Apart from oxygen, no drug has been shown to reduce the increased risk of death in patients with COPD. For this reason drugs are prescribed predominantly to reduce symptoms, improve functional capacity, and prevent and treat exacerbations. Drugs are prescribed in a stepwise fashion.16 Mild symptoms can be managed with an inhaled short-acting beta agonist (SABA), taken when needed either before exercise or for the relief of exertional breathlessness.17 Patients who need inhalations several times a week are likely to benefit from adding a long-acting muscarinic antagonist (LAMA) or a long-acting beta agonist (LABA).18,19
The choice of second-line drug depends on the patient’s response and preference.18,20,21 While there are few clinically important differences between the LAMAs,22 there are differences between LABAs which may be more obvious to patients, and are important in affecting their choice.23 Most importantly, formoterol, indacaterol and vilanterol have a relatively fast onset of action, of 5–10 minutes, while salmeterol has a 30-minute onset. These differences may not be important once patients are taking long-acting bronchodilators regularly. Like salmeterol, formoterol and indacaterol, the newly available LABAs vilanterol and olodaterol have statistically and clinically significant effects on lung function, exercise tolerance, SABA use, dyspnoea, quality of life and exacerbations.24 LABAs are well tolerated and there are negligible differences between them in relation to adverse effects.25 Tremor and tachycardia appear to occur less commonly with LABAs than SABAs.
LAMAs include tiotropium, umeclidium, glycopyrronium and aclidinium. There are only small differences between them in efficacy.26 The duration of action of aclidinium is shorter and therefore it is the only LAMA prescribed in a twice-daily regimen.27 These drugs have adverse effects which include urinary retention in patients with prostatic enlargement, worsening of glaucoma and atrial arrhythmias. While these effects had a very low prevalence in clinical trials,28 most studies have excluded patients at risk,19,27 so it is difficult to know the true prevalence of these adverse effects in the general population of patients with COPD. In a large safety study of tiotropium with cardiac end points, there was no increased mortality or major adverse cardiac effects with tiotropium 5 microgram or 2.5 microgram inhaled daily for a median of one year.29
Combination therapy
Guidelines have recommended the addition of inhaled corticosteroids to long-acting bronchodilators when the FEV1 is less than 50% predicted and the patient has had more than one exacerbation in the previous 12 months.4,17 In the stepwise management of stable COPD, combination inhaled corticosteroids/LABA therapy is recommended for this group of patients.16 Many patients will already have been taking a LAMA, so they will be stepping up from a single long-acting bronchodilator to ‘triple therapy’. The availability of dual bronchodilators, LABA and a LAMA combined in a single device, has changed this paradigm.
Although there is debate regarding the clinical value of LAMA plus LABA together, compared to either alone, in randomised controlled trials, the combination is generally superior to either drug alone.18,30-32 Most recently dual bronchodilators have been shown not only to improve lung function, exercise capacity, dyspnoea and reduce the use of short-acting bronchodilators, compared to either LABA or LAMA alone, but also to reduce COPD exacerbations.33,34
Since exacerbation reduction is the most important effect of inhaled corticosteroids, the question has arisen whether the addition of inhaled corticosteroids is still the most appropriate step for all patients who have frequent exacerbations. Several studies have tested this using different designs – either withdrawal of inhaled corticosteroids or a comparison of LAMA plus LABA with inhaled corticosteroids plus LABA.35,36 In one study in which patients took placebo or inhaled corticosteroid during a progressive drop in the dose of inhaled corticosteroids over 12 weeks, the corticosteroid withdrawal was not associated with an increased risk of exacerbations.35 Patients on placebo lost slightly more lung function than those who received inhaled corticosteroids, but subsequent analysis suggests that this effect plateaus and lung function is not lost at a faster rate in the long term. More studies are required to verify this.
Another problem is the adverse effects of corticosteroids. There is a substantial database and evidence from randomised controlled trials that high-dose inhaled corticosteroids (>500 microgram/day fluticasone propionate or equivalent) are associated with an increased risk of pneumonia in patients with COPD.37-39