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(Chest. 2002;121:1401-1406.)
© 2002 American College of Chest Physicians

Comparison of the Effects of Salmeterol and Formoterol in Patients With Severe Asthma*

Julia A. Nightingale, PhD; Duncan F. Rogers, PhD and Peter J. Barnes, DM

* From the Department of Thoracic Medicine, Imperial College School of Medicine at the National Heart & Lung Institute, London, UK.

Correspondence to: Julia A. Nightingale, PhD, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, United Kingdom


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo. However, to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma.

Design: We undertook a randomized, placebo-controlled, crossover study to compare 4 weeks of treatment with inhaled formoterol (12 µg twice daily) or salmeterol (50 µg twice daily) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids (ie, >= 1,500 µg daily) or with regular oral corticosteroid treatment. Morning pretreatment peak expiratory flow (PEF) during the last 14 days of the treatment period was the primary outcome variable. Patients recorded morning and evening pretreatment PEF, daytime and nighttime symptom scores, and any use of rescue medication. Spirometry and bronchial reversibility were performed after each treatment.

Results: Forty-two nonsmoking patients (29 women; mean age, 45 ± 2 years; mean [± SEM] FEV1, 61.8 ± 3.4% of predicted) took part in the trial, and 27 patients completed the trial. The mean morning PEF was greater in patients receiving formoterol (mean increase, 14.4 L/min; 95% confidence interval [CI]. 0.2 to 28.6) or salmeterol (mean increase, 14.8 L/min; 95% CI, 0.5 to 29.1) compared with those receiving placebo, but there was no difference between these treatments. There were no significant treatment effects for any of the secondary outcome variables (ie, FEV1, FVC, mean evening PEF, mean daytime symptom score, or nighttime symptom score).

Conclusion: We conclude that the long-acting ß2-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs.

Key Words: formoterol • salmeterol • severe asthma


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled ß2-agonists are recognized as effective bronchodilators for the relief of and prophylaxis for airway narrowing in the treatment of patients with asthma.1 Formoterol and salmeterol are long-acting ß2-agonists with a duration of action of > 12 h,2 3 making them suitable for twice-daily treatment and for providing protection from nocturnal symptoms. Additionally, both drugs protect against airways challenge with methacholine for a period of 12 h.2 4 International guidelines on asthma management5 6 have recommended that they be added to the treatment of patients with symptoms that are not controlled by therapy with regular high-dose inhaled corticosteroids.

Several studies7 8 9 have demonstrated the superiority of salmeterol and formoterol to regular treatment with either albuterol or placebo. However, most of these trials included patients with mild-to-moderate asthma rather than very severe asthma. Although salmeterol and formoterol have a similar duration of action in asthma patients, these two ß2-agonists differ pharmacologically, in that salmeterol acts as a partial agonist and formoterol acts as a full agonist.10 This difference may be of clinical relevance, particularly in patients with more severe asthma. There are few clinical studies comparing salmeterol and formoterol, and those studies that have been performed have looked at patients with mild-to-moderate asthma11 12 rather than those with severe asthma. In this trial, we compared the clinical effects of 4 weeks of treatment between these two drugs and against placebo in patients with severe asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Forty-two nonsmoking patients who met the American Thoracic Society criteria for asthma13 (13 men and 29 women; mean [± SEM] age, 45.4 ± 2.1 years) took part in the study. British Thoracic Society guidelines5 on asthma management currently define severity in terms of the treatment step needed to control symptoms, maintain lung function, and allow the activities of a normal life. All patients were receiving treatment with dosages of at least 1,500 µg of an inhaled steroid (eg, beclomethasone dipropionate, budesonide, or fluticasone propionate) or of regular oral steroids and had an FEV1 < 80% of predicted, reported daily asthma symptoms, and were using their rescue inhaler on most days. According to these criteria, all patients were at steps 4 or 5 of the British Thoracic Society guidelines.5 No patient had taken long-acting ß2-agonists for at least 4 weeks prior to the study. All patients continued to receive the same maintenance medication throughout the trial to prevent bias between treatment periods. If patients had an exacerbation of their asthma requiring a change in the maintenance treatment, they were withdrawn from the study. All patients had documented bronchial reversibility of at least 15%, either spontaneously during the run-in period or following the inhalation of 200 µg albuterol. No patients experienced an exacerbation of asthma or an upper respiratory tract infection in the 4 weeks prior to the study, and all were nonsmokers. Written informed consent was obtained from each patient, and the study was approved by the Ethics Committee of The Royal Brompton Hospital.

Study Design
This was a randomized, placebo-controlled study of crossover design comparing the effects of 4 weeks of treatment with salmeterol, 50 µg twice daily, (Serevent diskhaler [50 µg]; GlaxoSmithKline; Stockley Park West, UK), formoterol, 12 µg twice daily (Foradil dry powder inhaler [12 µg per capsule]; Novartis; Frimley, UK), or placebo. A salmeterol placebo was not available, therefore an identical formoterol inhaler device with identical capsules was used as the placebo. Investigators were blinded throughout the trial. Patients were only partially blinded. They were unaware of whether they were receiving formoterol or placebo but were aware of treatment with salmeterol because the inhaler differed in appearance.

At the initial screening visit, a full medical history was taken and a physical examination was performed. Baseline spirometry and peak expiratory flow (PEF) were measured, and airways reversibility was established by repeating these tests 15 min after inhaling 200 µg albuterol. Venous blood (5 mL) was taken for determination of serum potassium levels. All patients had normal ECG findings.

Patients then underwent a 2-week run-in period, during which they were asked to keep a daily diary card. The diary card was used to record morning and evening PEF measurements (prior to ß2-agonist use), daytime and nighttime symptom scores, and rescue inhaler use. Patients were trained in the proper use of the peak flowmeter during their initial visit. Following the run-in period, patients returned to the laboratory where spirometry, PEF, and bronchial reversibility were reassessed. Patients then were randomized to receive salmeterol (50 µg), formoterol (12 µg), or placebo (1 capsule), which they were asked to take twice daily for 4 weeks. They were seen again after this 4-week period for identical measurements. Patients then were switched to the second study inhaler and were reassessed after 4 weeks. They were then given the final inhaler, and at the end of 4 weeks of treatment returned to the hospital for a final visit.

Patients were asked to record symptoms, PEF, and daily rescue inhaler use throughout the study. Patients were asked not to use their short-acting ß2-agonist medication for 6 h and not to use their long-acting ß2-agonist medication for 12 h prior to each visit if possible. Patients receiving therapy with long-acting ß2-agonists prior to the trial stopped them after the screening visit and underwent a 4-week run-in period. Baseline data for these patients was recorded during the final 2 weeks of the run-in period (ie, 2 weeks after stopping therapy with long-acting ß2-agonists), and they entered the initial treatment period after a 4-week washout from therapy with long-acting ß2-agonists. Patients were given either albuterol (Diskhaler) or terbutaline (Turbohaler; AstraZeneca; Kings Langley, UK) to use as rescue medication to coincide with their prescribed relief medication prior to the study. Capsule/disk counts were made at each visit as a check on compliance.

Spirometry and PEF
FEV1 and FVC were measured using a dry wedge spirometer (Vitalograph; Buckingham, UK). All volunteers were trained in the use of the apparatus prior to beginning the study. Baseline values were measured after 15 min of rest and were recorded as the highest of three readings made at 1-min intervals. Single readings only were taken at other times. PEF was measured using a standard peak flowmeter (Mini-Wright; Clement Clarke International Ltd; Harlow, Essex, UK). These meters were used for measurements in the laboratory and were given to patients for the daily measurement of PEF at home.

Bronchial Reversibility
Bronchial reversibility was assessed by the measurement of spirometry before and 15 min after the inhalation of 200 µg albuterol from a metered-dose inhaler (MDI) via a spacer. Percentage reversibility was calculated as

Symptom Scores
Patients were asked to record a daytime and a nighttime symptom score. Symptom scores were recorded every 12 h in the diary card using a 4-point scale (0, no symptoms; 1, mild; 2, moderate; 3, severe).

Statistical Analysis
Statistical analysis consisted of comparisons between treatments using a generalized linear model. This model consisted of fitting patient, period, and treatment effects. Since formoterol and salmeterol have proven efficacy in a twice-daily regimen, the sensitivity of the trial was established by analyzing the contrast of the mean effect of the active treatments compared with placebo performed one-sided at the 5% significance level. Should the trial have proven sensitivity, the efficacy of formoterol and salmeterol was to be compared using a two-sided test at the 5% level. All three possible pairwise contrasts were calculated, together with 95% confidence intervals (CIs) and associated p values for both primary and secondary efficacy variables. The mean prebronchodilator morning PEF was the primary outcome variable, other measurements (ie, evening PEF, symptom scores, rescue inhaler use, and spirometry) were secondary outcome variables. Mean values were calculated from the final 2 weeks of diary card values for each treatment period, with the first 2 weeks of each treatment period acting as an active washout period. All patients with data recorded for two or more treatment periods were included in the analysis. Values are expressed as the means with 95% CIs or the mean ± SEM. Assuming that an increase of 20 L/min in the median morning PEF is clinically relevant, a sample size of 36 patients would have 85% power to detect such a difference, and a sample size of 30 patients would have 78% power.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Withdrawals, Adverse Events, and Compliance
Forty-two patients were randomized, and of these 38 (90%) were included in the intention-to-treat population. Fifteen of the 42 randomized patients (36%) withdrew from the study, and therefore 27 patients completed the trial. Of these 27 patients, 11 had taken long-acting ß2-agonists prior to the trial. Seven patients withdrew while taking the placebo, five patients withdrew while taking formoterol, and three patients withdrew while taking salmeterol (Table 1 ). All withdrawals were due to asthma exacerbations requiring treatment with oral steroids, except for one patient who did not attend follow-up sessions. The number of reported adverse events was higher for patients receiving placebo (18 of 37 patients; 49%) and formoterol (17 of 35 patients; 49%) than for those receiving salmeterol (13 of 33 patients; 39%). There were two serious adverse events. One patient experienced attacks of angina while taking the placebo, and one patient experienced a transient ischemic attack while taking formoterol.


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  		Table 1.. Summary of Patients Who Withdrew From the Study

 
Compliance was assessed by capsule/disk count at the end of each treatment period. Medication was not returned for 12 visits. For the remaining visits, the mean compliance was 91% (SEM, 1%). There was no difference in compliance between treatments.

Concomitant Medications
All patients were receiving at least 1,500 µg inhaled steroid daily, and 11 patients were treated with regular oral steroids (Table 2 ). All patients who were receiving regular oral steroids also were receiving inhaled steroids. Fifteen patients were taking long-acting ß2-agonist medications prior to entry into the trial (salmeterol, 14 patients; formoterol, 1 patient), and these patients were stopped from taking more of the medications at the screening visit and underwent a 4-week run-in period to allow for a sufficient washout period.


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  		Table 2.. Concomitant Medication Use

 
Baseline Lung Function
At the initial screening visit, patients had a mean FEV1 of 1.83 ± 0.12 L (61.8 ± 3.4% predicted) with an average reversibility of 17 ± 2.2%, and a mean PEF of 333 ± 14 L/min. During the run-in period, patients had a mean morning PEF of 290 ± 14 L/min, a mean evening PEF of 317 ± 14 L/min, a mean daytime symptom score of 1.2 ± 0.1, and a mean nighttime symptom score of 0.9 ± 0.1. The mean rescue inhaler use during the run-in period was 6.1 ± 0.7 puffs per day, and in the five patients using home nebulizers, mean nebulizer use was 5.3 ± 2.2 nebulizers per day.

Lung Function
Following treatment, there was a statistically significant increase in the mean morning PEF for patients receiving both formoterol and salmeterol compared with placebo (p < 0.05 for both) [Fig 1 ]. The mean increase for formoterol was 14.4 L/min (95% CI, 0.2 to 28.6), and the mean increase for salmeterol was 14.8 L/min (95% CI, 0.5 to 29.1). There was no significant difference in the mean morning PEF between the two active treatments.



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  		Figure 1.. Mean morning PEF for the final 2 weeks of a 4-week treatment period with placebo (open bar; n = 31), formoterol (12 µg twice daily; filled bar; n = 31), or salmeterol (50 µg twice daily; hatched bar; n = 33). Values are given as the mean and one SEM. * = p < 0.05 compared with placebo.

 
There were no significant treatment effects for any of the secondary outcome variables (ie, FEV1, p = 0.2; FVC, p = 0.7; mean evening PEF, p = 0.5; mean daytime symptom score, p = 0.5; mean nighttime symptom score, p = 0.2) [Tables 3 and 4 ]. There was a trend for improvement in spirometry and PEF measurements following treatment with salmeterol and formoterol compared with placebo treatment (Table 3) , but no significant differences among the three groups. Bronchial reversibility to albuterol was greater following placebo treatment compared with active treatments, although not significantly so. However, the postbronchodilator FEV1 measurements were the same for all three treatments.


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  		Table 3.. Lung Function Parameters at the End of Treatment*

 

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  		Table 4.. Summary of Data From Diary Cards for Last 2 Weeks of Each Treatment Period*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study compared the clinical effects of 4 weeks of treatment with inhaled formoterol (12 µg twice daily) or inhaled salmeterol (50 µg twice daily) in patients with severe asthma whose symptoms were not controlled by treatment with high-dose inhaled or regular oral corticosteroids. We found that the mean morning PEF was greater for patients receiving both formoterol and salmeterol compared with placebo, but with no difference between the active treatments.

Formoterol and salmeterol are both highly selective and potent ß2-adrenoceptor agonists that relax bronchial smooth muscle in vitro.14 However, formoterol is more potent than salmeterol in vitro, with a faster onset but a shorter duration of action.15 In addition, formoterol is a nearly full agonist, and salmeterol is only a partial agonist at the ß2-adrenoceptor.10

Single-dose studies with salmeterol and formoterol found that formoterol has a more rapid onset of bronchodilator action than salmeterol in asthmatic patients16 but has a similar bronchodilator effect at 12 h. Relative potency estimates show that 50 µg salmeterol corresponds to 9 µg formoterol.16 In addition, formoterol has a faster action in reversing methacholine-induced bronchoconstriction than salmeterol.17 Also, 12 µg formoterol and 50 µg salmeterol provide equal protection against methacholine-induced bronchoconstriction for up to 24 h.18 However, formoterol has a greater maximal protective effect than salmeterol against methacholine-induced bronchoconstriction in asthmatic patients, confirming that salmeterol is a partial agonist compared with formoterol in human airways in vivo.19

Previous studies7 9 20 21 22 23 24 25 26 have demonstrated the effectiveness of regular treatment with salmeterol or formoterol compared with albuterol or placebo. In common with the present study, these studies showed improvements in morning PEF with long-acting ß2-agonist treatment. However, unlike the present study, these studies demonstrated improvements in evening PEF, decreased symptom scores, and decreased use of rescue inhalers. There are two possible reasons for these discrepancies. First, many of the previous studies looked at patient populations with milder asthma. Previous studies9 20 21 23 24 included patients with mild-to-moderate asthma and patients receiving either low-dose inhaled corticosteroids or those receiving no regular steroid treatment. Second, some studies7 22 used a higher dose of formoterol (ie, 24 µg twice daily) than was used herein. Three trials25 26 27 of salmeterol in severe asthmatics demonstrated improvements in PEF values, symptom scores, and rescue inhaler usage. However, in two of these trials the dose of salmeterol used was 100 µg twice daily25 26 compared with the present dose of 50 µg twice daily. The third trial27 used the same dose of salmeterol as was used herein, although the patients may have had milder disease than those in the present study. They included patients receiving doses of 800 µg daily of inhaled steroids (compared with > 1,500 µg daily in the present study), and only 1 of 20 patients was receiving regular oral steroid treatment (compared with 11 of 42 patients herein).

The present study is one of the few to examine the effects of therapy with long-acting ß2-agonists in patients with severe and uncontrolled asthma. Our data suggest that both salmeterol and formoterol are less effective in this population than has been reported previously in patients with less severe asthma. The study of patients with severe asthma poses problems, including a high dropout rate, with 33% of patients being withdrawn from the study due to asthma exacerbations. This meant that the power of the study was reduced to 65%. Another explanation for the apparently poor response could be down-regulation of ß2-adrenoceptors by the use of high doses of short-acting ß2-agonists.28 This also may explain the lack of difference in efficacy between treatments. Third, the addition of a leukotriene antagonist to the treatment of patients with severe asthma did not result in any clinical benefit.29 This, together with the results of the present study, suggests that in patients with continuing unsatisfactory control of their asthma despite treatment with high doses of inhaled steroids, the lack of benefit from additional treatments may not be purely related to lack of efficacy. Other factors such as compliance and psychosocial issues also may be relevant. Also, 11 of the patients who completed the present trial received therapy with long-acting ß2-agonists prior to entering the study. Of these patients, some remained symptomatic despite this therapy. This may have preselected a proportion of patients that would not respond favorably to the trial medications. In addition, in allergic asthma patients, the morning PEF may be affected by allergen exposure, which is affected by various measures including high-efficiency particulate air filtration and air conditioning.6 However, we do not have any information regarding the use of such devices by patients in the present study.

Two previous studies11 12 have compared salmeterol and formoterol treatment in asthmatic patients. The first was a large parallel-group study of 6 months of treatment using the same doses as those used herein.12 Like the present study, there was no difference in mean morning PEF, rescue medication use, or symptom scores, although the evening PEF was better with formoterol at 2, 3, and 4 months. The second trial11 also showed improvements in morning and evening PEF values, symptom scores, and rescue inhaler use with two formulations of salmeterol (MDI and Serevent Accuhaler; GlaxoSmithKline) and with formoterol compared with baseline values. The only difference between treatments was a greater improvement in daytime symptoms in patients receiving formoterol compared with those using the salmeterol inhaler (Accuhaler) but not compared with the salmeterol MDI. These two studies differed from the present study in three ways. There was no placebo control, both trials were of an open-label design, and the patients who were studied had milder cases of asthma, with higher PEF rates, lower rescue inhaler use, and lower steroid doses than those recorded herein.

A large trial30 investigating the cost-effectiveness of inhaled formoterol compared with salmeterol in asthma patients found no difference in median medical costs over a 6-month treatment period. This finding coupled with our finding of no difference in efficacy between treatments suggests that it is not possible to recommend the use of one drug over the other for patients with severe asthma. However, long-term treatment with formoterol added to budesonide decreases the exacerbation rate in patients with less severe asthma.31 The present short-term study did not investigate exacerbation rates, and a longer trial in this severe patient group, similar to that performed by van der Molen and colleagues,22 would be of interest.

We conclude that the long-acting ß2-agonist medications salmeterol and formoterol improve morning PEF in patients with severe asthma but without any difference in efficacy between the two drugs.


   Acknowledgements
 
The authors thank Novartis Pharmaceuticals for sponsorship and for the supply of the study inhalers, and the nurses of the asthma laboratory, particularly Julie Mohammed, for help with trial visits.


   Footnotes
 
Abbreviations: CI = confidence interval; MDI = metered-dose inhaler; PEF = peak expiratory flow

This research was supported by a grant from Novartis Pharmaceuticals.

Received for publication May 24, 2001. Accepted for publication October 30, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Nelson, HS (1997) ß-adrenergic bronchodilators. N Engl J Med 333,499-506[Free Full Text]
  2. Derom, EY, Pauwels, RA, Van der Straeten, ME (1992) The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours. J Allergy Clin Immunol 89,811-815[CrossRef][ISI][Medline]
  3. Derom, EY, Pauwels, RA (1992) Time course of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic. Thorax 47,30-33[Abstract/Free Full Text]
  4. Ramsdale, EH, Otis, J, Kline, PA, et al (1991) Prolonged protection against methacholine-induced bronchoconstriction by the inhaled ß2-agonist formoterol. Am Rev Respir Dis 143,998-1001[ISI][Medline]
  5. . British Thoracic Society. (1997) Asthma in adults and schoolchildren. Thorax 52(suppl),S2-S8
  6. . National Asthma Education and Prevention Program (April, 1997) Expert panel report 2: guidelines for the diagnosis and management of asthma. National Institutes of Health Bethesda, MD. Publication No. 97–405
  7. Midgren, B, Melander, B, Persson, G (1992) Formoterol, a new long-acting ß2-agonist, inhaled twice daily, in stable asthmatic subjects. Chest 101,1019-1022[Abstract/Free Full Text]
  8. Ullman, A, Hedner, J, Svedmyr, N (1990) Inhaled salmeterol and salbutamol in asthmatic patients: an evaluation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 142,571-575[ISI][Medline]
  9. Dahl, R, Earnshaw, JS, Palmer, JBD (1991) Salmeterol: a four week study of a long-acting beta-adrenoceptor agonist for the treatment of reversible airways disease. Eur Respir J 4,1178-1184[Abstract]
  10. Jeppsson, A-B, Källström, B-L, Waldeck, B (1992) Studies on the interaction between formoterol and salmeterol in guinea-pig trachea in vitro. Pharmacol Toxicol 71,272-277[ISI][Medline]
  11. Campbell, LM, Anderson, TJ, Parashchak, MR, et al (1999) A comparison of the efficacy of long-acting ß2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Respir Med 93,236-244[CrossRef]
  12. Vervloet, D, Ekström, T, Pela, R, et al (1998) A 6-month comparison between formoterol and salmeterol in patients with reversible obstructive airways disease. Respir Med 92,836-842[CrossRef][ISI][Medline]
  13. . American Thoracic Society. (1987) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 136,225-244[ISI][Medline]
  14. Lindén, A, Rabe, KF, Löfdahl, CG (1996) Pharmacological basis for duration of effect: formoterol and salmeterol versus short-acting beta 2-adrenoceptor agonists. Lung 174,1-22[ISI][Medline]
  15. Naline, E, Zhang, Y, Qian, Y, et al (1994) Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus. Eur Respir J 7,914-920[Abstract]
  16. Palmqvist, M, Persson, G, Lazer, L, et al (1997) Inhaled dry powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 10,2484-2489[Abstract]
  17. Politiek, MJ, Boorsma, M, Aalbers, R (1999) Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J 13,988-992[Abstract]
  18. Rabe, KF, Jörres, R, Nowak, D, et al (1993) Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis 147,1436-1441[ISI][Medline]
  19. Palmqvist, M, Ibsen, T, Mellén, A, et al (1999) Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 160,244-249[Abstract/Free Full Text]
  20. Steffensen, I, Faurschou, P, Riska, H, et al (1995) Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airways disease. Allergy 50,657-663[ISI][Medline]
  21. Kesten, S, Chapman, KR, Broder, I, et al (1991) A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma. Am Rev Respir Dis 144,622-625[ISI][Medline]
  22. van der Molen, T, Postma, DS, Turner, MO, et al (1996) Effects of the long acting ß agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. Thorax 52,535-539[Abstract]
  23. Taylor, DR, Town, GI, Herbison, GP, et al (1998) Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 53,744-752[Abstract/Free Full Text]
  24. Pearlman, DS, Chervinsky, P, LaForce, C, et al (1992) A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 327,1420-1425[Abstract]
  25. Boyd, G (1995) Salmeterol xinofoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. Eur Respir J 8,1494-1498[Abstract]
  26. Faurschou, P, Steffensen, I, Jacques, L (1996) Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. Eur Respir J 9,1885-1890[Abstract]
  27. Lai, CKW, Chan, CHS, Ho, SS, et al (1995) Inhaled salmeterol and albuterol in asthmatic patients receiving high-dose inhaled corticosteroids. Chest 108,36-40[Abstract/Free Full Text]
  28. Sears, MR, Taylor, DR (1994) The beta 2-agonist controversy: observations, explanations and relationship to asthma epidemiology. Drug Saf 11,259-283[ISI][Medline]
  29. Robinson, DS, Campbell, D, Barnes, PJ (2001) Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 357,2007-2011[CrossRef][ISI][Medline]
  30. Rutten-van Mölken, MPMH, van Doorslaer, EKA, Till, MD (1998) Cost-effectiveness analysis of formoterol versus salmeterol in patients with asthma. Pharmacoeconomics 14,671-684[CrossRef][ISI][Medline]
  31. Pauwels, RA, Löfdahl, CG, Postma, DS, et al (1997) Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 337,1405-1411[Abstract/Free Full Text]



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