P5. Long-acting bronchodilators

P5.1 Antimuscarinics

A Cochrane review of nine RCTs (6,584 patients) found that tiotropium reduced the odds of a COPD exacerbation (OR 0.74, 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64, 95% CI 0.51 to 0.82) compared to placebo or ipratropium. The number of patients who would need 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 (Barr 2005) [evidence level I]. Another systematic review of 22 trials with 15,276 participants found that anticholinergic (antimuscarinic) use also significantly reduced respiratory deaths (RR 0.27, 95% CI 0.09 to 0.81) compared with placebo. It would be necessary to treat 278 patients with anticholinergic (antimuscarinic) agents to prevent one death (Salpeter 2006) [evidence level I].

A randomised double blind placebo controlled trial of four years duration found that tiotropium was associated with a reduced risk of death at end of treatment (Hazard Ratio 0.84, 95% CI 0.73-0.97) (Celli 2009). It would be necessary to treat at least 53 patients to prevent one death. The precise statistical significance varied with the period of analysis. The hazard ratio for tiotropium compared to placebo varied from 0.87 (95%CI 0.76-0.99, p=0.034) for the full 4 years to 0.89 (0.79-1.02, p=0.086) for 4 years+ 30 days [evidence level II]. A pre-specified subgroup analysis of this four year trial (Decramer 2009) found that tiotropium reduced the rate of decline of post-bronchodilator FEV1 in patients with GOLD II COPD (43mls/year versus 49ml/year, p=0.024). However, the of pre-bronchodilator FEV1 decline was not different between the groups.

P5.2 Comparison of inhaled medications

A systematic review examined the relative effectiveness of inhaled medications to reduce the risk of exacerbations of COPD (Puhan 2009a). The authors identified 35 randomised controlled trials of at least 4 weeks duration that enrolled 26,786 patients with COPD of whom 27% had one or more exacerbations. All regimes significantly reduced the odds of exacerbation compared with placebo – no single inhaled medication was more effective than another. If FEV1 was ≤ 40% predicted, long acting antimuscarinics, inhaled corticosteroids and combination treatment reduced exacerbations significantly compared with long-acting beta agonists alone. However the authors did not have FEV1 data for individual patients.

In 2012, Chong et al (Chong 2012) performed a meta-analysis that compared tiotropium to a range a long acting beta-agonists, data from over 11,000 patients were included and trials were at least 3 months long. Chong reported that tiotropium was more effective in preventing COPD exacerbations leading to hospitalisation (odds ratio 0.86; 95% CI 0.79 to 0.93). There was no difference in mortality, all-cause hospitalisations, quality of life and lung function. There were fewer serious adverse events with tiotropium (OR 0.88; 95% CI 0.78 to 0.99).