The Proceedings of the American Thoracic Society 1:161-166 (2004)
© 2004 The American Thoracic Society
Effect of Corticosteroids on Exacerbations of Asthma and Chronic Obstructive Pulmonary Disease
Peter M. A. Calverley
Department of Medicine, University Hospital Aintree, Liverpool, United Kingdom
Correspondence and requests for reprints should be addressed to P. M. A. Calverley, M.D., Department of Medicine, University Hospital Aintree, Clinical Sciences Centre, Longmoor Lane, Liverpool L9 7AL, UK. E-mail: pmacal{at}liverpool.ac.uk
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ABSTRACT
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Periodic exacerbations of disease severity, which may lead to hospitalization, are a characteristic feature of asthma and chronic obstructive pulmonary disease (COPD), becoming more prevalent as disease severity increases. Oral corticosteroids increase the rate of resolution of these episodes in both diseases. Inhaled corticosteroids are much less effective at conventional doses and are not recommended as a primary treatment for exacerbations of either disease. Maintenance therapy with inhaled corticosteroids significantly reduces the chance that a further exacerbation will occur in asthma. In general, increasing doses of inhaled corticosteroids are more effective than placebo therapy in preventing exacerbations, at least until patients become persistently symptomatic and regular users of inhaled corticosteroid therapy. Thereafter, the gains from doubling the dose of inhaled corticosteroid maintenance therapy are modest and generally inferior to those that result from adding other antiinflammatory or bronchodilator agents to the treatment regime. The reduction in the incidence of exacerbations with inhaled corticosteroids, compared with placebo, ranges from 15 to 20% in COPD versus almost 50% in severe asthma. However, given the impact of exacerbations on overall quality of life in COPD, even this modest reduction is likely to be clinically important.
Key Words: inhaled corticosteroids • long-acting ß2-agonists • maintenance therapy
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THE DEFINITION OF EXACERBATION
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The natural history of both bronchial asthma and chronic obstructive pulmonary disease (COPD) is punctuated by periods when the symptoms associated with these conditions increase in intensity for several days or longer, episodes that are generally described as disease exacerbations. In both conditions, there are problems associated with developing a precise definition that can be applied both clinically and in research studies. In both diseases there is some day-to-day fluctuation in the intensity of symptoms, and for an exacerbation to be a significant event, it should exceed that normal day-to-day variability. This is most obvious in patients suffering from bronchial asthma. It is interesting that the clearest evidence of exacerbations in this disorder has been seen in a clinical trial in which treatment was optimized for a period before patients were randomized to therapy (1). By lessening the background variability and symptomatology, it becomes easier to observe periods when there is a sustained loss of control of asthma symptoms.
Careful analysis of such data was possible during the FACET study (Formoterol and Corticosteroids Establishing Therapy), in which peak flow was recorded on daily diary cards for 12 months while patients with bronchial asthma were randomized to a number of different treatment regimens (2). The number of exacerbations differed between regimens, but their characteristics were generally rather similar. They were associated with increased periods of breathlessness, showing some sign of deterioration in the week before the patient sought medical help, with a rapid increase in symptomatology in the 48 hours before treatment began. Patients in this study were treated with oral corticosteroids for their exacerbations, and there was a relatively rapid return to baseline symptomatology as the asthmatic episode resolved. Importantly, in this study, the percentage change in peak flow from baseline was very similar to the percentage change in symptomatology and provided a signal that could be monitored throughout the diary card dataset. As a result, at least in this population of patients with moderately severe and symptomatic asthma, robust definitions of severe and mild episodes characterized by deterioration in asthma control could be derived. The extent of the change in peak flow seen in this study may reflect the baseline severity of the lung disease.
In a group of patients with milder asthma participating in the OPTIMA study (Oxis and Pulmicort Turbuhaler In the Management of Asthma), a rather smaller change in peak flow was required to characterize a severe deterioration in asthma control, although the absolute change in peak flow in each investigation was similar (3). Other authors have opted for simpler end points in large studies of asthma treatment, looking at the time to the first hospitalization or even mortality (an end point that proved robust in the large international START [Steroid Treatment As Regular Therapy] study) (4). However, in most clinical trials that have tried to assess the efficacy of treatment, smaller numbers of patients have participated for shorter periods, and definitions of exacerbation based on peak flow and symptoms remain the most common way of identifying these episodes.
In COPD, changes in peak flow during exacerbations are relatively modest when studied in ambulatory outpatients (5,6), amounting to 4.5% of the baseline value, in contrast to the 30% seen in patients with bronchial asthma. Still, patients tend to be more symptomatic, as judged from their diary card score. These scores increase in a similar fashion to those recorded by patients with asthma (7); however, there is significant individual variation in the pattern of exacerbations. Thus, it has proven more difficult in COPD than in asthma to define episodes of exacerbation in an individual patient that could be subjected to an externally valid definition. Instead, a more operational approach is adopted that relies on counting the number of episodes of sustained worsening of the patient's condition from the stable state (beyond normal day-to-day variation) that are acute at onset and necessitate a change in regular medication (8). Although this "consensus definition" seems a rather indefinite way of defining exacerbations, it has proven remarkably robust from study to study and shows a clear relationship with the severity of the underlying airflow obstruction (9). Exacerbations of COPD appear to be more prolonged in duration than those in individuals with asthma (6), which may perhaps reflect the selection of the more severe and clinically upsetting episodes when the definition proposed here is used.
Although this operational definition is used in most intervention trials, some do report "mild" exacerbations as an increase in rescue therapy use for a specified period. How such episodes relate to the "consensus" definition is not clear, and given the uncertainty about their validity as an isolated event, they will not be considered further here. Conversely, the need for hospitalization is usually considered to indicate a severe exacerbation and is normally reported. However, there is a problem with this approach, as most studies long enough to include a reasonable estimate of exacerbation frequency will select patients thought likely to complete the study period and hence least likely to require emergency hospitalization! As a result hospitalization rates in most reported data are low, and the studies are usually underpowered to show a treatment effect. These episodes are normally captured by the consensus definition and are commonly reported as the combined total of moderate and severe events.
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CORTICOSTEROID THERAPY IN ASTHMA AND COPD
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Although both asthma and COPD are associated with persistent inflammation within the airways, the pathologic characteristics of these disorders differ markedly, as do the responses to corticosteroids (10). It has proven much easier to demonstrate significant changes in airway pathology after treatment with an inhaled corticosteroid (ICS) in airways of patients with asthma (10) than in patients with COPD (11). Despite this, there is empirical evidence in both conditions that high-dose oral corticosteroids (usually equivalent to at least 30 mg prednisone per day) given during an exacerbation can speed the rate of resolution of the episode. This treatment has long been used in the management of acute severe asthma, based on studies that are now several decades old (12). Attempts to replicate this beneficial action with inhaled corticosteroids have been less successful. Initial studies suggested that doubling the dose of the maintenance inhaled corticosteroid was as effective as giving oral corticosteroids, at least in exacerbations occurring in outpatients with asthma (13). More recent carefully conducted randomized controlled trials have found no evidence of a reduction in the subsequent need for oral corticosteroids when this is done (14, 15).
It has taken longer to establish a role for oral corticosteroids in exacerbations of COPD. Careful studies in large populations of patients hospitalized and followed for weeks or months after hospitalization have now given robust evidence to support the view that whether based on clinical outcomes (16) or the rate of improvement of postbronchodilator lung function (17), oral corticosteroids are indicated in exacerbations of COPD. Although no good dose-ranging studies have been conducted, review of the existing information suggests that high-dose therapy is no more effective than moderate- or low-dose therapy. About 10 to 14 days of treatment of an individual exacerbation appears to be satisfactory, although more recent data suggest that oral corticosteroids reduce the subsequent relapse rate for 28 days after an exacerbation (18). Whether a similar effect could be achieved with maintenance ICS therapy is less clear. High-dose nebulized corticosteroids have been shown to increase the rate of improvement in lung function in COPD exacerbations, but they do not appear to be superior to the cheaper and more convenient therapy with oral prednisolone (19). The significant safety issues associated with high-dose oral corticosteroid therapy have been widely recognized (20).
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PREVENTING EXACERBATIONS OF ASTHMA WITH AN ICS
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Regular treatment with an ICS is associated with fewer asthma exacerbations when instituted after the patient concludes oral corticosteroid treatment (21). In large studies of patients maintained on oral corticosteroid therapy, fewer exacerbations have occurred when the oral treatment was withdrawn and high-dose ICS therapy was substituted (22). Initially, studies were conducted over a 3- to 4-month period to establish these effects, but recently a series of 1-year clinical trials of large numbers of patients have allowed us to evaluate the relative importance of ICS in preventing exacerbations of asthma (Table 1). These studies have the virtues of having prespecified definitions of exacerbation and of looking at different treatment intensities in all degrees of disease severity.
The largest such study to date was the START study of more than 7,000 patients with asthma in 32 countries (4). Patients had to have had symptoms for less than 2 years and had to have been symptomatic on a less than daily basis but at least once each week. They were randomized either to as-needed short-acting ß2-agonist treatment or to once-daily budesonide, delivered from a dry powder reservoir in a dose of 400 µg or 200 µg for children younger than 11 years. The principal outcome measure was the number of severe exacerbations, prespecified as those involving hospitalization or death. The patients had relatively mild disease, their post-bronchodilator FEV1 being 96% of the predicted value. Despite this, approximately 6% of the population managed with conventional as-needed rescue treatment was hospitalized during the course of the study, compared with just over 3% of those receiving the once-daily ICS. Similar but less striking differences were seen in the number of courses of glucocorticoids given for presumed exacerbations of disease. After 3 years of treatment 117 patients receiving budesonide had experienced a severe asthma-related event (9 life threatening) compared with 198 events (24 life threatening) in those receiving placebo (p < 0.001 for the total events, p < 0.009 for life-threatening attacks).
Patients with somewhat more severe disease (prebronchodilator FEV1 
80% predicted) were included in the OPTIMA study, separated into those who had never been given an ICS and those who were already using one (3). In the former group, patients continued their present treatment, used 100 µg budesonide twice daily, or used the same dose of budesonide together with 4.5 µg formoterol twice daily. The ICS-experienced patients were assigned to twice-daily doses of 100 µg budesonide, 200 µg budesonide, 100 µg budesonide plus 4.5 µg formoterol, or 200 µg budesonide plus 4.5 µg formoterol. The patients who had not been thought to need an ICS benefited from the addition of budesonide, having fewer exacerbations during the year of the study; randomization of these patients to extra formoterol was not of any advantage. However, adding formoterol was helpful in reducing exacerbations in those who had already received an ICS and was preferable to doubling the dose.
The FACET study did not include a placebo arm, because the patients enrolled already had significant airflow obstruction for a group with asthma (FEV1 75% predicted) (2). However, after a period of treatment intensification with oral corticosteroids and an inhaled long-acting ß2-agonist, it was clear that those who received a low dose of inhaled budesonide did less well than those who received a dose four times greater (200 µg vs. 800 µg daily, respectively). There was a 26% reduction in the number of severe exacerbations in the patients on the higher dose of ICS (0.91 vs. 0.46 episodes per patient per year on low-dose therapy compared to higher dose budesonide). There was a fall from 35.4 to 22.3 mild episodes per patient per year when low- and high-dose regimens were compared. The results in the group that received high-dose budesonide alone were marginally better than those of the patients who received low-dose budesonide plus formoterol, but not as good as those of the patients who received high-dose budesonide plus formoterol.
In a series of large studies, which went on long enough to give a realistic assessment of the number of exacerbations, ICS were effective in preventing exacerbations whenever ICS were used. However, there was a clear interaction between the underlying severity of the disease, as crudely assessed by spirometry in these studies, and the effects of ICS. In patients with more severe disease, doubling the dose of ICS does not seem to be as effective as adding another agent, such as a long-acting ß2-agonist. Moreover, data from complex statistical modeling analyses suggest that the average dose of ICS required is significantly lower than that proposed by the manufacturers and the regulators (23). Whether this form of post hoc analysis translates into clinical improvement is speculative, and it is difficult to see how it takes into account the interaction with underlying disease severity, which is plain from reviewing the larger studies. Nonetheless, the principle of using the smallest effective dose remains one to which we should adhere when using ICS therapy.
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PREVENTING EXACERBATIONS OF COPD WITH ICS
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Compared with the case of asthma, there is much more controversy about the role of ICS in preventing exacerbations of COPD. Because these episodes are less frequent in COPD than in asthma, larger studies that clearly define exacerbations are needed if there is to be adequate statistical power to determine whether a drug effect is really present. Clinical trials using inhaled fluticasone proprionate over 6 months suggested that there was a change in the pattern of exacerbation severity, with patients treated with inhaled fluticasone proprionate reporting more mild and fewer severe episodes (24). High-dose inhaled budesonide appeared to be less effective in a small Canadian study (25). Studies of exacerbation rates have now been published in a number of large clinical trials lasting at least one year that span the range of disease severity (Table 2). Four large studies examining the effects of ICS on the rate of lung function decline have shown consistent negative outcomes irrespective of disease severity (26–29). These studies covered a range of baseline lung function with only the Danish study reporting any kind of surrogate for exacerbation number in patients with milder disease.and no effect of ICS therapy on exacerbations was seen (26). However, the total number of exacerbations was tiny during the 3-year follow-up period, reflecting the mild nature of the disease under investigation. The patients participating in the Lung Health Study of Inhaled Triamcinolone reported fewer new symptoms or unscheduled physician visits when they were randomized to the active treatment arm, but no formal definition of exacerbations was specified at the outset (28).
Participants in the ISOLDE (Inhaled Steroid in Obstructive Lung Disease in Europe) study did have to meet a prespecified definition of exacerbation, similar to the consensus definition given above (29). In this trial a group of symptomatic patients with COPD with a mean post-bronchodilator FEV1 of 50% predicted were followed up for 3 years. As in the FACET study in asthma, withdrawal was mandatory if patients required three courses of oral corticosteroids in a 3-month period. Unlike the FACET study, a substantial number of patients left the ISOLDE investigation because of this fact, amounting to almost half of the total study withdrawals. Moreover, there was a clear differential effect, with more patients withdrawing because of repeated exacerbations in the placebo arm than in the active treatment arm, where they received fluticasone proprionate 500 µg twice daily by inhalation. Overall, the annual exacerbation rate in ICS-treated patients was 0.99 events per year compared with 1.32 events in patients receiving placebo. However, these data disguise the effect of baseline lung function. When the analysis was restricted to only those patients whose FEV1 was above 50% predicted, there were fewer exacerbations and a nonsignificant treatment effect on annual rate of exacerbation. The benefits of therapy were due to improvement in those whose lung function was below 50% of predicted (Figure 1) (9). However, a slightly different result obtained if the outcome was the number of patients having at least one exacerbation per year (Figure 1, right panel) where treatment was effective irrespective of baseline lung function. Which measure is the better guide to clinically important benefit is still unresolved.
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Figure 1. Effect of inhaled corticosteroid (ICS) therapy on exacerbations of chronic obstructive pulmonary disease (COPD). In the ISOLDE trial, among patients with moderate or severe COPD (FEV1 < 50%), inhaled fluticasone proprionate (FP) significantly reduced the number of exacerbations per year and the number of patients who experienced at least one exacerbation. An effect of fluticasone on the number experiencing at least one exacerbation was present irrespective of baseline lung function (right panel), but was not observed if median exacerbation rate was the outcome variable (left panel). (Adapted with permission from Ref. 9.)
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Three further large multicenter studies have now been reported in which exacerbations were evaluated using a similar definition in a large number of patients followed up for 1 year. Rather surprisingly, in all three studies no relation was seen between self-reported smoking status and response to therapy. In the TRISTAN (TRial of Inhaled STeroids ANd long-acting ß2-agonists) investigation, ICS therapy was associated with an approximate 20% reduction in the overall number of exacerbations compared with placebo, although patients in the placebo limb were again more likely to be withdrawn (30). The effect was similar for exacerbations treated with oral corticosteroids, which have conventionally been thought to be more severe episodes.
Two studies of inhaled budesonide for COPD exacerbations in almost identical patient populations have now been reported, both examining patients with a significantly lower prebronchodilator FEV1 than in the TRISTAN study (36 versus 43% predicted, respectively). The first of them, by Szafranski and colleagues, used a design similar to that of the TRISTAN study but included patients with an FEV1 below 50% predicted (31). The exacerbation rate while receiving placebo was 1.8 episodes per year, almost 50% greater than in the placebo limb of the TRISTAN study, where it was 1.3 episodes per year. There was a small reduction in the exacerbation rate among individuals treated with inhaled budesonide, a finding confirmed in a subsequent study by Calverley and colleagues, which adopted a design modeled on the FACET investigation in asthma (32). In the latter study there was an effect of budesonide on the number of courses of oral prednisolone, but in neither of these investigations, in which budesonide was given at a dose of 400 µg twice daily, did ICS treatment produce a statistically significant reduction in the number of exacerbations (Figure 2).
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Figure 2. Effect of inhaled budesonide/formoterol on exacerbations of COPD. In two independent studies, the reduction in the rate of severe exacerbations, compared with placebo, was significantly greater with combination therapy than with formoterol alone. (Left-hand graph adapted from Ref. 31; right-hand graph adapted from Ref. 32.)
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Support for these conclusions comes from the COPE study, where 244 patients with stable COPD (mean FEV1 57.5% predicted) received 500 µg inhaled fluticasone twice daily for 4 months and were then randomized to continue active therapy or receive a placebo inhaler (33). There were significantly more exacerbations in the 6-month follow-up period in those who switched to placebo (26 placebo vs. 6 on corticosteroid), and this was paralleled by better maintained health status in the active treatment limb.
Thus, the picture in COPD is more complex than in asthma, and clearly ICS are much less effective in preventing exacerbations. There is a suggestion, by inference, that the high dose of corticosteroids given in studies involving fluticasone proprionate may have been more effective in preventing exacerbations than the lower dose of inhaled budesonide. However, the added effect of the long-acting ß2-agonist in the two budesonide studies was striking and in keeping with the effects seen in the most severe subgroup of the TRISTAN patients (unpublished results). Thus, the benefits of additional therapy on top of an ICS may be marked in patients with COPD, especially when the disease becomes more advanced (Figure 2). This may be a more attractive treatment approach in these patients than pushing the ICS dose to higher levels with the attendant risks of systemic absorption.
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FUTURE PROGRESS
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The currently available large body of data on both asthma and COPD indicates that there are definite biological effects of ICS, which differ somewhat between the diseases but clearly demonstrate some capacity for reducing the risk of distressing exacerbations. If anything, these studies are likely to underestimate the true effectiveness of treatment. This is particularly true in COPD, for which pharmacoepidemiology studies have suggested that individuals given an ICS are significantly less likely to be rehospitalized with COPD exacerbations, a change that may translate into reduced mortality (34). The dose response for the effect on exacerbations appears to be moderately shallow, with beneficial effects being seen at very low doses in patients with mild asthma but rather higher doses being necessary in severe disease and in patients with COPD. The development of safer corticosteroids may allow these latter groups to be treated more effectively, although current data suggest that adding other treatment modalities can be more effective than pursuing a relentlessly increased dose of corticosteroids. Reduction of the degree of airway wall inflammation appears to be a plausible mechanism for the effects of these drugs in bronchial asthma, although how this prevents an exacerbation itself is not clear. Other mechanisms must also be operative to account for the biological effects in COPD, given the very mild changes observed on direct histology in those treated with ICS (11). Research into this area is likely to shed important light on the mechanisms that determine the onset of exacerbations of these airway diseases.
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ACKNOWLEDGMENTS
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P.M.A.C. received $6,000 in 2002 and $7,000 in 2003 for speaking at conferences organized by GlaxoSmithKline (GSK) and $5,000 in 2002 and $10,000 in 2003 for speaking at conferences organized by AstraZeneca and $8,000 in 2003 for speaking at conferences organized by Boehringer-Ingelheim and he has served on Advisory Boards for GSK receiving $4,000 in 2002 and $1,500 in 2003 and he has also served on an Advisory Board for AstraZeneca in 2003 receiving $1,500 and his department received a research grant for $384,000 during 2001/2002 to support research into the genetic basis of COPD.
(Received in original form February 17, 2004; accepted in final form August 3, 2004)
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ABSTRACT
THE DEFINITION OF EXACERBATION
