O1. Inhaled bronchodilators

01.1 Short-acting bronchodilators

O1.1.1 Short-acting beta-agonists

Regular short-acting beta-agonists improve lung function and daily breathlessness scores. A systematic review of randomised controlled trials⁴⁹ 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.⁴⁶ Short-acting beta-agonists are now usually prescribed for use as “rescue” medication, i.e. for relief of breathlessness, rather than for regular use.

O1.1.2 Short-acting anticholinergics

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.⁵⁰ Ipratropium bromide improved 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,. 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, Number Needed to Harm (NNH) = 32 (95% CI 20 to 316). There was a lesser need to add or increase the dose of oral glucocorticoids for participants receiving ipratropium bromide with 15 (95% CI 12 – 28) people requiring treatment with ipratropium bromide to prevent one receiving additional oral glucocorticoids.

Ipratropium bromide is associated with an increased risk of adverse cardiovascular effects.^51,52 A nested case-control study⁵¹ [evidence level III-2] found an increased risk of cardiovascular death associated with the prescription of ipratropium, OR 1.34 (95% CI 1.22 to 1.47). A meta-analysis of randomised controlled trials⁵² found an increased risk for a combined cardiovascular endpoint of cardiovascular death, myocardial infarction and stroke, estimated NNH for cardiovascular death 40 (95% CI 18 to 185) per year. The consistent finding across these studies suggests the cardiovascular adverse effects are likely to be real [evidence level I].

O1.1.3 Short-acting bronchodilator combinations

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.⁵⁰ There was a significant benefit for the combination in 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 glucocorticoids compared to ipratropium bromide alone, 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 alone; 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. Combining two classes of bronchodilator may provide added benefits without compounding adverse effects.

O1.2 Long-acting bronchodilators

Long-acting bronchodilators produce significant improvements in lung function, symptoms and quality of life, as well as decreasing exacerbations. These benefits come at a cost of increased adverse effects, which are generally of mild to moderate severity.

O1.2.1 Long-acting anticholinergics

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.^53,54 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. The number of patients needed to treat (NNT) with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo or ipratropium.

The beneficial effects come at a cost of increased adverse drug effects. A pooled study of placebo controlled trials⁵⁵ found an increased risk of dry mouth (RR=3.60; 95% CI, 2.56 to 5.05) and urinary retention (RR=10.93, 95% CI, 1.26 to 94.88), although the latter occurred infrequently.⁵⁵ These effects have been confirmed in a large four-year randomised-controlled trial⁵⁶ which found no increase in death from any cause, RR 0.89 (95% CI 0.79 to 1.02) [evidence level II]. There was a decreased rate of serious adverse cardiac events in patients randomised to tiotropium compared to placebo.

O1.2.2 Long-acting beta-agonists

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 trials⁵⁷ 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. It would be necessary to treat 24 (95% CI 14 to 98) patients with salmeterol to prevent one exacerbation.

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.

O1.2.3 Long-acting bronchodilator combinations

The efficacy of long-acting beta-agonists compared to ipratropium bromide, alone or in combination, have also been combined in a systematic review.⁵⁰ 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).

O1.3 Assessment of response and continuation of bronchodilator therapy

In some patients a response to bronchodilator therapy may require treatment for up to two months.  Symptomatic and functional benefits can often be demonstrated in the absence of an increase in FEV₁. Other objective measurements, such as an increase in exercise capacity (e.g., six-minute walk distance) or an increased inspiratory reserve capacity, may be useful indicators of physiological improvement.

Subjective measurements, such as quality of life, breathlessness and functional limitation (e.g., MRC Dyspnoea Scale), can determine the patient’s perception of benefit.

If there is no improvement:

• check inhaler technique;
• consider psychosocial issues and deconditioning; and
• exclude other causes of exercise impairment (consider specialist referral or a cardiopulmonary exercise test).

O2. Oral bronchodilators

O2.1 Methylxanthines

Theophylline has a modest effect on FEV₁ and FVC⁵⁸ and slightly improves arterial blood gas tensions in moderate to severe COPD. However, theophyllines have gone out of favour in many countries because of their narrow therapeutic index and potential for significant side effects.^59,60 Some patients with disabling breathlessness may, however, derive benefit from their use.^61-63 Theophyllines may have an anti-inflammatory effect or reduce muscle fatigue.^64,65 Recent studies have suggested lower dose preparations than had previously been used (achieving plasma levels of 5-10mg/L) may have anti-inflammatory or immuno-modulatory effects.^66,67 A randomised placebo controlled trial in China demonstrated that doses of 100mg twice daily reduced exacerbations compared with placebo.⁶⁸ Evidence supports only the slow-release formulation. Theophylline is effective in COPD but due to its potential toxicity (the most common adverse reactions being gastric irritation, nausea, vomiting, anorexia, epigastric pain, reactivation of peptic ulcer, gastro-oesophageal reflux, haematemesis, tachycardia, palpitations, headache, CNS stimulation, reflex hyperexcitability, insomnia and tremor⁶⁹), inhaled bronchodilators are preferred when available.¹¹ Theophylline has an extensive drug interaction profile that may present potential adverse effects in patients on some multi-medication regimens. The macrolide antibiotics, particularly erythromycin and quinolone antibiotics when used concurrently can lead to increased theophylline plasma concentrations and reduced antibiotic concentrations.

O2.2 Phosphodiesterase type-4 inhibitors

Inhibitors of phosphodiesterase type-4 (PDE-4) act by increasing intracellular concentrations of cyclic adenosine monophosphate and causing a range of anti-inflammatory effects. Two drugs, cilomilast and roflumilast, have been developed, but neither has been approved for use in Australia or New Zealand at this time. Placebo controlled studies up to six months duration^70,71 have found that PDE-4 inhibitors attenuate decline in lung function and quality of life, and decrease acute exacerbations when compared to placebo [evidence level II]. PDE-4 inhibitors significantly increase the FEV₁, by an order of 40 - 100ml, compared to placebo. They improve quality of life, measured by the SGRQ total score, by 1.6 - 4.1 units compared to placebo, but the changes did not reach statistical significance in all studies. PDE-4 inhibitors significantly reduced acute exacerbations, whether measured by the mean number of exacerbations or exacerbation-free survival. Drug related adverse effects mainly affected the gastrointestinal system; diarrhoea, abdominal pain, nausea and vomiting, and were approximately twice as common in subjects taking PDE-4 inhibitors as in those taking placebo. PDE-4 inhibitors are promising candidates for the treatment of chronic obstructive pulmonary disease. Further research is required to determine their long-term impact and role when used with other treatments including glucocorticoids and long-acting bronchodilators.