Anticholinergics for patients with asthma?

T h e n e w e ng l a n d j o u r na l o f m e dic i n e Anticholinergics for Patients with Asthma?
Current guidelines for treating patients with asth- ondary comparison, which was for noninferior- ma whose symptoms are not controlled by a low ity, was between adding tiotropium and adding dose of an inhaled glucocorticoid alone recom- salmeterol.
mend either doubling the glucocorticoid dose or The addition of tiotropium resulted in a greater adding a long-acting beta-agonist (LABA).1 How- improvement in PEF and FEV1 and better symp- ever, inhaled glucocorticoids have a relatively flat tom control than doubling the dose of the in- dose–response curve, so doubling the dose may haled glucocorticoid. This finding is not totally result in little or no improvement in individual surprising, since entry into the study required patients.2 LABAs are generally more effective,1,3 either a bronchodilator response or a positive but an increased concern about infrequent but life- methacholine challenge, and after the run-in pe- threatening exacerbations4 has reduced enthusi- riod when patients received an inhaled glucocor- asm for the use of these drugs. Alternatives to ticoid alone, levels of exhaled nitric oxide and the addition of LABA therapy include high doses sputum eosinophils were in the normal range. of inhaled glucocorticoids, leukotriene modifiers, The latter results suggest an antiinflammatory ef- theophylline, anti-IgE therapy for selected patients, fect of the baseline inhaled glucocorticoid treat- ment. The unanticipated and quite exciting find- In this issue of the Journal, Peters and col- ing is that the addition of tiotropium was not leagues5 describe the results of a study exploring inferior to the addition of salmeterol.
the role of a long-acting anticholinergic agent, Considering that short-acting inhaled anticho- tiotropium, as add-on therapy for adults with linergic agents have been available for the treat- asthma whose disease is not adequately controlled ment of airway disease, including asthma, for with a low dose of an inhaled glucocorticoid (bec- decades and that the long-acting anticholinergic lomethasone at a dose of 80 μg twice daily). Us- tiotropium was approved for use in patients with ing a triple-blind, placebo-controlled, three-way chronic obstructive pulmonary disease (COPD) in crossover design, with each treatment period last- the United States in early 2004, why has it taken ing 14 weeks and a 2-week washout between treat- so long to do a study like this? Early studies of ments, the investigators compared three regimens: short-acting anticholinergic agents such as ipratro- adding tiotropium (at a dose of 18 μg once daily) pium in heterogeneous groups of patients with to the low dose of inhaled glucocorticoid, dou- both asthma and COPD showed that adding such bling the dose of inhaled glucocorticoid (160 μg drugs to an inhaled beta-agonist alone did not re- twice daily), or adding the LABA salmeterol (at a sult in significant improvement in lung function dose of 50 μg twice daily) to the low dose of in- or symptoms.6 Furthermore, the use of such drugs haled glucocorticoid. The primary outcome varia- was no more effective than inhaled beta-agonists ble was the morning peak expiratory flow (PEF). in patients with asthma alone.7 Clinically, anti- Secondary outcomes included the forced expira- cholinergic agents became the treatment of choice tory volume in 1 second (FEV1), symptoms, quality for patients with COPD and beta-agonists for pa- of life, and asthma control days. The primary tients with asthma. In addition, the initial large comparison was between adding tiotropium and clinical trials of tiotropium focused on patients doubling the inhaled glucocorticoid dose; the sec- with COPD, in whom there was a major unmet Downloaded from www.nejm.org on September 22, 2010. For personal use only. No other uses without permission. From the NEJM Archive Copyright 2010 Massachusetts Medical Society. medical need. However, there is increasing inter- so that we can determine whether tiotropium and est in using tiotropium for the treatment of asth- possibly other long-acting anticholinergic agents ma: the study by Peters et al. is only one of several are effective and safe alternatives to LABAs for the trials, both large and small, that are exploring long-term treatment of asthma.
the drug’s role in asthma therapy (ClinicalTrials Disclosure forms provided by the author are available with the .gov numbers, NCT00546234, NCT00772538, full text of this article at NEJM.org.
From the Department of Medicine, Northwestern University, Are the risks associated with tiotropium less Chicago.
than those reported with LABA therapy? A recent This article (10.1056/NEJMe1009429) was published on Sep- report by Singh and colleagues suggested there tember 19, 2010, at NEJM.org.
is an association between tiotropium and car- 1. National Heart, Lung, and Blood Institute, National Asthma
diovascular events.8 Subsequent evaluation of an Education and Prevention Program. Expert Panel report 3: extensive database and publication of the results guidelines for the diagnosis and management of asthma. 2007. (http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.) from a large clinical trial9 provided sufficient 2. Bousquet J, Ben-Joseph R, Messonnier M, Alemao E, Gould
comfort for the Food and Drug Administration AL. A meta-analysis of the dose-response relationship of inhaled to determine that tiotropium is not associated corticosteroids in adolescents and adults with mild to moderate persistent asthma. Clin Ther 2002;24:1-20.
with an increased risk of cardiovascular events or 3. Greening AP, Ind PW, Northfield M, Shaw G. Added salmet-
death. However, the drug’s bronchodilator prop- erol versus higher-dose corticosteroid in asthma patients with erties (which are similar to those of LABAs) have symptoms on existing inhaled corticosteroid. Lancet 1994; the potential to mask underlying airway inflam- 4. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM.
mation not adequately controlled by an inhaled The Salmeterol Multicenter Asthma Research Trial: a compari- glucocorticoid. If tiotropium becomes a frequent- son of usual pharmacotherapy for asthma or usual pharmaco- therapy plus salmeterol. Chest 2006;129:15-26.
ly used treatment for asthma, careful assessment 5. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bro-
of its risk in this population of patients will be mide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010. DOI: 10.1056/NEJMoa1008770.
6. Kerstjens HAM, Brand PLP, Hughes MD, et al. A comparison
What do the results of this study mean for of bronchodilator therapy with or without inhaled corticosteroid practitioners caring for patients with asthma? therapy for obstructive airways disease. N Engl J Med 1992; Some clinicians have already begun substituting 327:1413-9.
7. Westby M, Benson M, Gibson P. Anticholinergic agents for
tiotropium for LABAs, such as salmeterol and for- chronic asthma in adults. Cochrane Database Syst Rev 2004;3: moterol, in patients who remain symptomatic on CD003269.
low doses of inhaled glucocorticoids, and the 8. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and
risk of major adverse cardiovascular events in patients with study by Peters et al. provides encouraging results chronic obstructive pulmonary disease: a systematic review and with respect to lung function and symptoms in meta-analysis. JAMA 2008;300:1439-50.
such patients. However, the limited duration of 9. Celli B, Decramer M, Kesten S, et al. Mortality in the 4-year
trial of tiotropium (UPLIFT) in patients with chronic obstructive each treatment period in this study does not per- pulmonary disease. Am J Respir Crit Care Med 2009;180:948-55.
mit a determination of whether tiotropium reduc- 10. Lane S, Molina J, Plusa T. An international observational
es asthma exacerbations, an important marker of prospective study to determine the cost of asthma exacerbations disease control and resource utilization,10 to the 11. Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose
same extent as LABAs.11 Nevertheless, this report inhaled corticosteroids plus salmeterol versus higher doses of in- supports the need for additional studies to explore haled corticosteroids in symptomatic asthma. Thorax 2005;60: these important outcomes as well as safety issues Copyright 2010 Massachusetts Medical Society. Downloaded from www.nejm.org on September 22, 2010. For personal use only. No other uses without permission. From the NEJM Archive Copyright 2010 Massachusetts Medical Society.

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