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NIHR Signal Adding low dose theophylline to inhaled corticosteroids does not reduce COPD exacerbations

Published on 15 January 2019

doi: 10.3310/signal-000708

Taking low-dose theophylline tablets in addition to inhaled corticosteroids did not significantly reduce chronic obstructive pulmonary disease flare-ups (exacerbations). This NIHR funded study found that people taking the combination and those taking an inhaled steroid had the same number of exacerbations - just over two per year.

People who experience frequent exacerbations are often prescribed steroid inhalers to reduce inflammation of the airways. Theophylline also helps open up the airways, but the amount needed to be effective can produce unwanted side effects. 

Some earlier evidence suggested that low-dose theophylline might improve the anti-inflammatory effects of inhaled steroids and therefore could be useful for those who continue to suffer exacerbations and hospital admissions.

However, the results of this study confirm guideline recommendations that, for the majority of people, the combination of oral theophylline plus inhaled steroid is not useful. 

  •   Medicines, Respiratory disorders, Primary care, Acute and general medicine
Adding low dose theophylline to inhaled corticosteroids does not reduce COPD exacerbations

Why was this study needed?

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease costing the NHS approximately £1 billion annually. Estimates vary, but it is thought over one million people are living with COPD in the UK. This figure is probably not a true reflection as many cases remain undiagnosed.

There is no cure, but with maintenance treatment, the symptoms can be managed although many people still experience frequent exacerbations. Exacerbations are associated with hospital admission and lung function decline. 

Theophylline tablets can aid breathing but may have severe side effects at the doses usually used. NICE guidance recommends the use of this drug only when inhaled bronchodilators are not possible

Some small studies have suggested that lower doses of theophylline can increase the anti-inflammatory effect of inhaled corticosteroids and might thereby reduce the risk of exacerbations. This larger scale study helps address this uncertainty.

What did this study do?

This UK-based trial randomised 1,567 participants to receive either low-dose theophylline or placebo over a year in addition to their corticosteroid inhaler. Theophylline dose was determined by body weight and smoking status.

The majority of participants had either moderate to severe COPD, and 80% were using triple therapy of inhaled corticosteroids, and two inhaled long-acting bronchodilators (long-acting beta agonists and long-acting muscarinic antagonists). Participants were categorised as frequent exacerbators, with a mean number of 3.59 self-reported exacerbations in the previous 12 months.

The primary outcome was the number of exacerbations requiring treatment with antibiotics and corticosteroids. This was measured through participant recall collected via face to face assessments at the start of the trial, six months and one year.

This was a well-designed study, and the results are likely to be reliable.

What did it find?

  • In total there were 3,430 exacerbations: 1,727 in the intervention group (mean 2.24 exacerbations per year) versus 1,703 in the placebo group (mean 2.23 exacerbations per year).
  • There were slightly fewer more serious exacerbations requiring hospitalisation in the theophylline group, with 134 episodes compared to 185 in the placebo group (adjusted incidence rate ratio 0.72, 95% confidence interval 0.55 to 0.94).
  • Adverse events were also comparable. Cardiac adverse events occurred in 2.4% of those receiving theophylline and 3.4% receiving placebo. Gastrointestinal adverse events happened in 2.7% of those in the theophylline group compared to 1.3% in the placebo group.

What does current guidance say on this issue?

NICE guidance on COPD says that slow-release theophylline tablets should only be used in cases where patients are unable to use inhalers or when a trial of short-acting bronchodilators and long-acting bronchodilators has already taken place.

They warn that plasma levels and interactions need to be monitored closely.

Current guidance does not include a recommendation on use of theophylline as an adjunct to inhaled steroids for reducing exacerbations.

What are the implications?

Although in theory, the addition of low dose theophylline sounded promising for reducing exacerbations, the results of this study suggest it is not beneficial in practice.

Inhaled corticosteroids are currently widely used for many people with more advanced COPD. Alongside inhaled bronchodilators, oral slow-release theophylline has a minor place as treatment for people who cannot take inhalers.

Other treatments exist for reducing exacerbations including antibiotic prophylaxis, surgery and pulmonary rehabilitation. These may also have more of an impact on quality of life.

Citation and Funding

Devereux G, Cotton S, Fielding S et al. Effect of theophylline as adjunct to inhaled corticosteroids on exacerbations in patients with COPD. JAMA. 2018;320(15):1548–59.

This project was funded by the National Institute for Health Research HTA programme (project number 11/58/15) and cosponsored by the University of Aberdeen and NHS Grampian.

Bibliography

British Lung Foundation. Chronic obstructive pulmonary disease (COPD) statistics. London: British Lung Foundation; 2016.

NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NG115. London: National Institute for Health and Care Excellence; 2018.

NHS website. Chronic obstructive pulmonary disease (COPD) London: Department of Health and Social Care; updated 2016.

Expert commentary

Preclinical laboratory studies suggest that low-dose theophylline may improve clinical outcomes in chronic obstructive pulmonary disease (COPD) due to improved sensitivity to corticosteroids and enhanced anti-inflammatory effects.

However, these results convincingly show that the addition of low-dose theophylline to inhaled corticosteroids does not reduce the number of exacerbations (primary efficacy outcome) or improve a range of secondary outcomes in patients with COPD who gave a history of frequent exacerbations.

For clinicians in both primary and secondary care, these findings indicate that theophylline should not be used to prevent future exacerbations in COPD patients treated with inhaled corticosteroids and long-acting bronchodilators.

Neil C Thomson, Emeritus Professor of Respiratory Medicine, University of Glasgow

The commentator declares no conflicting interests