Physicians are often faced with a dilemma as to which medications to add on when patients with asthma fail to respond to initial treatment. The current study was designed to evaluate the effectiveness of adding low-dose theophylline (300 mg/day) or montelukast (10 mg/day) to suboptimal asthma therapy. Asthmatic patients (N=489) with evidence of poorly controlled asthma (Juniper Asthma Control Score: 2.3 ± 0.6) were randomized with equal probability of allocation to three study arms: placebo (P), low-dose theophylline [Theochron-Inwood Laboratories] (LD-T) or montelukast [Singulair, Merck] (M).
METHODS, RESULTS, and CLINICAL IMPLICATIONS:
Patients were followed for 6 months with three clinic visits and by completing daily asthma diaries. The primary outcome variable was asthma exacerbation rate (events/person-year) defined as consistent falls in peak expiratory flow, an increase in the use of rescue β-agonists, a new course of oral corticosteroid therapy, or seeking unscheduled medical help for asthma. While the asthma exacerbation rate was lower in both LD-T (6.3, 95% CI: 4.8, 8.4) and M (6.2, 95% CI: 4.7, 8.1.) compared to placebo (7.7 95% CI: 5.9, 10.0), these differences were not statistically significant (p=0.47). LD-T was associated with improved lung function as compared to placebo (mean change in post-bronchodilator FEV1 was 0.046 L vs -0.02 L, respectively; p<0.005). While LD-T was associated with significant symptoms commonly associated with the use of theophylline, only insomnia persisted after the first month of treatment. When data from those patients who had not been on inhaled corticosteroids at randomization (N=31, 41, and 35 for LD-T, M, and P groups respectively) were analyzed separately, LD-T had a lower exacerbation rate than placebo (2.2 95% CI: 1.4, 3.5 vs 11.2 95% CI: 6.9, 18.0; p<0.001). On the other hand, M (6.4, 95% CI: 3.8, 10.5; p=0.11) was not associated with a lower exacerbation rate than placebo. We conclude that when added to inhaled corticosteroids, neither low-dose theophylline nor montelukast are efficacious in reducing the asthma exacerbation rate. Nevertheless, low-dose theophylline as monotherapy shows promise as an effective, yet inexpensive, asthma therapy in patients not receiving inhaled corticosteroids.