Tiotropium Bromide Step-up Therapy for Adults With Uncontrolled Asthma
Peters SP, Kunselman SJ, Icitovic N, et al.
N Engl J Med. 2010;363:1715-1726
When asthma is not adequately controlled with anti-inflammatory therapy alone, guidelines recommend either increasing the dosage of the anti-inflammatory agent or adding an LABA. Adding an LABA has been shown to be more effective than increasing the anti-inflammatory agent, but there have been recent concerns about the safety of LABAs. The present study tested the possibility that a long-acting anticholinergic agent (LAMA), tiotropium bromide, might be an alternative step-up agent for patients whose asthma is not well controlled on a low to medium dose of an inhaled corticosteroid (ICS) alone.
Peters and associates enrolled 210 patients in their study, with the primary aim of comparing the effect on asthma control of either doubling the dose of the inhaled steroid or adding tiotropium to the modest dose of ICS. To determine whether tiotropium was as effective as the currently recommended step-up (LABA) therapy, the study also included a salmeterol-ICS treatment phase. Therefore, the study was a 3-way crossover trial, with each treatment being given for 14 weeks in random sequence to each patient. The patients' mean age was 42 years, with a mean duration of asthma of 26 years; mean forced expiratory volume (FEV1) at baseline was 72% of predicted; mean morning peak expiratory flow (PEF) was 377 L/min; and mean daily symptom score was 0.46 (the worst possible score being 3).
Results were as follows: the primary outcome (morning PEF) was 26 L/min greater (P < .001) in the tiotropium step-up treatment phase than in the doubling-ICS phase. A similar superiority of tiotropium step-up was observed with most secondary outcomes (evening PEF, proportion of asthma control days, prebronchodilator FEV1, and daily asthma symptom scores). Tiotropium step-up was also shown to be non-inferior to salmeterol step-up, and was sometimes superior. The investigators concluded that the addition of tiotropium to a moderate-dose ICS "appeared to be equivalent to...the addition of salmeterol" in poorly controlled asthma.
When asthma is not well controlled with modest doses of an ICS, increasing the dose of the ICS has generally not been as effective as adding an LABA. Other alternatives to the LABA have been to add a leukotriene modifier or theophylline or anti-immunoglobulin E therapy, each of which has disadvantages. Inhaled anticholinergic agents, both long- and short-acting, have not been considered as important bronchodilators for asthma and have not been approved for an asthma indication in the United States. However, they do have a bronchodilating action in asthma, albeit usually less than that of a beta-agonist and the effect is somewhat inconsistent among patients. For these reasons, few studies have explored the maintenance use of an LAMA in asthma. The present study suggests that, like the well-known effect of LABAs, tiotropium might be an effective add-on therapy for asthma that is poorly controlled on an ICS alone. This will be important for patients who are intolerant of LABAs or if the prescriber is reluctant to use an LABA because of safety concerns.
Before it can be concluded that tiotropium (or another LAMA when others become available) could be used as step-up treatment for inadequately controlled asthma, additional studies are called for. The present study was exploratory in that a relatively small number of patients were involved and the duration of treatment was relatively short at 14 weeks. However, the present results are encouraging, and if confirmed, could signify a change in our present asthma guidelines.
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