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Meta-Analysis
. 2002;2002(4):CD003901.
doi: 10.1002/14651858.CD003901.

Regular treatment with long acting beta agonists versus daily regular treatment with short acting beta agonists in adults and children with stable asthma

E H Walters  1 , J A Walters, P W Gibson
Affiliations
Meta-Analysis

Regular treatment with long acting beta agonists versus daily regular treatment with short acting beta agonists in adults and children with stable asthma

E H Walters et al. Cochrane Database Syst Rev. 2002.

Abstract

Background: Selective beta-adrenergic agonists for use in asthma are: short acting (2-6 hours) and long acting (>12 hours). There has been little controversy about using short acting beta-agonists intermittently, but long acting beta-agonists are used regularly, and their regular use has been controversial.

Objectives: To determine the benefit or detriment of treatment with regular short- or long acting inhaled beta-agonists in chronic asthma.

Search strategy: A search was carried out using the Cochrane Airways Group register. Bibliographies of identified RCTs were searched for additional relevant RCTs. Authors of identified RCTs were contacted for other published and unpublished studies.

Selection criteria: All randomised studies of at least two weeks duration, comparing a long acting inhaled beta-agonist given twice daily with any short acting inhaled beta-agonist of equivalent bronchodilator effectiveness given regularly in chronic asthma.

Data collection and analysis: Two reviewers performed data extraction and study quality assessment independently. Authors of studies were contacted for missing data.

Main results: 31 studies met the inclusion criteria, 24 of parallel group and 7 cross over design. Salmeterol xinafoate was used as long acting agent in 22 studies and formoterol fumarate in 9. Salbutamol was the short acting agent used in 27 studies and terbutaline in 5. The treatment period was over 2 weeks in 29 studies, and at least 12 weeks in 20. 25 studies permitted a variety of co-intervention treatments, usually inhaled corticosteroid or cromones. One study did not permit inhaled corticosteroid. Long acting beta-agonists were significantly better than short acting for a variety of lung function measurements including morning PEF (Weighted Mean Difference (WMD) 33 l/min 95% CI 25, 42) or evening PEF (WMD 26 l/min 95% CI 18, 33); and had significantly lower scores for day and night time asthma symptom scores and percentage of days and nights without symptoms. They were also associated with a significantly lower use of rescue medication both during the day and night. Risk of exacerbations was not different between the two types of agent, but most studies were of short duration which limits the power to test for such differences.

Reviewer's conclusions: Long acting inhaled beta-agonists have advantages across a wide range of physiological and clinical outcomes for regular treatment.

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Conflict of interest statement

E H Walters has taken part in collaborative clinical pharmacology studies with a number of pharmaceutical companies including GlaxoWellcome, Astra Zeneca, Pfizer, Boehringer, Schering Plough, SKB, and Novartis. He has, in the past, held consultancies with GlaxoWellcome, Pfizer and Zeneca. He has had sponsorship to meetings from a number of the companies listed over the past 15 years.

Figures

1.1
1.1. Analysis
Comparison 1 All studies, Outcome 1 Peak expiratory flow: morning l/min.
1.2
1.2. Analysis
Comparison 1 All studies, Outcome 2 Peak expiratory flow: evening l/min.
1.3
1.3. Analysis
Comparison 1 All studies, Outcome 3 Change in PEF morning.
1.4
1.4. Analysis
Comparison 1 All studies, Outcome 4 Change in PEF evening.
1.5
1.5. Analysis
Comparison 1 All studies, Outcome 5 Amplitude PEF: diurnal variation (l/min or %).
1.6
1.6. Analysis
Comparison 1 All studies, Outcome 6 FEV1 (litres).
1.7
1.7. Analysis
Comparison 1 All studies, Outcome 7 % Predicted FEV1.
1.8
1.8. Analysis
Comparison 1 All studies, Outcome 8 Change in FEV (litres).
1.9
1.9. Analysis
Comparison 1 All studies, Outcome 9 Forced Vital Capacity (litres).
1.10
1.10. Analysis
Comparison 1 All studies, Outcome 10 FEF25‐75 (litres/sec).
1.11
1.11. Analysis
Comparison 1 All studies, Outcome 11 Symptom score ‐ whole day.
1.12
1.12. Analysis
Comparison 1 All studies, Outcome 12 Symptom score ‐ day time.
1.13
1.13. Analysis
Comparison 1 All studies, Outcome 13 Symptom score: night time.
1.14
1.14. Analysis
Comparison 1 All studies, Outcome 14 %days without asthma symptoms.
1.15
1.15. Analysis
Comparison 1 All studies, Outcome 15 % nights without asthma awakenings.
1.16
1.16. Analysis
Comparison 1 All studies, Outcome 16 Rescue bronchodilator use: whole day.
1.17
1.17. Analysis
Comparison 1 All studies, Outcome 17 Rescue bronchodilator use: day time.
1.18
1.18. Analysis
Comparison 1 All studies, Outcome 18 Rescue bronchodilator use: night time.
1.19
1.19. Analysis
Comparison 1 All studies, Outcome 19 Change in use of rescue bronchodilator/day.
1.20
1.20. Analysis
Comparison 1 All studies, Outcome 20 Quality of life score: overall.
1.21
1.21. Analysis
Comparison 1 All studies, Outcome 21 Quality of life score: symptoms.
1.22
1.22. Analysis
Comparison 1 All studies, Outcome 22 Quality of life score: emotions.
1.23
1.23. Analysis
Comparison 1 All studies, Outcome 23 Quality of life score: exposure to environmental stimuli.
1.24
1.24. Analysis
Comparison 1 All studies, Outcome 24 Qualtiy of life score: activity limitations.
1.25
1.25. Analysis
Comparison 1 All studies, Outcome 25 Bronchial hyperreactivity‐ log PD20/PC20 methacholine or histamine.
1.26
1.26. Analysis
Comparison 1 All studies, Outcome 26 Bronchoprotection to methacholine challenge(protection ratio vs. baseline).
1.27
1.27. Analysis
Comparison 1 All studies, Outcome 27 Adverse events‐all.
1.28
1.28. Analysis
Comparison 1 All studies, Outcome 28 Adverse events‐ palpitations.
1.29
1.29. Analysis
Comparison 1 All studies, Outcome 29 Adverse events‐headache.
1.30
1.30. Analysis
Comparison 1 All studies, Outcome 30 Adverse events‐ tremor.
1.31
1.31. Analysis
Comparison 1 All studies, Outcome 31 Adverse events‐ cramps.
1.32
1.32. Analysis
Comparison 1 All studies, Outcome 32 Exacerbations asthma‐major.
1.33
1.33. Analysis
Comparison 1 All studies, Outcome 33 Asthma attacks ‐ day.
1.34
1.34. Analysis
Comparison 1 All studies, Outcome 34 Asthma attacks ‐ night.
1.35
1.35. Analysis
Comparison 1 All studies, Outcome 35 Major excerbation rate ‐ yearly (number/patient /year).
1.36
1.36. Analysis
Comparison 1 All studies, Outcome 36 Minor exacerbation rate (number/patient/year).
1.37
1.37. Analysis
Comparison 1 All studies, Outcome 37 Deaths related to asthma.
1.38
1.38. Analysis
Comparison 1 All studies, Outcome 38 Global assessment of efficacy by patient ‐ very good/good.
1.39
1.39. Analysis
Comparison 1 All studies, Outcome 39 Global assessment of efficacy by investigator ‐ very good/good.
2.1
2.1. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 1 Peak expiratory flow: morning l/min.
2.2
2.2. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 2 Peak expiratory flow: evening l/min.
2.3
2.3. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 3 Change in PEF morning.
2.4
2.4. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 4 Change in PEF evening.
2.5
2.5. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 5 Amplitude PEF: diurnal variation.
2.6
2.6. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 6 FEV1 litres.
2.7
2.7. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 7 Change in FEV1.
2.8
2.8. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 8 Symptom score‐ day time.
2.9
2.9. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 9 Symptom score: night time.
2.10
2.10. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 10 Rescue bronchodilator use: whole day.
2.11
2.11. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 11 Rescue bronchodilator use: day‐time.
2.12
2.12. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 12 Rescue bronchodilator use: night time.
2.13
2.13. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 13 Quality of life score: overall.
2.14
2.14. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 14 Bronchial hyperreactivity.
2.15
2.15. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 15 Adverse events ‐ all.
2.16
2.16. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 16 Adverse events ‐ palpitations.
2.17
2.17. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 17 Adverse events ‐ headache.
2.18
2.18. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 18 Adverse events ‐ tremor.
2.19
2.19. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 19 Adverse events ‐ cramps.
2.20
2.20. Analysis
Comparison 2 Studies with all subjects using ICS, Outcome 20 Exacerbations asthma ‐ major.
3.1
3.1. Analysis
Comparison 3 Childrens studies, Outcome 1 Adverse events ‐ palpitations.
3.2
3.2. Analysis
Comparison 3 Childrens studies, Outcome 2 Adverse events ‐ headache.
3.3
3.3. Analysis
Comparison 3 Childrens studies, Outcome 3 Adverse events ‐ tremor.
3.4
3.4. Analysis
Comparison 3 Childrens studies, Outcome 4 Exacerbations asthma ‐ major.
3.5
3.5. Analysis
Comparison 3 Childrens studies, Outcome 5 Adverse events‐all.
3.6
3.6. Analysis
Comparison 3 Childrens studies, Outcome 6 Peak expiratory flow: morning l/min.
3.7
3.7. Analysis
Comparison 3 Childrens studies, Outcome 7 Peak expiratory flow: evening l/min.
3.8
3.8. Analysis
Comparison 3 Childrens studies, Outcome 8 FEV1 litres.
3.9
3.9. Analysis
Comparison 3 Childrens studies, Outcome 9 Bronchial hyperreactivity ‐ log PD/PC 20 methacholine or histamine.
4.1
4.1. Analysis
Comparison 4 Asthma severity, Outcome 1 Peak expiratory flow: morning l/min.
4.2
4.2. Analysis
Comparison 4 Asthma severity, Outcome 2 Peak expiratory flow: evening l/min.
4.3
4.3. Analysis
Comparison 4 Asthma severity, Outcome 3 Change in PEF morning.
4.4
4.4. Analysis
Comparison 4 Asthma severity, Outcome 4 Change in PEF evening.
4.5
4.5. Analysis
Comparison 4 Asthma severity, Outcome 5 Amplitude PEF: diurnal variation (l/min or %).
4.6
4.6. Analysis
Comparison 4 Asthma severity, Outcome 6 FEV1 (litres).
4.7
4.7. Analysis
Comparison 4 Asthma severity, Outcome 7 % Predicted FEV1.
4.8
4.8. Analysis
Comparison 4 Asthma severity, Outcome 8 Change in FEV (litres).
4.9
4.9. Analysis
Comparison 4 Asthma severity, Outcome 9 Forced Vital Capacity (litres).
4.10
4.10. Analysis
Comparison 4 Asthma severity, Outcome 10 FEF25‐75 (litres/sec).
4.11
4.11. Analysis
Comparison 4 Asthma severity, Outcome 11 Symptom score ‐ whole day.
4.12
4.12. Analysis
Comparison 4 Asthma severity, Outcome 12 Symptom score ‐ day time.
4.13
4.13. Analysis
Comparison 4 Asthma severity, Outcome 13 Symptom score: night time.
4.14
4.14. Analysis
Comparison 4 Asthma severity, Outcome 14 %days without asthma symptoms.
4.15
4.15. Analysis
Comparison 4 Asthma severity, Outcome 15 % nights without asthma awakenings.
4.16
4.16. Analysis
Comparison 4 Asthma severity, Outcome 16 Rescue bronchodilator use: whole day.
4.17
4.17. Analysis
Comparison 4 Asthma severity, Outcome 17 Rescue bronchodilator use: day time.
4.18
4.18. Analysis
Comparison 4 Asthma severity, Outcome 18 Rescue bronchodilator use: night time.
4.19
4.19. Analysis
Comparison 4 Asthma severity, Outcome 19 Quality of life score: overall.
4.20
4.20. Analysis
Comparison 4 Asthma severity, Outcome 20 Bronchial hyperreactivity.
4.21
4.21. Analysis
Comparison 4 Asthma severity, Outcome 21 Adverse events ‐ all.
4.22
4.22. Analysis
Comparison 4 Asthma severity, Outcome 22 Adverse events ‐ palpitations.
4.23
4.23. Analysis
Comparison 4 Asthma severity, Outcome 23 Adverse events ‐ headache.
4.24
4.24. Analysis
Comparison 4 Asthma severity, Outcome 24 Adverse events ‐ tremor.
4.25
4.25. Analysis
Comparison 4 Asthma severity, Outcome 25 Adverse events ‐ cramps.
4.26
4.26. Analysis
Comparison 4 Asthma severity, Outcome 26 Exacerbations asthma ‐ major.
4.27
4.27. Analysis
Comparison 4 Asthma severity, Outcome 27 Global assessment of efficacy by patient ‐ very good/good.
See this image and copyright information in PMC

Comment in

References

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Bhagat 1995 {published data only}
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Bishop 1994 {published data only}
    1. Bishop AL, Chervinsky P, Liddle R, et al. Salmeterol for treatment of reversible obstructive airways disease in children. Journal of Allergy & Clinical Immunology 1994;93:248.
Blake 1999 {published data only}
    1. Blake K, Pearlman D, Scott C, Wang Y, Stahl E, Arledge T. Prevention of exercise‐induced bronchospasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol. Annals of Allergy, Asthma, & Immunology 1999;82:205‐11. - PubMed
Booth Bish 1996 {published data only}
    1. Booth H, Bish R, Walters J, Whitehead F, Walters EH. Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 1996;51:1100‐4. - PMC - PubMed
Booth 1993 {published data only}
    1. Booth H, Fishwick K, Harkawat R, Devereux G, Hendrick DJ, Walters EH. Changes in methacholine induced bronchoconstriction with the long acting beta2 agonist salmeterol in mild to moderate asthmatic patients. Thorax 1993;48(11):1121‐4. - PMC - PubMed
Boulet Cartier 1998 {published data only}
    1. Boulet L, Cartier A, Milot J, Cote J, Malo JL, Laviolette M. Tolerance to the protective effects of salmeterol on methacholine‐induced bronchoconstriction: influence of inhaled corticosteroids. European Respiratory Journal 1998;11(5):1091‐7. - PubMed
Boulet Turcot 1997 {published data only}
    1. Boulet L, Turcotte H, Boutet M, Dube J, Gagnon M, Laviolette M. Influence of salmeterol on chronic and allergen‐induced airway inflammation in mild allergic asthma : A pilot study. Current Therapeutic Research ‐ Clinical and Experimental 1997;58:240‐59.
Bowers 1997 {published data only}
    1. Bowers BW, Cox FM, Kalberg C, et al. The impact of salmeterol on asthma specific quality of life in patients reporting nocturnal asthma awakenings due to asthma [abstract]. Annals of Allergy, Asthma, & Immunology 1997;78:110.
Boyd 1995 {published data only}
    1. Boyd G. Salmeterol xinafoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. UK Study Group. European Respiratory Journal 1995;8:1494‐8. - PubMed
Brambilla 1994 {published data only}
    1. Brambilla C, Chastang C, Georges D, et al. Salmeterol compared with slow release terbutaline in nocturnal asthma: a multi center randomised double blind double dummy sequential clinical trial. Allergy 1994;49:421‐6. - PubMed
Busse 1998 {published data only}
    1. Busse WW, Casale TB, Murray JJ, Petrocella V, Cox F, Rickard K. Efficacy, safety, and impact on quality of life of salmeterol in patients with moderate persistent asthma. American Journal of Managed Care 1998;4(11):1579‐87. - PubMed
Campbell 2000 {published data only}
    1. Campbell LM, Berggren F, Emmas C. The cost effectiveness of eformoterol via Turbohaler(TM) and salmeterol via pressurised metered dose inhaler and metered dose powder inhaler in mild to moderate asthma. Journal of Medical Economics 2000;3:49‐60.
Carlsen 1995 {published data only}
    1. Carlsen K, Roksund O, Olsholt K, Nja F, Leegaard J, Bratten G. Overnight protection by inhaled salmeterol on exercise‐induced asthma in children. European Respiratory Journal 1995;8:1852‐5. - PubMed
Charpin 1992 {published data only}
    1. Charpin D, Vervloet D. Quality of life in moderate chronic asthma: salmeterol versus current treatments [abstract]. Allergy 1992;47(12 Suppl):230.
Chervinsky 1999 {published data only}
    1. Chervinsky P, Goldberg P, Galant S, Wang Y, Arledge T, Welch MB, et al. Long‐term cardiovascular safety of salmeterol powder pharmacotherapy in adolescent and adult patients with chronic persistent asthma: A randomized clinical trial. Chest 1999;115(3):642‐8. - PubMed
Cheung 1992 {published data only}
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Clark 1993 {published data only}
    1. Clark CE, Ferguson AD, Siddorn J. Respiratory arrests in young asthmatics on salmeterol. Respiratory Medicine 993;87:227‐8. - PubMed
Clauzel 1998 {published data only}
    1. Clauzel AM, Molimard M, Gros V, Lepere E, Febvre N, Michel FB. Use of formoterol dry powder administered for three months via a single dose inhaler in 1,380 asthmatic patients. Journal of Investigational Allergology and Clinical Immunology 1998;8:265‐0. - PubMed
Cockcroft 1997 {published data only}
    1. Cockcroft DW, Swystun VA, Bhagat R. Salmeterol and airway response to allergen. Canadian Respiratory Journal 1997;4:37‐40.
Dahl 1991 {published data only}
    1. Dahl R, Earnshaw JS, Palmer JBD. Salmeterol: a 4 week study of a long acting beta2 adrenoceptor agonist for the treament of reversible airways disease. European Respiratory Journal 1991;4:1178‐84. - PubMed
Derom 1992 {published data only}
    1. Derom EY, Pauwels RA, Straten MEF. The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours. Journal of Allergy & Clinical Immunology 1992;89:811‐5. - PubMed
Di‐Lorenzo 1995 {published data only}
    1. Di‐Lorenzo G, Morici G, Norrito F, Mansueto P, Melluso M, Purello‐D'Ambrosio F, et al. Comparison of the effects of salmeterol and salbutamol on clinical activity and eosinophil cationic protein serum levels during the pollen season in atopic asthmatics. Clinical and experimental allergy 1995;25(10):951‐6. - PubMed
Droszcz 1999 {published data only}
    1. Droszcz P, Droszcz W. Results of 30 days and 12 months treatment with salmeterol in patients with asthma and COPD. Polske Merkuriusz Lekarski 1999;6:266‐7. - PubMed
Faurschou 1991 {published data only}
    1. Faurschou P. Chronic dose‐ranging studies with salmeterol. European Respiratory Journal 1991;1(4):282‐87.
Faurschou 1992 {published data only}
    1. Faurschou P. Salmeterol and Salbutamol: long term efficacy and safety. European Respiratory Journal 1992;5 Supp (15):317‐8.
Faurschou Dahl 1997 {published data only}
    1. Faurschou P, Dahl R, Jeffery P, et al. Comparison of the anti‐inflammatory effects of fluticasone and salmeterol in asthma: A placebo controlled, DB CO with bronchoscopy, bronchial methacholine provocation and lavage. European Respiratory Journal 1997;10 Suppl:243.
Fitzpatrick 1990 {published data only}
    1. Fitzpatrick MF, MacKay T, Driver H, Douglas H. Salmeterol in nocturnal asthma: a double blind , placebo controlled trial of a long acting inhaled beta agonist. British Medical Journal 1990;301:1365‐8. - PMC - PubMed
Fuglsang 1998 {published data only}
    1. Fuglsang G, Vikre‐Jorgensen J, Agertoft L, Pedersen S. Effect of salmeterol treatment on nitric oxide level in exhaled air and dose‐response to terbutaline in children with mild asthma. Pediatric Pulmonology 1998;25(5):314‐21. - PubMed
Gardiner 1994 {published data only}
    1. Gardiner PV, Ward C, Booth H, et al. Effect of eight weeks treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. American Journal of Respiratory & Critical Care Medicine 1994;150:1006‐11. - PubMed
Giannini 1995 {published data only}
    1. Giannini D, Carletti A, Dente FL, et al. Tolerance to salbutamol in allergen induced bronchoconstriction. American Journal of Respiratory & Critical Care Medicine 1995;151:A39.
Giannini Bacci 1999 {published data only}
    1. Giannini D, Bacci E, Dente FL, Franco A, Vagagginin B, Testi R, et al. Inhaled beclomethasone diproprionate reverts tolerance to the protective effect of salmeterol on allergen challenge. Chest 1999;115:629‐34. - PubMed
Gong 1996 {published data only}
    1. Gong H, Linn WS, Shamou DA, et al. Effect of inhaled salmeterol on sulfur dioxide induced bronchoconstriction in asthmatic subjects. Chest 1996;110:1229‐35. - PubMed
Gotz 1995 {published data only}
    1. Gotz MH, Taak NK. The efficacy and safety of inhaled salmeterol 50mcg bd compared with salbutamol 200mcg prn in children with asthma [abstract]. European Respiratory Journal 1995;8 Suppl (19):517.
Green 1992 {published data only}
    1. Green C, Price J. Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Archives of Disease in Childhood 1992;67:1014‐7. - PMC - PubMed
Greening 1994 {published data only}
    1. Greening AP, Ind PW, Norhtfield M, et al. Added salmeterol versus higher dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219‐24. - PubMed
Grove 1995 {published data only}
    1. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995;346:201‐6. - PubMed
Grove Lipworth 1996 {published data only}
    1. Grove A, Lipworth BJ. Effects of prior treatment with salmeterol and formoterol on airway and systemic beta 2 responses to formoterol. Thorax 1996;51:585‐9. - PMC - PubMed
Hacki 1993 {published data only}
    1. Hacki M, Ritter A, Medici T. Formoterol: three years therapy in asthma. European Respiratory Journal 1993;6 Suppl (17):529.
Hyland 1994 {published data only}
    1. Hyland ME, Kenyon CAP, Jacobs P. Sensitivity of quality of life domains and constructs to longitudinal change in a clinical trial comparing salmeterol and placebo in asthmatics. Quality of Life Research 1994;3:121‐6. - PubMed
Jartti 1998 {published data only}
    1. Jartti TT, Kaila TJ, Tahvanainen KUO, Kuusela TA, Vanto TT, Valimaki IAT. Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children. Clinical Physiology 1998;18(4):345‐53. - PubMed
Jones 1994 {published data only}
    1. Jones K. Salmeterol xinafoate in the treatment of mild to moderate asthma in primary care. UK Study Group. Thorax 1994;49:971‐5. - PMC - PubMed
Juniper 1999 {published data only}
    1. Juniper E, Svensson K, O'Byrne P, Barnes P, Bauer C, Lofdahl C‐G, et al. Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. European Respiratory Journal 1999;14(5):1038‐43. - PubMed
Kalra 1996 {published data only}
    1. Kalra S, Swystun V, Bhagat R, Cockcroft DW. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 1996;109:953‐6. - PubMed
Kavuru 2000 {published data only}
    1. Kavuru M, Melamed J, Gross G, LaForce C, House K, Prillaman B, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double‐blind, placebo‐controlled trial. Journal of Allergy & Clinical Immunology 2000;105(6):1108‐16. - PubMed
Kemp Cook 1998 {published data only}
    1. Kemp J, Cook D, Incaudo G, Corren J, Kalberg C, Emmett A, et al. Salmeterol improves quality of life in patients with asthma requiring inhaled corticosteroids. Salmeterol Quality of Life Study Group. Journal of Allergy & Clinical Immunology 1998;101:188‐95. - PubMed
Kemp 1993 {published data only}
    1. Kemp J, Bukstein D, Busse W. Effective salmeterol, salbutamol and placebo in the prevention of exercise induced bronchospasm. Chest 1993;104 Suppl:10.
Kemp DeGraff 1999 {published data only}
    1. Kemp J, DeGraff A, Pearlman D, Chervinsky P, Galant S, Goldberg P, et al. A 1‐year study of salmeterol powder on pulmonary function and hyperresponsiveness to methacholine. Journal of Allergy & Clinical Immunology 1999;104(6):1189‐97. - PubMed
Kemp Dockhorn 1994 {published data only}
    1. Kemp JP, Dockhorn RJ, Busse WW, et al. Prolonged effect of inhaled salmeterol against exercise induced bronchoconstriction after chronic dosing with salmeterol. American Journal of Respiratory & Critical Care Medicine 1994;150:1612‐5. - PubMed
Kesten 1992 {published data only}
    1. Kesten S, Chapman KR, Broder I, Cartier A, Hyland RH, Knight A, et al. Sustained improvement in asthma with long‐term use of formoterol fumarate. Annals of Allergy 1992;69(5):415‐20. - PubMed
Kia 1997 {published data only}
    1. Kia Soong T, Grove A, McLean A, Gnosspelius Y, Hall IP, Lipworth BJ. Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. American Journal of Respiratory & Critical Care Medicine 1997;156(1):28‐35. - PubMed
Kraft 1997 {published data only}
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Langley 1998 {published data only}
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Langton 1995 {published data only}
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Li Ward 1999 {published data only}
    1. Li X, Ward C, Thien F, Bish R, Bamford T, Bao X, et al. An antiinflammatory effect of salmeterol, a long‐acting beta2 agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. American Journal of Respiratory & Critical Care Medicine 1999;160:1493‐9. - PubMed
Li 1998 {published data only}
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Lipworth Aziz 2000 {published data only}
    1. Lipworth B, Aziz I. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Chest 2000;117(1):156‐62. - PubMed
Lipworth Demps 2000 {published data only}
    1. Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous Glycine‐16 beta2 adrenoceptor polymorphism. Chest 2000;118(2):321‐8. - PubMed
Lipworth Aziz 1999 {published data only}
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Lockey 1999 {published data only}
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Lotvall 1992 {published data only}
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Mahajan 1998 {published data only}
    1. Mahajan P, Stahl E, Arledge T. Quality of life in pediatric asthma patients treated with salmeterol and impact on the daily activities of their parents. Pediatric Asthma Allergy & Immunology 1998;12(1):21‐8.
Malo 1992 {published data only}
    1. Malo J‐L, Ghezzo H, Trudeau C. Salmeterol a new inhaled beta2 agonist, has a longer blocking effect than albuterol on hyperventilation induced bronchoconstriction. Journal of Allergy & Clinical Immunology 1992;89:567‐74. - PubMed
Malozowski 1998 {published data only}
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Mann 1996 {published data only}
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Martin 1999 {published data only}
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McIvor 1998 {published data only}
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Meijer 1995 {published data only}
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Midgren 1992 {published data only}
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Molimard 2001 {published data only}
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Nathan 1999 {published data only}
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Nelson 1999 {published data only}
    1. Nelson H, Berkowitz R, Tinkelman D, Emmett A, Rickard K, Yancey S. Lack of Subsensitivity to Albuterol After Treatment with Salmeterol in Patients with Asthma. American Journal of Respiratory & Critical Care Medicine 1999;159:1556‐61. - PubMed
Nelson 1998 {published data only}
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Newnham 1993 {published data only}
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Newnham 1994 {published data only}
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Newnham 1995 {published data only}
    1. Newnham DM, Grove A, McDevitt DG, Lipworth BJ. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995;50(5):475‐504. - PMC - PubMed
Nichol 1990 {published data only}
    1. Nichol G, Nix A, Barnes P, Chung K. Prolonged attenuation of BHR to methacholine by long acting b2adrenoceptor agonist formoterol. American Review of Respiratory Disease 1990;141:A 210.
Nielsen 1999 {published data only}
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Nix 1990 {published data only}
    1. Nix A, Nichol G, Robson A, Barnes P, Chung K. Effect of formoterol, a long‐lasting beta2adrenoceptor agonist, against methacholine‐induced bronchoconstriction. British Journal of Clinical Pharmacology 1990;29:321‐4. - PMC - PubMed
Norhaya 1999 {published data only}
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Nowak 1992 {published data only}
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Palmer 1992 {published data only}
    1. Palmer JBD, Stuart AM, Shepherd GL, Viskum K. Inhaled salmeterol in the treatment of patients with moderate to severe ROAD‐ a 3 mth comparison of the efficacy and safety of bd salmeterol (100mcg) and salmeterol (50mcg). Respiratory Medicine 1992;86:409‐17. - PubMed
Pauwels 1997 {published data only}
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Pearlman 1996 {published data only}
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Pearlman 1999 {published data only}
    1. Pearlman D, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, et al. Inhaled salmeterol and fluticasone: A study comparing monotherapy and combination therapy in asthma. Annals of Allergy 1999;82(3):257‐65. - PubMed
Pederson 1993 {published data only}
    1. Pederson B, Dahl R, Larsen BB, et al. The effect of salmeterol on the early and late phase reaction to bronchial allergen and post challenge variation in BHR, blood eosinophils, serum ECP and serum eosinophil protein X. Allergy 1993;48:377‐82. - PubMed
Quebe‐Fehling 1996 {published data only}
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Rabe 1993 {published data only}
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Ramage Lipworth 1994 {published data only}
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Ramsdale 1991 {published data only}
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Ringbaek 1996 {published data only}
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Roberts 1999 {published data only}
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Roberts 1992 {published data only}
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Rosenthal 1997 {published data only}
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Rosenthal 1999 {published data only}
    1. Rosenthal R, Busse W, Kemp J, Baker J, Kalberg C, Emmett A, et al. Effect of long‐term salmeterol therapy compared with as‐needed albuterol use on airway hyperresponsiveness. Chest 1999;116(3):595‐602. - PubMed
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Schaaning 1996 {published data only}
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Schreurs 1996 {published data only}
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Shapiro 2000 {published data only}
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Shepherd 1991 {published data only}
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Simons 1997 {published data only}
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Simons 2 1997 {published data only}
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Simons Gerst 1997 {published data only}
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Smyth 1993 {published data only}
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Tattersfield 2001 {published data only}
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Tattersfield 1999 {published data only}
    1. Tattersfield A, Postma D, Barnes P, Svensson K, Bauer C, O'Byrne P, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. American Journal of Respiratory & Critical Care Medicine 1999;160(2):594‐9. - PubMed
Taylor 1992 {published data only}
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Totterman 1998 {published data only}
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Twentyman 1990 {published data only}
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Van der Molen 1996 {published data only}
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Van der Molen 1998 {published data only}
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Verberne 1996 {published data only}
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Verberne 1998 {published data only}
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Verberne 2000 {published data only}
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Verini 1998 {published data only}
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Viskum 1990 {published data only}
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Von Berg 1996 {published data only}
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Von Berg 1998 {published data only}
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Wallin 1999 {published data only}
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Walters 1992 {published data only}
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Weinstein 1997 {published data only}
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Wong 1997 {published data only}
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Woolcock 1996 {published data only}
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Wronska 1998 {published data only}
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Yates 1995 {published data only}
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Yates 1997 {published data only}
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Zarkovic 1998 {published data only}
    1. Zarkovic J, Gotz MH, Holgate ST, Taak NK. Effect of long‐term regular salmeterol treatment in children with moderate asthma. Clinical Drug Investigation 1998;15(3):169‐75.
Zellweger 1994 {published data only}
    1. Zellweger JP, Plenninger M, Ruff P. 24 hour protective effect of salmeterol 50mg v formoterol 24 mg against methacholine induced bronchoconstriction in mild to moderate asthmatic patients: a randomised double blind crossover single dose trial. European Respiratory Journal 1994 Suppl (18);suppl 18:422.

References to studies awaiting assessment

Cloosterman 2001 {published data only}
    1. Cloosterman SG, Bijl‐Hofland ID, Herwaarden CL, et al. A placebo‐controlled clinical trial of regular monotherapy with short‐acting and long‐acting beta(2)‐agonists in allergic asthmatic patients. Chest 2001;119:1306‐15. - PubMed
Rhee 1997 {published data only}
    1. Rhee YK. A comparison of salmeterol with salbutamol inhalation in treatment of mild to moderate asthma. Tuberculosis and Respiratory Diseases 1997;44(4):815‐21.
Sprogoe‐Jakobsen 92 {published data only}
    1. Sprogoe‐Jakobsen U, Viktrup L, Davidsen O, Viskum K. Bronchial asthma treated with long‐acting beta 2 agonist. Comparison between formoterol (12 mu/g) inhaled twice daily and salbutamol (200 mu/g) inhaled 4 times daily. Ugeskr‐Laeger 1992;154(3):325‐8. - PubMed
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