Symptom relief

Inhaled bronchodilators

Short-acting bronchodilators

Regular short-acting beta-agonists improve lung function and daily breathlessness scores. A systematic review of randomised controlled trials⁴³ found a significant increase in post-bronchodilator spirometry when compared to placebo; weighted mean difference = 140mls (95% CI 40 to 250) for FEV₁ and 300mls (95% CI 20 to 580) for FVC. There were also improvements in post-bronchodilator morning and evening PEF: weighted mean difference = 29.17 l/min (95% CI 0.25 to 58.09) for morning and 36.75 l/min (95% CI 2.57 to 70.94) for evening measurements. The relative risk of dropping out of the study was 0.49 (95% CI 0.33 to 0.73), giving a number needed to treat of 5 (95% CI 4 to 10) to prevent one treatment failure. There was no significant benefit on functional capacity, measured by walking tests, or symptoms other than breathlessness, although one randomised controlled trial has found a significant improvement in six-minute walking distance and quality of life.⁴⁰ Short-acting beta-agonists are now usually prescribed for use as “rescue” medication, i.e. for relief of breathlessness, rather than for regular use.

The duration of action of short-acting anticholinergics is greater than short-acting beta-agonists. A systematic review of randomised controlled trials comparing ipratropium bromide alone, or in combination with short-acting beta-agonists, against short-acting beta-agonists alone found significant benefits for regimens containing ipratropium bromide.⁴⁴ Ipratropium bromide improved pre-drug spirometry over short-acting beta-agonists alone, weighted mean difference = 30mls (95% CI 0 to 60) for FEV₁ and 70mls (95% CI 10 to 140) for FVC, although there was no significant difference between peak post-drug measurements. Ipratropium bromide improved quality of life, with a statistically significant improvement in all domains of the Chronic Respiratory Disease Questionnaire. These benefits occurred with fewer adverse drug effects, Peto odds ratio = 0.71 (95% CI 0.53 to 0.97), number needed to harm = 32 (95% CI 20 to 316). There was a lesser need to add or increase the dose of oral corticosteroids for participants receiving ipratropium bromide, Peto odds ratio = 0.52 (95% CI 0.37 – 0.74), with 15 (95% CI 12 – 28) people requiring treatment with ipratropium bromide to prevent one receiving additional oral corticosteroids.

For combination therapy with ipratropium bromide and short-acting beta-agonists, there was no significant difference in pre-drug spirometry compared to ipratropium bromide alone. There was a significant benefit for the combination for post-drug spirometry measurements; weighted mean difference = 70 mls (95% CI 50 to 90) for FEV₁ and 120mls (95% CI 80 to 160) for FVC. There was no significant difference between interventions for quality of life or adverse drug effects, but combination treatment decreased the need to add or increase oral corticosteroids compared to ipratropium bromide alone, Peto odds ratio = 0.69 (95% CI 0.50 to 0.94), number needed to treat = 20 (95% CI 12 to 108).

In summary, short-acting bronchodilators, either beta-agonists or ipratropium bromide, significantly increase lung function measurements in COPD. Ipratropium bromide has a significantly greater effect on lung function compared to beta-agonists, in addition to improving quality of life and decreasing need for oral corticosteroid treatment. These benefits occurred with a decreased risk of adverse drug effects.

Long-acting bronchodilators

Long-acting beta-agonists (eg salmeterol, eformoterol) cause prolonged bronchodilatation, for at least 12 hours, and can thus be administered twice daily. A systematic review of randomised controlled trials⁴⁵ found that compared to placebo, long-acting beta-agonists used for at least four weeks produce statistically significant benefits in lung function, quality of life, use of ‘reliever’ short-acting bronchodilators and acute exacerbations. This review compared different drugs and doses independently, the commonest being salmeterol 50 mcg daily which involved up to 3363 participants.

The review did not find evidence that higher doses of salmeterol were more beneficial than 50mcg/day. Fewer studies of the effect of eformoterol were included and they were not combined in a meta-analysis, but some benefits similar to those of salmeterol were seen for a range of outcomes across a range of doses. Adverse drug effects were not reported.

The efficacy of long-acting beta-agonists compared to ipratropium bromide, alone or in combination, have also been combined in a systematic review.⁴⁴ Comparisons of monotherapy found a greater increase in FEV₁, weighted mean difference = 60 mls (95% CI 0 to 110), and morning PEF, weighted mean difference = 10.96 l/min (95% CI 5.83 to 16.09) for salmeterol over ipratropium bromide. There were no significant differences between interventions for quality of life, functional capacity, symptoms, acute exacerbations or adverse events. Comparisons of the combination of ipratropium bromide and salmeterol with ipratropium bromide alone showed varying effects on lung function and symptoms, but a small, significant reduction in reliever use; weighted mean difference = -0.67 puffs/day (95% CI -1.11 to -0.23).

Tiotropium is a long-acting anticholinergic agent with duration of action of over 24 hours and is used once daily. Two systematic reviews of randomised controlled trials of its clinical effects have been published.^46,47 These had differing inclusion criteria, particularly the duration of treatment, and consequently slightly different results. Compared to placebo, the reviews found tiotropium produced a significant increase in FEV₁ in the order of 130mls and improved quality of life, decreasing the mean St George’s Respiratory Questionnaire by about 3 units. Tiotropium had a beneficial effect on acute exacerbations, odds ratio of 0.75, and hospitalisation, odds ratio 0.64. These effects came at the cost of an increased risk of adverse drug effects, particularly dry mouth which is 4-5 times more likely with tiotropium. Comparisons of tiotropium with ipratropium bromide or long-acting beta-agonists are limited by scanty data, producing conflicting results.

In summary, long acting bronchodilators produce significant improvements in lung function, symptoms and quality of life, as well as decrease exacerbations. Tiotropium increases the likelihood of developing hoarseness, while adverse effects associated with long-acting beta-agonists were not well reported.

Theophyllines

Theophylline has a modest effect on FEV₁ and FVC and slightly improves arterial blood gas tensions in moderate to severe COPD. However, theophyllines are rarely used because of their narrow therapeutic index and potential for significant side effects^{48, 49} [evidence level I]. Some patients with disabling breathlessness may derive benefit from their use.^{50, 51, 52}  Theophyllines may have an anti-inflammatory effect or reduce muscle fatigue.^53,54Evidence supports only the slow-release formulation. Theophylline is effective in COPD but due to its potential toxicity, inhaled bronchodilators are preferred when available. ⁹ Recent placebo-controlled studies of members of the phosphodiesterase-4 inhibitor family (cilomilast and roflumilast) up to six months duration, suggest these drugs may decrease time to first exacerbation, as well as improving lung function and quality of life. However, more clinical data are awaited before any recommendations can be made as to the role, if any, of these drugs in the management of COPD.^55-57