The Proceedings of the American Thoracic Society 1:105-108 (2004)
© 2004 The American Thoracic Society
Pharmacologic Interventions to Reduce the Risk of Asthma Exacerbations
Paul M. O'Byrne
Firestone Institute for Respiratory Health, St. Joseph's Hospital, Hamilton, Ontario, Canada
Correspondence and requests for reprints should be addressed to Paul M. O'Byrne, M.B., F.R.C.P.I., F.R.C.P.C., Firestone Institute for Respiratory Health, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6 Canada. E-mail: obyrnep{at}mcmaster.ca
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ABSTRACT
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Inhaled corticosteroids (ICS) are known to reduce the risk of asthma exacerbations and asthma fatalities. In addition, an increased dose of ICS at the onset of exacerbation can reduce the need for systemic corticosteroids, although this may require a fourfold increase in dose. The overuse of short-acting ß2-agonists or long-acting inhaled ß2-agonists, used as monotherapy, increases these risks. By contrast, the use of long-acting ß2-agonists together with ICS has been demonstrated to reduce the doses of ICS needed for ideal asthma control, as well as to reduce asthma exacerbations. This has been best demonstrated in the Formoterol and Corticosteroids Establishing Therapy and Oxis and Pulmicort Turbuhaler in the Management of Asthma studies, which demonstrated that the combination of inhaled budesonide and formoterol reduced the risk of asthma exacerbations over that achieved by budesonide alone. Even the "as needed" use of inhaled formoterol added to ICS reduces asthma exacerbations. The combination inhaler, Symbicort, containing both budesonide and formoterol, reduced the risk of asthma exacerbations to a similar extent as the monocomponents, given separately. Treatment with either leukotriene receptor antagonists or anti-IgE also reduces the risks of asthma exacerbations, but the magnitude of the benefit compared with the combination of ICS and long-acting ß2-agonists is not yet known.
Key Words: asthma • exacerbation • inhaled corticosteroids • long-acting inhaled ß2-agonists
Reducing the risk of asthma exacerbations has been identified as an important outcome in obtaining ideal asthma control (1, 2). Indeed, it may be considered the most important outcome, because asthma exacerbations are not only the period of greatest risk and cause of anxiety to patients with asthma, but are also the greatest stress on health care providers and greatest cost to the health care system in asthma management. Despite the importance in reducing exacerbations with asthma therapy, it has not, until relatively recently, been a major outcome variable in studies of the efficacy of drug treatment in asthma.
Severe asthma exacerbations are a common clinical manifestation of patients with severe, poorly controlled asthma, and partly as a result of this, little attention has been paid to the importance of exacerbations in patients thought to have mild asthma. This view has been challenged by the results of a number of studies in patients, believed by their managing physician to have mild, stable asthma. Robertson and coworkers (3) made the important observation that 33% of 51 children, who died of acute severe asthma exacerbations over a 3-year period in the State of Victoria, Australia, were thought to have mild or trivial asthma before their final attack. Also, in a study of patients considered by their primary care physician to have such mild asthma that they would not derive any clinical benefit from inhaled corticosteroids (ICS), up to 70% of the patients were experiencing nocturnal or early morning symptoms in the month before entering the study, and 30% of the patients receiving placebo therapy had a severe asthma exacerbation during the 4 months of the study (4). A much larger study, the OPTIMA (Oxis and Pulmicort Turbuhaler in the Management of Asthma) trial (5), also evaluated patients with mild asthma, not using ICS, and demonstrated that 33% had a severe asthma exacerbation during treatment with placebo. Similarly, in the CAMP (Childhood Asthma Management Program) study of children with mild to moderate asthma (6), more than 60% of the patients receiving placebo treatment had a severe asthma exacerbation during the first year. These studies indicate that the prevalence of severe asthma exacerbations is much higher in patients with mild asthma than was previously believed.
In a study of the development and resolution of severe exacerbations, Tattersfield and coworkers (7) showed that, in a group of patients with moderate to severe asthma, exacerbations developed on average over 5–7 days before being recognized and treated (Figure 1). Once treatment with oral corticosteroids was started, the exacerbation resolved over 5–7 days. However, in occasional patients, severe life-threatening exacerbations can develop over minutes to hours.
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Figure 1. Measurements of asthma symptoms and PEF made for 15 days before a severe asthma exacerbation was identified and then for 15 days after treatment with oral corticosteroids was started. (Modified and published by permission from Tattersfield and colleagues [7].)
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EFFICACY OF INHALED CORTICOSTEROIDS
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Inhaled corticosteroids are known to reduce the risk of asthma exacerbations (4–6) and of asthma fatalities (8). By contrast, overuse of short-acting inhaled ß2-agonists is associated with increased risks (9). All studies of the efficacy of ICS, in which exacerbations have been evaluated, are remarkably consistent in the demonstration of a marked beneficial effect of even low doses of ICS in reducing the risks of both mild and severe exacerbations. This benefit has been best shown in the OPTIMA (5) and FACET (Formoterol and Corticosteroids Establishing Therapy) (10) clinical trials. In OPTIMA, treatment with inhaled budesonide at 200 µg/day, in patients with mild asthma not receiving regular treatment with ICS before the study, reduced the risk for the first severe asthma exacerbation by 60% and the total exacerbation rate by 40% (Figure 2). In the same study, in patients already taking low doses of ICS before the study, increasing the dose from 200 to 400 µg/day did not provide any additional benefit. By contrast, in a more moderate to severe population studied in the FACET trial (10), increasing budesonide from 200 to 800 µg/day reduced the rate of severe asthma exacerbations by almost 50% (Figure 3). The beneficial effect of a fourfold increase in corticosteroid dose, in reducing the risk of asthma exacerbations, has been confirmed by others (11, 12). Taken together, these studies demonstrate that low doses of ICS are effective in reducing the risk for severe asthma exacerbations. If patients are already taking low doses and experience frequent exacerbations, a fourfold higher dose may be required to reduce this risk. In addition, at the onset of an exacerbation, a fourfold increase in dose may be required to reduce the risk of this developing into a severe exacerbation. These studies have, however, been conducted only by comparing a low dose (i.e., budesonide at 200 µg/day) with four times that dose. It is not known whether a similar beneficial effect would be seen in patients already using a high dose.
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Figure 2. Rate of severe asthma exacerbations, expressed as number per patient per year, measured in the patients in Group A of the OPTIMA study over 1 year of treatment. These were patients with mild asthma, not taking ICS; rather, they were treated with either placebo or budesonide at 200 µg/day, with or without formoterol at 6 µg twice daily. Budesonide alone reduced exacerbations, with no additional benefit from formoterol. (Reprinted by permission from O'Byrne and colleagues [5].)
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Figure 3. Rate of severe asthma exacerbations, expressed as number per patient per year, measured in patients in the FACET study over 1 year of treatment. These patients were treated with budesonide at 200 µg/day with or without formoterol (12 µg twice daily), or with budesonide at 800 µg/day with or without formoterol (12 µg twice daily). A fourfold increase in the dose of budesonide reduced the rate of exacerbations by almost 50%, with an additional benefit demonstrated with the addition of formoterol. (Reprinted by permission from Pauwels and colleagues [10].)
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EFFICACY OF COMBINATION THERAPY WITH ICS AND LONG-ACTING INHALED ß2-AGONISTS
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The use of long-acting inhaled ß2-agonists together with ICS has been demonstrated to reduce the doses of ICS required to maintain ideal asthma control (13). This treatment alternative, however, has raised concerns that patients, achieving short-term benefit from this combination, would be put at risk over the longer term of increased exacerbations. This concern existed because of the potential detrimental effect of reducing doses of ICS on the progression of airway inflammation. Indeed, in studies in which ICS were discontinued, and patients were treated with long-acting inhaled ß2-agonists alone, asthma exacerbations were shown to increase (14).
The question of whether adding the long-acting inhaled ß2-agonist, formoterol, to low dose or fourfold higher doses of inhaled budesonide increased the risk of asthma exacerbations was evaluated by the FACET study (10). This study evaluated patients with moderate to severe asthma, who had moderate airflow obstruction while receiving an average daily dose of ICS of close to 800 µg. The study compared the effects of a low dose of inhaled budesonide (200 µg/day), with and without inhaled formoterol (12 µg twice daily), with a high dose of budesonide (800 µg/day), with and without formoterol (12 µg twice daily). The primary outcome variable in the trial was the rate of severe asthma exacerbations over 1 year of treatment. Indeed, this study was the first large prospective clinical trial to use asthma exacerbations as a primary variable and to power the study accordingly. The study demonstrated that the combination of inhaled budesonide and formoterol not only improved asthma control, but also significantly reduced, rather than increased, the rate of both mild and severe asthma exacerbations over and above that achieved by either low or high doses of budesonide alone (Figure 3). Furthermore, another study has demonstrated that even the "as needed" use of inhaled formoterol, when added to ICS, reduces asthma exacerbations when compared with the "as needed" use of a short-acting inhaled ß2-agonist, terbutaline (15). The effect of the combination of low doses of inhaled budesonide plus formoterol, compared with high doses of budesonide alone, on airway inflammation in asthma has also been evaluated (16). This study confirmed that eosinophilic airway inflammation did not worsen in patients taking the combination therapy, when compared with patients taking the higher dose of budesonide alone.
Treatment with a combination of the inhaled corticosteroid beclomethasone dipropionate and the long-acting inhaled ß2-agonist salmeterol has not been demonstrated to reduce asthma exacerbations, when compared with increasing the dose of inhaled corticosteroid alone, in subjects with moderately severe asthma (17, 18). However, salmeterol, but not the short-acting inhaled ß2-agonist salbutamol, reduced asthma exacerbations when added to the patient's current dose of ICS (19). In addition, a metaanalysis of studies comparing treatment with combined inhaled corticosteroid fluticasone propionate and salmeterol showed a 2.42% reduction in moderate or severe asthma exacerbations (20).
The combination inhaler Symbicort (AstraZeneca, London, UK), containing both budesonide and formoterol, has also been shown to improve overall asthma control as well as reduce the risk of asthma exacerbations. Zetterström and colleagues (21) have compared the use of the combination inhaler with its monocomponents budesonide and formoterol, given separately, and with budesonide alone. This study demonstrated that the combination inhaler was at least as effective as the monocomponents given separately and significantly better that budesonide alone in reducing the risk of asthma exacerbations (Figure 4).
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Figure 4. A Kaplan-Meier survival curve for the time to the first severe exacerbation in patients treated for 3 months with Symbicort (160/4.5 µg twice daily), or with budesonide (200 µg twice daily) plus formoterol (4.5 µg twice daily), or with budesonide (200 µg twice daily) plus placebo (twice daily). Both Symbicort alone and budesonide plus formoterol significantly increased the time to the first asthma exacerbation when compared with budesonide alone. (Reprinted by permission from Zetterström and colleagues [21].)
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EFFICACY OF OTHER THERAPIES
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Other treatment options for asthma have been evaluated for their ability to reduce asthma exacerbations. The cysteinyl leukotriene receptor antagonists zafirlukast (22), montelukast (23), and pranlukast (24) have all been shown to reduce the rate of asthma exacerbations. However, direct comparisons with ICS alone indicate that this treatment option is less effective than ICS in improving overall asthma control, although the effect on reducing the risk of asthma exacerbations may be similar (23). There are no published studies comparing the efficacy of leukotriene receptor antagonists with the combination of ICS and long-acting ß2-agonists in reducing asthma exacerbations.
Omalizumab, a humanized monoclonal antibody directed against IgE, also significantly reduced asthma exacerbations, by as much as 50%, in patients with moderate asthma, already taking ICS (25). This suggests that a significant proportion of exacerbations are allergen mediated, requiring IgE. Again, no studies have been reported comparing the efficacy of omalizumab with the combination of ICS and long-acting ß2-agonists in reducing asthma exacerbations.
CONCLUSIONS
Severe asthma exacerbations are common in patients with all grades of asthma severity. Most exacerbations develop over several days before being identified and treated. Even low doses of inhaled corticosteroids markedly reduce the risk of developing an asthma exacerbation. If patients are using a low dose of ICS and identify the onset of an exacerbation, a fourfold increase in inhaled corticosteroid dose may reduce the risk of the exacerbation progressing. The combination of ICS and long-acting inhaled ß2-agonists also reduces the risks of exacerbations to a greater extent than high-dose ICS alone. This has been best demonstrated with the combination of budesonide and formoterol. Other treatments including leukotriene receptor antagonists and anti-IgE also reduce the risks of asthma exacerbations. Their benefit, in this regard, has not yet been compared with the combination of ICS and long-acting inhaled ß2-agonists.
(Received in original form June 25, 2003; accepted in final form September 29, 2003)
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ABSTRACT
EFFICACY OF INHALED...
