice daily dose (400 μg in the morning and at bedtime) of either inhaled budesonide or placebo, separated by 4 weeks when no steroids were taken, in a double-blind cross-over design. Both ‘responders to steroids’ (increase in FEV1 > 20% following therapy) and ‘non-responders to steroids’ were randomized again to receive a 6-week course of a twice daily dose of either 800 μg (in the morning and at bedtime) of inhaled budesonide or 400 μg of inhaled budesonide and two puffs of placebo in the morning and at bedtime, in a double-blind cross-over design. Both placebo and active (200 μg of budesonide per puff) aerosols were generated from metered-dose inhalers and delivered via a spacer (Aerochamber).

In the third stage of the study, both ‘responders to inhaled steroids’ and ‘non-responders to inhaled steroids’ were randomized once again to receive a 6-week course of either prednisone 40 mg day−1 or placebo in a double-blind cross-over design. The three stages were separated by a ‘wash-out’ period of 4 weeks when no steroids were taken.

Response to steroids was assessed by spirometry, carried out before the onset of the trial and every 2 weeks thereafter. Spirometry was performed at least three times and the data from the best of these were used in the analysis. Spirometry was performed after at least 12 h of withholding β2-agonist inhalation.

The patients kept a diary to document the medications used on a daily basis and inhaled β2-agonist consumption was also recorded daily, 6 weeks before treatment, and following either regimen of treatment.

Data analysis

Comparisons of lung function between the groups and the effect of the treatment on these parameters and the inhaled β2-agonist consumption were carried out using the two-way repeated measures analysis of variance (anova).

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

The characteristics of 168 stable patients with COPD that were evaluated for the study are summarized in Table 1. Forty-four patients (26%) increased their FEV1 by more than 20% as compared with baseline values ('responders to bronchodilators'), while 124 patients had no significant increase in FEV1 ('non-responders to bronchodilators'). The ‘responders to bronchodilators’ did not differ by age, weight, sex or baseline spirometric values from the ‘non-responders to bronchodilators’.

Following administration of 800 μg day−1 of inhaled budesonide, there was a significant increase, compared with baseline, in the mean FEV1 in group A (responders to bronchodilators) but not in group B (non-responders to bronchodilators). There was also a statistically significant difference between the two groups, starting at the 2 week measurements and lasting until the end of the study (< 0.001, 0.001, 0.001, 0.01, 0.001, 0.005, 0.001, 0.001 and 0.05, respectively). Two weeks after the initiation of treatment, a statistically significant increase in the mean FEV1 was already noted (from 1.40 ± 0.20 to 1.92 ± 0.22 L, < 0.001; Fig. 2). These values remained almost stable for the next 4 weeks (1.96 ± 0.25 and 1.90 ± 0.23 L at 4 and 6 weeks, respectively). In contrast, there was no significant increase in FEV1 during the 6-week course of a placebo in this group (1.31 ± 0.19, 1.33 ± 0.21 and 1.35 ± 0.22 L at 2, 4 and 6 weeks, respectively), as well as during the active drug (1.43 ± 0.25, 1.48 ± 0.24 and 1.47 ± 0.21 L, respectively) and placebo (1.29 ± 0.18, 1.31 ± 0.20 and 1.28 ± 0.20, respectively) in the ‘non-responders to bronchodilators’ group ( Table 2). Ten patients, three from group A and seven from group B, were excluded from the study at this stage, six because of lack of compliance and four because of exacerbation.

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Figure 2.  Mean (± SEM) change in FEV1 following administration of either 800 μg day−1 for 6 weeks followed by administration of 1600 μg day−1 for 6 more weeks of inhaled budesonide, followed by administration of 40 mg day−1 of prednisone for 6 more weeks or placebo. *, statistically significant.

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Table 2.   Mean (± SEM) FEV1 (L) in ‘responders’ and ‘non-responders’ to bronchodilators (BD) following treatment with corticosteroids Thumbnail image of

The mean FEV1 did not change following the increase in the treatment dose of inhaled budesonide to 1600 μg day−1 (1.93 ± 0.22, 1.96 ± 0.21 and 1.94 ± 0.22 L in the ‘responders to bronchodilators’, and 1.54 ± 0.26, 1.48 ± 0.24, 1.50 ± 0.25 L in the ‘non-responders to bronchodilators’ at 2, 4 and 6 weeks, respectively) or during the placebo (1.33 ± 0.20, 1.40 ± 0.26 and 1.38 ± 0.26 L in the ‘responders to bronchodilators’, and 1.31 ± 0.24, 1.33 ± 0.25 and 1.31 ± 0.21 in the ‘non-responders to bronchodilators’, respectively); nor did it change during the treatment period with prednisone 40 mg day−1 (1.98 ± 0.25, 2.00 ± 0.26 and 1.96 ± 0.23 L in the ‘responders to bronchodilators’, and 1.48 ± 0.27, 1.48 ± 0.26 and 1.51 ± 0.27 L in the ‘non-responders to bronchodilators’, respectively) or placebo (1.37 ± 0.25, 1.41 ± 0.22 and 1.40 ± 0.25 L in the ‘responders to bronchodilators’, and 1.33 ± 0.25, 1.40 ± 0.27 and 1.37 ± 0.21 L in the ‘non-responders to bronchodilators’, respectively), in all patients ('responders and non-responders to bronchodilators' and ‘responders and non-responders to inhaled steroids’). Twenty more patients were excluded from the study during the budesonide 1600 μg day−1 period (14 because of lack of compliance and six because of exacerbation), while 20 more patients were excluded during the prednisone period (11 because of lack of compliance and nine because of exacerbation).

Analysing the individual response in FEV1 to inhaled budesonide, it was demonstrated that in 29 (71%) out of the 41 remaining patients defined as ‘responders to bronchodilators’, there was a significant improvement in the FEV1 (defined as > 20% compared with the placebo period) following inhaled budesonide; they were defined as ‘responders to inhaled steroids’ ( Fig. 3). Twelve subjects (29%) showed no significant increase in FEV1 and were defined as ‘non-responders to inhaled steroids’

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Figure 3.  The individual response in FEV1 to inhaled ‘regular’ dose, ‘high’ dose of budesonide or prednisone. Abbreviations as Fig. 1.

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In 10 patients (8.5%) out of the 117 remaining patients from group B, there was a significant improvement in the FEV1 following inhaled budesonide, and they were also defined as ‘responders to inhaled steroids’.

Nine patients (6.5%) demonstrated an additional effect with the higher dose of budesonide (additional increase in FEV1 > 10%), nine deteriorated (a decrease in FEV1 > 10%) and the remaining 122 patients, from all the groups, showed no effect.

Twenty patients (91%) in group A who were also ‘responders to inhaled steroids’ maintained the improved FEV1 during the ‘prednisone period’ as well. In the ‘responders to bronchodilators’/'non-responders to inhaled steroids' group, three patients (37.5%) improved their FEV1 > 20% and were defined as ‘responders to oral steroids’. All eight ‘non-responders to bronchodilators’/'responders to inhaled steroids' were also ‘responders to oral steroids’, while 11 patients (13.5%) in the ‘non-responders to bronchodilators’/'non-responders to inhaled steroids' group could be defined as ‘responders to oral steroids’.

Over the 6 weeks, before entering the study, the 44 ‘responders to bronchodilators’ reported mean β2-agonist consumption of 6.3 ± 0.4 puffs patient−1 day−1; this was 6.7 ± 0.7 in the 124 ‘non-responders to bronchodilators’ ( Fig. 4). Following administration of 800 μg day−1 of inhaled corticosteroids, there was a significant decrease in β2-agonist consumption to 3.3 ± 0.3 puffs patient−1 day−1 in group A. This was also significantly lower than the β2-agonist consumption during the placebo period (5.8 ± 0.5 puffs patient−1 day−1). The same trend was also noted during the ‘higher budesonide’ and ‘prednisone’ periods. In group B, similar β2-agonist consumption was found during both periods of treatment. However, the small group of patients from group B who responded to either inhaled or oral steroids decreased the β2-agonist consumption to 3.7 ± 0.2 and 3.5 ± 0.3 puffs patient−1 day−1, respectively.

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Figure 4.  Mean inhaled β2-agonist consumption before the study, and during the treatment period of either 800 or 1600 βg day−1 of inhaled budesonide or prednisone.

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Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

The results of the current study suggest that in COPD patients who are ‘responders to bronchodilators’, treatment with inhaled budesonide is efficacious in about 75%. Those who do not respond to inhaled steroids may respond to oral corticosteroids (two out of four in the present study). In the ‘non-responders to bronchodilators’ group, only a significant minority respond to either inhaled (8.5%) or oral (21%) steroids. Doubling the dose of inhaled steroids resulted in no additional effect in both ‘responders to steroids’ and ‘non-responders to steroids’. In addition, most of the corticosteroid responders also show a significant decrease in inhaled β2-agonist consumption, suggesting a better control of their symptoms.

Steroid responsiveness of a patient with COPD may lead to improvement in airflow rate and a better quality of life. However, only a minority of patients with COPD have a favourable response to corticosteroids [ 9–12], and, in addition, the benefit of corticosteroid treatment may be outweighed by the side-effects of the drug [ 13, 14]. Therefore, long-term administration of inhaled steroids, which carry with them a relative low systemic steroid effect, may be attractive in the treatment of stable COPD patients. In recent years, several studies [ 3, 9–10, 12] have demonstrated the efficacy of inhaled steroids taken with good technique, at least in a proportion of COPD patients. In addition, our studies suggest that only 20–25% of stable COPD patients will respond to inhaled steroids, but the rate of response is about 75% when inhaled steroids are administered to patients whose airway resistance is significantly decreased following β2-agonist inhalation. In several studies [ 5, 7], corticosteroid responders also showed a response to inhaled bronchodilators. However, certain others [ 9, 11] have shown a failure of β2-agonist reversibility to predict steroid response. The most likely factor to account for some studies finding positive correlation while others found no correlation between steroids and β2-agonist responders would seem to be the characteristics of the patient population studied. In addition, in the present study, as well as in other studies, the reversibility of the airflow obstruction was usually only partial.

Our findings relate only to short-term treatment. There is always a possibility that a failure to produce a short-term improvement has no long-term detriment. In addition, a short-duration study, such as the present one, cannot evaluate the effect of long-term treatment in patients who have responded acutely to corticosteroids. Recently, Renkema et al. [ 15] have shown beneficial effects of long-term (2 years) daily treatment with inhaled corticosteroids on pulmonary symptoms in patients with mild-to-moderate COPD. These results were achieved despite the fact that the majority of the patients failed to increase acutely their FEV1 (> 20%) in response to the treatment. In contrast, other studies [ 16, 17] showed improvement of FEV1 with long-term treatment with inhaled corticosteroids in patients with COPD. The difference in results may be due to patient selection.

Even in the studies that showed a favourable effect of corticosteroids, it is clear that the beneficial effects are less prominent in patients with COPD than in patients with asthma.

It was suggested that higher doses of corticosteroids are needed in patients with COPD. Our results do not support this. Increasing the dose of inhaled budesonide, from 800 to 1600 μg day−1 resulted in no additional effect.

It can be concluded that only a significant minority of patients with COPD show a favourable objective response to steroid therapy (increase in FEV1 > 20%). The response to inhaled β2-agonist may serve as a criterion for differentiating who will respond to steroids from other patients with COPD, since three-quarters of ‘responders to bronchodilators’ (increase in FEV1 > 20% following β2-agonists) will also increase their FEV1 following corticosteroids. Since other studies have shown some beneficial influence of long-term daily treatment with inhaled steroids, despite the absence of objective improvement, a trial of inhaled steroids or prednisone is warranted in the majority of ‘non-responders to corticosteroids’. However, the side-effects of the drug, administered orally, might be troublesome particularly in the elderly. Our findings also suggest that treatment with 800 μg day−1 of inhaled budesonide, using a good technique, provides maximal response and there is no additional benefit in using a higher dose of inhaled steroids.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References
  • 1
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Received 9 February 1998; accepted 4 June 1998.