We report two findings with implications for the treatment of asthma in adults. First, our study shows that the use of tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid for patients whose symptoms were inadequately controlled while they were receiving inhaled beclomethasone alone at a dose of 80 μ
g twice a day. Second, among patients in our study who were similar to those in trials showing the clinical efficacy of LABA therapy,3,4
tiotropium was noninferior to salmeterol on the basis of predefined criteria, a finding that meets the standards established in the FDA’s draft guidance for industry on noninferiority clinical trials.22
Our selection of the morning PEF as the primary outcome might attract criticism, even though the trial was adequately powered and analyzed for another key patient-centric outcome, the proportion of asthma-control days. Our rationale was that pulmonary function remains an important element of asthma control, improvements in the PEF were similar to those in previous Asthma Clinical Research Network trials comparing an active treatment with placebo,23,24
and improvements in pulmonary function that were induced by tiotropium were accompanied by improvements in both asthma symptoms and the proportion of asthma-control days.
We did not evaluate whether increasing the dose of an inhaled glucocorticoid by more than a factor of two would provide an increased benefit. Although an increase in the dose of an inhaled glucocorticoid by a factor of four has been reported to reduce asthma exacerbations,25
low doses of an inhaled glucocorticoid have been reported to provide a benefit equivalent to that of a high dose with respect to measures of asthma control,26
the outcomes that we studied. In addition, combinations of inhaled glucocorticoids and LABA therapy have been reported to provide superior asthma control, as compared with an increased dose of an inhaled glucocorticoid, even when the dose was more than doubled.27
Although the effects of tiotropium and salmeterol were similar in general, measures of the prebronchodilator FEV1
favored tiotropium. The small decrease in FEV1
after four puffs of albuterol among patients receiving salmeterol (0.05 liters) suggests possible tachyphylaxis to the effect of an additional dose of a beta-agonist, a finding not observed in the tiotropium group (with an increase of 0.02 liters). At baseline, the short-term response to four puffs of albuterol (reversibility of airway obstruction of 14.9%) was similar to the response to four puffs of ipratropium (reversibility of 12.4%), which suggests that ipratropium could be considered as an acute bronchodilator for patients with asthma, as was shown in the Asthma Clinical Research Network’s Long-Acting Beta Agonist Response by Genotype (LARGE) trial (NCT00200967).28
The exploratory response analysis provides several insights. In evaluating the response to treatment on the basis of the very stringent three-dimensional measurement, we found that only 36% of patients receiving a bronchodilator and an inhaled glucocorticoid had such a response, as compared with less than 10% of patients receiving a double dose of an inhaled glucocorticoid (). These data could be used to examine how treatment responses are distributed in a population of patients with asthma. For example, if the less stringent two-dimensional criteria were applied and if the goal were to treat the greatest number of patients with a drug to which they had a response and to maximize the use of inhaled glucocorticoids, 53.1% of patients would be treated with a double dose of an inhaled glucocorticoid, 8.8% with tiotropium plus an inhaled glucocorticoid, and 8.1% with salmeterol plus an inhaled glucocorticoid, leaving 20.6% to be treated with either one of the bronchodilators combined with a low-dose inhaled glucocorticoid and 9.4% who had no response to any treatment.
On the basis of our study’s design, we evaluated only a small number of patients, with no treatment lasting longer than 14 weeks. Since we could not examine either the rate of asthma exacerbations or long-term safety issues, our findings cannot be considered clinically directive. Additional studies that have sufficient statistical power to evaluate exacerbations and safety events are required to further establish the clinical efficacy of tiotropium. However, our data establish clinical equipoise to study larger cohorts of adults for longer periods of time with tiotropium as a therapy for asthma control.