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Meta-Analysis
. 2007 Jul 18;2007(3):CD001281.
doi: 10.1002/14651858.CD001281.pub2.

Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma

A K H Tee  1 , M S Koh, P G Gibson, T J Lasserson, A J Wilson, L B Irving
Affiliations
Meta-Analysis

Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma

A K H Tee et al. Cochrane Database Syst Rev. .

Abstract

Background: Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles.

Objectives: To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of adults and adolescents with asthma.

Search strategy: We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted authors of identified RCTs for other relevant published and unpublished studies and pharmaceutical manufacturers. Most recent search: November 2006.

Selection criteria: All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist.

Data collection and analysis: In original review, two reviewers independently assessed trial quality and extracted data, similarly in this update two reviewers undertook this. Study authors were contacted for additional information.

Main results: Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV(1) predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16).

Authors' conclusions: Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.

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Conflict of interest statement

None known.

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References

References to studies included in this review

Filiz 2002 {published data only}
    1. Filiz A, Bozkurt N. Addition of salmeterol or theophylline to an inhaled corticosteroid regimen in patients with severe asthma. Turkish Respiratory Journal 2002;3(3):98‐101.
Fjellbirkeland 1994 {published data only}
    1. Fjellbirkeland L, Gulsvik A, Palmer JB. The efficacy and tolerability of inhaled salmeterol and individual dose‐titrated, sustained‐release theophylline in patients with revesible airways disease. Respiratory Medicine 1994;88(8):599‐607. - PubMed
Malolepszy 2002 {published data only}
    1. Malolepszy J. Efficacy and tolerability of oral theophylline slow release versus inhaled formoterol in moderate asthma poorly controlled on low dose steroids [Wirksamkeit und Vertraglichkeit einer oralen Theophyllin ‐Retardzubereitung im Vergleich zu inhaliertem Formoterol bei mittelschwerem, mit niedrig dosierten Steroiden unzureichend kontrolliertem Asthma]. Atemwegs‐ und Lungenkrankheiten 2002;28:78‐87.
Muir 1992 {published data only}
    1. Muir JF, Bertin D, French Multicentre Study group. Salmeterol versus slow‐release theophylline combined with ketotifen in nocturnal asthma: a multicentre trial. European Respiratory Journal 1992;5(10):1197‐200. - PubMed
    1. Muir JF, Georges D. Effect of salmeterol in nocturnal asthma: comparative study with combination theophylline and ketotifen [Apport du salmétérol dans l'asthme nocturne: étude comparative à l'association théophlline LA‐kétotifène]. Revue des Maladies Respiratoires 1992;9:23‐6. - PubMed
Nutini 1998 {published data only}
    1. Nutini S, Martini T, Righi R. Long‐term treatment of asthmatic patients with salmeterol vs slow‐release theophylline. Respiratory Medicine 1998;92(4):683‐90. - PubMed
Paggiaro 1996 {published data only}
    1. Paggiaro PL, Giannini D, Franco A, Testi R. Comparison of inhaled salmeterol and individually dose‐titrated slow‐release theophylline in patients with reversible airway obstruction. European Respiratory Journal 1996;9(8):1689‐95. - PubMed
Pastorello 1998 {published data only}
    1. Pastorello AE, Mauro M, Incorvaia C. Comparison of efficacy and safety of inhaled salmeterol and slow‐release oral theophylline in patients with moderate/severe asthma [Confronto di efficacia e tollerabilita tra salmeterolo per via inalatoria e teofillina orale e lento rilascio in pazienti affetti da asma di grado medio/grave]. L'internista 1998;6:101‐7.
Pollard 1997 {published data only}
    1. Pollard SJ, Sheldon LS, Yancey SW, Cox FM, Emmett A. Salmeterol versus theophylline in the treatment of asthma. Annals of Allergy, Asthma & Immunology 1997;78(5):457‐64. - PubMed
Selby 1997 {published data only}
    1. Selby C, Engleman HM, Fitzpatrick MF, Sime PM, Mackay TW, Douglas NJ. Inhaled salmeterol or oral theophylline in nocturnal asthma?. American Journal of Respiratory & Critical Care Medicine 1997;155(1):104‐8. - PubMed
Ukena 1997 {published data only}
    1. Ukena D, Koper I, Braun H, Leutz M, Schlimmer P, Sybrecht GW. Treatment of Nocturnal Asthma: Salmeterol Versus Once Per Evening Dose of Sustained Release Theophylline. Comparison of Efficacy and Tolerability [Therapie des nachtlichen Asthmas: Salmeterol versus abendliche Einnahme von retardiertem Theophyllin ‐ Vergleich der Wirksamkeit und der Vertraglichkeit]. Pneumologie 1997;51:317‐23. - PubMed
Wiegand 1999 {published data only}
    1. Wiegand L, Mende CN, Zaidel G, Zwillich CW, Petrocella VJ, Yancey SW, et al. Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma. Chest 1999;115(6):1525‐32. - PubMed
Yurdakul 2002 {published data only}
    1. Yurdakul AS, Calisir HC, Tuncan B, Ogretensoy M. Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Respiratory Medicine 2002;96(5):322‐9. - PubMed
Zwillich 1989 {published data only}
    1. Zwillich CW, Neagley SR, Cicutto L, White DP, Martin RJ. Nocturnal asthma therapy: Inhaled bitolterol versus sustained‐release theophylline. American Review of Respiratory Disease 1989;139(2):470‐4. - PubMed

References to studies excluded from this review

Avidsson 1991 {published data only}
    1. Avidsson P, Larsson S, Lofdahl CG, Melander B, Svedmyr N, Wahlander L. Inhlaed formoterol during one year in asthma: a comparison with salbutamol. European Respiratory Journal 1991;4(10):1168‐73. [ISSN 0903‐1936] - PubMed
Barnes 1992 {published data only}
    1. Barnes PJ. New drugs for asthma. European Respiratory Journal 1992;5(9):1126‐36. [ISSN 0903‐1936] - PubMed
Brogden 1991 {published data only}
    1. Brogden RN, Faulds D. Salmeterol xinafoate. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 1991;42(5):895‐912. [ISSN 0012‐6667] - PubMed
Brogden 1992 {published data only}
    1. Brogden RN, Faulds D. Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Allergologia et Immunopathologia 1992;20(2):72‐84. [ISSN 0301‐0546] - PubMed
Cheung 1998 {published data only}
    1. Cheung D, Wever AM, Goeij JA, Graaf CS, Steen H, Sterk PJ. Effects of theophylline on tolerance to the bronchoprotective actions of salmeterol in asthmatics in vivo. American Journal of Respiratory & Critical Care Medicine 1998;158(3):792‐6. - PubMed
Davies 2000 {published data only}
    1. Davies B, Brooks G, Devoy M. The efficacy and safety of salmeterol compared to theophylline: meta‐analysis of nine controlled studies. Respiratory Medicine 1998;92(2):256‐63. - PubMed
Donohue 2001 {published data only}
    1. Donohue JF, Ohar JA. New combination therapies for asthma. Current Opinion in Pulmonary Medicine 2001;7(2):62‐8. - PubMed
Dutta 2002 {published data only}
    1. Dutta EJ, Li JTC. Beta‐ agonists. Medical Clinics of North America 2002;86(5):991‐1008. - PubMed
Eda 1993 {published data only}
    1. Eda R, Sugiyama H, Hopp RJ, Okada C, Bewtra AK, Townley RG. Inhibitory effects of formoterol on platlet‐activating factor induced eosinophil chemotaxis and degranulation. International Archives of Allergy & Immunology 1993;102(4):391‐8. [ISSN 1018‐2438] - PubMed
Faulds 1991 {published data only}
    1. Faulds D, Hollingshead LM, Goa KL. Formoterol. A review of tis pharmacological properties and therapeutic potential in reversible obstrcutive airways disease. Drugs 1991;42(1):115‐37. [ISSN 0012‐6667] - PubMed
Gokhale 2002 {published data only}
    1. Gokhale AB, Saraf MN. Recent developments in asthma therapy. Indian Drugs 2002;39(3):121‐32.
Hancox 2001 {published data only}
    1. Hancox RJ, Taylor DR. Long‐acting beta‐agonist treatment in patients with persistent asthma already receiving inhaled corticosteroids. Biodrugs 2001;15(1):11‐24. - PubMed
Holimon 2001 {published data only}
    1. Holimon TD, Chafin CC, Self TH. Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long‐acting beta2 agonists. Drugs 2001;61(3):391‐418. - PubMed
Hunt 2002 {published data only}
    1. Hunt LW. The critical components of asthma management. Drug Benefit Trends 2002;14(1):21‐22, 24‐25, 28, 30.
Kleerup 1997 {published data only}
    1. Kleerup EC. Bronchodilators: new drugs and controversies. Current Opinion in Pulmonary Medicine 1997;3(1):17‐22. [ISSN 1078‐1641] - PubMed
Lockey 1999 {published data only}
    1. Lockey RF, Dubuske LM, Friedman B, Petrocella V, Cox F, Rickard K. Nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes. Chest 1999;115(3):666‐73. - PubMed
Lotvall 1992 {published data only}
    1. Lotvall J, Lunde H, Ulman A, Tornquist H, Svedmyr N. Twelve months, treatment with inhaled salmeterol in asthmatic patients. Effects on beta 2‐receptor function and inflammatory cells. Allergy 1992;47(5):477‐83. [ISSN 0105‐4538] - PubMed
Manchee 1996 {published data only}
    1. Manchee GR, Eddershaw PJ, Ranshaw LE, Herriot D, Park GR, Bayliss MK, et al. The aliphatic oxidation of salmeterol to alpha‐hydroxysalmeterol inhuman liver microsomes in catalyzed by CYP3A. Drug Metabolism and Disposition 1996;24(5):55‐9. [ISSN 0090‐9556] - PubMed
Meier 1997 {published data only}
    1. Meier CR, Jick H. Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. Thorax 1997;52(7):612‐7. [ISSN 0040‐6376] - PMC - PubMed
Midgren 1992 {published data only}
    1. Midgren B, Melander B, Persson G. Formoterol, a new long‐acting beta2 agonist, inhaled twice daily, in stable asthmatic subjects. Chest 1992;101(4):1019‐22. [ISSN 0012‐3692] - PubMed
Morice 1999 {published data only}
    1. Morice AH, Taylor ME. A randomised trial of the initiation of asthma treatment. Asthma in General Practice 1999;7(1):7‐9.
Nelson 1996 {published data only}
    1. Neslon HS. New developments in bronchodilator therapy. Current Opinion in Pulmonary Medicine 1996;2(1):35‐9. [ISSN 1078‐1641] - PubMed
Nightingale 1995 {published data only}
    1. Nightingale CH. Cost comparison of beta2 agonist bronchodilators used in the treatment of asthma. Pharmacotherapy 1995;15(5):677‐81. [ISSN 0277‐0008] - PubMed
Paciorek 1991 {published data only}
    1. Paciorek PM, Burden DT, Gater PR, Hawthorne YM, Spence AM, Taylor JC, et al. Inhibition by Ro 31‐6930 of agonist and allergen induced bronchoconstriction in anaesthetised guinea‐pigs and cats. Pulmonary Pharmacology 1991;4(4):225‐32. [ISSN 0952‐0600] - PubMed
Rossi 2002 {published data only}
    1. Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, et al. [Comparison of the efficacy, tolerability and safety of formoterol dry powder and oral, sustained‐release theophylline in the treatment of COPD]. Chest 2002;121(4):1058‐69. - PubMed
Skloot 2002 {published data only}
    1. Skloot GS. Nocturnal asthma: mechanisms and management. Mount Sinai Journal of Medicine 2002;69(3):140‐7. - PubMed
Taburet 1994 {published data only}
    1. Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma treatment. Clinical Pharmacokinetics 1994;26(5):396‐418. [ISSN 0312‐5963] - PubMed
Taccola 1999 {published data only}
    1. Taccola M, Bancalari L, Ghignoni G, Paggiaro PL. Salmeterol versus slow release theophylline. Monaldi Archive of Chest Disease 1999;54(4):302‐6. - PubMed
Thomson 1998 {published data only}
    1. Thomson NC. Asthma therapy: theophylline. Canadian Respiratory Journal 1998;5(Suppl A):60‐3. - PubMed
Tomac 1996 {published data only}
    1. Tomac N, Tuncer A, Saraclar Y, Adalioglu G. Efficacy of salmeterol in the treatment of childhood asthma. Acta Paediatrica Japonica 1996;38(5):489‐94. [ISSN 0374‐5600] - PubMed
Vatrella 2005 {published data only}
    1. Vatrella A, Ponticiello A, Plaia G, Parrella R, Cazzola M. Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma. Pulmonary Pharmacology & Therapeutics 2005;18(2):89‐92. - PubMed
Weinstein 1997 {published data only}
    1. Weinstein S, Chervinsky P, Pollard SJ, Bronsky EA, Nathan RA, Prenner B, et al. A one‐week dose‐ranging study of inhaled salmeterol in children with asthma. Journal of Asthma 1997;34(1):43‐52. [ISSN 0277‐0903] - PubMed

Additional references

Davis 1997
    1. Davis R, Noble S. Management of Asthma: Defining the Role of Salmeterol. Auckland, New Zealand: Adis International Limited, 1997.
Kaliner 1991
    1. Kaliner MA, Barnes PJ, Persson CGA (Editors). Asthma: Its Pathology and Treatment. New York: Marcel Dekker, Inc, 1991.
Salpeter 2006
    1. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta‐analysis: effect of long‐acting beta‐agonists on severe asthma exacerbations and asthma‐related deaths. Annals of Internal Medicine 2006;144(12):904‐12. - PubMed

References to other published versions of this review

Shah 2003
    1. Shah L, Wilson AJ, Gibson PG, Coughlan J. Long‐acting beta2‐agonists versus theophylline for maintenance treatment of asthma (Cochrane Review). Cochrane Database of Systematic Reviews 2003, Issue 3. - PubMed
Wilson 2000
    1. Wilson AJ, Gibson PG, Coughlan J. Long acting beta‐agonists versus theophylline for maintenance treatment of asthma (Cochrane Review). Cochrane Database of Systematic Reviews 2000, Issue 2. - PubMed

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