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Dr. Sears is from the Asthma Research Group, McMaster University, Firestone Regional Chest and Allergy Unit, St Joseph’s Hospital, Hamilton.
Correspondence to: Malcolm R. Sears, MB, Professor of Medicine, Asthma Research Group, McMaster University, Firestone Regional Chest and Allergy Unit, St Joseph’s Hospital, Hamilton, Ontario L8N 4A6, Canada; e-mail: searsm@mcmaster.ca
Just over a decade ago, a year-long, crossover, randomized, placebo-controlled trial1 2 of regular vs as-needed, inhaled short-acting ß2-agonist in 64 New Zealand asthmatic patients, most of whom used inhaled corticosteroids, found a deleterious effect of dry-powder fenoterol, 400 µg qid, on the control of asthma. Control was judged by within-patient between-treatment comparisons of symptoms, exacerbations, lung function, and airway responsiveness to methacholine challenge. The study confirmed earlier suggestions3 4 that regular short-acting inhaled ß-agonists may enhance airway responsiveness, and showed, in a clinical context, that this resulted in increased morbidity from asthma.
This report added to the controversy arising from a concurrent epidemiologic study5 in New Zealand suggesting an increased risk of mortality among asthmatic patients prescribed fenoterol. That increased risk was subsequently confirmed by an independent study6 in Canada and analyses7 8 of data from different time periods in New Zealand. The Canadian study6 further suggested that the increased risk of mortality was a dose-related class effect of inhaled short-acting ß-agonists, as not only fenoterol, but also increased doses of albuterol, were risk factors for fatal asthma.
Further studies helped to elucidate mechanisms by which such adverse effects on morbidity and mortality may arise. Airway responsiveness to allergen (both early-phase and late-phase reactions) were enhanced by regular use of albuterol.9 10 Also, regular albuterol use reduced the degree of protection from an additional dose of "rescue" albuterol before challenge.9 11
Debate as to the relevance and consistency of the adverse effects has continued, with one large US study12 reporting no clinically relevant adverse effects of albuterol as monotherapy in patients with mild asthma, although there was a significant increase in airway responsiveness associated with regular albuterol use early in the trial. In the United Kingdom, a similar study13 14 found minimal differences between regular and as-needed use of albuterol. There is general consensus15 16 that there is no benefit from regularly scheduled use of inhaled short-acting ß-agonists in asthma patients. The deleterious effects of the more potent agent fenoterol on asthma severity is now also widely accepted as explaining the rise and fall in asthma mortality and morbidity in New Zealand.17 18
Long-acting ß-agonists were introduced in the United Kingdom in 1990, just days before the first article1 reporting the deleterious effects of regular use of short-acting ß-agonist was published. Concern that the adverse effects of regular short-acting inhaled ß-agonist on asthma morbidity might also occur with long-acting ß-agonist has been a major factor in many clinical studies19 20 21 22 of salmeterol and formoterol over the subsequent decade. Findings have been largely reassuring, although the threefold risk of death from asthma found in the large postmarketing surveillance study19 of salmeterol in the United Kingdom, although not quite statistically significant, was disturbing. A more recent study21 of formoterol used in conjunction with inhaled corticosteroid has shown a significant reduction in exacerbations resulting from the addition of a long-acting ß-agonist rather than deterioration. A nonsignificant small reduction in exacerbations with the addition of salmeterol to inhaled corticosteroid therapy has been reported,22 although a meta-analysis23 of studies in which salmeterol was added to inhaled corticosteroid therapy did not show any substantive reduction of exacerbations.
Against this background, the report of Cloosterman et al in this issue of CHEST (see page 1306) is of considerable interest. In a placebo-controlled trial, these investigators compared the effects of regular short-acting (albuterol) and long-acting (formoterol) ß-agonists on symptom control and lung function in subjects with house-dust mite allergy and mild asthma. The primary end points, based on between-group comparisons, did not differ significantly among the three groups. However, subjects receiving regular albuterol, 200 µg qid, showed a highly significant within-group decrease in FEV1 over 12 weeks of treatment (- 6.6%) and a within-group worsening of airway responsiveness (- 1.2 doubling doses) of borderline statistical significance. In contrast, there were no significant within-group changes in these parameters in asthmatic patients treated with formoterol or placebo.
There was no interaction between the effects of short-acting ß-agonist and high or low allergen exposure as determined by dust samples from mattress covers assayed for the house dust mite allergen Der p 1. However, the levels of mite allergen in the subgroup not subject to environmental intervention were not as high as often reported,24 and so this study does not clearly confirm or negate the suggestion25 that regular short-acting ß-agonists may exert an adverse effect by enhancing responsiveness to allergen via mast cell tachyphylaxis.
The study of Cloosterman et al not only adds to previous studies showing that regular inhaled short-acting ß-agonist may have deleterious effects on asthma control, but also provides reassurance that these effects are not seen with long-acting ß-agonists. With respect to short-acting ß-agonists, studies showing a deleterious effect include the study of fenoterol in New Zealand,1 2 studies with albuterol in the Netherlands,3 26 27 and a recent German study28 showing worsening asthma control associated with regular albuterol or fenoterol. Large US12 and UK13 studies reported no adverse effects (but no benefit) from regularly scheduled albuterol treatment, and Chapman et al29 found no adverse effects of regular albuterol treatment in a brief, 2-week crossover study. However, a review30 of 16 studies in which there are adequate data to assess the effect of regular short-acting ß-agonists on airway responsiveness shows the weight of evidence clearly indicates a deleterious effect.
One possible explanation for differences between studies of the effect of short-acting ß-agonists is the prevalence of different ß-receptor polymorphisms, which impact both the severity of asthma (more nocturnal asthma reported with Gly16 polymorphism)31 and the response to ß-agonists (greater bronchodilator desensitization reported in Gly16 homozygotes).32 In the present study, ß-receptor polymorphisms were not determined, and so the relevance of this factor in these Dutch asthmatic patients cannot be ascertained. ß-Receptor polymorphism status should be determined as a baseline characteristic in future studies of effects of ß-agonists, and studies should be designed with stratification or even selection for relevant receptor polymorphisms.
Although the subjects studied by Cloosterman et al had very mild asthma as judged by their need for rescue ß-agonists, and would likely not be treated in real life with regular short-acting or long-acting ß-agonists, the results of this study together with the literature available to date indicate that short-acting ß-agonists should not be prescribed as regularly scheduled therapy, but used as-needed for symptom relief only. There are no data to justify regular use of short-acting inhaled ß-agonists. Rather, several studies,1 3 4 9 10 including the present study, have shown such treatment can lead to decreased lung function, increased airway responsiveness, and worse asthma control. On the other hand, many subjects with persistent symptoms and impaired lung function despite treatment with inhaled corticosteroids respond to long-acting ß-agonists, which do not appear to worsen asthma control. Clearly, a regular long-acting inhaled ß-agonist is to be preferred to frequent use of a short-acting ß-agonist.
Notwithstanding the present study in which formoterol was used as monotherapy, there are many reasons to recommend the concomitant use of inhaled corticosteroid in any patient with asthma needing regular long-acting ß-agonist,20 21 given the lack of effect of long-acting ß-agonists on the airway inflammation that underlies asthma. The possibility that, even with use of inhaled corticosteroids, better asthma control may require increased anti-inflammatory medication rather than simply adding a long-acting ß-agonist should also be borne in mind, given that long-acting ß-agonists have the potential to mask the clinical effects of increasing eosinophilic airway inflammation when the steroid dose is insufficient.33
References
This article has been cited by other articles:
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  A. Senthilselvan, J. A. Lawson, D. C. Rennie, and J. A. Dosman Regular Use of Corticosteroids and Low Use of Short-Acting {beta}2-Agonists Can Reduce Asthma Hospitalization Chest, April 1, 2005; 127(4): 1242 - 1251. [Abstract] [Full Text] [PDF]
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S. Shrewsbury, S. Pyke, and M. R. Sears MIASMA : Asthma Exacerbation Reduction With Salmeterol Chest, March 1, 2002; 121(3): 1002 - 1003. [Full Text] [PDF]
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