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.(Barr et al., 2006),(Barr et al., 2005) 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 be treated with tiotropium for one year was 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.

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 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).  There was no difference in mortality.

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 94.88), although the latter occurred infrequently. (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. 

In another study by Lee (Lee et al., 2009) using a retrospective cohort design, combination therapy with tiotropium plus inhaled glucocorticoid and long-acting beta agonist was associated with decreased mortality compared with the combination therapy alone, whereas when tiotropium was added to combination therapy with ipratropium (in combination with inhaled glucocorticoid or long acting beta agonist or theophylline), in a so called “real world” scenario, mortality risk was increased [evidence level III-2].