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Low-dose theophylline is minimally helpful, if at all, in preventing COPD exacerbations
Clinical Question
Is low-dose theophylline effective as add-on therapy to inhaled corticosteroids for the prevention of acute chronic obstructive pulmonary disease exacerbations in adults?
Bottom line
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. 1b
Reference
Study design: Randomized controlled trial (double-blinded)
Funding: Government
Setting: Outpatient (any)
Synopsis
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.
Reviewer
David C. Slawson, MD
Professor and Vice Chair of Family Medicine for Education and Scholarship
Atrium Health
Professor of Family Medicine, UNC Chapel Hill
Charlotte, NC
Comments
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Wasn't much good in actually treating acute asthma etc, even in large IV doses back in the day either. Better than nothing I guess, but went out of use in a heartbeat when helpful treatment appeared.
Learning about the ineffectiveness of theophylline was one of my most impactful learning experiences of the value of evidenced based medicine in the 1980's. For years as a resident I vividly recall doing blood levels and giving boluses and drips of aminophylline to asthmatics and COPDers in emerg because "that's what was done". Then came our a series of controlled trials showing how ineffective this was. I was disappointed and thrilled at the same time but quickly stopped offering this dogmatic but useless therapy. I have absolutely no idea why the study reviewed today was ever done but the results were entirely predictable. I guess it at least serves as a testament to the enduring value and validity of evidence based medicine.
In my practice I am not using low -dose theothylline to prevent COPD exacerbation. But I use low- dose theophylline with corticosteriods prevent acute exacerbations in Asthma. I do not know whether research study on this. But in my practice I find it very useful.
It’s hard to see how the placebo matches the caffeine like side effects of theophylline for these patients. One might reasonably expect an improvement in outcomes with polytherapy. With frequent severe side effects from more robust dosages I would not consider it in future
good poem
Not too many theophyllines are available on the market now.