EDITORIAL

Anticholinergics for Patients with Asthma?

Lewis J. Smith, M.D.
N Engl J Med 2010; 363:1764-1765 l October 28, 2010

Article
Current guidelines for treating patients with asthma whose symptoms are not controlled by a low dose of an inhaled glucocorticoid alone recommend either doubling the glucocorticoid dose or adding a long-acting beta-agonist (LABA). However, inhaled glucocorticoids have a relatively flat doseresponse curve, so doubling the dose may result in little or no improvement in individual patients. LABAs are generally more effective, but an increased concern about infrequent but life-threatening exacerbations has reduced enthusiasm for the use of these drugs. Alternatives to the addition of LABA therapy include high doses of inhaled glucocorticoids, leukotriene modifiers, theophylline, anti-IgE therapy for selected patients, and oral glucocorticoids. In this issue of the Journal, Peters and colleagues describe the results of a study exploring the role of a long-acting anticholinergic agent, tiotropium, as add-on therapy for adults with asthma whose disease is not adequately controlled with a low dose of an inhaled glucocorticoid (beclomethasone at a dose of 80 g twice daily) . Using a triple-blind, placebo-controlled, three-way crossover design, with each treatment period lasting 14 weeks and a 2-week washout between treatments, the investigators compared three regimens: adding tiotropium (at a dose of 18 g once daily) to the low dose of inhaled glucocorticoid, doubling the dose of inhaled glucocorticoid (160 g twice daily), or adding the LABA salmeterol (at a dose of 50 g twice daily) to the low dose of inhaled glucocorticoid. The primary outcome variable was the morning peak expiratory flow (PEF). Secondary outcomes included the forced expiratory volume in 1 second (FEV1), symptoms, quality of life, and asthma control days. The primary comparison was between adding tiotropium and

doubling the inhaled glucocorticoid dose; the secondary comparison, which was for noninferiority, was between adding tiotropium and adding salmeterol. The addition of tiotropium resulted in a greater improvement in PEF and FEV1 and better symptom control than doubling the dose of the inhaled glucocorticoid. This finding is not totally surprising, since entry into the study required either a bronchodilator response or a positive methacholine challenge, and after the run-in period when patients received an inhaled glucocorticoid alone, levels of exhaled nitric oxide and sputum eosinophils were in the normal range. The latter results suggest an antiinflammatory effect of the baseline inhaled glucocorticoid treatment. The unanticipated and quite exciting finding is that the addition of tiotropium was not inferior to the addition of salmeterol. Considering that short-acting inhaled anticholinergic agents have been available for the treatment of airway disease, including asthma, for decades and that the long-acting anticholinergic tiotropium was approved for use in patients with chronic obstructive pulmonary disease (COPD) in the United States in early 2004, why has it taken so long to do a study like this? Early studies of short-acting anticholinergic agents such as ipratropium in heterogeneous groups of patients with both asthma and COPD showed that adding such drugs to an inhaled beta-agonist alone did not result in significant improvement in lung function or

symptoms. Furthermore, the use of such drugs was no more effective than inhaled beta-agonists in patients with asthma alone. Clinically, anticholinergic agents became the treatment of choice for patients with COPD and beta-agonists for patients with asthma. In addition, the initial large clinical trials of tiotropium focused on patients with COPD, in whom there was a major unmet medical need. However, there is increasing interest in using tiotropium for the treatment of asthma: the study by Peters et al. is only one of several trials, both large and small, that are exploring the drug's role in asthma therapy (ClinicalTrials.gov numbers, NCT00546234, NCT00772538, NCT00776984, and NCT01172821). Are the risks associated with tiotropium less than those reported with LABA therapy? A recent report by Singh and colleagues suggested there is an association between tiotropium and cardiovascular events. Subsequent evaluation of an extensive database and publication of the results from a large clinical trial provided sufficient comfort for the Food and Drug Administration to determine that tiotropium is not associated with an increased risk of cardiovascular events or death. However, the

drug's bronchodilator properties (which are similar to those of LABAs) have the potential to mask underlying airway inflammation not adequately controlled by an inhaled glucocorticoid. If tiotropium becomes a frequently used treatment for asthma, careful assessment of its risk in this population of patients will be needed. What do the results of this study mean for practitioners caring for patients with asthma? Some clinicians have already begun substituting tiotropium for LABAs, such as salmeterol and formoterol, in patients who remain symptomatic on low doses of inhaled glucocorticoids, and the study by Peters et al. provides encouraging results with respect to lung function and symptoms in such patients. However, the limited duration of each treatment period in this study does not permit a determination of whether tiotropium reduces asthma exacerbations, an important marker of disease control and resource utilization, to the same extent as LABAs. Nevertheless, this report supports the need for additional studies to explore these important outcomes as well as safety issues so that we can determine whether tiotropium and possibly other long-acting anticholinergic agents are effective and safe alternatives to LABAs for the long-term treatment of asthma. This article (10.1056/NEJMe1009429) was published on September 19, 2010, at NEJM.org.
SOURCE INFORMATION

From the Department of Medicine, Northwestern University, Chicago.

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