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

Theophylline and long acting beta2-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-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. 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 Authors of identified RCTs were contacted for other relevant published and unpublished studies.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-agonist.

Potentially relevant trials, identified by screening titles and/or abstracts, were obtained. Two reviewers independently assessed full text versions of these trials to decided 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authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies.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 met the inclusion criteria. Five used salmeterol and one, biltoterol. They were of varying quality. There was a trend for salmeterol to improve FEV1 more than theophylline in three studies and salmeterol use was associated with more symptom free nights. 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 (Relative Risk 0.38; 95%Confidence Intervals 0.25, 0.57). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.51; 95%Confidence Intervals 0.30, 0.88) and gastrointestinal adverse events (Relative Risk 0.32; 95%Confidence Intervals 0.17, 0.59).

Salmeterol may be more effective than theophylline in reducing asthma symptoms including night waking and improving lung function. More adverse events occurred in subjects using theophylline when compared to salmeterol.