Is low-dose theophylline effective as add-on therapy to inhaled corticosteroids for the prevention of acute chronic obstructive pulmonary disease exacerbations in adults?

This study found minimal, if any, benefit of adding low-dose theophylline to inhaled corticosteroids for preventing acute chronic obstructive pulmonary disease (COPD) exacerbations in adults. (LOE = 1b)

Devereux G, Cotton S, Fielding S, et al. Effect of theophylline as adjunct to inhaled corticosteroids on exacerbations in patients with COPD. A randomized clinical trial. JAMA 2018;320(15):1548-59.  [PMID:30326124]

Randomized controlled trial (double-blinded)

Government

Concealed

Outpatient (any)

Current recommended management strategies remain uncertain on the value of low-dose theophylline therapy for preventing exacerbations in adults with COPD. These investigators enrolled adults (N = 1578), 40 years or older, who met standard diagnostic criteria for COPD, with a smoking history of more than 10 pack-years, current use of inhaled corticosteroids, and 2 or more exacerbations treated with antibiotics, oral steroids, or both in the previous year. Patients randomly received (concealed allocation assignment) 52-week treatment with either theophylline or identical placebo. In order to achieve a steady plasma theophylline concentration of 1 mg/L to 5 mg/L, nonsmokers or smokers with ideal body weight (IBW) less than or equal to 60 kg took 200 mg daily; smokers with IBW greater than 60 kg took 200 mg twice daily. The primary outcome was participant self-reported COPD exacerbations requiring antibiotics, oral steroids, or both. Patients, their clinicians, and investigators remained masked to treatment group assignment. Complete follow-up occurred for 98% of participants at 52 weeks. Approximately three-fourths (76.9%) of participants met the criteria for moderate to severe COPD,13.5% for very severe COPD, and 9.2% for mild COPD. Using both intention-to-treat analysis and per-protocol (excluding participants taking less than 70% of prescribed doses) analysis, no significant differences occurred in the mean number of exacerbations between the theophylline and placebo groups (2.24 vs 2.23 and 2.20 vs 2.14, respectively). Among a number of secondary outcomes, only the mean number of severe COPD exacerbations requiring hospitalization was significantly less in the theophylline group compared with placebo group (mean difference -0.07; 95% CI -0.13 to -0.01). The authors note that the large number of secondary outcomes makes it possible that significant outcomes are due only to chance and not truly significant. No significant group differences occurred in the number of episodes of pneumonia, quality of life scores, or mortality. In addition, there was no evidence of a treatment effect for any prespecified subgroups, including age, sex, body mass index, smoking status, or Global Initiative for Obstructive Lung Disease (GOLD) staging. The study was 90% powered to detect a predetermined clinically important 15% reduction in COPD exacerbations.