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

Materials and Methods

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.

Patients entered a 2-week run-in period during which their regular treatment for COPD was stopped and they received salbutamol as required. They were then 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, after giving their informed consent. Salmeterol and fluticasone were administered from an MDI and holding chamber (AeroChamber; Trudell Medical International; London, Ontario, Canada) with mouthpiece.

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

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).

Salbutamol always caused a significant dose-dependent increase in FEV₁ (p < 0.001), although the 800-μg dose never induced further significant benefit (p > 0.05) when compared with 400-μg dose (Fig 2 ). After 3 months, the mean maximum increase in FEV₁ over presalbutamol values induced by salbutamol, 800 μg, was 0.100 L (95% CI, 0.0048 to 0.152 L) in the group receiving salmeterol, 50 μg bid; 0.188 L (95% CI, 0.089 to 0.287 L) in the group receiving salmeterol, 50 μg, plus fluticasone propionate, 250 μg bid; 0.232 L (95% CI, 0.163 to 0.30 L) in the group receiving salmeterol, 50 μg, plus fluticasone propionate, 500 μg bid; and 0.138 L (95% CI, 0.034 to 0.233 L) in the group receiving salmeterol, 50 μg, plus titrated theophylline bid. However, only the dose-response curve for salbutamol in the group receiving salmeterol, 50 μg, plus fluticasone propionate, 500 μg bid, was significantly different (p < 0.05) when data after 3 months of treatment were compared with those obtained after 2 months of treatment.

Mean FEV₁ values after inhalation of salbutamol, 800 μg, in all the four treatments were statistically different (p < 0.05) from their corresponding pretreatment levels after 3 months of treatment. After 3 months, salbutamol, 800 μg, induced the highest FEV₁ improvement (0.283 L; 95% CI, 0.106 to 0.459 L) in the patients receiving salmeterol, 50 μg, plus fluticasone propionate, 250 μg bid, and the lowest FEV₁ improvement (0.152 L; 95% CI, 0.065 to 0.238 L) in those receiving salmeterol, 50 μg bid.

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

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 β₂-agonists may result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.³⁴¹¹

Unfortunately, there are concerns about the effectiveness of prolonged therapy with long-acting β₂-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.¹²¹³

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 β₂-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 β₂-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 β₂-agonist because they are partial β₂-receptor agonists and in the presence of a full β-agonist they may act as a β₂-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,²¹²² 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 β₂-adrenoceptor number and induce an increase in the rate of synthesis of receptors through a process of increased β₂-adrenoceptor gene transcription.²⁷ Such effects may have clinical implications, not only for preventing the development of tolerance to β₂-agonists in patients treated with β-agonist bronchodilators, but, likely, also for increasing the bronchodilator response to β₂-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,⁸²⁸ 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 β-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 β₂-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 β₂-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.