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 dose–response
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 μg 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 μg once
daily) to the low dose of inhaled glucocorticoid, doubling the dose of inhaled
glucocorticoid (160 μg twice daily), or adding the LABA salmeterol (at a dose of 50
μg 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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