Differences in the pharmacodynamics of budesonide/formoterol and salmeterol/fluticasone reflect differences in their therapeutic usefulness in asthma

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1 Review Differences in the pharmacodynamics of budesonide/formoterol and salmeterol/fluticasone reflect differences in their therapeutic usefulness in asthma Therapeutic Advances in Respiratory Disease (2008) 2(5) DOI: / ß SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore Bertil Lindmark Abstract: Although the available inhaled corticosteroid (ICS)/long-acting b 2 -agonist (LABA) combinations principally work in a similar fashion, they differ in several important ways, leading to different efficacy. The ICS/LABA combination product budesonide/formoterol can be used as both maintenance and reliever therapy, providing a fixed maintenance dose, which does not change, and replacing short-acting b 2 -agonists as relievers thereby allowing intervention to address the underlying inflammation at the earliest sign of symptomatic worsening. This approach is not suitable for other combination products such as salmeterol/fluticasone. Here we review the pharmacological differences of budesonide/ formoterol and salmeterol/fluticasone that permit the use of budesonide/formoterol as both maintenance and reliever therapy. Keywords: budesonide/formoterol, salmeterol/fluticasone, asthma, maintenance and reliever therapy, pharmacodynamics, clinical efficacy, exacerbations Introduction Asthma is a chronic inflammatory disease of the airways [Global Initiative for Asthma, 2007] that, if untreated or inadequately treated, can dramatically impair quality of life and can be life-threatening. More than 3 million people in the UK alone suffer from asthma and the disease places a significant personal, social and financial burden on individuals, their families and the healthcare systems that support them [Masoli et al. 2004]. The nature of the disease is characterised by periodic symptomatic worsenings and when additional controller treatment is needed these are normally classified as exacerbations. In patients with a history of multiple exacerbations the risk for long-term progressive decline in lung function has been established [Bai et al. 2007] although no association has been seen in patients without exacerbations. This means that patients require long-term support and medication and prevention of exacerbations is essential to reduce future risk for patients. Well-controlled asthma, according to the Global Initiative for Asthma (GINA) clinical guidelines [2007], is defined by no troublesome day- or night-time symptoms, little or no requirement for reliever medication, near normal lung function and no exacerbations. Pharmacotherapy for patients with mild to moderate asthma generally consists of an inhaled corticosteroid (ICS), with or without a longacting b 2 -agonist (LABA), taken daily to prevent symptoms emerging along with a short-acting b 2 -agonist (SABA) such as salbutamol or terbutaline taken as needed to relieve any emergent symptoms. Asthma medications are usually administered via inhalation as this offers the most direct route to their primary site of action, the lungs. Despite the efficacy of available medications, many patients remain confused about when to use which inhaler and there is still an over-reliance on SABAs, an approach that treats symptoms but fails to address the Correspondence to: Bertil Lindmark AstraZeneca R&D, Lund, Sweden. Bertil.E.Lindmark@ astrazeneca.com 279

2 underlying cause of the worsening symptoms airway inflammation. As b-agonists do not have any substantial anti-inflammatory properties they can, in the worst case, mask asthma deterioration, placing patients at increased risk of a severe, potentially life-threatening exacerbation. Moreover, many asthma patients remain inadequately controlled according to clinical guideline targets and continue to suffer a reduced quality of life as a result of their disease [Adachi et al. 2008; Desfougeres et al. 2007; Partridge et al. 2006; Rabe et al. 2004, 2000]. Suboptimal asthma control can present many challenges in the demanding primary care setting where levels of poor control can often remain hidden from the healthcare provider [Chapman et al. 2008; Levy, 2008]. A survey of primary care physicians and their asthma patients in Canada revealed that 59% of the 10,428 patients who took part met the criteria for uncontrolled asthma according to current clinical guidelines [Chapman et al. 2008]. Other surveys have demonstrated similarly high levels of uncontrolled asthma in real-world evaluations [van den Nieuwenhof et al. 2008; Cazzoletti et al. 2007]. Given the prevalence and morbidity of asthma, the clinical challenge is to find effective ways to help patients with suboptimal asthma control. These may include the development and implementation of individualised asthma plans and asthma clinics. However, such approaches require a significant time investment that is not always achievable, particularly in the primary care setting. Indeed, while primary care physicians are generally aware of the recommendations for the management of asthma patients, implementation is often poor [Levy, 2008]. It is important to emphasise that approaches that rely on a significant deterioration in asthma symptoms and action plans have been shown to be ineffective at preventing exacerbations [Fitzgerald et al. 2004; Harrison et al. 2004]. Alternative medication strategies also offer an effective method to control asthma symptoms, reduce the risk and/or severity of exacerbations and can complement other approaches to asthma management. Combination inhalers, containing both an ICS and a LABA, offer one such alternative medication strategy and are included in the current GINA clinical guidelines for the management of asthma [GINA, 2007]. For adults whose asthma is not controlled on low/moderate dose ICS alone, the GINA guidelines [2007] recommend an ICS in combination with a LABA, at a dose related to the severity of asthma. Combination inhalers are preferred to two separate inhalers as they probably improve compliance with the ICS component [NICE Technology Appraisal Guidance 138, 2008]. The two most commonly used fixed-dose combinations are budesonide/ formoterol (Symbicort Õ, AstraZeneca, Lund, Sweden) and salmeterol/fluticasone (Seretide TM, GlaxoSmithKline, Uxbridge, UK), although more recently another fixed-dose combination product of beclomethasone/formoterol (Foster TM, Chiesi Farmaceutica, Parma, Italy) has become available in some European countries as fixed-dose maintenance therapy only [Papi et al. 2007]. However, for the purposes of this review the focus will be on the two most commonly used combinations of budesonide/formoterol and salmeterol/fluticasone. Despite both combination inhalers containing an ICS and a LABA, there are important pharmacological and pharmacodynamic differences between the respective components in each combination, and these differences impact on the way the products can be used clinically. Specifically, the pharmacodynamic profile of budesonide/formoterol but not that of salmeterol/fluticasone offers the possibility to use budesonide/formoterol both as a daily maintenance treatment and as a reliever therapy as needed the Symbicort Õ maintenance and reliever therapy (Symbicort SMART Õ ) approach. While there are clear difference between the two ICS components, budesonide and fluticasone, and between the two LABA components, formoterol and salmeterol, some investigators believe that it is the difference in the LABA components that allows budesonide/formoterol to be used as both a maintenance and reliever therapy [Barnes, 2007; Cazzola and Curradi, 2007]. This approach provides patients with an adequate maintenance dose and in addition an increased dose of the anti-inflammatory component of their medication (the budesonide component of the combination) when they have symptoms and addresses the underlying cause of the symptomatic worsening while avoiding confusion on which inhaler to use. It should be noted that 80/4.5 mg and 160/ 4.5 mg strength pmdis are approved for use in some markets (Symbicort Õ in the US, Australia and South Africa; and Vannair Õ in Venezuela, New Zealand and Switzerland) as fixed-dose therapy for asthma and not as maintenance and 280

3 Review reliever therapy (Symbicort SMART Õ ), which is approved using the Turbuhaler Õ. At this time, these pmdi strengths/devices have not been studied for maintenance and reliever therapy and require two actuations per delivered dose. In addition, dosing with two actuations results in a higher dose of formoterol per dose than is currently received with Symbicort SMART Õ. For these reasons, the currently available pmdi devices at these strengths are not appropriate for use as single maintenance and reliever therapy. % increase in FEV * Budesonide/formoterol 160/4.5 µg 1 inhalation Salmeterol/fluticasone 50/250 µg 1 inhalation Placebo 1 inhalation * *p<0.001 vs salmeterol/fluticasone Symbicort Õ maintenance and reliever therapy has now been extensively studied both in comparison with ICS monotherapy (two- to four-fold higher maintenance) and higher fixed-dose combination therapy. This review will examine the pharmacological and pharmacodynamic properties of the components of the budesonide/formoterol and salmeterol/fluticasone combinations and evaluate the available clinical data as a basis for informing clinical decision-making. Pharmacological and pharmacodynamics of combination therapies for asthma management LABA component Formoterol is a b 2 -agonist of similar or higher intrinsic efficacy than salbutamol and terbutaline. Formoterol added to ICS has proven effective in improving asthma control as maintenance therapy in all types of asthma patients [O Byrne et al. 2005; Pauwels et al. 1997] and also as a reliever medication, significantly reducing the exacerbation rate and improving symptoms [Cheung et al. 2006; Rabe et al. 2006b; Pauwels et al. 2003; Tattersfield et al. 2001]. Formoterol is a potent airway smooth muscle relaxant and shows high affinity and selectivity for b 2 -adrenoceptors [Anderson, 1993]. Like short-acting b-agonists (SABAs), formoterol exhibits a dose response curve with increasing doses providing greater bronchoprotective and bronchodilator effects [Cheung et al. 2006; van der Woude et al. 2004; Boonsawat et al. 2003; Seberova and Andersson, 2000; Anderson, 1993; Faulds et al. 1991]. Moreover, formoterol delivers this increased efficacy as rapidly as salbutamol and terbutaline [Anderson, 1993; Faulds et al. 1991], with a duration of action in excess of 12 hours [Lötvall et al. 2006]. Finally, adequate water solubility and moderate lipophilicity of formoterol ensures rapid diffusion to b 2 -adrenoceptors on the Time (minutes) Figure 1. Onset of bronchodilator action (percentage increase in FEV 1 from baseline) of single doses of salmeterol/fluticasone and budesonide/formoterol at 3 and 15 minutes in patients with stable asthma [Palmqvist et al. 2001]. airway smooth muscle cells and a rapid bronchodilator effect [Lötvall, 2001]. Like formoterol, salmeterol is a b 2 -agonist that achieves bronchodilation via relaxation of the airway smooth muscle. However, salmeterol has lower intrinsic efficacy and slower onset of effect than all other b-agonists that have been developed for clinical use [Anderson, 2000]. The onset of action (measured as increase in FEV 1 ) of salmeterol/fluticasone and budesonide/ formoterol are shown in Fig. 1 [Palmqvist et al. 2001]. Salmeterol may diffuse more slowly to the b 2 -adrenoceptors because of its high lipophilicity, and this may explain the slower onset of action [Lötvall, 2001]. Salmeterol is administered at its maximally effective dose in clinical practice as there is no evidence of a dose response relationship above 50 mg twice daily [Pohunek et al. 2004; Palmqvist et al. 2001, 1999]; indeed, double-dose formoterol has greater additional bronchoprotective effects, which may be important in preventing exacerbations, than doubledose salmeterol [van der Woude et al. 2004; Currie et al. 2003]. Because of the slow onset of action and the lack of dose response, salmeterol is not considered to be suitable for use as a reliever medication. The systemic activity of these two agents also distinguishes between them, again supporting the use of formoterol but not salmeterol as a reliever medication. The systemic activity of formoterol is short-lived, comparable with 281

4 that reported for salbutamol or terbutaline [Seberova and Andersson, 2000]. Consequently, the risk of a longer duration of systemic side effects with formoterol compared with salbutamol or terbutaline is minimal. In contrast, the systemic effect of salmeterol is long-lasting and repeated dosing increases the risk for persistence of b-agonist related adverse systemic side-effects [Guhan et al. 2000; Bennett and Tattersfield, 1997]. Corticosteroid component The corticosteroid components of the formoterol/ budesonide and salmeterol/fluticasone combination products also have distinct pharmacological and pharmacodynamic profiles that are of relevance in terms of their clinical use. Inhaled budesonide has been available for the management of asthma since the early 1980s. Budesonide exerts a pronounced and long-lasting anti-inflammatory effect on airway tissues when given via inhalation [Laitinen et al. 1992] achieving significant and sustained improvements in both symptoms and lung function [Juniper et al. 1990]. Budesonide has a relatively high water solubility and is readily dissolved in mucosal fluids; as a consequence, budesonide is rapidly absorbed into airway tissues. Importantly, the absorption of budesonide into airways tissue does not appear to be affected by lung function, with comparable plasma concentrations achieved following pulmonary delivery in healthy and asthmatic individuals [Harrison and Tattersfield, 2003]. Once absorbed intracellularly, budesonide undergoes reversible conjugation with intracellular fatty acids, which prolongs its retention within the airways its principle site of therapeutic action and its duration of action [Miller-Larsson et al. 1998; Wieslander et al. 1998]. A dose response relationship has been demonstrated for budesonide [Miyamoto et al. 2000; Busse et al. 1998] and an increase in the dose and frequency of budesonide administration has been shown to be beneficial in quickly reducing inflammation and bronchoconstriction in patients with unstable asthma [Toogood et al. 1982]. Moreover, increasing the dose and frequency of dosing of budesonide at the first sign of worsening asthma has been shown to effectively manage an exacerbation as well as a regular four-fold higher maintenance dose of budesonide [Foresi et al. 2000]. Like budesonide, fluticasone also has an antiinflammatory effect on airway tissues when given via inhalation and has an approximately 2:1 potency vs budesonide in vitro [GINA, 2007]. However, in contrast to budesonide, fluticasone does not undergo the intracellular esterification process and consequently is not as well retained within the airway tissue [Tunek et al. 1997]. Unlike budesonide, the absorption of fluticasone is affected by lung function with markedly lower plasma concentrations achieved in asthmatic individuals compared with non-asthmatics [Harrison and Tattersfield, 2003]. Moreover, fluticasone is highly lipophilic and while this results in a long plasma elimination half-life it is also suggestive of greater systemic accumulation of the steroid upon repeat dosing [Thorsson et al. 2001]. Importantly, highly lipophilic drugs such as fluticasone are more likely to be retained in the lumen of the airways for longer than less lipophilic drugs and as a result can be more affected by airway (mucociliary) clearance and coughing, suggesting that a reduced dosage remains in the lungs [Edsbäcker et al. 2008]. The pharmacodynamic differences described above between formoterol/salmeterol and budesonide/fluticasone impact on the clinical use of the two products, with the pharmacological and pharmacodynamic properties of budesonide/formoterol allowing for the use of the combination as both maintenance and reliever therapy. Clinical effectiveness Clinical effectiveness of combination therapy For both the budesonide/formoterol and salmeterol/fluticasone combinations, the addition of a LABA to the ICS component for patients not adequately controlled on ICS alone has been shown to produce greater improvements in pulmonary function and symptomatology and reduction in the exacerbation rate than higher doses of ICS alone [Barnes, 2007; Heyneman et al. 2002; O Byrne et al. 2001; Shrewsbury et al. 2000; Pauwels et al. 1997; Woolcock et al. 1996; Greening et al. 1994]. O Byrne and colleagues [2001] reported the results of a one-year trial in which patients with mild persistent asthma were stratified according to whether they were currently receiving an ICS or not. Among 698 patients who were initially corticosteroid-free, treatment with budesonide plus formoterol resulted in comparable reductions in the risk of severe exacerbations and symptom-free days as budesonide alone 282

5 Review (60% and 48%, respectively) but an improvement in lung function. For patients already receiving an ICS (n ¼ 1272), addition of formoterol proved more effective than doubling the ICS dose alone, reducing the risk for severe exacerbations by 43% and reducing the number of poorly controlled days by 30%. In a separate study, the addition of formoterol to ongoing budesonide therapy reduced the rates of severe and mild asthma exacerbations by 63% and 62%, respectively, compared with a reduction of 49% and 37% for the same dose of budesonide alone [Pauwels et al. 1997]. Similar beneficial effects have been reported when salmeterol was added to ICS therapy. The addition of salmeterol to beclomethasone achieved greater improvements in lung function than increasing the dose of beclomethasone alone among patients poorly controlled with ICS alone [Greening et al. 1994]. Consistent with this, Woolcock and coworkers [1996] found that the addition of salmeterol to beclomethasone among patients not controlled with beclomethasone alone achieved greater improvements in lung function and significantly greater symptom control compared with doubling the beclomethasone dose alone. In this study, doubling the dose of salmeterol from 50 to 100 mg twice daily in combination with beclomethasone had no added benefit on efficacy but increased the reporting of b-agonist-related adverse events [Woolcock et al. 1996]. The beneficial effect of adding salmeterol to fluticasone has also been compared with an increased dose of fluticasone alone in patients with moderate to severe asthma, with marked improvements in lung function and symptom control [Heyneman et al. 2002]. However, in a non-specialist practice setting the addition of salmeterol to ongoing antiinflammatory therapy (beclomethasone) was no more effective that placebo in preventing exacerbations, although it did significantly improve peak expiratory flow and reduce salbutamol use [D Urzo et al. 2001]. Having established the efficacy of the fixed-dose budesonide/formoterol and salmeterol/ fluticasone combination therapies in the treatment of uncontrolled asthma, several studies have performed direct comparisons between the two as part of their design. The 6-month COMPASS study recruited adults and adolescents who were symptomatic on their existing ICS dose alone during a two-week run-in and randomised 1105 patients to fixed-dose budesonide/formoterol (640 mg/day; BDP equivalent 1000 mg/day) and 1123 patients to fixed-dose salmeterol/fluticasone (500 mg/day; BDP equivalent 1000 mg/day). The effects of both fixed-dose regimens were similar for all of the efficacy parameters except for a statistically significant increase in asthma-related hospital admissions/ emergency room treatments with salmeterol/ fluticasone [Kuna et al. 2007]. The much smaller comparator study by Aalbers et al. [2004] also found similar efficacy and levels of wellcontrolled asthma (primary endpoint) with the same fixed-doses of budesonide/formoterol and salmeterol/fluticasone combination therapies. In a third study, a large 24-week double-blind study (EXCEL) comparing the same fixed-dose of budesonide/formoterol (400/12 mg twice daily [metered dose]; BDP equivalent 1000 mg/day) and fixed-dose salmeterol/fluticasone (50/250 mg twice daily; BDP equivalent 1000 mg/day) in adults with asthma, Dahl and colleagues reported that both regimens produced equal improvements in well-controlled asthma and lung function, and similar reductions in the overall asthma exacerbation rate, which was the primary variable [Dahl et al. 2006]. The published study attempted to suggest that fixed-dose salmeterol/fluticasone was superior to budesonide/formoterol in reducing the rate of moderate/severe exacerbations using post hoc analyses on the last 8 weeks of the study but the weaknesses in this post hoc analysis and failure to fully report the most severe exacerbations by treatment group, which were reduced in the budesonide/formoterol group, have been highlighted in the literature [Naya and Andersson, 2007]. In a meta-analysis of the effectiveness of fixeddose maintenance therapy including all of the above studies with either budesonide/formoterol or salmeterol/fluticasone [Edwards et al. 2007] there were no differences between the fixeddose ICS/LABA combinations apart from one, namely the increased risk of severe exacerbations resulting in emergency treatment, which were consistently higher in all three studies in patients receiving salmeterol/fluticasone with an overall 49% increase that was statistically significant [Edwards et al. 2007]. Meta-analyses focusing on hospital admissions due to exacerbations The reported reduction in the risk of asthma-related hospitalisations/er visits with 283

6 budesonide/formoterol versus salmeterol/fluticasone is supported by other independent meta-analyses of fixed-dose combinations versus ICS alone that have excluded studies with the potential for LABA monotherapy. Jaeschke and coworkers [2007] analysed data from 18 clinical studies including formoterol with ICS in patients with asthma and found that the addition of formoterol resulted in a 41% reduction in asthma-related hospitalisation admissions versus a similar or higher dose of ICS alone [Jaeschke et al. 2007], whereas a separate meta-analysis of 52 studies in which salmeterol was added to ICS therapy found no change in the risk of hospitalisation admissions [Nelson et al. 2007]. The greater reduction in the risk of asthmarelated hospitalisation/emergency room visits seen with fixed-dose budesonide/formoterol compared with fixed-dose salmeterol/fluticasone is most likely due to the different pharmacology of the LABAs as discussed above; that is, the greater intrinsic activity and bronchoprotective effect of formoterol compared with salmeterol during periods with severe exacerbations ensures that this LABA provides greater protection from severe exacerbations. Responding to changing symptoms Asthma exacerbations have considerable impact on patients quality of life together with healthcare resource use and costs. Thus, responding promptly to worsening symptoms with the aim of preventing or ameliorating an exacerbation is a key clinical aim of asthma management. Although it is not possible to predict with any accuracy when an exacerbation might occur or how severe such an event might be, reliever use with SABA increases, on average, 5 7 days prior to an exacerbation [Tattersfield et al. 1999]. This presents a window of opportunity to intervene early with a higher efficacy b-agonist for increased bronchoprotection and additional ICS anti-inflammatory therapy at the time of increasing symptoms with the aim of preventing the development of a full exacerbation (Fig. 2). As mentioned previously, SABAs do not have significant anti-inflammatory properties and can, in the worst case scenario, mask underlying asthma deterioration by achieving acute but temporary symptomatic relief but failing to address the underlying inflammatory process. Studies have shown that as a result of the pharmacological and pharmacodynamic properties of the components, the budesonide/formoterol combination is suitable for as needed treatment of worsening symptoms in addition to its proven use as a maintenance medication. Formoterol, when used as needed, is the only b-agonist shown to reduce asthma exacerbations [Pauwels et al. 2003; Rabe et al. 2006b; Tattersfield et al. 2001]. This benefit is also seen irrespective of background maintenance therapy. Moreover, budesonide is also the only ICS that when used as needed has been shown to reduce asthma exacerbations [Rabe et al. 2006b]. Maintenance and as-needed reliever therapy Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Õ ) is a new concept % Change from day Window of opportunity to increase anti-inflammatory? Night-time symptoms SABA rescue use Hypothetical outcome Days before and after an exacerbation Figure 2. Asthma exacerbations: a descriptive study of 425 severe exacerbations showing change in SABA reliever use and night-time symptoms in the 14 days prior to and after an exacerbation, adapted from Tattersfield et al. [1999], and a hypothetical window of opportunity to ameliorate or abort these events through early intervention with as needed budesonide/formoterol

7 Review focusing on maintenance and as-needed therapy using the same controller/anti-inflammatory inhaler. This new treatment approach is endorsed in the GINA guidelines [2007]. The therapy approach increases controller therapy on demand when control deteriorates; when stability is regained (symptoms abate) patients default to fixed-dose maintenance therapy that is usually at a lower dose than is possible with a standard fixed-dose ICS/LABA regimen. Thus, the greatest benefits are seen when control is lost but during periods of stable control patients default to a lower maintenance dose without any increase in as-needed doses. This is feasible with budesonide/formoterol but not salmeterol/fluticasone because of the pharmacodynamic properties of formoterol and budesonide, as discussed earlier. In the budesonide/formoterol clinical trial programme, studies were conducted to address how budesonide/formoterol maintenance and reliever therapy compared with: higher-dose ICS [Rabe et al. 2006a; O Byrne et al. 2005; Scicchitano et al. 2004]; alternative reliever therapy and the same maintenance dose of ICS/ LABA [Rabe et al. 2006b; O Byrne et al. 2005]; and higher doses of maintenance ICS/LABA therapy [Bousquet et al. 2007; Kuna et al. 2007; Vogelmeier et al. 2005]. The studies were performed in patients with uncontrolled asthma assessed on maintenance ICS alone in the majority of studies; the main differences between them lay in the types of treatment patients were on when their asthma control was assessed (see Table 1). These studies included over 15,000 asthma patients aged 12 years and have confirmed the efficacy and safety of the budesonide/formoterol maintenance and reliever therapy approach compared with two- four-fold higher doses of ICS plus a SABA as reliever therapy as well as with similar or higher doses of ICS/LABA combinations (Tables 2 and 3). In all of these studies a severe exacerbation was defined as hospitalisation/emergency department (ED) treatment due to asthma worsening, the need for oral steroid therapy for 3 days because of asthma (as judged by investigator), while for the STAY, STEAM and STEP studies [Rabe et al. 2006a; O Byrne et al. 2005; Scicchitano et al. 2004]; the definition of a severe exacerbation was as above but also included a decrease in peak expiratory flow (PEF). Budesonide/formoterol maintenance and reliever therapy vs higher-dose ICS The efficacy of the budesonide/formoterol maintenance and reliever approach has been compared with higher doses of ICS alone in three double-blind studies: STEAM [Rabe et al. 2006a], STEP [Scicchitano et al. 2004], and STAY [O Byrne et al. 2005]. The STAY study [O Byrne et al. 2005] was a 12-month, double-blind, randomised, parallelgroup study in patients aged 4 80 years with asthma treated with mg/day of ICS (adults; mg/day children). The study was primarily conducted to examine the efficacy of adding budesonide/formoterol as reliever therapy for patients already receiving budesonide/formoterol as maintenance therapy with SABA as reliever medication. In total, 2760 patients were randomised to either budesonide/ formoterol maintenance and reliever regimen, budesonide/formoterol maintenance therapy (80/4.5 mg twice daily; 250 mg/day BDP equivalent) plus terbutaline (0.4 mg) as needed, or higher-dose budesonide (320 mg twice daily; 1000 mg/day BDP equivalent) plus terbutaline (0.4 mg) as needed. Children received half the maintenance dose given at night. Budesonide/formoterol maintenance and reliever therapy significantly prolonged the time to first severe exacerbation (defined as hospitalisation/ed treatment due to asthma worsening, the need for oral steroid therapy for 3 days or a PEF less than 70% of baseline on two consecutive days) compared with budesonide/formoterol maintenance therapy plus SABA and higherdose budesonide plus SABA (p for both), resulting in a 45 47% lower exacerbation risk vs the other two treatment groups. Budesonide/formoterol maintenance and reliever therapy also prolonged the time to the first, second and third exacerbation requiring medical intervention (p50.001) compared with the alternative regimens. Patients treated with the therapy regimen experienced significantly fewer severe exacerbations overall and fewer severe exacerbations that required hospital or emergency room treatment. Similarly, lung function and asthma symptoms were significantly improved among patients receiving the budesonide/formoterol maintenance and reliever regimen compared with those treated with the higher-dose budesonide plus terbutaline regimen (Tables 2 and 3) [O Byrne et al. 2005]

8 Table 1. Budesonide/formoterol maintenance and reliever therapy clinical study program: treatment step when asthma control was assessed as insufficient prior to randomisation Individual double-blind SMART studies COSMOS Open-label study n ¼ 2143 GINA STEAM STEP STAY SMILE COMPASS AHEAD n ¼ 2309 [Vogelmeier Treatment n ¼ 697 n ¼ 1890 n ¼ 2760 n ¼ 3394 [Rabe n ¼ 3335 [Bousquet et al. 2005] step [Rabe [Scicchitano [O Byrne et al. 2006b] [Kuna et al. et al. 2007] et al. 2006a] et al. 2004] et al. 2005] 2007] Step II (% patients) Step III (% patients) Step IV (% patients) # Test treatments SMART regimen Comparator regimen 2 80/4.5 mg once daily plus as needed Bud 400 mg once daily plus SABA as needed 2 160/ 4.5 mg once daily plus as needed Bud 400 mg bid plus SABA as needed 80/4.5 mg bid plus as needed* Bud 400 mg bid plus SABA as needed and bud/ form 80/ 4.5 mg bid plus SABA as needed 160/4.5 mg bid plus as needed Bud/form 160/ 4.5 mg bid plus SABA as needed and bud/form 160/4.5 mg bid plus formoterol as needed 160/4.5 mg bid plus as needed Bud/form 320/9 mg bid plus SABA as needed and SFC 250/50 mg bid plus SABA as needed 2 160/4.5 mg bid plus as needed SFC 50/500 mg bid plus SABA as needed 1or2 160/ 4.5 mg bid plus as needed SFC 250/50 mg bid plus SABA as needed although SFC titration allowed the dose to increase to 500/50 mg bid or decrease to 100/50 mg bid Step II ¼ low to moderate dose ICS alone (1000 mg/day BDP equivalent). Step III ¼ high-dose ICS (41000mg/day BDP equivalent) or low to moderate dose ICS (1000 mg/day BDP equivalent) þ LABA. Step IV ¼ high-dose ICS þ LABA (41000 mg/day BDP equivalent). *All patients on high-dose ICS (4800 mg budesonide equivalent) without LABA. #All patients on low-dose ICS/LABA at 50% of the recommended upper limit for step III (400 mg budesonide equivalent per day). This study was to assess if add-on efficacy could be detected with both as needed budesonide and as needed formoterol in patients on low dose combination therapy. Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone

9 Review Table 2. Budesonide/formoterol maintenance and reliever therapy clinical study program: exacerbations requiring at least oral steroids and improvements in lung function Study and citation Study duration (months) Study treatments N Mean ICS dose, mg/day (BDP equivalent) Rate reduction for first exacerbation Reduction in hospitalisations and emergency room visits Effects on lung function STEAM mildto-moderate asthma [Rabe et al. 2006a] STEP moderate-tosevere asthma [Scicchitano et al. 2004] STAY [O Byrne et al. 2005] 6 Budesonide/ formoterol (2 80/ 4.5 mg qd) SMART Budesonide (2 160 mg qd) plus (375) 76% fewer severe exacerbations required hospital/emergency room visits and oral (500) steroid courses with SMART (p50.001) 90% fewer asthmarelated hospital and emergency visits with SMART (p50.001) Significant improvements in favour of bud/form SMART. Between-treatment differences: Morning PEF: 25 L/min (p50.001) SABA Evening PEF: 18.8 L/min (p50.001) 12 Budesonide/ formoterol (2 160/ 4.5 mg qd) SMART Budesonide (2 160 mg bid) plus (728) 45% fewer severe exacerbations required hospital/emergency room visits or oral (1000) corticosteroid use with SMART (p50.001) Fewer asthma-related hospital/emergency room visits with SMART: 15 vs 25 FEV1: L (p50.001) Significant improvements in favour of bud/form SMART. Between-treatment differences: events (not significant) Morning PEF: 20.3 L/min (p50.001) SABA Evening PEF: 14.0 L/min (p50.001) 12 Budesonide/ formoterol (80/ 4.5 mg bid) SMART Budesonide/ formoterol (80/ 4.5 mg bid) plus SABA Budesonide (320 mg bid) plus SABA (250) 160 (250) 50% fewer severe exacerbations required hospital/emergency room visits or oral steroid use with SMART vs bud/form þ SABA (1000) 45% fewer severe exacerbations required hospital/emergency room visits or oral steroid use with SMART vs bud þ SABA Fewer asthma-related hospital/emergency room visits with SMART vs bud/form þ SABA: 25 vs 32 events (not significant) Fewer asthma-related hospital/emergency room visits with SMART vs bud þ SABA: 25 vs 29 events (not significant) FEV1: 0.10 L (p50.001) Significant improvements in favour of bud/form SMART vs both bud/form þ SABA and bud þ SABA for: Morning and evening PEF (p both comparisons) SMART: 355/360 L/min Bud/form þ SABA: 346/ 349 L/min Bud/form þ SABA: 346/ 349 L/min Bud þ SABA: 339/345 L/min FEV 1 (p both comparisons) SMART: 2.51 L Bud/form þ SABA: 2.43 L Bud þ SABA: 2.41 L (Continued) 287

10 Table 2. Continued. Study and citation Study duration (months) Study treatments N Mean ICS dose, mg/day (BDP equivalent) Rate reduction for first exacerbation SMILE [Rabe et al. 2006b] 12 Budesonide/formoterol (160/4.5 mg bid) SMART Budesonide/formoterol (2 160/4.5 mg bid) plus formoterol (4.5 mg) Budesonide/formoterol (2 160/4.5 mg bid) plus SABA (514) 640 (1000) 640 (1000) 27% lower risk with SMART vs formoterol as-needed (HR: 0.73 [95% CI: ]) 45% lower risk with SMART vs terbutaline as-needed (HR: 0.55 [95% CI: ]) COSMOS [Vogelmeier et al. 2005] 12 Budesonide/formoterol SMART (320/9 to 640/ 18 mg) Salmeterol/fluticasone (100/200 to 100/ 1000 mg) plus SABA Flexible 25% lower risk with SMART vs SFC (p ¼ ) Reduction in hospitalisations and emergency room visits 27% fewer overall with SMART vs formoterol as-needed (98 vs 70 events; p ¼ 0.046) 39% fewer overall with SMART vs terbutaline as-needed (70 vs 115 events; p ¼ 0.001) Fewer asthma-related hospital/emergency room visits with SMART vs SFC: 44 vs 50 events (not significant) Effects on lung function Significant improvements in favour of bud/form SMART vs both formoterol and terbutaline as needed for: Morning and evening PEF change from baseline (p both comparisons) SMART: 15.3/13.8 L/min Form as-needed: 10.6/ 8.5 L/min Terb as-needed: 7.9/ 7.5 L/min FEV 1 change from baseline (p both comparisons) SMART: 0.06 l Form as-needed: 0.01 l Bud as-needed: 0.02 l Early, sustained and comparable improvement in FEV 1 between the treatment arms 288

11 Review COMPASS [Kuna et al. 2007] 6 Budesonide/formoterol (160/4.5 mg bid) SMART Fixed-dose budesonide/ formoterol (320/9 mg bid plus SABA Fixed-dose salmeterol/ fluticasone (2 25/ 125 mg bid) plus SABA (755) 640 (1000) 500 (1000) AHEAD [Bousquet et al. 2007] 6 Budesonide/formoterol (2 160/4.5 mg bid) SMART High-dose salmeterol/ fluticasone (50/500 mg bid) plus SABA (1238) 1000 (2000) Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone. 26% lower risk with SMART vs fixed-dose bud/form þ SABA (p ¼ 0.026) 33% lower risk with SMART vs SFC (p ¼ 0.003) Time to first exacerbation not significantly different between treatment groups (hazard ratio 0.82; p ¼ 0.12). 21% reduction in overall exacerbation rate with SMART vs high-dose SFC (25 vs 31 events/100 patients/year; p ¼ 0.039) 3% fewer asthmarelated hospital/emergency room visits with SMART vs fixed-dose bud/form plus SABA (5 vs 5 events/100 patients/6 months; p ¼ 0.87) 39% fewer asthmarelated hospital/emergency room visits with SMART vs SFC (5 vs 8 events/100 patients/6 months; p ¼ ) 31% reduction in asthma-related hospital/emergency room visits with SMART vs SFC (9 vs 13 events/100 patients/year; p ¼ 0.046) Comparable improvements in all three treatment arms Morning and evening PEF SMART: 363/368 L/min Bud/form þ SABA: 362/ 366 L/min SFC: 367/370 L/min FEV 1 (p both comparisons) SMART: 2.69 l Bud/Form þ SABA: 2.66 l SFC: 2.67 l Comparable improvements in lung function Morning PEF: SMART: L/min SFC: L/min Evening PEF SMART: L/min SFC: L/min 289

12 Table 3. Budesonide/formoterol maintenance and reliever therapy clinical study program: adjusted mean changes in secondary endpoints Study and citation Study treatments N Symptom-free days Night-time awakenings Reliever inhalations/day STEAM [Rabe et al. 2006a] STEP [Scicchitano et al. 2004] STAY [O Byrne et al. 2005] SMILE [Rabe et al. 2006b] COSMOS [Vogelmeier et al. 2005] COMPASS [Kuna et al. 2007] Budesonide/formoterol (2 80/4.5 mg qd) SMART Budesonide (2 160 mg qd) plus SABA Budesonide/formoterol (2 160/4.5 mg qd) SMART Budesonide (2 160 mg qd) plus SABA Budesonide/formoterol (2 80/4.5 mg qd) SMART Budesonide/formoterol (2 80/4.5 mg qd) plus SABA Budesonide (320 mg bid) plus SABA Budesonide/formoterol (2 160/4.5 mg qd) SMART Budesonide/formoterol (2 160/4.5 mg qd) plus formoterol (4.5 mg) Budesonide/formoterol (2 160/4.5 mg qd) plus SABA Budesonide/formoterol SMART (640/18 to 320/9 mg) Salmeterol/fluticasone (10/200 to 100/1000 mg) plus SABA Budesonide/formoterol (2 160/4.5 mg qd) SMART Fixed-dose budesonide/formoterol (320/9 mg bid plus SABA Fixed-dose salmeterol/fluticasone (2 25/125 mg bid) plus SABA Significantly more with SMART (between-treatment difference): 6.5% (p ¼ ) Significantly more with SMART (between-treatment difference): 7.5% (p50.001) Significantly improved vs bud þ SABA and comparable with bud/form þ SABA (% of days) 54% (p vs bud þ SABA) 53% 46% 2% reduction vs formoterol as-needed (p ¼ 0.079) 2% reduction vs terbutaline as-needed (p ¼ 0.16) Significantly fewer with budesonide/formoterol SMART (between-treatment difference): Significantly fewer with budesonide/formoterol SMART (betweentreatment difference): 2.2% (p ¼ 0.065) 0.34 (p50.001) Significantly fewer with Significantly fewer with budesonide/formoterol budesonide/formoterol SMART (betweentreatment SMART (between-treatment difference): difference): 3.3% (p50.001) 0.52 (p50.001) Significantly fewer (% of nights) vs bud þ SABA and bud/form þ SABA 9% (p both comparisons) 12% 12% Significantly fewer with SMART vs formoterol or terbutaline as-needed 2% reduction vs formoterol as-needed (p ¼ 0.018) 3% reduction vs terbutaline as-needed (p ¼ ) Significantly improved vs bud þ SABA and bud/form þ SABA 0.73/day (p both comparisons) 0.84/day 1.03/day Significantly greater reduction with SMART vs formoterol or terbutaline asneeded: 0.17/day reduction vs formoterol as-needed (p50.001) 0.20/day reduction vs terbutaline as-needed (p50.001) Not reported Not reported Significantly fewer with SMART: 0.35/day (p50.001) Comparable between treatments: 2% reduction vs SFC (not significant) 1% reduction vs bud/form (not significant) Comparable between treatments: 1% reduction vs SFC (not significant) 1% reduction vs bud/form (not significant) Comparable between treatments: 0.07 additional inhalations/ day vs SFC (not significant) 0.03 fewer inhalations/day vs bud/form (not significant) AHEAD Budesonide/formoterol 1154 Comparable: Comparable: Comparable: [Bousquet et al. 0.5% reduction vs SFC 1% increase vs SFC 2007] 1155 (p ¼ 0.73) (p ¼ 0.73) (2 160/4.5 mg qd) SMART High-dose salmeterol/fluticasone (50/500 mg bid) plus SABA 0.04 fewer inhalations/day vs SFC (p ¼ 0.36) Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone

13 Review The STAY study included patients from 4 to 80 years of age and confirmed the efficacy and safety of the SMART approach in children as well as adults [O Byrne et al. 2005]. The STEAM study was a 6-month, randomised, double-blind, parallel-group study in patients with mild-to-moderate asthma (mean baseline forced expiratory volume over 1 min [FEV 1 ] 75% expected, mean ICS 348 mg/day; n ¼ 697) [Rabe et al. 2006a]. Patients received either budesonide/formoterol 80/4.5 mg two inhalations once daily plus additional inhalations as needed for symptom relief (mean ICS dose 375 mg/day BDP equivalent) or budesonide only (160 mg two inhalations once daily; 500 mg/day BDP equivalent) plus terbutaline (0.4 mg) as needed. Patients who received budesonide/formoterol maintenance and reliever experienced 90% fewer asthma-related hospitalisations or emergency room visits than those randomised to higher dose budesonide plus terbutaline. The risk of having a severe exacerbation (hospitalisation/ed treatment, oral steroid therapy for 3 days, or 30% decrease from baseline in morning PEF on two consecutive days) was 54% lower for those patients who received budesonide/formoterol maintenance and reliever than for those receiving higher dose budesonide plus terbutaline (p50.01) (Table 2). Lung function was also significantly improved among those receiving in terms of both PEF (34.5 l/min vs 9.5 l/min; p50.001) and FEV 1 (0.210 l vs l, respectively; p50.001). Patients on the budesonide/formoterol maintenance and reliever regimen also needed required fewer as-needed inhalations each day (treatment difference: 0.34 [95% CI: 0.51 to 0.17]; p50.001), had more symptomfree days (treatment difference: 6.5 [95% CI: 2.0 to 11.0]; p ¼ ) and more asthma control days (treatment difference: 7.6 [95% CI: 3.0 to 12.3]; p ¼ ) than those on higher dose budesonide plus terbutaline (Table 3). The overall frequency of adverse events was comparable in the two treatment arms; 38% of patients in the budesonide/formoterol maintenance and reliever arm reported at least one adverse event compared with 41% of patients in the higher dose budesonide plus terbutaline arm. Respiratory infection was the most common adverse event in both treatment groups and while aggravated asthma was reported by five patients receiving higher-dose budesonide plus terbutaline, this event was reported by only one patient in the therapy group. The STEP study compared the budesonide/formoterol maintenance and reliever regimen 160/ 4.5 mg two inhalations once daily plus additional inhalations as needed (mean ICS dose 728 mg/day BDP equivalent) for symptom relief with a higher-dose budesonide regimen (320 mg twice daily; 1000 mg/day BDP equivalent) in patients with moderate to severe asthma (mean baseline FEV 1 70% predicted, mean ICS 746 mg/day). STEP was a 12-month study and recruited 1890 patients the majority of whom (83%) were classed as having severe asthma. Among this group of patients the budesonide/formoterol maintenance and reliever regimen reduced the risk of a severe exacerbation (hospitalisation/ed treatment, oral steroid therapy for 3 days, or morning PEF 70% of baseline on two consecutive days) by 39% compared with higher-dose budesonide plus terbutaline (p50.001). Moreover, 45% fewer severe exacerbations per patient required medical intervention with the regimen (p vs higher-dose budesonide plus terbutaline) (Table 2). As observed in the STEAM study in patients with mild-to-moderate asthma, a significantly greater improvement in lung function was achieved by patients treated with budesonide/formoterol maintenance and reliever regimen than among those who received higher-dose budesonide plus terbutaline (morning PEF: mean treatment difference 20.3 l/min, p50.001; FEV 1 mean treatment difference: 0.10 l, p50.001) (Table 2). The regimen resulted in more symptom-free and asthma-control days (between-treatment difference: 7.5% and 8.6%, respectively) and significantly fewer as-needed inhalations per day (0.9 vs 1.42, respectively; p50.001) (Table 3). Again, a similar proportion of patients reported at least one adverse event in each treatment arm (56% vs 57%, respectively) with the most common adverse event being respiratory infection. The improved efficacy observed in the STEAM, STEP and STAY studies with the budesonide/ formoterol maintenance and reliever approach compared with higher-dose ICS plus SABA was achieved at a lower overall steroid load (total ICS and oral steroid treatment days) (Fig. 3). This is particularly relevant for the treatment of asthmatic children because of the 291

14 Asthma exacerbations/100 patients/year A B B A A=O Byrne et al (2005) B=Rabe et al (2006b) C=Kuna et al (2007) D=Vogelmeier et al (2005) E=Bousquet et al (2007) Low 250 to 500 C C B C Medium 501 to 1000 Maintenance plus as needed ICS dose Budesonide/formoterol + SABA Budesonide/formoterol + formoterol Salmeterol/fluticasone + SABA Symbicort SMART High >1000 D&E D& E (BDP equiv. µg/d) Figure 3. Asthma exacerbation rate (events/100 patients/year) in moderate-to-severe asthma patients receiving either therapy (Symbicort SMART Õ ) or fixed-dose budesonide/formoterol or salmeterol/fluticasone þ separate reliever in five clinical studies stratified by mean daily ICS dose (BDP equivalents). All individual points represent the mean ICS dose range and exacerbation rate from over 900 patients receiving each ICS/LABA combination. For simplicity, all ICS doses have been summarised as low, medium or high dose in accordance with GINA guidelines. For budesonide maintenance and reliever therapy (Symbicort SMART Õ ) the overall ICS dose includes both maintenance and as needed therapy. Note that within studies (A E) the exacerbation rate was significantly lower with Symbicort SMART Õ compared with all other comparators (all p50.05). The dotted lines represent a trend analysis highlighting the likelihood of dose-related increases in efficacy in preventing exacerbations with fixed-dose ICS/LABA and with Symbicort SMART Õ. potential impact of high doses of steroids on growth. The STAY study showed that children who were treated using the budesonide/formoterol fixed dose or maintenance and reliever regimens grew significantly more than those treated with higher-dose budesonide plus terbutaline [O Byrne et al. 2005]. The results from STAY for children aged 4 11 years have been published in further detail [Bisgaard et al. 2006]. Budesonide/formoterol maintenance and reliever therapy was compared with fixed-dose budesonide/formoterol (80/4.5 mg/day; 250 mg/day BDP equivalent) plus as-needed terbutaline (0.4 mg) or higher-dose budesonide (320 mg/day; 500 mg/day BDP equivalent) plus as-needed terbutaline (0.4 mg) [Bisgaard et al. 2006]. Budesonide/formoterol maintenance and reliever therapy prolonged the time to first exacerbation (hospitalisation/ed treatment, oral steroid therapy for 3 days, increase in ICS or additional treatment, or morning PEF 70% of baseline on two consecutive days) vs fixed-dose budesonide (p ¼ 0.02) and fixed-dose budesonide/formoterol (p50.001). Rates of exacerbation requiring medical intervention were reduced by 70 79% with budesonide/ formoterol maintenance and reliever therapy vs fixed-dose budesonide and fixed-dose combination (0.08/patient vs 0.28/patient and 0.40/ patient, respectively; both p50.001). As reported in the primary publication of the STAY study by O Byrne et al. (2005), yearly growth improved by 1.0 cm vs fixed-dose budesonide (p50.01). Budesonide/formoterol maintenance and reliever therapy vs alternative reliever plus maintenance ICS/LABA Two studies have directly compared with approach with budesonide/formoterol plus an alternative as-needed SABA regimen: STAY [O Byrne et al. 2005] and SMILE [Rabe et al. 2006b]. As noted earlier, the STAY study was primarily conducted to compare the efficacy of the budesonide/formoterol maintenance and reliever approach with that of budesonide/formoterol maintenance plus as-needed SABA [O Byrne 292

15 Review et al. 2005]. In this study, the maintenance and reliever regimen reduced the risk of experiencing a severe exacerbation (hospitalisation/ed treatment, oral steroid therapy for 3 days, or morning PEF 70% of baseline on two consecutive days) by 45% and the risk of a severe exacerbation requiring hospitalisation/ed treatment by 50% compared with the budesonide/formoterol plus SABA regimen (Table 2). Lung function (morning and evening PEF and FEV 1 ) was also significantly improved with the budesonide/ formoterol maintenance and reliever approach (Table 2) as were night-time awakenings (p50.001) and daily reliever use (p50.001) (Table 3). Improvements in other symptom measures were comparable between the two regimens including the proportion of symptomfree days and asthma control days; with both regimens offering significantly greater improvements compared with higher-dose budesonide plus SABA (Table 3). The overall frequency of adverse events was comparable between the three treatment arms; 57% of patients reported at least one adverse event in the higher-dose budesonide plus SABA arm compared with 52% and 54% in the budesonide/formoterol plus SABA and the budesonide/formoterol maintenance and reliever arms, respectively. Aggravated asthma occurred in 2 patients treated with the budesonide/formoterol maintenance and reliever regimen and 13 and 8 patients in the budesonide/ formoterol plus SABA and higher-dose budesonide plus SABA arms, respectively. The SMILE study was a 12-month study in asthmatic patients 12 years of age and older designed to compare the budesonide/formoterol maintenance and reliever regimen (mean ICS dose 514 mg/day BDP equivalent) with budesonide/formoterol as maintenance (mean ICS dose 500 mg/day BDP equivalent) combined with either formoterol or a SABA (terbutaline) for as-needed therapy [Rabe et al. 2006b]. The budesonide/formoterol maintenance and reliever regimen significantly prolonged the time to the first severe exacerbation (i.e. that requiring hospital/ed room treatment or oral steroid therapy for 3 days) compared with either of the two alternative regimens (p ¼ vs budesonide/ formoterol plus formoterol as-needed; p vs budesonide/formoterol plus terbutaline as-needed). The rate of severe exacerbations was 37, 29 and 19 per 100 patients/year for budesonide/formoterol plus terbutaline asneeded, budesonide/formoterol plus formoterol as-needed and budesonide/formoterol maintenance and reliever therapy. The budesonide/formoterol maintenance and reliever regimen also reduced the overall proportion of patients who required hospital or emergency room visits during the 12-month study period (5% vs 7% [p ¼ 0.079] and 8% [p ¼ ] for the formoterol and terbutaline as-needed regimens, respectively) (Table 2). With the inclusion of the budesonide/formoterol plus formoterol as-needed treatment arm, the SMILE study provides compelling support for the contribution to the effect of the ICS component alongside formoterol when patients require additional as-needed medication in order to reduce the frequency of asthma exacerbations and the likelihood of requiring medical intervention. Lung function improved to the greatest extent in the arm (Table 2). Overall symptoms also improved more for patients in the budesonide/formoterol maintenance and reliever arm who achieved the greatest number of asthma control days and the greatest reductions in night-time awakenings and daily as-needed inhalations (Table 3). No adverse safety signals were revealed with all three regimens being well tolerated throughout the study period although fewer patients withdrew due to adverse events in the budesonide/formoterol maintenance and reliever arm (n ¼ 1) compared with the formoterol as-needed (n ¼ 14) and terbutaline as-needed (n ¼ 10) groups. Budesonide/formoterol maintenance and reliever therapy vs alternative higher doses of maintenance ICS/LABA As discussed above, the alternative ICS/LABA combination salmeterol/fluticasone is not suitable for a maintenance and reliever regimen. However, the efficacy of budesonide/formoterol maintenance and reliever has been compared with a higher fixed-dose of salmeterol/fluticasone plus SABA or a titrated dose of salmeterol/fluticasone in three studies, COMPASS [Kuna et al. 2007], COSMOS [Vogelmeier et al. 2005] and AHEAD [Bousquet et al. 2007]. The COSMOS study directly compared budesonide/formoterol maintenance (initial dose 160/ 4.5 mg two inhalations bid) and reliever using Turbuhaler Õ with fixed-dose salmeterol/fluticasone (initial dose 50/250 mg twice daily) plus salbutamol as-needed in 2143 adolescents and adults (mean FEV 1 73% predicted, mean daily ICS at study entry 884 mg) 293