Individuals with mild persistent asthma constitute a major portion of patients with the disease, who might be considered the “silent majority” of patients with asthma, because they rarely attend their physician with symptoms of asthma, and even more rarely are seen in a secondary or tertiary health care setting, where most physicians with a focused interest in asthma management are based. It is partly for this reason that, until recently, very little attention has been paid to the morbidity associated with mild persistent asthma and very few studies have evaluated their responses to treatment. Fortunately, this omission has been rectified over the past 4 to 5 years. The studies that have evaluated the treatment responses in this patient population have resulted in some controversy as to the benefits of regular treatment with inhaled corticosteroids, which will be considered in this debate.
Since the late 1980s, asthma treatment consensus guidelines have been developed, which have classified patients with asthma into intermittent (very mild) asthma and mild, moderate, and severe persistent asthma (1, 2). The defining characteristics of mild persistent asthma are that asthma symptoms occur more often than every week, but less than every day. The Global Initiative for Asthma (GINA) guidelines (1) describe mild persistent asthma as having asthma symptoms more than weekly, but less than daily, nocturnal symptoms more than twice monthly, but less than weekly, with normal lung function (FEV1 or PEF > 80%) between asthma episodes (1).
There has been a lot of published evidence that asthma is undertreated. This evidence includes surveys of patients managed in primary care practice (3) and more recent telephone surveys in Europe (4), Asia (5), the United States (5), and Canada (6), all of which demonstrate that most individuals with asthma do not benefit from ideal asthma control, albeit having very effective and safe medications available to treat asthma. The reasons for this are complex, but one likely reason is a lack of appreciation by individuals with asthma (including many with mild persistent asthma), and their managing physicians, that good asthma control can and should be achieved.
Most large studies of treatment approaches in asthma have not included any (or very few) patients with mild persistent asthma. For example, two very large, recently published studies in this journal, the GOAL study (7) and the STAY study (8), included about 10% of the patient population with mild persistent asthma.
There have, however, been several recent studies examining the benefits of ICS in patient populations selected to have mild persistent asthma. The first published was the OPTIMA trial (9). In this study, two groups of patients were selected to evaluate the efficacy of budesonide alone compared with combination therapy with budesonide and formoterol. The first group of patients (Group A) consisted of almost 700 ICS-naive patients, selected to have mild persistent asthma, with a mean prebronchodilator baseline FEV1 of 89% predicted normal, asthma symptoms on approximately 40% of days, and nocturnal symptoms on approximately 10% of nights not using ICS. In this group budesonide alone (200 μg/day) was compared with budesonide and formoterol or placebo for 1 year of treatment. The primary outcome variable in the study was the rate of severe asthma exacerbations, defined by a decline of PEF > 25% from baseline for 2 consecutive days, or a physician's decision to use oral corticosteroids, or an Emergency Room visit requiring systemic corticosteroid administration.
The rate of severe asthma exacerbations was 0.77 severe exacerbations per patient per year in the placebo-treated group. This rate was markedly reduced to 0.26 per patient per year with the low-dose budesonide alone (Figure 1)
Figure 1. (A) Kaplan-Meier survival curve for the time to the first severe asthma exacerbation. (B) proportion (%) of poorly controlled asthma days over 1 year of treatment for patients in Group A of the OPTIMA study. (Adapted with permission from Reference 9.) Bud = budesonide; F = formoterol.
[More] [Minimize]The second large study evaluating ICS in mild persistent asthma is the START trial (10). This study examined the effects of early intervention with ICS (again budesonide) in new-onset persistent asthma. The majority of patients enrolled (> 80%) had mild persistent asthma. The mean prebronchodilator FEV1 at entry was 90% predicted normal in patients with symptoms or β2-agonist use more than weekly, but less than daily. The study enrolled more than 7,000 patients, treated with low-dose budesonide or placebo for 3 years. Almost 34% of the patients in the placebo arm required additional corticosteroid treatment, and 4% had a truly severe asthma exacerbation, which required an emergency room visit or hospitalization, during the first year of that study. This was reduced by budesonide treatment to 20% requiring corticosteroid treatment and 2% needing an emergency room visit (Figure 2)
Figure 2. Kaplan-Meier plot of cumulative probability of having a first severe asthma-related event over 3 years of treatment for patients in the START study, defined as events requiring hospitalization or emergency treatment due to worsening of asthma or death due to asthma. (Adapted with permission from Reference 10.) The numbers below the figures indicate the number of patients at risk at each time point.
[More] [Minimize]The final, and most recently published, study evaluating ICS in patients with mild persistent asthma was reported by Boushey and coworkers (11). This study randomly allocated 225 adult patients to treatment with inhaled budesonide 400 μg/day, or the anti-leukotriene, zafirlukast, or placebo for 1 year. A symptom-based action plan was available to all patients. This patient population appeared to almost identical in baseline characteristics to the other two larger studies, with patients having a mean FEV1 of between 87 and 90% predicted and symptoms on 8 of the 14 days of run-in (albeit with a much longer duration of asthma than in the other studies). The authors concluded that it may be possible for patients with mild persistent asthma to be treated with intermittent courses of inhaled or oral corticosteroids, together with an action plan. This despite the fact that the regular use of inhaled budesonide was significantly better than intermittent use in improving prebronchodilator FEV1, asthma control scores, number of symptom-free days, airway hyperresponsiveness, and markers of airway inflammation (sputum eosinophils and exhaled nitric oxide). The outcomes which were not significantly better were asthma quality of life scores, morning PEF measurements, and postbronchodilator FEV1. Importantly, the percentage of patients with severe asthma exacerbations was not different between the groups. However, the percentage of patients needing a course of prednisone throughout the year was very low (11.1%) and the rate of exacerbations was 0.13/patient/year (in contrast to the OPTIMA study of 0.77/patient/year). Thus, the rate of exacerbations in the intermittent group present study is much lower than previously described in similar populations, making it almost impossible to find a treatment effect for regular budesonide in a study of this size.
All of the studies in patients with mild persistent asthma have used low doses of ICS (maximal doses 400 μg/day). There is a wealth of data demonstrating the safely of these low doses in adults (12). In children, however, the START trial did demonstrate a significant reduction in growth velocity in the children in the study of 1.5 cm over the 3 years of treatment with budesonide 200 μg/day. This is unlikely to have any effect on the final height of these children, as the one study that has followed children treated with inhaled budesonide to final height did not show any detrimental effect, even with an average dose of 500 μg/day (13).
The most widely used primary outcome variables in asthma efficacy trials (improvements in FEV1 or morning PEF), are not the best choice in studies of patients with mild persistent asthma. This is because, by definition, these measurements will be normal or close to normal, most of the time. Even using asthma symptom scores, asthma control questionnaires, or asthma quality of life tools would require large sample sizes to be adequately powered, because of the small magnitude of change likely to be seen, as these patients are asymptomatic much of the time.
It could be argued, therefore, that as these patients are so close to being normal, the benefits demonstrated in the large trials are not worth the effort needed to achieve them, by using low-dose ICS daily (albeit often only once daily). However, to fit into this classification, patients with mild persistent asthma have to have some persistent symptoms most weeks, with nocturnal symptoms occasionally, and rates of severe asthma exacerbations, if untreated, which are higher than most expected (in two of the three studies which have examined this) before these studies were conducted. It is also well established that many individuals with persistent asthma minimize symptoms, or come to accept that they are part of everyday life. There is no doubt that efficacy can be demonstrated in all studies which have evaluated ICS in mild persistent asthma, and also that in some (perhaps even many) patients with mild persistent asthma regular low-dose ICS will provide the magnitude of clinical benefit that will ensure that patients will continue to use the medication. If this benefit is not achieved, it is unlikely that the patient will continue to use ICS on a regular basis, and will revert to using the medication intermittently, as recommended by the study by Boushey and coworkers (11). However, if a therapeutic trial is not attempted, the magnitude of the clinical effectiveness will never be known. Therefore, all patients with mild persistent asthma deserve the opportunity to decide whether the benefit from their use is worth the effort of taking a very safe medication, usually once daily.
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