© 2005 American Thoracic Society doi: 10.1164/rccm.2410004
A Single Inhaler for Asthma?National Heart and Lung Institute, Imperial College London, United Kingdom Despite the availability of highly effective therapies, many patients with asthma continue to suffer symptoms and exacerbations, with considerable disruption to their daily life (1). This may reflect underdiagnosis and inappropriate therapy, as well as poor adherence to regular prophylactic therapy. Inhaled corticosteroids are the mainstay of asthma therapy, but there is now compelling evidence that addition of a long-acting inhaled ß2-agonist (LABA: salmeterol or formoterol) gives better control in terms of reduced symptoms, improved lung function, and reduced exacerbations in patients with mild, moderate, and persistent asthma (2–4). This has led to the development of fixed combination inhalers (salmeterol/fluticasone, formoterol/budesonide), which are now increasingly used in asthma management (5, 6). Combination inhalers are more convenient to use, control asthma at lower doses of corticosteroids, ensure that the corticosteroid is not discontinued when the bronchodilator is used, and are cost effective. There is a convincing scientific rationale for giving an LABA and corticosteroid together, as they have complementary actions on the complex pathophysiology of asthma and may enhance each other's effects at a molecular level (7). It is normal practice to administer these combination inhalers twice daily at a dose that is related to the severity of asthma and to use a short-acting ß2-agonist (SABA), such as albuterol, as required to relieve any breakthrough symptoms. Frequent use of the SABA indicates either poor compliance or the need for a higher maintenance dose of the combination inhaler. A recently published large study (over 3,000 patients) attempted to achieve better, and if possible total, control of asthma by progressively increasing the dose of the controller inhaler (8). Control was more easily and rapidly achieved with the salmeterol/fluticasone combination inhaler than fluticasone alone and at a lower total dose of inhaled corticosteroid. However, some patients required rather high doses of the combination inhaler to achieve satisfactory control of their asthma. This issue of the Journal (pp. 129–136) presents a new study that takes this approach a step further (9). It had previously been shown that formoterol could be used as a reliever medication in asthma, as it has a rapid onset of action with a long bronchodilator effect, yet systemic side effects are of a similar duration to an SABA (10). In the new double-blind controlled parallel group study (involving over 2,500 patients) formoterol/budesonide combination inhaler was used as maintenance therapy twice daily, but additional puffs were used as needed for symptom relief (9). This was compared with the same maintenance dose and to a fourfold greater dose of budesonide alone, both with terbutaline as needed. The remarkable, and somewhat unexpected, finding was that the treatment with combination inhaler for both maintenance and relief markedly reduced the number of severe exacerbations (the primary outcome measure) over the 1-year treatment period compared with the other treatments, but also reduced the need for oral corticosteroids, improved symptom control, and lung function compared with the other treatment regimens. A concern about this approach is that some patients might end up using the combination inhaler frequently and therefore receive an unacceptably high dose of inhaled corticosteroid. However, this was not the case, as the mean number of additional doses of combination inhaler was only one dose per day and very few patients used high doses. Combination inhalers have generally been less effective in children with asthma (11), as LABA do not appear to have such a large add-on effect. In this study, children aged 4–11 years (12% of study population) were also included, but there is no information provided on how they responded to the different treatment strategies compared with adults. How can these surprisingly good results be explained mechanistically? Asthma is characterized by variable symptoms with day-to-day variability. One approach to deal with such variability is by giving a high dose of combination inhaler to prevent the emergence of symptoms, as adopted by the salmeterol/fluticasone study (8). An alternative approach is to increase the treatment at the time asthma worsens. We know from the careful analysis of asthma exacerbations in a large controlled trial that they evolve slowly over a few days (12). This provides the opportunity to intervene before the exacerbation develops fully. It is now clear that doubling the maintenance dose of inhaled corticosteroid is insufficient to prevent an exacerbation (13), whereas a fourfold increase is effective (2), and confirmed by the present study. It is likely that the combination inhaler not only provided an effective bronchodilator to relieve symptoms, but also a steroid at a time when it is needed. It is now emerging that inhaled corticosteroids work much more rapidly than previously recognized, with significant antiinflammatory and bronchoprotective effects detectable after a few hours (14, 15). The reason why the additional rescue treatment with the combination inhaler on top of the maintenance dose is so effective is presumably related to timing and its effect of "nipping in the bud" the evolution of an exacerbation. It is likely that the corticosteroid component is most important in this respect, although this needs to be demonstrated in a controlled trial using formoterol, rather than terbutaline, as the rescue therapy. It may, however, be the combination of the two drugs that is important, with some critical interaction between the LABA and the corticosteroid which enhances the effectiveness of this approach. Further research is now needed to understand the molecular mechanism involved and whether this approach more effectively controls airway inflammation. The study by O'Byrne and colleagues may lead to changes in the paradigm of asthma management, where a single inhaler is used for both maintenance and rescue (9). This simplifies asthma therapy for the patients (and the doctor) and is likely to improve compliance. It also follows more closely what patients do in the real world, where they tend take more medication in response to increased symptoms. It is also likely that this treatment strategy will be more cost effective as better control of asthma reduces the costs of treating exacerbations and hospital admissions. We now need effectiveness studies in the real world to see whether this simplified approach is applicable to treating asthma patients in the community (16). FOOTNOTES Am J Respir Crit Care Med Vol 171. pp 95–97, 2005 Internet address: www.atsjournals.org Conflict of Interest Statement: P.J.B. has served on Scientific Advisory Boards, received lecture fees and research funding for GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Altana, Pfizer, Scios, and Millennium. REFERENCES
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