Tiotropium bromide triple combination therapy improves lung function and decreases asthma exacerbations
- Wake Forest School of Medicine, Center for Genomics, Medical Center Boulevard, Winston-Salem, North Carolina, USA
- Correspondence to: Professor Stephen P Peters
Wake Forest School of Medicine, Center for Genomics, Medical Center Boulevard, Winston-Salem, NC 27157, USA;
Commentary on: Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198–207.
Three recent well-designed clinical trials demonstrated that tiotropium bromide, when added to an inhaled corticosteroid (ICS), provides asthma control which is non-inferior to adding a long-acting β-agonist (LABA).1–3 The third of these trials also suggested that adding tiotropium to an ICS–LABA combination also provides additional benefit, as measured by an improvement in lung function (FEV1).3 Whether adding tiotropium to patients inadequately controlled on combination ICS–LABA therapy would provide additional benefit by improving long-term asthma control and decreasing severe asthma exacerbations was the subject of the present article.
In two replicate trials of 912 patients inadequately controlled (Asthma Control Questionnaire-7 score ≥1.5) while taking high-dose ICS (≥800 µg budesonide) the effect of adding tiotropium (5 μg/day by misthaler) or placebo for 48 weeks of treatment was determined. These patients with severe asthma (18–75 years of age, asthma diagnosed before the age of 40, and asthma for ≥5 years) were non-smokers (<10 pack-years total, and current non-smokers). They were similar to those with chronic obstructive pulmonary disease (COPD) in that they were required to have persistent airflow limitation, which was defined as a postbronchodilator FEV1 of 80% or less of the predicted value, and an FEV1/FVC ratio of 70% or less, 30 min after the inhalation of four puffs of 100 μg of salbutamol or 90 μg of albuterol.
The addition of tiotropium resulted in an improvement of lung function (FEV1) at 24 weeks of 86±34 (SE) ml in trial 1 (p=0.01) and 154±32 ml in trial 2 (p<0.001). In the combined trials by per protocol analysis, addition of tiotropium increased the time to the first severe exacerbation (282 days vs 226 days), with a 21% reduction in the risk of a severe exacerbation (HR 0.79; 95% CI 0.62 to 1.00; p=0.03). In these patients, with severe asthma poorly controlled, on an ICS–LABA combination, the addition of tiotropium provided both a modest improvement in lung function and prolonged the time to the first asthma exacerbation.
Data reported previously have suggested that tiotropium is an effective asthma controller when added to an ICS, and that its activity is non-inferior in comparison with an LABA.1–3 The data reported in this study by Kerstjens and colleagues suggest that tiotropium could play a role in treating patients with severe asthma who are inadequately controlled on combination ICS–LABA therapy when used as a third controller. While the effects on lung function (86–153 ml improvement in FEV1) and asthma exacerbations (21% reduction (95% CI −0% to 38%) were modest, the reduction in asthma exacerbations is an important finding in our attempts to provide improved treatment options to these difficult-to-control patients.
These data add to the growing literature that the anticholinergic agent tiotropium could play an important role in treating patients with moderate-to-severe asthma who are inadequately controlled either on an ICS alone, or on an ICS–LABA combination. Although the positive effects on asthma exacerbations are encouraging, they need to be replicated. In addition, we need additional data to establish the safety of tiotropium when used to treat patients with asthma. A number of additional clinical trials of tiotropium in asthma are in progress and we are hopeful that an application will be soon submitted to the Food and Drug Administration (FDA) and other regulatory agencies to grant approval for its use in patients with asthma.
Competing interests SPP has received grants from NHLBI (AsthmaNet, SARP, SPIROMICS), the American Lung Association (Asthma Clinical Research Centers) and is an Advisor to DCC. He serves as a consultant to AstraZeneca, Aerocrine, Airsonett AB, GlaxoSmithKline, Merck, Targacept and TEVA and has provided lectures for Merck and Integrity CE.