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

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.

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

Randomised, controlled trials (RCTs) were identified using the Cochrane Airways Group register. The register was searched using the following terms: asthma and theophylline and long acting beta-agonist or formoterol or foradile or eformoterol or salmeterol or bambuterol or bitolterol. Date of last search was April 2003. Titles and abstracts were then screened to identify potentially relevant studies. The bibliography of each RCT was searched for additional RCTs. Authors of identified RCTs were contacted for other relevant published and unpublished studies.

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.

Potentially relevant trials, identified by screening titles and/or abstracts, were obtained. Two reviewers independently assessed full text versions of these trials to decide whether the trial should be included in the review, and assessed its methodological quality. Where there was disagreement between reviewers, this was resolved by consensus, or reference to a third party. Data were extracted by two independent reviewers. Inter-rater reliability was assessed by simple agreement. Study authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies. Relevant pharmaceutical manufacturers were also contacted.

Six trials originally met the inclusion criteria. Five used salmeterol and one, bitolterol. In an updated version of the review, six more trials were included. Four trials used salmeterol and two used formoterol. They were of varying quality. Salmeterol improved FEV1 significantly more than theophylline in five studies and salmeterol use was associated with significantly more symptom free nights in all the studies comparing these agents. 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. Subjects 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), NNT 9 (6, 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95%Confidence Intervals 0.29, 0.86), Risk Difference -0.07(95% CI -0.12, -0.02), NNT 14(8, 50) and gastrointestinal adverse events (Relative Risk 0.30; 95%Confidence Intervals 0.17, 0.55), Risk Difference -0.11(-0.16, -0.06), NNT 9(6, 16).

Long-acting beta-2 agonists are at least as effective than theophylline in reducing asthma symptoms including night waking and improving lung function. Fewer adverse events occurred in subjects using long-acting beta-2 agonists(salmeterol and formoterol) as compared to theophylline.