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Additive Effects of Salmeterol and Fluticasone or Theophylline in COPD^*

^* From A. Cardarelli Hospital (Drs. Cazzola, Di Perna, and Calderaro), Division of Pneumology and Allergology and Respiratory Clinical Pharmacology Unit, Naples; University of Palermo, Institute of Internal Medicine and Geriatrics (Dr. Di Lorenzo), Palermo; GlaxoWellcome Italy (Dr. Testi), Medical Department, Verona; and University of Milan (Dr. Centanni), San Paolo Hospital, Respiratory Unit, Milan, Italy.

Correspondence to: Mario Cazzola, Divisione di Pneumologia e Allergologia e Unità di Farmacologia Clinica Respiratoria, Ospedale A. Cardarelli, Via del Parco Margherita 24, 80121 Napoli, Italy; e-mail: mcazzola{at}qubisoft.it

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: ß₂-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma, but this has not been established in COPD.

Methods: Eighty patients with well-controlled COPD were randomized to receive 3 months of treatment in one of four treatment groups: (1) salmeterol, 50 µg bid; (2) salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid; (3) salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid; and (4) salmeterol, 50 µg, plus titrated theophylline bid. At each visit, a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 µg.

Results: A gradual increase in FEV₁ was observed with each of the four treatments. Maximum significant increases in FEV₁ over baseline values that were observed after 3 months of treatment were as follows: salmeterol, 50 µg bid, 0.163 L (95% confidence interval [CI], 0.080 to 0.245 L); salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid, 0.188 L (95% CI, 0.089 to 0.287 L); salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid, 0.239 L (95% CI, 0.183 to 0.296 L); and salmeterol, 50 µg, plus titrated theophylline bid, 0.157 L (95% CI, 0.027 to 0.288 L). Salbutamol always caused a significant dose-dependent increase in FEV₁ (p < 0.001), although the 800-µg dose never induced further significant benefit when compared with the 400-µg dose. The mean differences between the highest salbutamol FEV₁ after salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid, and that after salmeterol, 50 µg, plus titrated theophylline bid or salmeterol, 50 µg bid, were statistically significant (p < 0.05).

Conclusion: These data show that both long-acting ß₂-agonists and inhaled corticosteroids have a role in COPD. The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone. Moreover, it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol, although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect. In any case, patients must be treated for at least 3 months before a real improvement in lung function is achieved.

Key Words: COPD • fluticasone propionate • salbutamol • salmeterol • theophylline • tolerance

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Although originally designed for the treatment of bronchial asthma, use of long-acting ß₂-agonist bronchodilators is about to become a leading therapeutic approach in COPD.^{1 2} In fact, several clinical studies have documented that the protracted treatment of COPD with these agents can induce an improvement in respiratory function.^{3 4}

Unfortunately, there is evidence for downregulation of ß₂-adrenoceptor protein and messenger RNA after selective long-acting ß₂-adrenoceptor agonist treatment in human lung,⁵ and this may limit their therapeutic efficacy in obstructive airways disease.

The changes induced in ß₂-receptors by exposure to ß₂-agonists may be attenuated or reversed by the addition of corticosteroids.⁶ In effect, ß₂-agonists can interact with corticosteroids to produce beneficial effects on airway function in asthma,⁶ but this has not been established in COPD. In particular, the efficacy of inhaled corticosteroids in the treatment of COPD remains controversial.⁷ Obviously, also the impact of long-acting ß₂-agonists on combinations with corticosteroids is still unclear.

The present study aimed to investigate the potential additive effect of two different doses of inhaled fluticasone propionate in patients with stable COPD who received inhaled salmeterol, 50 µg bid, administered with a metered-dose inhaler (MDI). Moreover, we examined the effectiveness of fluticasone for preventing the development of subsensitivity to bronchodilator effects of salbutamol after regular inhaled salmeterol. We also asked the question whether the addition of theophylline to treatment with long-acting ß₂-agonists could be justified. In fact, theophylline, which has anti-inflammatory properties, could also provide adequate bronchodilation when used in combination with ß₂-agonists and prevent the development of tolerance to the bronchoprotective effect of salmeterol.⁸ It has yet to be tested whether the association of a long-acting ß₂-agonist with theophylline induces an increase in the bronchodilator effect caused by either of the two drugs.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Eighty patients with well-controlled COPD (our definition of COPD was consistent with the criteria proposed by the American Thoracic Society),⁹ who had previously been individually dose titrated with slow-release theophylline to a serum theophylline level of 10 to 20 µg/mL, were recruited. Inclusion criteria were as follows: > 50 years old with at least a 20-year smoking history; a change in FEV₁ 12% as a percent of the predicted normal value following salbutamol, 400 µg; postbronchodilator FEV₁ < 85%; and good MDI technique. Exclusion criteria were as follows: current evidence of asthma as primary diagnosis; unstable respiratory disease requiring oral/parenteral corticosteroids within 4 weeks prior to beginning the study; upper or lower respiratory tract infection within 4 weeks of the screening visit; unstable angina or unstable arrhythmias; concurrent use of medications that affected COPD or interacted with methylxanthine products, such as macrolides or fluroquinolones; and evidence of alcohol abuse. Table 1 outlines some characteristics and the smoking history of the population studied.

At each visit, three FEV₁ and FVC measurements were taken, and the highest of each was recorded. Spirometric testing was performed according to the procedures described in the American Thoracic Society 1987 update.¹⁰ These measurements were performed on the morning of each visit, before any drug had been taken. Soon after, a dose-response curve to inhaled salbutamol was constructed using doses of 100, 100, 200, and 400 µg from an MDI with spacer and mouthpiece, for a total cumulative dose of 800 µg salbutamol. Doses were given at 20-min intervals, and the measurements were made 15 min after each dose.

Serum theophylline levels in patients receiving salmeterol, 50 µg, plus titrated theophylline bid were measured monthly during the 3-month treatment period. Adverse events were collected through nonspecific questioning or direct observation by investigators at each clinic visit and through spontaneous reports by patients.

In order to qualify for efficacy analysis, the patient had to complete the 3-month treatment period. The predose-response curve to the salbutamol FEV₁ value was chosen as the primary outcome variable. Analysis of spirometric data for each treatment was performed using the Student’s t test for paired variables. Mean responses were also compared by multifactorial analysis of variance to establish any significant overall effect among all four treatments. In the presence of a significant overall analysis of variance, Duncan’s multiple range testing with 95% confidence limits was used to identify where differences were significant. A probability level of p < 0.05 was considered as being of significance for all tests.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
All patients who enter the run-in period were randomized to treatment in blocks of four according to a list of randomized codes; of these, 69 patients completed the 3-month treatment period: 18 patients receiving salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid; 18 patients receiving salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid; 16 patients receiving salmeterol, 50 µg, plus titrated theophylline bid; and 17 patients receiving salmeterol, 50 µg bid. Patients were withdrawn for various reasons, the most common of which were poor compliance with the protocol, exacerbation, and tachycardia.

There were no significant differences among the baseline spirometric values of the four treatment groups (FEV₁, p > 0.05).

A gradual increase in FEV₁ was observed with each of the four treatments (Fig 1 ). Maximum significant (p < 0.05) increases in FEV₁ over baseline values that were observed after 3 months of treatment were as follows: salmeterol, 50 µg bid, 0.163 L (95% confidence interval [CI], 0.080 to 0.245 L); salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid, 0.188 L (95% CI, 0.089 to 0.287 L); salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid, 0.239 L (95% CI, 0.183 to 0.296 L); and salmeterol, 50 µg, plus titrated theophylline bid, 0.157 L (95% CI, 0.027 to 0.288). However, the mean differences between the highest FEV₁ after salmeterol, 50 µg bid, treatment and that after salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid (- 0.011 L; 95% CI, - 0.327 to 0.306 L), salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid (- 0.031 L; 95% CI, - 0.320 to 0.257 L), or salmeterol, 50 µg, plus titrated theophylline bid (- 0.071 L; 95% CI, - 0321 to 0.208 L) were not statistically significant (p > 0.05).

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Mean FEV1 values (in liters) during 3 months of therapy with salmeterol, 50 µg bid; salmeterol, 50 µg plus fluticasone propionate, 250 µg bid; salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid; or salmeterol, 50 µg, plus titrated theophylline bid. SLM = salmeterol; THEO = theophylline; FP = fluticasone propionate.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Mean dose-response curve to inhaled salbutamol (100 µg/puff) constructed during 3 months of therapy with salmeterol, 50 µg bid; salmeterol, 50 µg, plus fluticasone propionate, 250 µg bid; salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid; or salmeterol, 50 µg, plus titrated theophylline bid. See Figure 1 legend for abbreviations.

Patients receiving salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid, showed the highest mean improvement in FEV₁ (0.472 L; 95% CI, 0.386 to 0.557 L) over the presalbutamol baseline (pretreatment) value; patients receiving salmeterol, 50 µg bid, showed the lowest mean improvement in FEV₁ (0.263 L; 95% CI, 0.195 to 0.331 L). The mean differences between the highest salbutamol FEV₁ after salmeterol, 50 µg, plus fluticasone propionate, 500 µg bid, and that after salmeterol, 50 µg, plus titrated theophylline bid or salmeterol, 50 µg bid, were statistically significant (p < 0.05). Two patients receiving salmeterol, 50 µg bid, and one patient treated with salmeterol 50 µg, plus titrated theophylline bid experienced exacerbations.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The present data show that patients with COPD must be treated for at least 3 months before a real improvement in lung function is achieved. In this study, the bronchodilator effect elicited by regular treatment with salmeterol was progressive. This finding is in agreement with the results of several reports that have shown that treatment with long-acting ß₂-agonists may result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.^{3 4 11}

Unfortunately, there are concerns about the effectiveness of prolonged therapy with long-acting ß₂-adrenoceptor agonists. In fact, in mild to moderate asthma, salmeterol appears to rapidly lose its ability to control both specific and aspecific bronchial hyperresponsiveness, while it is effective in maintaining a well-sustained bronchodilation despite a small degree of tachyphylaxis.^{12 13}

The present study demonstrates that the regular treatment with salmeterol leads to significant bronchodilation and, moreover, does not interfere with the effects of standard doses of short-acting ß₂-agonist in patients suffering from partially reversible COPD. This is, in our opinion, an important finding, considering that when the airway obstruction becomes more severe, the therapeutic option is to add a short-acting inhaled ß₂-agonist, such as salbutamol, as rescue medication to cause rapid relief of bronchospasm.

However, the long-term treatment with formoterol and salmeterol could reduce the airways responses to repeated doses of a short-acting inhaled ß₂-agonist because they are partial ß₂-receptor agonists and in the presence of a full ß-agonist they may act as a ß₂-antagonist.¹⁴ In fact, it has been demonstrated that asthmatic patients treated with salmeterol had reduced bronchodilator responses to salbutamol in terms of FEV₁ and peak expiratory flow rate than those treated with placebo.¹⁵ The reduction in response equated with a 2.5-fold and a fourfold greater dose of salbutamol being required to produce a given FEV₁ and peak expiratory flow rate, respectively.

Our study confirms and extends our previous documentation that salbutamol causes additional bronchodilation when salmeterol has already caused its bronchodilatory effect in patients suffering from partially reversible COPD.¹⁶ This is consistent with the results of Langley et al,¹⁷ who showed that regular salmeterol usage did not lead to reduced efficacy of usual or higher-than-usual doses of salbutamol in adult patients with stable asthma. However, all patients in that study were receiving inhaled corticosteroids, while in the present study, the same effect has been observed also in COPD patients who were treated with only regular salmeterol. In any case, Nelson et al¹⁸ have documented that, irrespective of concurrent corticosteroid treatment, long-term therapy with salmeterol does not result in tolerance to the bronchodilator effects of salbutamol.

Although salmeterol was beneficial to our patients with COPD, the combination of salmeterol with fluticasone did not induce a greater bronchodilation than salmeterol alone. This finding contrasts with the documentation that asthmatic patients treated with salmeterol combined with fluticasone propionate have improvements over baseline in FEV₁ at endpoint that were at least twice as great as improvements in patients treated with salmeterol or fluticasone propionate alone.¹⁹ Moreover, the addition of salmeterol therapy to patients who remain symptomatic while using a low dose of fluticasone propionate is clinically and statistically superior to increasing the dose of fluticasone propionate.²⁰ Inhaled corticosteroids and salmeterol target different aspects of the underlying disease process, and, consequently, combined therapy is frequently more effective than monotherapy.²⁰

Because of the very little evidence to date on the effect of inhaled corticosteroids in COPD,^{21 22} there is disagreement over corticosteroid treatment in this disease. Even the improvement in airflow limitation conferred by beclomethasone dipropionate, 3 µg, when used in combination with high doses of bronchodilators was small on average.²³

However, Paggiaro et al²⁴ have recently demonstrated that fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Moreover, Calverley et al²⁵ have shown that fluticasone induces higher FEV₁ compared with placebo throughout a 3-year treatment period, although it has no effect on rate of decline in FEV₁.

Thus, the type of inhaled corticosteroid may apparently have an important role in the long-term treatment of COPD. In effect, there are significant differences in the pharmacokinetics and pharmacodynamics of inhaled corticosteroids.²⁶ For example, long pulmonary residence time has been calculated for fluticasone propionate, but budesonide appears to disappear rapidly.²⁶ Moreover, budesonide and beclomethasone dipropionate show comparable antiasthma effects at equal doses, where fluticasone propionate is approximately twice as potent as either steroid.²⁶ These differences might be of importance in patients with COPD.

It is important to highlight that corticosteroids can prevent homologous downregulation of ß₂-adrenoceptor number and induce an increase in the rate of synthesis of receptors through a process of increased ß₂-adrenoceptor gene transcription.²⁷ Such effects may have clinical implications, not only for preventing the development of tolerance to ß₂-agonists in patients treated with ß-agonist bronchodilators, but, likely, also for increasing the bronchodilator response to ß₂-agonists. In fact, in this study, the combination of salmeterol with fluticasone allowed a greater improvement in lung function after salbutamol than salmeterol alone.

Theophylline improves airflow, reduces pulmonary artery pressure, increases arterial oxygen tension, improves diaphragmatic strength and endurance, increases right ventricular function, and may produce anti-inflammatory effects. However, the magnitude of these changes is small, the therapeutic index is narrow, and side effects are common, even when serum theophylline levels are within the therapeutic range.⁸ For these reasons, the recent British Thoracic Society guidelines for the management of COPD state that the addition of oral theophylline should be considered only if inhaled treatments have failed to provide enough benefit.⁷

Nevertheless, as the drug has been shown to have anti-inflammatory and immunomodulatory effects in patients with asthma,^{8 28} it is possible that theophylline might also attenuate the airflow limitation caused by airway inflammation in COPD.²⁹ In any case, we must stress that regular theophylline treatment neither prevents nor worsens the development of tolerance to the bronchoprotective effect of salmeterol in vivo.³⁰

A number of clinical studies support the combined use of theophylline and a ß-agonist in patients with COPD.³¹ In fact, Giessel et al³² have recently demonstrated that the combination of salmeterol plus theophylline was significantly better in improving FEV₁ area under curve than theophylline or salmeterol alone in patients with COPD. However, our study demonstrates that the addition of theophylline to a treatment with salmeterol is not justified because there is not a true advantage on a treatment with salmeterol alone. In any case, the addition of salmeterol to fluticasone propionate seems to be better.

In conclusion, this study confirms that both long-acting ß₂-agonists and inhaled corticosteroids have a role in COPD. The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone after a treatment period of 3 months. Moreover, it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol, although regular salmeterol use is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect. Therefore, the results of the present study seem to support the use of combined therapy. However, the true impact of long-acting ß₂-agonists on combinations is still unclear. Regular assessment of the patient’s physiologic status will determine the clinical usefulness of these drugs. Therefore, carefully designed studies with larger population are required to define their role and, possibly, to develop a new treatment algorithm for COPD.

	Footnotes

 
Abbreviations: CI = confidence interval; MDI = metered-dose inhaler

Dr. Cazzola has received financial support for research and attending meetings and has received fees for speaking and consulting by GlaxoWellcome Italy. Dr. Di Lorenzo has received financial support for research and has spoken at some meetings financially supported by GlaxoWellcome Italy. Dr. Testi is employed by GlaxoWellcome Italy. Fluticasone propionate and salmeterol are manufactured by GlaxoWellcome.

Received for publication June 17, 1999. Accepted for publication June 20, 2000.

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TOP Abstract Introduction Materials and Methods Results Discussion References

 

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