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 (antimuscarinics)
Long-acting anticholinergic (antimuscarinic) agents e.g. tiotropium, aclidinium bromide cause bronchodilation with a duration of action of over 24 hours and are used once daily. (Maltais et al., 2011) Systematic reviews (Barr et al., 2006),(Barr et al., 2005) found tiotropium produced a significant increase in FEV1 of the order of 130mls compared to placebo. A more recent meta-analysis(Yohannes et al., 2011) comparing tiotropium with placebo, ipratropium and the long-acting beta-agonist, salmeterol, included a larger number of patients (16,301) and found superior efficacy for quality of life, dyspnoea and exacerbation rates compared with placebo and ipratropium. The number of patients needed to treat with tiotropium was 22 (95% CI 13 to 65) to prevent one exacerbation compared to placebo. No significant differences between tiotropium and salmeterol were found for any outcome. Dry mouth was the most common adverse event reported and the proportion of patients experiencing a dry mouth was higher in those using tiotropium than any of placebo, ipratropium or salmeterol (NNH compared to placebo = 25, 95%CI 12 to 66). Pneumonia rates were not analysed.
Many of these effects have been confirmed in a large four-year randomised-controlled trial, whose primary outcome was the effect of tiotropium on the rate of decline in lung function. (Tashkin et al., 2008) Tiotropium produced no effect on the rate of decline of FEV1 or FVC, but both measurements were significantly higher in the tiotropium group when compared to placebo at all time points following randomisation (mean pre-bronchodilator difference in FEV1 = 87 to 103 mls). Tiotropium was associated with improved HRQL at all time points (mean difference in total SGRQ for all time points = 2.7, 95% CI 2.0 to 3.3) and a delay to time of first exacerbation (tiotropium = 16.7 months vs. placebo = 12.5 months).
In an international, multi-centre, double blind placebo controlled trial, Vogelmeier et al randomised over 7000 patients with moderate to severe COPD and a history of exacerbations to either salmeterol or tiotropium. (Vogelmeier et al., 2011) 40% of patients were on inhaled corticosteroids and these were allowed to be continued. The investigators found that tiotropium increased the time to which 25% of the group experienced their first exacerbation by 42 days (187 vs. 145). This corresponds to a reduction in risk by 17% (hazard ratio, 0.83; 95% CI, 0.77 to 0.90; P<0.001) [evidence level II].
The beneficial effects come at a cost of increased adverse drug effects. A pooled study of placebo controlled trials (Kesten et al., 2006) 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 9.5). A population based nested case control study of COPD patients found that if 514 (95% CI 336-905) men with benign prostatic hypertrophy were commenced on inhaled antimuscarinics, one would develop acute urinary retention (Stephenson et al., 2011) [evidence level III-2]. (Kesten et al., 2006) These effects have been confirmed in a large four-year randomised-controlled trial (Tashkin et al., 2008) 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.
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COPD-X Plan - Version 2.34 - November 2012