Tiotropium in asthma poorly controlled with standard combination therapy

A substantial proportion of patients with asthma have poorly controlled disease, with recurring symptoms and exacerbations despite the use of preferred controller drugs, ie. inhaled glucocorticoids with or without inhaled long-acting β-agonists (LABAs). For these patients, alternative treatment options may have substantial limitations, including marginal efficacy, cumbersome routes of administration, side-effects and high cost. 

The option of adding a second long-acting inhaled bronchodilator in patients with uncontrolled asthma has been supported by results from recent studies that examined the efficacy of tiotropium, a long-acting anticholinergic bronchodilator approved for the treatment of chronic obstructive pulmonary disease (COPD) but not for the treatment of asthma. Three studies with durations ranging from eight to 16 weeks have shown the efficacy of the addition of tiotropium in patients with asthma who were already receiving standard treatment regimens. The effect of tiotropium had not been evaluated in long-term clinical trials of sufficient duration and power to permit assessment of key endpoints, such as exacerbation frequency, in patients with poorly controlled asthma.

In this study, co-ordinated at Groningen in the Netherlands,¹ the results of two replicate, randomised, placebo-controlled trials, PrimoTinA-asthma 1 and PrimoTinA-asthma 2 (hereafter referred to as trial 1 and trial 2) are reported. The trials looked at the efficacy and safety of adding tiotropium delivered by a soft-mist inhaler, as compared with placebo delivered by the same system, to a treatment regimen of glucocorticoids and LABAs. The effects on lung function, exacerbation frequency, and other endpoints were evaluated during a 48-week period in patients with poorly controlled asthma.

All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in one second (FEV1) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year

The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (± SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86 ± 34ml in trial 1 (p = 0.01) and 154 ± 32ml in trial 2 (p < 0.001). 

The pre-dose (trough) FEV1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88 ± 31ml (p = 0.01) and 111 ± 30ml (p < 0.001), respectively. 

The addition of tiotropium increased the time to the first severe exacerbation (282 days versus 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; p = 0.03). No deaths occurred; adverse events were similar in the two groups.

In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation.

Reference

1. Kerstjens H, Engel M, Dahl R et al, N Engl J Med 2012; 367: 1198-1207