Q J Med 2003; 96: 435-440
© 2003 Association of Physicians
Airway-stabilizing effect of long-acting ß2-agonists as add-on therapy to inhaled corticosteroids
From the Asthma & Allergy Research Group, 1Department of Public Health & Epidemiology, Ninewells University Hospital & Medical School, University of Dundee, and 2Tayside Centre for General Practice, University of Dundee, Dundee, UK
Received 20 January 2003 and in revised form 26 March 2003
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Summary |
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Background: The protection afforded by long-acting ß2-agonists against bronchoconstrictor stimuli can be regarded as a surrogate for their stabilizing effects on airway smooth muscle.
Aim: To determine the magnitude of residual bronchoprotection after chronic dosing with long-acting ß2-agonists.
Design: Retrospective meta-analysis
Methods: Medline, BIDS and Cochrane Library databases were searched from 1990. A meta-analysis was then performed of 13 eligible randomized placebo-controlled trials (596 patients) in which second-line treatment with a long-acting ß2-agonist (salmeterol or formoterol) was used for 1 week or more. The residual protection against bronchoconstrictor stimuli as doubling dose/dilution shift was the main outcome measure.
Results: Data were assessed according to Quorum criteria. Combining the results of the meta-analysis, the overall estimated protection amounted to a 0.79 (95%CI 0.63–0.96) doubling dose/dilution shift from placebo. Subgroup analysis showed greater protection at peak vs. trough, but no difference between formoterol vs. salmeterol, or between direct vs. indirect challenge. There was no evidence of significant heterogeneity across all the studies, or within any of the subgroups.
Discussion: When used as second-line treatment, the overall additive protective effect of long-acting ß2-agonists amounts to a 0.8 doubling dose/dilution shift. This stabilizing effect on airway smooth muscle may explain their beneficial effects on exacerbations.
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Introduction |
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Long-acting ß2-agonists such as salmeterol and formoterol are recommended for use in conjunction with inhaled corticosteroids to improve symptom control, according to current guidelines.1 They act directly upon bronchial smooth muscle ß2-adrenoreceptors, and suppress the release of inflammatory mediators from primed mast cells in the airway. As a result, the two main beneficial effects are bronchodilatation and protection against bronchoconstrictor stimuli. When used on a regular twice-daily basis, long-acting ß2-agonists improve lung function, reduce reliever requirement, improve symptoms and reduce exacerbations.2–4 Despite these beneficial properties, controversy surrounds the mechanism by which long-acting ß2-agonists reduce exacerbations. Furthermore, it was demonstrated in the recent trials of Lazarus and Lemanske that salmeterol demonstrated no meaningful anti-inflammatory activity in patients who either reduced or discontinued their inhaled corticosteroid.5,6
Long-acting ß2-agonists have two important properties: a bronchodilator effect in the presence of low bronchomotor tone, and a protective effect in the presence of increased bronchomotor tone (so-called ‘functional antagonism’). For instance, beneficial effects upon airway hyper-responsiveness and airway calibre are significantly better with inhaled corticosteroids and LABAs combined, than with the former alone.7 Functional antagonism can be tested by performing bronchial challenge tests, and provides a means of assessing the protective effects of ß2-agonists in the laboratory. Bronchoprotection with long-acting ß2-agonists can be considered to be a surrogate for airway stabilization on smooth muscle. As it is important to determine how much protection will be afforded during an acute episode of bronchoconstriction, we carried out a meta-analysis to evaluate the effects of chronic dosing with long-acting ß2-agonists on residual bronchoprotection in asthmatic patients.
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Methods |
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Study selection and data extraction
A computerized Medline, BIDS and Cochrane Library search was done for the period 1990 to June 2002, to identify randomized placebo-controlled trials comparing residual bronchoprotection with long-acting ß2-agonists (salmeterol or formoterol) vs. placebo following dosing of a week or more. Both authors carried out the search independently by checking for suitable trials as evident from the title and abstract; only those in English were considered. Potentially relevant trials were then retrieved and examined to assess inclusion criteria. All authors read the trials fulfilling eligibility criteria, and the adequacy was discussed and agreed upon. Study suitability was assessed using Quorum criteria.8 The following keywords were used in the search: long acting ß-agonist, salmeterol, formoterol, inhaled corticosteroids, bronchial hyperresponsiveness, hyperreactivity, methacholine, histamine, adenosine monophosphate, tolerance, subsensitivity, tachyphylaxis.
The eligibility criteria were:
- All patients were maintained on inhaled corticosteroids. This was in accordance with current guidelines and to reflect real-life practice. Additionally there is evidence that disease-modifying drugs such as corticosteroids may influence the development of ß2-adrenoceptor subsensitivity induced by long-acting ß2-agonists.9–11
- The bronchoprovocative stimuli methacholine, histamine or adenosine monophosphate (AMP) were used. These challenges are commonly used for everyday diagnostic purposes and, unlike stimuli such as exercise or allergen, can be quantified in the same way, in terms of doubling doses/dilutions. We included stimuli which act both indirectly (AMP) and directly (methacholine and histamine) in the airway to provoke bronchoconstriction.
- The residual last-dose protection compared to placebo, and 95%CIs were included in, or calculable from, the published results.
Statistical analysis
The specified primary outcome was the magnitude of doubling dose/dilution shift of long-acting ß2 agonists compared to placebo. The data for all the trials were logarithmically converted to evaluate the doubling dose or dilution shift for the provocative dose or dilution of the agent that provoked a 20% fall in forced expiratory volume in 1 s (FEV1), i.e. PD20 or PC20 value. Where necessary, the doubling dose/dilution difference was calculated as the log10 difference divided by log10 2 (i.e. 0.3010). The weighted estimate of overall protection with 95%CIs was calculated from the data from each of the trials, with the heterogeneity and 
2 values being calculated from the inverse of the variance. A further analysis was performed according to long-acting ß2-agonist studied, peak or trough measurement and bronchial challenge. It is important to point out, however, that this was an exploratory analysis alone, as we did not want to confound the overall alpha error for the whole sample.
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Results |
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Thirteen12–24 randomized controlled trials fulfilled the eligibility criteria. The Quorum flow diagram illustrates the main reasons for trial exclusion (Figure 1). Studies which involved different drugs and/or doses and/or frequencies of administration were subdivided into, for example, 1A, 1B and 1C. A summary of the demographics of the 13 eligible trials is shown in Table 1. The residual bronchoprotection after chronic dosing compared to placebo in terms of doubling dose/dilution shift in PD20/PC20 for each trial is shown in Figure 2.
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A
2 test of heterogeneity for the 19 results gave a value of 17.21 (p = 0.51). The calculated estimate of overall protection amounted to a 0.79 (95%CI 0.63–0.96) doubling dose/dilution shift. Table 2 illustrates the bronchoprotective effects according to challenge (direct or indirect), time of measurement (peak or trough) and long acting ß2-agonist (salmeterol or formoterol).This showed no evidence of significant heterogeneity within each subgroup. There was greater protection at peak vs. trough as indicated by the 95%CIs, which were not overlapping. There were no differences between formoterol vs. salmeterol or between direct vs. indirect challenge.
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Discussion |
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After chronic dosing with long-acting ß2-agonists, the overall estimated residual protection amounted to a 0.8 doubling dose/dilution. As the lower end of the CI was >0, this indicates an overall statistically significant effect compared to placebo, while the upper end of the CI was approximately one doubling dose/dilution. This beneficial action of long-acting ß2-agonists might therefore explain their additive effects to inhaled corticosteroids in reducing exacerbations. The stabilizing effect on airway smooth muscle (functional antagonism) is likely to be complementary to the anti-inflammatory effects of inhaled corticosteroids.
In the meta-analysis by Shrewsbury et al.2 and in the study by Pauwels et al.,3 the addition of long-acting ß2-agonists to suboptimal doses of inhaled corticosteroids resulted in a reduction in exacerbations. Woolcock et al. showed that adding salmeterol to a suboptimal dose of inhaled corticosteroid improved peak expiratory flow and symptoms, and reduced rescue inhaler use, compared to doubling the corticosteroid dose, whereas bronchial hyper-responsiveness and exacerbations were no different.25 Moreover, long-acting ß2-agonists do not seem to exert meaningful anti-inflammatory activity in vivo.26–28 This is supported by the trial of Lazarus et al.,5 where patients controlled with triamcinolone 800 µg/day were randomly switched to salmeterol or continued with triamcinolone. Patients assigned the former group experienced more exacerbations and demonstrated an increase in sputum and blood inflammatory markers. Moreover, Lemanske demonstrated that in patients not controlled on triamcinolone 800 µg/day, halving the dose of corticosteroid followed by elimination over 4 months, with or without salmeterol as add-on therapy, showed no significant impact on exacerbations.6
Chronic dosing with long-acting ß2-agonists is recognized to be associated with subsensitivity to their bronchoprotective effects.29 It is therefore pertinent to consider the relative protection afforded by a single dose as compared with chronic dosing with long-acting ß2-agonists. For example, in our own study of 67 patients included in the meta-analysis, for formoterol 24 µg twice daily there was a 3.3 and 0.7 doubling dose protection against methacholine for first vs. last dose, respectively.12 This suggests that at least for its bronchoprotective effects, it is preferable to use formoterol on demand, rather than on a regular basis. In patients taking regular twice-daily formoterol or salmeterol, there is also cross-tolerance, as blunting of the protection afforded by salbutamol is observed.16 Moreover, for bronchodilator effects, there is approximately 50% loss in improvement in peak expiratory flow within the first 2 weeks of formoterol treatment in patients taking concomitant budesonide.3 Indeed, formoterol now has a licence in Europe to be used on demand in corticosteroid-treated patients. Our results suggest that the degree of protection was not significantly different between salmeterol and formoterol, as the 95%CIs were overlapping. Furthermore, there was no difference between indirectly and directly acting airway stimuli, although as expected, the magnitude of protection was greater for peak than trough. There was also no evidence of significant heterogeneity across all the studies, or within each of the subgroups.
Long-acting ß2-agonists are indicated to be given in conjunction with inhaled corticosteroids when patients are still symptomatic, which we have shown results in an overall further 0.8 doubling dose/dilution protection. What then is the relative degree of protection compared with the alternative option of increasing the dose of inhaled corticosteroid? In a randomized placebo-controlled trial by Taylor et al.,30 there was a 1.4 doubling dilution improvement in AMP protection comparing 400 µg vs. 1600 µg ciclesonide, while in another study using AMP by Wilson et al.31,32 comparing 400 µg vs. 1600 µg budesonide, there was a 1.9 doubling dilution increase in protection. In the latter study, when a single dose of 400 µg salbutamol was given to patients taking 1600 µg inhaled budesonide, the protection rose by a further 1.4 doubling dilutions. This finding is in keeping with a large placebo-controlled study, where increasing the daily dose of budesonide from 200 µg to 800 µg resulted in significantly fewer severe exacerbations compared to adding regular formoterol to budesonide 200 µg.3
Inhaled corticosteroids and long-acting ß2-agonists have a separate but complementary role in the management of asthma. In a recent study, a disconnection upon airway hyper-responsiveness to methacholine and lung function was observed between inhaled corticosteroids alone and when combined with long-acting ß2-agonists.7 In another study, inhaled corticosteroids demonstrated a rather shallow dose-response curve in terms of effects upon airway hyper-responsiveness.33 In turn, this illustrates that inhaled corticosteroids and long-acting ß2-agonists exert effects upon airway hyper-responsiveness via different but complementary mechanisms. We would also highlight that LABAs are therefore most likely to influence airway hyper-responsiveness by means of functional antagonism,34 rather than any other mechanism.
In conclusion, when given in conjunction with inhaled corticosteroids, treatment with a long-acting ß2-agonist may confer beneficial effects due to its airway stabilizing effects on airway smooth muscle. This is evident by sustained protection given against bronchoconstrictor stimuli after chronic dosing. The airway-stabilizing effect may in turn provide an explanation for the beneficial effects of long acting ß2-agonists upon asthma exacerbations.
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Acknowledgments |
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Funding was provided by a University of Dundee anonymous research grant.
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Footnotes |
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Address correspondence to Professor B.J. Lipworth, Asthma & Allergy Research Group, Ninewells University Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK. e-mail: b.j.lipworth{at}dundee.ac.uk
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References |
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