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Acute asthma intervention: Insights from the STAY study
Asthma diagnosis and treatment Perspectives in asthma Asthma diagnosis and treatment
Acute asthma intervention: Insights from the STAY study Paul M. O’Byrne, MB, FRCP(C) Hamilton, Ontario, Canada
In some patients, asthma control is improved by combining inhaled corticosteroids with long-acting b2-agonists. However, fluctuating asthma control and exacerbations can still occur. The STAY study evaluated whether, in patients with moderate to severe asthma, replacing a short-acting b2-agonist reliever with the combination of budesonide/formoterol as reliever would both provide rapid symptom relief and reduce asthma exacerbations. The study evaluated 2760 patients with asthma (4-80 years) randomized to budesonide 400 mg twice daily (bid) and terbutaline as reliever, budesonide/formoterol 100/6 mg bid and terbutaline as reliever, or budesonide/formoterol 100/6 mg bid both as maintenance and reliever. Children (age 4-11 years) used a once-daily maintenance dose. Budesonide/ formoterol as maintenance and reliever significantly reduced severe exacerbation risk by 45% to 47% compared with the other 2 treatments and improved symptoms, awakenings, and lung function. The benefit was seen in patients of all ages. Subsequent studies have revealed that this beneficial effect of budesonide/formoterol as maintenance and reliever requires both components of the combination. (J Allergy Clin Immunol 2007;119:1332-6.) Key words: Asthma, exacerbations, inhaled corticosteroids, budesonide, long-acting b-agonists, formoterol
The use of combination therapy with low or moderate doses of inhaled corticosteroids (ICSs) with long-acting b2-agonists (LABAs) is now established as the optimal maintenance treatment for patients with moderate to severe asthma whose asthma is not well controlled on ICSs alone.1 This is because of the compelling evidence that ICS/LABA combinations improve asthma control in adults and reduces exacerbations compared with monotherapy with ICSs.2,3 The combinations currently
From the Firestone Institute for Respiratory Health, St Joseph’s Healthcare, Department of Medicine, McMaster University. Disclosure of potential conflict of interest: P. M. O’Byrne has consulting arrangements with AstraZeneca, GlaxoSmithKline, Topigen, and Resistencia and has received grant support from AstraZeneca, Boehringer, Genentech, Medimmune, Merck, and Wyeth. Received for publication February 23, 2007; accepted for publication March 1, 2007. Available online April 25, 2007. Reprint requests: Paul M. O’Byrne, MB, FRCP(C), HSC 3W10, McMaster University, 1200 Main St West, Hamilton, Ontario, Canada, L8N 3Z5. E-mail: [email protected]. 0091-6749/$32.00 Ó 2007 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2007.03.007
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Abbreviations used ICS: Inhaled corticosteroid LABA: Long-acting b2-agonist PEF: Peak expiratory flow SABA: Short-acting b2-agonist
available and used as a single inhaler are budesonide/ formoterol (Symbicort, AstraZeneca, Lund, Sweden) and fluticasone/salmeterol (Advair, GlaxoSmithKline, Middlesex, United Kingdom). The evidence, however, that the combinations are effective in pediatric patients is less compelling.4 The management of asthma has now focused on achieving optimal asthma control whenever possible, and this goal can be achieved in many but not all patients.5 Even in a clinical trial setting where the most benefit is likely to be achieved, 30% to 50% of patients with moderate to severe asthma did not achieve optimal control and still had a notable requirement for reliever therapy or experienced exacerbations.5 Until very recently, the standard of practice for asthma management has been to use inhaled b2-agonists for symptom relief, with either short-acting drugs (such as salbutamol or terbutaline) or long-acting drugs (such as formoterol). Interestingly, the use of formoterol as reliever therapy has been shown to reduce the risk of severe exacerbations compared with terbutaline.6 However, none of the inhaled b2-agonists, which provide rapid bronchodilation and symptom relief, have been convincingly shown to treat the underlying asthmatic inflammatory process.7 An interesting hypothesis has been developed: using a combination inhaler containing both an ICS and a LABA for both regular maintenance therapy and reliever therapy would be advantageous compared with using an inhaled b2-agonist as needed. This implies that the additional anti-inflammatory effect of the ICS achieved, when the combination was used for symptom relief, would provide additional clinical benefit, particularly in reducing the risks of severe asthma exacerbations, which are known to be associated with worsening airway inflammation as well as increasing symptoms. The evaluation of this hypothesis was possible with the combination inhaler containing budesonide/formoterol.
This is because formoterol has an onset of bronchodilator action within the first minute,8 with a similar efficacy and safety to salbutamol, even in patients with acute severe asthma,9 and its pharmacologic characteristics demonstrate a dose-response effect where increasing doses provide additional bronchodilation,8 which is not the case with salmeterol.10
THE STAY STUDY The initial studies that evaluated the benefit of using budesonide/formoterol both as maintenance and reliever therapy compared this approach with maintenance treatment with ICS alone with short-acting inhaled b2-agonists as reliever.11,12 These studies demonstrated a significant reduction of severe asthma exacerbations when the combination was used as maintenance and reliever, but were limited by the fact that the comparator (ICS plus inhaled b2-agonists as reliever) is not accepted as the ideal maintenance treatment for patients with moderate to severe asthma, who were the vast majority of the patients enrolled. This limitation was overcome in the STAY study,13 which was a randomized, double-blind, 1-year study that compared budesonide/formoterol both as maintenance and reliever to fixed dosing of either budesonide/formoterol or a 4-fold higher dose of budesonide alone, both with short-acting inhaled b2-agonists as reliever. The doses of medication chosen were based on the Formoterol and Corticosteroid Establishing Therapy (FACET) study,2 which had demonstrated that although both budesonide and formoterol had complementary effects on reducing severe asthma exacerbations in adults, a 4-fold higher budesonide dose was more effective at reducing severe asthma exacerbations compared with a low-dose budesonide/formoterol combination, despite the combination providing greater improvements in symptoms. Thus, the comparators were budesonide/formoterol 100 mg/6 mg twice daily with this dose used as needed as reliever, budesonide/formoterol 100 mg/6 mg twice daily with the short-acting b2-agonist (SABA), terbutaline 400 mg as reliever, and budesonide 400 mg twice daily with terbutaline 400 mg as reliever. The expectation was (from the results of the FACET study) that the higher-dose budesonide treatment with terbutaline as reliever would be significantly better in reducing the risks of severe exacerbations than the fixed-dose budesonide/formoterol combination with terbutaline as reliever. The question was whether using budesonide/formoterol as reliever instead of terbutaline would provide a benefit in reducing severe exacerbations similar to the higher-dose budesonide. The patients selected for the study were patients with moderate to severe asthma aged between 4 and 80 years. They were identified as patients with moderate to severe asthma by requiring treatment with 400 to 1000 mg/d ICS for adults and 200 to 500 mg/d for children (aged between 4 and 11 years), yet having a history of 1 asthma exacerbation in the last year, and using 12 inhalations (or 8 in children) of reliever medication during the last 10
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days of run-in. The patients also were required to have a baseline FEV1 60% predicted. There were 2760 patients randomized to treatment, of whom 341 were children (who were treated with half the maintenance dose of budesonide once daily). As a result of these selection criteria, the population studied had asthma for a mean of 9 years, with a mean FEV1 of 73% predicted and with 21% reversibility. The medication use before randomization was a mean dose of ICS of 600 mg/d, with 28% of patients also using LABA. Also, the mean reliever use was 1.7 puffs/d, and the average daily symptom score was 1.5 (on a scale from 0 to 6). Thus, these patients remained symptomatic while using moderate doses of medication. The primary outcome variable in the study was severe asthma exacerbations, defined as a deterioration in asthma resulting in hospitalization/emergency department treatment, oral steroid treatment (or an increase in ICS [via a separate inhaler] and/or other additional treatment for children aged 4-11 years), or morning peak expiratory flow (PEF) 70% of baseline on 2 consecutive days. Severe exacerbations confined to those requiring medical intervention were also analyzed separately. Secondary variables included daily pretreatment PEF; daily symptoms, awakenings, reliever medication use, and study drug use were recorded on diary cards. The results from the study demonstrated that budesonide/formoterol given both as maintenance and reliever significantly prolonged the time to the first severe exacerbation compared with both budesonide/formoterol as maintenance and terbutaline as reliever and higher-dose budesonide and terbutaline as reliever (Fig 1). The risk of experiencing a severe asthma exacerbation was 45% lower when budesonide/formoterol was used for maintenance and reliever compared with budesonide/formoterol and terbutaline as reliever, and 47% lower than a 4-fold higher dose of budesonide and terbutaline as reliever. This magnitude of the reduction in severe exacerbations was consistent in children, adolescents, and adults. Approximately half the severe exacerbations in all groups were identified a result of a fall in PEF (Fig 2). Somewhat surprisingly, they were mainly discovered on retrospective analysis of diary card data once the data set was locked and did not result in medical intervention in 87% of cases. When these PEF falls were removed and only severe exacerbations requiring medical intervention were assessed, there was still a 50% reduction in the risk of experiencing a severe asthma exacerbation requiring medical intervention with budesonide/formoterol as maintenance and reliever compared with the other 2 arms. The use of budesonide/formoterol as maintenance and reliever was also shown to prolong the time to repeat exacerbations significantly. A concern that has been raised about this treatment approach is that patients would overuse the budesonide/ formoterol reliever and receive inappropriately high doses of ICS. In fact, the mean number of reliever medication uses was significantly lower for patients using budesonide/formoterol as maintenance and reliever than for either comparator using SABA for relief. However, on occasions
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Asthma diagnosis and treatment FIG 1. All severe asthma exacerbations requiring medical intervention in the STAY study. Each exacerbation is represented by a line, and the length of the line represents the duration of the exacerbation. Patients receiving budesonide (Bud) 800 mg/d with terbutaline as reliever are in the upper panel; patients receiving budesonide/formoterol (Form) 200/6 mg/d with terbutaline as reliever are in the middle panel; and patients receiving budesonide/formoterol 200/6 mg/d with budesonide/formoterol as reliever are in the lower panel. Budesonide/formoterol as maintenance and reliever significantly reduced the number of severe exacerbations compared with the other 2 groups.
on which there were marked increases in reliever use in all 3 study arms, there was benefit for patients receiving the budesonide/formoterol reliever medication. There were 495 episodes with an increase in reliever medication to >4 inhalations/d over the baseline value in the budesonide/ formoterol maintenance and reliever group, with 37 associated with a severe exacerbation; 1347 episodes in the budesnide/formoterol and SABA group, with 120 associated with a severe exacerbation; and 1196 episodes in the budesonide alone and SABA group, with 96 associated with a severe exacerbation. Patients using budesonide/formoterol for maintenance and reliever also had fewer courses of oral steroids (0.19 courses/y for patients aged 12-80 years and 0.05 courses/y for children 4-11 years) compared with patients receiving budesonide/formoterol plus SABA (0.42 and 0.30 courses/y for patients aged 12-80 and 4-11 years, respectively) and budesonide plus SABA (0.38 and 0.25 courses/ y for patients aged 12-80 and 4-11 years, respectively).
THE BENEFITS IN CHILDREN A separate publication has described the benefits of the use of budesonide/formoterol as maintenance and reliever therapy in the children in the STAY study.14 As in the adult population studies, the children had moderate to severe asthma, not controlled on ICS therapy. Their mean FEV1 was 76% predicted, and they used 1.6 puffs of reliever/d with a mean symptom score of 1.2 (range, 0-6) while taking a mean dose of ICS of 320 mg/d. The group randomized to budesonide/formoterol for maintenance and reliever significantly prolonged the time to the first severe exacerbation compared with the other 2
FIG 2. Number of severe exacerbations in the STAY study during 1 year of treatment with budesonide (Bud) 800 mg/d with terbutaline as rescue inhaler, or budesonide/formoterol 200/6 mg/d with terbutaline as rescue inhaler, or budesonide/formoterol 200/6 mg/ d with budesonide/formoterol as rescue inhaler (left panel). Also shown are the number of exacerbations defined by the fall in PEF criterion (>30% from baseline for 2 consecutive days), or by the number of oral corticosteroid courses decided by the managing physician, or by a hospitalization of emergency department (ED) visit. Budesonide/formoterol used both as maintenance and reliever significantly reduced the number of exacerbations in all categories. Data from reference 13.
groups. Overall, 14% of the children had a severe exacerbation in the budesonide/formoterol for maintenance and reliever group compared with 38% in the budesonide/formoterol plus SABA group and 26% in the budesonide plus SABA group. The exacerbations that required medical intervention were reduced from 32 and 52 over the year of study in the groups using SABA for reliever to 11 in the budesonide/formoterol for maintenance and reliever group (Fig 3), and this was reflected by a reduction in days with oral corticosteroid use from 230 days and 141 days when SABA was used as reliever to 32 days. Linear growth was also measured in the children in the STAY study and was significantly greater (1 cm over the year of study) in both groups using budesonide/formoterol (and not different between them) compared with the higher-dose budesonide arm.
IMPLICATIONS OF THE STAY STUDY The STAY study demonstrated that budesonide/ formoterol for maintenance and relief significantly reduced total severe exacerbations, severe exacerbations requiring medication intervention, and exposure to oral steroids, as well as reducing reliever medication use and nighttime symptoms including awakenings and improving lung function compared with either budesonide/formoterol or a 4-fold higher dose of budesonide for maintenance therapy, both with SABA for relief. The benefits were seen in both children and adults with moderate to severe asthma not controlled on moderate doses of ICS (some also on LABA) at randomization. The asthma management approach evaluated in the study has evolved from the evidence that ICS plus LABA
reduces severe asthma exacerbations in patients treated with the addition of LABA to ICS compared with those receiving a 2-fold or 4-fold higher dose of ICS.2,3 The only notable benefit of the 4-fold higher dose of budesonide in the FACET study was to prevent repeated severe exacerbations.2 The STAY study was the first to show that a high maintenance dose of ICS is not necessary to reduce the incidence of first and repeated severe exacerbations requiring medical intervention. The magnitude of the benefit seen was clinically important, because the risk of a severe exacerbation requiring medical intervention was reduced by 45% with budesonide/formoterol for maintenance and reliever compared with patients using a 4-fold higher maintenance dose of budesonide with SABA for relief. In addition, the time to a second or third exacerbation was also significantly prolonged with budesonide/formoterol for maintenance and reliever. This suggests that this treatment approach is effective in patients with more severe asthma who experience repeat exacerbations. The benefits achieved with budesonide/formoterol for maintenance and reliever occurred with a mean daily dose of budesonide of 240 mg/d in adults and 126 mg/d in children, compared with a maintenance dose of budesonide of 640 mg/d in adults and 320 mg/d in children. This suggests that it is the timing of the increase in ICS dose, resulting from as-needed use of budesonide/formoterol to treat symptoms, rather than the total inhaled dose of ICS that improves efficacy. An analysis of all severe exacerbations in the FACET study has shown that there is a period of 5 to 7 days before a severe exacerbation is recognized and needs to be treated with oral corticosteroids, during which patients experience deteriorating symptoms and lung function.15 This suggests that there may be an opportunity to intervene early with an increase in ICS for several days before the exacerbation becomes severe enough to require medical intervention. However, studies that have doubled the maintenance dose of ICS well into the course of an exacerbation have failed to show added benefits.16,17 These interventions have usually been in response to a fixed increase in symptoms and decline in lung function (as dictated by the study protocol), which is likely too late for the increased dose of ICS to have benefit. The increased use of SABA or LABA alone to treatment symptoms as the exacerbation develops does not effectively treat the underlying inflammatory process causing the exacerbation. It is plausible, but not yet proven, that using budesonide/formoterol for maintenance and reliever, as ICSs are always delivered with reliever medication, more effectively treats the worsening inflammation and thereby prevents the exacerbation from developing. The issue of whether both components of the combination of budesonide/formoterol are needed for the benefit to be achieved was recently addressed in a more recently published study (SMILE study).18 This was done because previous studies had shown that patients using formoterol as reliever in addition to regular maintenance therapy with an ICS or an ICS/LABA combination have fewer severe exacerbations than patients using terbutaline6 or salbutamol as needed.19 The SMILE study compared 3 different
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FIG 3. All severe asthma exacerbations requiring medical intervention in the children (age 4-11 years) in the STAY study. Each exacerbation is represented by a line, and the length of the line represents the duration of the exacerbation. Patients receiving budesonide (Bud) 400 mg/d with terbutaline as reliever are in the upper panel; patients receiving budesonide/formoterol (Form) 100/6 mg/d with terbutaline as reliever are in the middle panel; and patients receiving budesonide/formoterol 100/6 mg/d with budesonide/formoterol as reliever are in the lower panel. Budesonide/formoterol as maintenance and reliever significantly reduced the number of severe exacerbations compared with the other 2 groups.
reliever inhalers added to budesonide/formoterol as maintenance in patients with moderate to severe asthma. These were the SABA, terbutaline, the LABA, formoterol, or the combination of budesonide/formoterol. The study confirmed that formoterol was more effective in reducing severe asthma exacerbations than terbutaline, but also demonstrated that budesonide/formoterol as reliever was significantly better than either terbutaline or formoterol.18 This indicated that part of the benefit achieved by using budesonide/formoterol as reliever is achieved by the rescue use of the ICS. Consistent with this observation, the combination of budesonide/formoterol provides greater protection from allergen-induced airway responses than either drug alone.20 Some patients overuse reliever medication; indeed, the immediate perceived benefit of a SABA, and the absence of this immediate benefit with ICS, can mean that patients will revert to using reliever medication only as needed, even though the advantages of maintenance therapy with ICS have been explained by the managing health care professional. In the STAY study, 55% of days were reliever use–free in the budesonide/formoterol maintenance plus reliever group, and the mean number of asneeded doses of budesonide/formoterol was 1 additional dose per day. Even with very effective treatment with combination therapy in moderate to severe asthma, this amount of as-needed reliever use is common.21,22 There were, however, many fewer episodes of high as-needed medication use (defined as at least 8 inhalations above baseline) in the budesonide/formoterol maintenance plus reliever group compared with the fixed dosing groups. The magnitude of benefit with this treatment approach was consistent across all age groups. This was a little
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surprising, because previous studies of combination therapy with ICS/LABA in children have shown little clinically useful benefit.4 The striking reduction in asthma exacerbations in children in the STAY study is likely explained by the fact that the population of children studied had more severe disease than in previous studies of combination therapy. Indeed, even in adult patients with mild asthma, combination therapy with ICS/LABA could not be shown to have clinically important benefits over ICS treatment alone.3 In summary, the STAY study has demonstrated that using budesonide/formoterol for both maintenance and reliever in patients with moderate to severe asthma reduces the risk of severe asthma exacerbations and the need for systemic steroids, and improves asthma symptoms and nocturnal awakenings, compared with a low fixed maintenance dose of ICS/LABA or a 4-fold increase in ICS dose. The effect demonstrated in reducing severe exacerbations is dependent on both the ICS and the LABA in the combination. This new approach to the treatment of moderate to severe asthma is now accepted for clinical use in many jurisdictions, such as Canada, Australia, and the European Community. REFERENCES 1. Global Strategy for Asthma Management and Prevention. NIH Publication No 02-3659. 2006. 2. Pauwels RA, Lofdahl C-G, Postma DS, O’Byrne PM, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-11. 3. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-7. 4. Bisgaard H. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 2003;36:391-8. 5. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med 2004; 170:836-44. 6. Tattersfield A, Lofdahl CG, Postman DS, Ekstrom T, Eivindson A, Schreurs A, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomized trial. Lancet 2001;357:257-61. 7. McIvor RA, Pizzichini E, Turner MO, Hussack P, Hargreave FE, Sears MR. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158:924-30.
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8. Anderson GP. Formoterol: pharmacology, molecular-basis of agonism, and mechanism of long-duration of a highly potent and selective beta(2)-adrenoceptor agonist bronchodilator. Life Sci 1993;52: 2145-60. 9. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther 2006;19:139-47. 10. Woolcock AJ, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481-8. 11. Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004;20:1403-18. 12. Vogelmeier C, D’Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S, et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J 2005;26:819-28. 13. O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu YJ, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171:129-36. 14. Bisgaard H, Le RP, Bjamer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest 2006;130:1733-43. 15. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O’Byrne PM, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999;160:594-9. 16. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271-5. 17. Fitzgerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-6. 18. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-53. 19. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, et al. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003;22:787-94. 20. Duong M, Gauvreau G, Watson R, Obminski G, Strinich T, Evans M, et al. The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge. J Allergy Clin Immunol 2007;119:322-7. 21. Ind PW, Dal NR, Colman NC, Fletcher CP, Browning D, James MH. Addition of salmeterol to fluticasone propionate treatment in moderateto-severe asthma. Respir Med 2003;97:555-62. 22. Zetterstrom O, Buhl R, Mellem H, Perpina M, Hedman J, O’Neill S, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J 2001;18: 262-8.
Acute asthma intervention: Insights from the STAY study Paul M. O’Byrne, MB, FRCP(C) Hamilton, Ontario, Canada
In some patients, asthma control is improved by combining inhaled corticosteroids with long-acting b2-agonists. However, fluctuating asthma control and exacerbations can still occur. The STAY study evaluated whether, in patients with moderate to severe asthma, replacing a short-acting b2-agonist reliever with the combination of budesonide/formoterol as reliever would both provide rapid symptom relief and reduce asthma exacerbations. The study evaluated 2760 patients with asthma (4-80 years) randomized to budesonide 400 mg twice daily (bid) and terbutaline as reliever, budesonide/formoterol 100/6 mg bid and terbutaline as reliever, or budesonide/formoterol 100/6 mg bid both as maintenance and reliever. Children (age 4-11 years) used a once-daily maintenance dose. Budesonide/ formoterol as maintenance and reliever significantly reduced severe exacerbation risk by 45% to 47% compared with the other 2 treatments and improved symptoms, awakenings, and lung function. The benefit was seen in patients of all ages. Subsequent studies have revealed that this beneficial effect of budesonide/formoterol as maintenance and reliever requires both components of the combination. (J Allergy Clin Immunol 2007;119:1332-6.) Key words: Asthma, exacerbations, inhaled corticosteroids, budesonide, long-acting b-agonists, formoterol
The use of combination therapy with low or moderate doses of inhaled corticosteroids (ICSs) with long-acting b2-agonists (LABAs) is now established as the optimal maintenance treatment for patients with moderate to severe asthma whose asthma is not well controlled on ICSs alone.1 This is because of the compelling evidence that ICS/LABA combinations improve asthma control in adults and reduces exacerbations compared with monotherapy with ICSs.2,3 The combinations currently
From the Firestone Institute for Respiratory Health, St Joseph’s Healthcare, Department of Medicine, McMaster University. Disclosure of potential conflict of interest: P. M. O’Byrne has consulting arrangements with AstraZeneca, GlaxoSmithKline, Topigen, and Resistencia and has received grant support from AstraZeneca, Boehringer, Genentech, Medimmune, Merck, and Wyeth. Received for publication February 23, 2007; accepted for publication March 1, 2007. Available online April 25, 2007. Reprint requests: Paul M. O’Byrne, MB, FRCP(C), HSC 3W10, McMaster University, 1200 Main St West, Hamilton, Ontario, Canada, L8N 3Z5. E-mail: [email protected]. 0091-6749/$32.00 Ó 2007 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2007.03.007
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Abbreviations used ICS: Inhaled corticosteroid LABA: Long-acting b2-agonist PEF: Peak expiratory flow SABA: Short-acting b2-agonist
available and used as a single inhaler are budesonide/ formoterol (Symbicort, AstraZeneca, Lund, Sweden) and fluticasone/salmeterol (Advair, GlaxoSmithKline, Middlesex, United Kingdom). The evidence, however, that the combinations are effective in pediatric patients is less compelling.4 The management of asthma has now focused on achieving optimal asthma control whenever possible, and this goal can be achieved in many but not all patients.5 Even in a clinical trial setting where the most benefit is likely to be achieved, 30% to 50% of patients with moderate to severe asthma did not achieve optimal control and still had a notable requirement for reliever therapy or experienced exacerbations.5 Until very recently, the standard of practice for asthma management has been to use inhaled b2-agonists for symptom relief, with either short-acting drugs (such as salbutamol or terbutaline) or long-acting drugs (such as formoterol). Interestingly, the use of formoterol as reliever therapy has been shown to reduce the risk of severe exacerbations compared with terbutaline.6 However, none of the inhaled b2-agonists, which provide rapid bronchodilation and symptom relief, have been convincingly shown to treat the underlying asthmatic inflammatory process.7 An interesting hypothesis has been developed: using a combination inhaler containing both an ICS and a LABA for both regular maintenance therapy and reliever therapy would be advantageous compared with using an inhaled b2-agonist as needed. This implies that the additional anti-inflammatory effect of the ICS achieved, when the combination was used for symptom relief, would provide additional clinical benefit, particularly in reducing the risks of severe asthma exacerbations, which are known to be associated with worsening airway inflammation as well as increasing symptoms. The evaluation of this hypothesis was possible with the combination inhaler containing budesonide/formoterol.
This is because formoterol has an onset of bronchodilator action within the first minute,8 with a similar efficacy and safety to salbutamol, even in patients with acute severe asthma,9 and its pharmacologic characteristics demonstrate a dose-response effect where increasing doses provide additional bronchodilation,8 which is not the case with salmeterol.10
THE STAY STUDY The initial studies that evaluated the benefit of using budesonide/formoterol both as maintenance and reliever therapy compared this approach with maintenance treatment with ICS alone with short-acting inhaled b2-agonists as reliever.11,12 These studies demonstrated a significant reduction of severe asthma exacerbations when the combination was used as maintenance and reliever, but were limited by the fact that the comparator (ICS plus inhaled b2-agonists as reliever) is not accepted as the ideal maintenance treatment for patients with moderate to severe asthma, who were the vast majority of the patients enrolled. This limitation was overcome in the STAY study,13 which was a randomized, double-blind, 1-year study that compared budesonide/formoterol both as maintenance and reliever to fixed dosing of either budesonide/formoterol or a 4-fold higher dose of budesonide alone, both with short-acting inhaled b2-agonists as reliever. The doses of medication chosen were based on the Formoterol and Corticosteroid Establishing Therapy (FACET) study,2 which had demonstrated that although both budesonide and formoterol had complementary effects on reducing severe asthma exacerbations in adults, a 4-fold higher budesonide dose was more effective at reducing severe asthma exacerbations compared with a low-dose budesonide/formoterol combination, despite the combination providing greater improvements in symptoms. Thus, the comparators were budesonide/formoterol 100 mg/6 mg twice daily with this dose used as needed as reliever, budesonide/formoterol 100 mg/6 mg twice daily with the short-acting b2-agonist (SABA), terbutaline 400 mg as reliever, and budesonide 400 mg twice daily with terbutaline 400 mg as reliever. The expectation was (from the results of the FACET study) that the higher-dose budesonide treatment with terbutaline as reliever would be significantly better in reducing the risks of severe exacerbations than the fixed-dose budesonide/formoterol combination with terbutaline as reliever. The question was whether using budesonide/formoterol as reliever instead of terbutaline would provide a benefit in reducing severe exacerbations similar to the higher-dose budesonide. The patients selected for the study were patients with moderate to severe asthma aged between 4 and 80 years. They were identified as patients with moderate to severe asthma by requiring treatment with 400 to 1000 mg/d ICS for adults and 200 to 500 mg/d for children (aged between 4 and 11 years), yet having a history of 1 asthma exacerbation in the last year, and using 12 inhalations (or 8 in children) of reliever medication during the last 10
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days of run-in. The patients also were required to have a baseline FEV1 60% predicted. There were 2760 patients randomized to treatment, of whom 341 were children (who were treated with half the maintenance dose of budesonide once daily). As a result of these selection criteria, the population studied had asthma for a mean of 9 years, with a mean FEV1 of 73% predicted and with 21% reversibility. The medication use before randomization was a mean dose of ICS of 600 mg/d, with 28% of patients also using LABA. Also, the mean reliever use was 1.7 puffs/d, and the average daily symptom score was 1.5 (on a scale from 0 to 6). Thus, these patients remained symptomatic while using moderate doses of medication. The primary outcome variable in the study was severe asthma exacerbations, defined as a deterioration in asthma resulting in hospitalization/emergency department treatment, oral steroid treatment (or an increase in ICS [via a separate inhaler] and/or other additional treatment for children aged 4-11 years), or morning peak expiratory flow (PEF) 70% of baseline on 2 consecutive days. Severe exacerbations confined to those requiring medical intervention were also analyzed separately. Secondary variables included daily pretreatment PEF; daily symptoms, awakenings, reliever medication use, and study drug use were recorded on diary cards. The results from the study demonstrated that budesonide/formoterol given both as maintenance and reliever significantly prolonged the time to the first severe exacerbation compared with both budesonide/formoterol as maintenance and terbutaline as reliever and higher-dose budesonide and terbutaline as reliever (Fig 1). The risk of experiencing a severe asthma exacerbation was 45% lower when budesonide/formoterol was used for maintenance and reliever compared with budesonide/formoterol and terbutaline as reliever, and 47% lower than a 4-fold higher dose of budesonide and terbutaline as reliever. This magnitude of the reduction in severe exacerbations was consistent in children, adolescents, and adults. Approximately half the severe exacerbations in all groups were identified a result of a fall in PEF (Fig 2). Somewhat surprisingly, they were mainly discovered on retrospective analysis of diary card data once the data set was locked and did not result in medical intervention in 87% of cases. When these PEF falls were removed and only severe exacerbations requiring medical intervention were assessed, there was still a 50% reduction in the risk of experiencing a severe asthma exacerbation requiring medical intervention with budesonide/formoterol as maintenance and reliever compared with the other 2 arms. The use of budesonide/formoterol as maintenance and reliever was also shown to prolong the time to repeat exacerbations significantly. A concern that has been raised about this treatment approach is that patients would overuse the budesonide/ formoterol reliever and receive inappropriately high doses of ICS. In fact, the mean number of reliever medication uses was significantly lower for patients using budesonide/formoterol as maintenance and reliever than for either comparator using SABA for relief. However, on occasions
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Asthma diagnosis and treatment FIG 1. All severe asthma exacerbations requiring medical intervention in the STAY study. Each exacerbation is represented by a line, and the length of the line represents the duration of the exacerbation. Patients receiving budesonide (Bud) 800 mg/d with terbutaline as reliever are in the upper panel; patients receiving budesonide/formoterol (Form) 200/6 mg/d with terbutaline as reliever are in the middle panel; and patients receiving budesonide/formoterol 200/6 mg/d with budesonide/formoterol as reliever are in the lower panel. Budesonide/formoterol as maintenance and reliever significantly reduced the number of severe exacerbations compared with the other 2 groups.
on which there were marked increases in reliever use in all 3 study arms, there was benefit for patients receiving the budesonide/formoterol reliever medication. There were 495 episodes with an increase in reliever medication to >4 inhalations/d over the baseline value in the budesonide/ formoterol maintenance and reliever group, with 37 associated with a severe exacerbation; 1347 episodes in the budesnide/formoterol and SABA group, with 120 associated with a severe exacerbation; and 1196 episodes in the budesonide alone and SABA group, with 96 associated with a severe exacerbation. Patients using budesonide/formoterol for maintenance and reliever also had fewer courses of oral steroids (0.19 courses/y for patients aged 12-80 years and 0.05 courses/y for children 4-11 years) compared with patients receiving budesonide/formoterol plus SABA (0.42 and 0.30 courses/y for patients aged 12-80 and 4-11 years, respectively) and budesonide plus SABA (0.38 and 0.25 courses/ y for patients aged 12-80 and 4-11 years, respectively).
THE BENEFITS IN CHILDREN A separate publication has described the benefits of the use of budesonide/formoterol as maintenance and reliever therapy in the children in the STAY study.14 As in the adult population studies, the children had moderate to severe asthma, not controlled on ICS therapy. Their mean FEV1 was 76% predicted, and they used 1.6 puffs of reliever/d with a mean symptom score of 1.2 (range, 0-6) while taking a mean dose of ICS of 320 mg/d. The group randomized to budesonide/formoterol for maintenance and reliever significantly prolonged the time to the first severe exacerbation compared with the other 2
FIG 2. Number of severe exacerbations in the STAY study during 1 year of treatment with budesonide (Bud) 800 mg/d with terbutaline as rescue inhaler, or budesonide/formoterol 200/6 mg/d with terbutaline as rescue inhaler, or budesonide/formoterol 200/6 mg/ d with budesonide/formoterol as rescue inhaler (left panel). Also shown are the number of exacerbations defined by the fall in PEF criterion (>30% from baseline for 2 consecutive days), or by the number of oral corticosteroid courses decided by the managing physician, or by a hospitalization of emergency department (ED) visit. Budesonide/formoterol used both as maintenance and reliever significantly reduced the number of exacerbations in all categories. Data from reference 13.
groups. Overall, 14% of the children had a severe exacerbation in the budesonide/formoterol for maintenance and reliever group compared with 38% in the budesonide/formoterol plus SABA group and 26% in the budesonide plus SABA group. The exacerbations that required medical intervention were reduced from 32 and 52 over the year of study in the groups using SABA for reliever to 11 in the budesonide/formoterol for maintenance and reliever group (Fig 3), and this was reflected by a reduction in days with oral corticosteroid use from 230 days and 141 days when SABA was used as reliever to 32 days. Linear growth was also measured in the children in the STAY study and was significantly greater (1 cm over the year of study) in both groups using budesonide/formoterol (and not different between them) compared with the higher-dose budesonide arm.
IMPLICATIONS OF THE STAY STUDY The STAY study demonstrated that budesonide/ formoterol for maintenance and relief significantly reduced total severe exacerbations, severe exacerbations requiring medication intervention, and exposure to oral steroids, as well as reducing reliever medication use and nighttime symptoms including awakenings and improving lung function compared with either budesonide/formoterol or a 4-fold higher dose of budesonide for maintenance therapy, both with SABA for relief. The benefits were seen in both children and adults with moderate to severe asthma not controlled on moderate doses of ICS (some also on LABA) at randomization. The asthma management approach evaluated in the study has evolved from the evidence that ICS plus LABA
reduces severe asthma exacerbations in patients treated with the addition of LABA to ICS compared with those receiving a 2-fold or 4-fold higher dose of ICS.2,3 The only notable benefit of the 4-fold higher dose of budesonide in the FACET study was to prevent repeated severe exacerbations.2 The STAY study was the first to show that a high maintenance dose of ICS is not necessary to reduce the incidence of first and repeated severe exacerbations requiring medical intervention. The magnitude of the benefit seen was clinically important, because the risk of a severe exacerbation requiring medical intervention was reduced by 45% with budesonide/formoterol for maintenance and reliever compared with patients using a 4-fold higher maintenance dose of budesonide with SABA for relief. In addition, the time to a second or third exacerbation was also significantly prolonged with budesonide/formoterol for maintenance and reliever. This suggests that this treatment approach is effective in patients with more severe asthma who experience repeat exacerbations. The benefits achieved with budesonide/formoterol for maintenance and reliever occurred with a mean daily dose of budesonide of 240 mg/d in adults and 126 mg/d in children, compared with a maintenance dose of budesonide of 640 mg/d in adults and 320 mg/d in children. This suggests that it is the timing of the increase in ICS dose, resulting from as-needed use of budesonide/formoterol to treat symptoms, rather than the total inhaled dose of ICS that improves efficacy. An analysis of all severe exacerbations in the FACET study has shown that there is a period of 5 to 7 days before a severe exacerbation is recognized and needs to be treated with oral corticosteroids, during which patients experience deteriorating symptoms and lung function.15 This suggests that there may be an opportunity to intervene early with an increase in ICS for several days before the exacerbation becomes severe enough to require medical intervention. However, studies that have doubled the maintenance dose of ICS well into the course of an exacerbation have failed to show added benefits.16,17 These interventions have usually been in response to a fixed increase in symptoms and decline in lung function (as dictated by the study protocol), which is likely too late for the increased dose of ICS to have benefit. The increased use of SABA or LABA alone to treatment symptoms as the exacerbation develops does not effectively treat the underlying inflammatory process causing the exacerbation. It is plausible, but not yet proven, that using budesonide/formoterol for maintenance and reliever, as ICSs are always delivered with reliever medication, more effectively treats the worsening inflammation and thereby prevents the exacerbation from developing. The issue of whether both components of the combination of budesonide/formoterol are needed for the benefit to be achieved was recently addressed in a more recently published study (SMILE study).18 This was done because previous studies had shown that patients using formoterol as reliever in addition to regular maintenance therapy with an ICS or an ICS/LABA combination have fewer severe exacerbations than patients using terbutaline6 or salbutamol as needed.19 The SMILE study compared 3 different
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FIG 3. All severe asthma exacerbations requiring medical intervention in the children (age 4-11 years) in the STAY study. Each exacerbation is represented by a line, and the length of the line represents the duration of the exacerbation. Patients receiving budesonide (Bud) 400 mg/d with terbutaline as reliever are in the upper panel; patients receiving budesonide/formoterol (Form) 100/6 mg/d with terbutaline as reliever are in the middle panel; and patients receiving budesonide/formoterol 100/6 mg/d with budesonide/formoterol as reliever are in the lower panel. Budesonide/formoterol as maintenance and reliever significantly reduced the number of severe exacerbations compared with the other 2 groups.
reliever inhalers added to budesonide/formoterol as maintenance in patients with moderate to severe asthma. These were the SABA, terbutaline, the LABA, formoterol, or the combination of budesonide/formoterol. The study confirmed that formoterol was more effective in reducing severe asthma exacerbations than terbutaline, but also demonstrated that budesonide/formoterol as reliever was significantly better than either terbutaline or formoterol.18 This indicated that part of the benefit achieved by using budesonide/formoterol as reliever is achieved by the rescue use of the ICS. Consistent with this observation, the combination of budesonide/formoterol provides greater protection from allergen-induced airway responses than either drug alone.20 Some patients overuse reliever medication; indeed, the immediate perceived benefit of a SABA, and the absence of this immediate benefit with ICS, can mean that patients will revert to using reliever medication only as needed, even though the advantages of maintenance therapy with ICS have been explained by the managing health care professional. In the STAY study, 55% of days were reliever use–free in the budesonide/formoterol maintenance plus reliever group, and the mean number of asneeded doses of budesonide/formoterol was 1 additional dose per day. Even with very effective treatment with combination therapy in moderate to severe asthma, this amount of as-needed reliever use is common.21,22 There were, however, many fewer episodes of high as-needed medication use (defined as at least 8 inhalations above baseline) in the budesonide/formoterol maintenance plus reliever group compared with the fixed dosing groups. The magnitude of benefit with this treatment approach was consistent across all age groups. This was a little
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surprising, because previous studies of combination therapy with ICS/LABA in children have shown little clinically useful benefit.4 The striking reduction in asthma exacerbations in children in the STAY study is likely explained by the fact that the population of children studied had more severe disease than in previous studies of combination therapy. Indeed, even in adult patients with mild asthma, combination therapy with ICS/LABA could not be shown to have clinically important benefits over ICS treatment alone.3 In summary, the STAY study has demonstrated that using budesonide/formoterol for both maintenance and reliever in patients with moderate to severe asthma reduces the risk of severe asthma exacerbations and the need for systemic steroids, and improves asthma symptoms and nocturnal awakenings, compared with a low fixed maintenance dose of ICS/LABA or a 4-fold increase in ICS dose. The effect demonstrated in reducing severe exacerbations is dependent on both the ICS and the LABA in the combination. This new approach to the treatment of moderate to severe asthma is now accepted for clinical use in many jurisdictions, such as Canada, Australia, and the European Community. REFERENCES 1. Global Strategy for Asthma Management and Prevention. NIH Publication No 02-3659. 2006. 2. Pauwels RA, Lofdahl C-G, Postma DS, O’Byrne PM, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-11. 3. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-7. 4. Bisgaard H. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 2003;36:391-8. 5. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med 2004; 170:836-44. 6. Tattersfield A, Lofdahl CG, Postman DS, Ekstrom T, Eivindson A, Schreurs A, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomized trial. Lancet 2001;357:257-61. 7. McIvor RA, Pizzichini E, Turner MO, Hussack P, Hargreave FE, Sears MR. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158:924-30.
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8. Anderson GP. Formoterol: pharmacology, molecular-basis of agonism, and mechanism of long-duration of a highly potent and selective beta(2)-adrenoceptor agonist bronchodilator. Life Sci 1993;52: 2145-60. 9. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther 2006;19:139-47. 10. Woolcock AJ, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481-8. 11. Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004;20:1403-18. 12. Vogelmeier C, D’Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S, et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J 2005;26:819-28. 13. O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu YJ, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171:129-36. 14. Bisgaard H, Le RP, Bjamer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest 2006;130:1733-43. 15. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O’Byrne PM, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999;160:594-9. 16. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271-5. 17. Fitzgerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-6. 18. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-53. 19. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, et al. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003;22:787-94. 20. Duong M, Gauvreau G, Watson R, Obminski G, Strinich T, Evans M, et al. The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge. J Allergy Clin Immunol 2007;119:322-7. 21. Ind PW, Dal NR, Colman NC, Fletcher CP, Browning D, James MH. Addition of salmeterol to fluticasone propionate treatment in moderateto-severe asthma. Respir Med 2003;97:555-62. 22. Zetterstrom O, Buhl R, Mellem H, Perpina M, Hedman J, O’Neill S, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J 2001;18: 262-8.