Combination Therapy of Long-acting β agonists and Inhaled Corticosteroids in the Management of Chronic Asthma Harold S. Nelson, MD

Address National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. E-mail: [email protected] Current Allergy and Asthma Reports 2005, 5:123–129 Current Science Inc. ISSN 1529-7322 Copyright © 2005 by Current Science Inc.

Both the Global Initiative for Asthma (GINA) and the National Heart, Lung and Blood Institute (NHLBI) Expert Panel guidelines recommend combination treatment with inhaled corticosteroids (ICSs) and inhaled longacting β-agonists (LABAs) for patients whose asthma is not adequately controlled by low doses of ICSs alone. Not only is this combination more effective than the combination of either theophylline or leukotriene modifiers with ICSs, there is suggestive evidence that the results with LABAs and ICSs may be more than additive. Through the effect of each one on the receptor for the other, they may have a synergistic action. This marked effectiveness of the combination, particularly when combined in the same device, has led to new objectives and novel applications. Therefore, for the first time, it appears that the Goals of Asthma Therapy, as outlined in the guidelines, are achievable for many patients with asthma. Also, at least for combination therapies including formoterol, adjustable dosing and perhaps even use as a rescue as well as a maintenance therapy may be possible.

Introduction The two most widely quoted guidelines for asthma therapy, the Global Initiative for Asthma (GINA) [1] and the National Heart, Lung and Blood Institute (NHLBI) Expert Panel Report (update 2002) [2], both recommend a step-wise approach to chronic asthma therapy. Patients with persistent asthma who have daily symptoms, nighttime awakening more than once weekly, or impaired pulmonary function when not acutely symptomatic are considered to have moderate asthma. Although the recommended treatment for those with mild, persistent asthma is low-dose inhaled corticosteroids (ICSs), for moderate asthma, the recommended treatment is a combination of

low-dose ICSs and an inhaled, long-acting β-adrenergic agonist (LABA) [1,2]. With asthma of even greater severity, LABAs, now combined with medium-to-high doses of ICSs still constitute the core of the treatment, although the addition of other controllers or even oral corticosteroids may be necessary to achieve asthma control. There are currently only two commercial products that combine an LABA (formoterol or salmeterol) and an ICS (budesonide or fluticasone) in a single device, although it can be anticipated that other combinations with the same LABAs combined with the same or a different ICS will follow. Although both guidelines recognize that other controller medications (theophylline and leukotriene modifiers) have some additive effect when combined with ICSs, both alternatives are less effective in comparative trials than LABAs and ICSs. Similarly, the combination of an LABA and an ICS has regularly proven to be more effective in achieving asthma control than is a higher dose of ICS alone. The marked superiority of the combination of an LABA and an ICS over the other alternatives at stage 3 of asthma therapy has raised the question whether the combination should be introduced even earlier in asthma therapy, in place of low-dose ICSs alone at step 2, treating mild, persistent asthma. Because of the remarkable effectiveness of the combination of an LABA and an ICS, several issues have arisen that would not have been considered with the less effective treatments of the past. One question is: Can asthma be totally controlled? Both the GINA and the NHLBI Expert Panel reports set Goals of Asthma Therapy (Table 1). Currently very few patients with asthma achieve these goals. Therefore, a prospective study was undertaken to determine to what extent these goals were achievable using combination LABA-ICS therapy. A second question is whether this potent combination therapy need be given continuously at the same dose, or whether the dose can be decreased when the patient is doing well and increased when asthma becomes unstable. Even more radical is the question: Can the combination of an LABA and an ICS be used, not only for maintenance therapy, but also as a rescue medication, so that patients need only one asthma medication for all purposes?

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Table 1. The Goals of Asthma Therapy Minimal or no chronic symptoms day and night Minimal or no exacerbations No limitations on activities: no school/work missed Maintain (near) normal pulmonary function Minimal use of short-acting inhaled β2 agonists (<1 time/d) Minimal or no adverse effects from medications Adapted from NHLBI [2].

Long-acting Inhaled β-adrenergic Agonists

Formoterol and salmeterol are both highly selective β2adrenergic agonists that have bronchodilating and bronchoprotective properties of long duration, and hence provide sustained bronchodilation with dosing every 12 hours [3,4]. Despite their similar performance when regularly administered, each possesses certain unique properties. Formoterol is a complete agonist for the β receptor [5], whereas salmeterol, like albuterol, is a partial agonist [6]. Thus far, no clear clinical importance has been identified for this difference. Another major difference is the rapidity of onset. Formoterol has an onset of action similar to that of albuterol (ie, within 3 minutes) [5]. Salmeterol, however, has a delayed onset of action, approaching 20 minutes before significant bronchodilation occurs [6]. For regular maintenance use, the time of onset may be of limited importance. It has emerged as a potentially significant difference with the contemplated use of formoterol and formoterol/budesonide combination as rescue medication. It is clear from controlled studies of asthmatics, only some of whom were employing ICSs, that regular administration of formoterol 12 µg every 12 hours [3] or salmeterol 50 µg every 12 hours [4] is more effective than either placebo or albuterol 180 µg four times daily, in producing sustained improvement in pulmonary function, and reduction in daily symptoms, nighttime awakenings, and rescue albuterol use. In a crossover study, it was first determined that there was no clear advantage to 24 µg of formoterol over 12 µg or of 100 µg of salmeterol over 50 µg [7]. The lower doses were then administered, and the subjects were followed for 24 hours. Both the forced expiratory volume in 1 second (FEV 1 ) and the PC20FEV1 methacholine were significantly elevated in both active treatment arms compared with placebo after 24 hours. Furthermore, there was no difference between the two drugs over the entire 24-hour period. However, issues have been raised regarding the use of the LABAs. Perhaps the most convincing of these was the Salmeterol or Corticosteroids (SOCS) study, conducted by the NHLBI-supported Asthma Clinical Research Network [8]. Patients were first treated with the ICS triamcinolone (TAA) 400 µg bid. Those patients whose asthma was well controlled on this treatment were then randomized to either remain on the same dose of TAA, or to have the

TAA replaced by either salmeterol 50 µg bid or placebo. During the ensuing 4 months, clinical markers of pulmonary function, symptoms, and rescue β agonist use were similar in the TAA and salmeterol groups, both of whom fared significantly better than those on placebo. However, markers of inflammation, including endothelial nitric oxide (eNO), sputum eosinophils, and methacholine sensitivity deteriorated in the salmeterol group similarly to those receiving placebo, and both salmeterol and placebo groups experienced significantly more exacerbations than the group continuing on TAA. This study reinforced the previous guideline recommendations that LABAs should be used only in conjunction with corticosteroids. There are several polymorphisms of the β-adrenergic receptor. Attention has been focused on the homozygous arginine genotype at the 16th position (Arg:Arg 16). This genotype has been reported to be associated with deterioration of asthma in patients receiving regular treatment with inhaled albuterol [9]. However, in that same double crossover comparison of 6 months treatment with albuterol four times daily, salmeterol twice daily, or placebo, no similar deterioration was evident in the Arg:Arg 16 subjects when they received salmeterol.

Inhaled Corticosteroids Two ICSs are currently available in combination with an LABA. They differ in their degree of oral bioavailability, budesonide being approximately 10% orally bioavailable, compared with approximately 1% for fluticasone [10]. The clinical importance of this is reduced by the fact that much of the drug deposited in the lung enters the circulation. Fluticasone has greater affinity for the glucocorticoid receptor, and, hence, is inherently approximately twice as potent as budesonide [11]. This difference in potency is also reduced by two factors. One is the formation of intracellular esters between budesonide and fatty acids that result in a depot-like effect, prolonging the residence time of budesonide in the lung tissue [12]. The second factor is the delivery devices used for the two preparations. The Turbuhaler (AstraZeneca, Wilmington, DE) delivers approximately 32% of the metered dose of budesonide into the lungs, compared with 26% with the fluticasone chlorofluorocarbon metered-dose inhaler (CFC-MDI) and 15% with the fluticasone Diskus (GlaxoSmithKline, London, UK) [13]. Therefore, when dry-powder inhalers are compared, budesonide and fluticasone approach equivalence in potency [14]. There may be a difference in the duration of effect of the two corticosteroids and, hence, their requirement for dosing frequency. This may reflect the fact that budesonide forms reversible intracellular esters with fatty acids, and fluticasone does not. Budesonide once daily appears to be adequate to control patients with mild-to-moderate asthma [15,16]. However, comparison of the same dose of fluticasone given once or twice daily demonstrated clear

Long-acting β Agonists and Inhaled Corticosteroids in Chronic Asthma • Nelson

superiority for twice-daily dosing. In fact, in 5 of 6 studies, once-daily dosing was not superior to placebo for the end point of FEV1 [17].

Combination LABA and ICS Although some of the patients in the pivotal studies of salmeterol [4] and formoterol [3] were receiving ICSs, no particular notice was made in those studies of any possible interaction between the two classes of asthma drugs. Therefore, the results of the study by Greening et al. [18] came as a surprise to most physicians. They studied 426 adult asthmatic patients who had symptoms despite maintenance treatment with low-dose ICSs (beclomethasone [BDP] 200 µg bid). Half were assigned to receive salmeterol 50 µg bid plus continue with BDP 200 µg bid, whereas the others received a higher dose of BDP (500 µg bid) for 6 months. The mean morning peak expiratory flow (PEF) increased more in the salmeterol group than in those receiving the higher dose of BDP at all time points (differences 16 to 21 L/min); mean evening PEF increased with salmeterol but not with the higher dose of BDP. Other significant differences in favor of salmeterol included diurnal variation of PEF, use of rescue bronchodilators, and daytime and nighttime symptoms. In this study, there were no significant differences in adverse effects or number of exacerbations of asthma, indicating that in these patients, regular β2-agonist therapy was not associated with any risk for deteriorating asthma control during the 6 months of the study. The results of this study were greeted with surprise and concern that salmeterol, although improving parameters of asthma control, might be doing so at the expense of masking inflammation [19]. These concerns were answered for most observers by the results of the Formoterol and Corticosteroids Establishing Therapy (FACET) study reported 3 years after the study by Pauwels et al. [20••]. In this yearlong study, 852 patients with asthma, concomitantly treated with ICSs, were first placed on 1 month of budesonide 800 µg bid, then randomized to either 100 µg or 400 µg of budesonide bid. Half in each group were, in addition, given formoterol 12 µg bid by inhalation. As in the Greening et al. [18] study, the addition of an LABA, in this case formoterol, to the lower dose of budesonide improved pulmonary function, daytime and nighttime symptoms, and β agonist use to a greater degree than the higher dose of budesonide alone. The primary outcome of the study was, however, the occurrence of mild and severe exacerbations of asthma. Both were reduced with the higher compared with the lower dose of budesonide. However, the addition of formoterol to either the low or the high dose of budesonide was also associated with a highly significant reduction in both mild and severe exacerbations. The reduction of exacerbations with the addition of an LABA to an ICS observed in the FACET study was

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confirmed in a meta-analysis of nine studies in which the addition of salmeterol to a dose of ICS not providing adequate control of asthma was compared with at least a doubling of the dose of ICS [21]. Seven of the nine studies were of 6-months duration, and the other two, 12 weeks, allowing ample time for the effect of the increased dose of ICS to become effective. Nevertheless, at the end of 6 months, there were significant improvements in pulmonary function, daytime and nighttime symptoms, and use of rescue medication and a significant reduction in the number of exacerbations with the addition of salmeterol compared with increasing the dose of ICSs.

Synergy of Long-acting β Agonists and Corticosteroids It was not surprising that the addition of an LABA improved pulmonary function and even reduced symptoms and rescue β-agonist use. When the addition of an LABA to an ICS resulted in a reduction in the number of asthma exacerbations, especially those requiring oral corticosteroids, it presented a problem in understanding based on the known actions of the LABAs. A breakthrough came with the observation that β agonists may enhance the actions of corticosteroids by priming the glucocorticoid receptor for translocation to the nucleus [22]. This β2 agonist effect on glucocorticoid receptor translocation, together with the known effect of corticosteroids of increasing β 2 -adrenergic receptor expression, made an attractive story for an additive or even synergistic action between the two classes of drugs. Most of the studies demonstrating synergy between β agonists and ICSs have been in in vitro systems. However, the observation that the administration of fluticasone and salmeterol from a single Diskus inhaler produced significantly greater improvement in morning peak flows than the same doses of the same two drugs delivered from separate Diskus devices is difficult to explain except by accepting that there is synergy when the two drugs are presented to the same airway cells [23]. Presumably, this matched delivery is favored by their being deposited during a single inhalation and perhaps because there is physical adherence between the particles of salmeterol and fluticasone when combined in the same Diskus device [23].

Combination of a Long-acting β Agonist and an Inhaled Corticosteroid in the Same Device In view of the degree of improvement of pulmonary function, symptoms, and rate of exacerbations observed with the combination of an LABA and an ICS, the next logical step was to combine the two classes of drugs in one device. This has now been done with formoterol and budesonide and with salmeterol and fluticasone. Both combinations are available in a dry-powder inhaler in multiple dosage forms: budesonide 80 µg and 160 µg

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each with 4.5 µg of formoterol and 320 µg with 9 µg of formoterol in the Turbuhaler [24]; fluticasone propionate 100, 250, and 500 µg combined with 50 µg of salmeterol in the Diskus [25] inhaler. Alternative preparations in metered dose inhalers with a hydrofluoralkane (HFA) propellant are currently under development for both combination products. The budesonide/formoterol combination Turbuhaler (BFC) has been found to deliver 32% to 44% of the stated (delivered from the device) dose of budesonide and 28% to 49% of the stated (delivered from the device) dose of formoterol to the lungs. The fluticasone/salmeterol combination (FSC) in the Diskus delivers a much lower percentage of the stated (metered from the capsule) dose to the lungs. Because of the similar particle size, delivery of FSC from the Diskus is unlikely to exceed the 15% lung dose from the fluticasone Diskus [15]. A few direct comparisons of the two combination products are available. At 3 hours after a single dose, the FEV 1 was increased significantly more with BFC 320/9 than with FSC 250/50 [26]. In a study of adjustable dosing with BFC, there was 1 month of double-blind dosing with either BFC 320/9 twice daily or FSC 250/50 twice daily, followed by 6 months open dosing in which two thirds of the 658 subjects continued to receive the above two fixed doses [27]. After both 1 month and 7 months, there was a significantly greater increase in FEV1 with BFC (0.050 and 0.058 L, respectively) compared with FSC. Otherwise, there were no significant differences in asthma symptoms, nighttime awakenings, or rescue β-agonist use after either 1 or 7 months between the two fixed treatments

Compliance with Combination Therapy It was anticipated that the combination of an ICS and an LABA in the same device would improve patient compliance with the ICS. In a study using pharmacy claims from a large, managed care organization in the United States, 2511 patients 12 years of age or older who had been seen for asthma were identified [28••]. Twelvemonth refill rates were determined for asthma medications. Patients who were prescribed FSC obtained significantly more refills (4.06) compared with the number of fluticasone refills, whether the fluticasone was prescribed alone (2.27), with salmeterol in separate containers (2.35), or with montelukast (1.83). The refill rate for FSC (4.06) was similar to that for montelukast (4.51). Thus, the use of a single inhaler containing both an ICS and an LABA increases the likelihood that patients will obtain optimal ICS therapy, as well as benefit from the additive effects of the LABA.

Comparison with Other Combination Treatments Both GINA [1] and NHLBI Expert Panel Report [2] list the combination of low-dose ICSs with either leukotriene

pathway modifiers or sustained-release theophylline as not-preferred alternatives to the LABA plus ICS combination for step 3 therapy. Although the combinations of ICSs with theophylline or with an LABA have not been specifically studied, a meta-analysis was conducted of nine studies in which sustained-release theophylline was compared with salmeterol in 1330 subjects, most of whom were using ICSs [29]. Salmeterol was significantly more effective at increasing AM PEF (10 L/min) and in increasing symptom-free days (51% vs 39%) and symptom-free nights (63% vs 52%) than theophylline. The alternative of the addition of a leukotriene receptor antagonist or salmeterol to an ICS has been addressed in five studies. In 948 patients still symptomatic on various ICSs, the addition of salmeterol compared with montelukast resulted in significantly greater improvement in pulmonary function, daytime symptoms, nighttime symptoms, and rescue inhaler use [30]. There was no difference in the rate of asthma exacerbations. In a year-long study in 1490 subjects, still symptomatic despite low-dose fluticasone, the addition of salmeterol 50 µg bid was compared with the addition of montelukast [31]. There was no significant difference in the primary outcome, the percentage of subjects with at least one exacerbation. Pulmonary function parameters were improved significantly more with salmeterol but there were no significant differences in nocturnal awakenings or asthma-specific quality of life scores. Other asthma symptoms or rescue medication use were not reported. A second study, very similar in design, enrolled 1473 subjects who were symptomatic on low-dose fluticasone (220 µg/d) and randomized them to the addition of salmeterol (42 µg/bid) or montelukast 10 mg/d [32]. In this study, there were significant advantages for the addition of salmeterol over montelukast for AM PEF, symptom-free days, nocturnal awakenings, β-agonist use, and asthma-specific quality of life. The risk for an asthma attack in the montelukast subjects was 1.2 compared with the salmeterol group, but this difference was not statistically significant Compared with these three studies, in which separate devices were used for the ICS and the LABA, two studies have examined the response to fluticasone by Diskus plus montelukast compared with the FCS combination also by Diskus [33,34••]. It is possible that the improved compliance that has been documented for the FCS compared with the same drugs from separate inhalers accounts for the difference in results from those in the three previous studies. The 1253 subjects in the two studies were still symptomatic on low-dose fluticasone by Diskus. They then entered a double-blind, randomized phase in which they either had montelukast 10 mg added to the fluticasone or were switched to the FCS containing the same dose of fluticasone. Increase in AM PEF was almost twice as great with the FCS. In one study, FCS also significantly improved symptom-free days and symptomfree nights compared with the montelukast/fluticasone

Long-acting β Agonists and Inhaled Corticosteroids in Chronic Asthma • Nelson

combination. In the second study, the number of puffs of albuterol and the number of days with albuterol use were significantly reduced by FCS compared with fluticasone/ montelukast. Most striking were the differences in exacerbations between the two treatments—9.6% and 2% of the FCS subjects experienced exacerbations, compared with 14.6% and 6% receiving fluticasone and montelukast. The differences in both studies were statistically significant. There were no outcomes favoring the fluticasone/ montelukast combination in either study

Special Studies Conducted with Long-acting β Agonist/Inhaled Corticosteroid Combinations

The GOAL Study A series of telephone interviews of patients with asthma were conducted in the United States, Eastern and Western Europe, Japan, and Southeast Asia. They revealed that only 5% of the responders were achieving the Goals of Asthma Therapy as outlined in GINA and NHLBI Guidelines [35]. A major contributor to this poor asthma control appeared to be the limited use of ICSs. In response to these observations, a major study was undertaken called The Gaining Optimal Asthma Control, or GOAL study [36]. This was a 1-year, randomized, double-blind, parallelgroup study in 3421 persons with uncontrolled asthma of varying degrees of severity. Progressively increasing treatments with fluticasone propionate or FSC were compared to see if totally controlled or well-controlled asthma could be achieved. At the end of 1 year of dose escalation, total control was achieved in 41% treated with FCS and 28% treated with fluticasone alone. Well-controlled asthma, with symptoms equivalent to the guidelines category of mild intermittent asthma, was achieved in 71% on FCS and 59% on fluticasone alone. The group treated with FCS, compared with those receiving fluticasone alone, had fewer exacerbations and greater improvement in asthmaspecific quality of life. This study demonstrates that most patients with asthma can achieve adequate control of their asthma with the use of ICSs, and especially with the combination of an ICS and an LABA.

Once-daily, Variable Dosing, and As-needed Use with Combination Long-acting β agonists and Inhaled Corticosteroids Both ICSs and LABAs are customarily administered twice daily. Because budesonide is approved for once-daily dosing, it was of interest to see if the combination of budesonide and formoterol could also be effective if given once daily. Following a 2-week run-in on budesonide 200 µg bid, 523 subjects were randomly assigned to continue on the same treatment or receive budesonide/formoterol 160/4.5 bid or 320/9 in the evening [37]. There was no difference between the two BFC regimens, and both were superior for most outcomes to the budesonide alone.

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Three studies have examined variable dosing with the BFC device. In a study of 658 subjects who were symptomatic on medium doses of ICS, all were initially treated with a fixed-dose regimen of either BFC or FCS double-blind, for 1 month [27]. At the end of that period, two thirds were continued on one of the two fixed-dose regimens and one third were placed on adjustable dosing with BFC. The adjustable dose patients were placed on either one or two inhalations of BFC 160/4.5 twice daily, depending on how well their asthma had been controlled during the double-blind run-in. They were instructed to increase their BFC to four inhalations bid for 7 to 14 days if their asthma deteriorated as indicated by: 1) the need for more than three puffs of rescue β agonist per day for three consecutive days, or 2) nocturnal awakening on two consecutive nights. During the 6-month open-label portion of the study, the group with adjustable dosing had better odds of achieving a well-controlled asthma week compared with fixed-dose BFC and had significantly fewer exacerbations than those on fixed-dose FCS. They also used rescue β agonists less and had fewer nocturnal awakenings than they did with fixed doses of either combination. A reduction to one inhalation of FCS was made in 45% of the subjects, whereas 43% temporarily increased their dose to four inhalations bid. Overall, the group on adjustable dosing used less study medication than those on fixed-dose BFC—3.4 inhalations per day versus 4.0 inhalations per day. Another adjustable dosing study in 995 subjects began with a 1-month, open-label run-in during which subjects took BFC either 160/9 µg bid or 320/9 µg bid [38]. They then were randomized to 5 months of either fixed or adjustable dosing. Criteria for adjustments in dosing were pre-set (Table 2). The group on adjustable dosing used an average of only 2.51 inhalations per day of study medicine compared with an average of 3.92 inhalations per day by those on the fixed dose. The primary efficacy variable was exacerbations (added inhaled or oral corticosteroids, emergency department visits, asthma-related serious adverse event [SAE], or need for additional asthma treatment) and severe exacerbations (use of oral corticosteroids, emergency department visit, or asthma-related SAE). The group on adjustable dosing had significantly fewer of each category: for all exacerbations, 4.0% versus 8.9%, and for severe exacerbations, 3.6% versus 6.3%. There were no significant differences in symptoms or rescue β-agonist use. In the adjustable group, 93% reduced their dose to 1 inhalation bid, most during the first week of randomization. Thirty-two percent met the criteria for stepping up to four inhalations twice daily, and 20% of the adjustable group stepped up their dose at least once. A third adjustable dose study was conducted in 1553 subjects in primary care practices [39]. Seventy-nine percent reduced medication at some time, and 28% increased at some time to four inhalations bid. Overall, the only differences in outcome were the use of less study

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Table 2. Adjustable dosing: criteria for step up and step down Dosing

Criteria for step up and step down

Initial step down to one inhalation twice daily

The patient felt well in his/her asthma, and in the previous 7 days both: Used reliever medication on two occasions Had no noctural awakenings due to asthma Step up to four inhalations twice daily for 7 to 14 days On 2 consecutive days or nights of the individual medication, any of the following: Reliever medication = 3 occasions/d Nocturnal awakening due to asthma AM PEF < 85% mean baseline value Step down from four inhalations to previous dose During the previous 2 days and nights, individual met all of the following: No more asthma symptoms than before worsening of asthma No reliever medication use No nocturnal awakenings due to asthma AM PEF = 85% of mean baseline value. PEF—peak expiratory flow. Adapted from FitzGerald et al. [38].

medication (3.2/d vs 3.8/d) and significantly less use of inhaled rescue medication by the adjustable dose group. Although as-needed use of the BFC has not yet been reported, except as abstracts, use of the formoterol component alone has been [40,41]. In a comparison with salbutamol in the emergency department as a rescue therapy, formoterol provided equally rapid and greater improvement in lung function during a 4-hour period [40]. In a 6month study in 18,124 patients who were 4 to 91 years of age, subjects were randomized to use either formoterol 4.5 µg by Turbuhaler or albuterol 200 µg by MDI up to 12 inhalations per day for rescue medication [41]. Compared with salbutamol, all types of asthma exacerbations were reduced 12% to 16% by formoterol. There was no difference in adverse events. A logical extension of the adjustable dosing studies with BFC and as-needed use of formoterol is use of the BFC as the sole treatment for asthma. Studies on this regimen are being conducted.

Conclusions Based on solid scientific evidence, both the GINA and the NHLBI Expert Panel guidelines recommend combination treatment with ICSs and LABAs for patients whose asthma is not adequately controlled by low doses of ICSs alone. Not only is this combination more effective than the combination of either theophylline or leukotriene modifiers with ICSs, there is suggestive evidence that the results with LABAs and ICSs may be more than additive. Through the effect of each one on the receptor for the other, they may have a synergistic action. This marked effectiveness of the combination, particularly when combined in the same device, has led to new objectives and novel applications. Therefore, for the first time, it appears that the Goals of Asthma Therapy, as outlined in the guidelines, are achievable for many patients with asthma. Also, at least for combination therapy including formoterol,

adjustable dosing and perhaps even use as a rescue as well as a maintenance therapy may be possible.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Long-acting β Agonists and Inhaled Corticosteroids in Chronic Asthma • Nelson

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28.•• Stoloff SW, Stempel DA, Meyer J, et al.: Improved refill persistence with fluticasone dipropionate and salmeterol in a single inhaler compared with other controller therapies. J Allergy Clin Immunol 2004, 113:245–251. It was thought that the addition of an LABA to an ICS would improve patient adherence to the ICS prescription. This study confirms that subjects refilled their ICS almost twice as often if it was combined in the same device with an LABA rather than the two being prescribed in separate devices. 29. Davies B, Brooks G, Devoy M: The efficacy and safety of salmeterol compared to theophylline: a meta-analysis of nine controlled studies. Respir Med 1998, 92:556–563. 30. Fish JE, Israel E, Murray JJ, et al.: Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001, 120:423–430. 31. Bjermer L, Bustard H, Bouquet J, et al.: Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbations in adults: one year, double blind, randomised, comparative trial. BMJ 2003, 327:891–896. 32. Ilowite J, Webb R, Friedman B, et al.: Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double blind, multicenter study. Ann Allergy Asthma Immunol 2004, 92:641–648. 33. Nelson HS, Busse WW, Kerwin E, et al.: Fluticasone propionate/ salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000, 106:1088–1095. 34.•• Ringdal N, Eliraz A, Pruzinec P, et al.: The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma. Respir Med 2003, 97:234–241. This study compares the addition of a leukotriene receptor antagonist (LTRA) or an LABA to fluticasone in patients not adequately controlled on low-dose ICS. In this study the combination fluticasone/salmeterol (FSC) inhaler was used. All outcomes favored FSC over adding montelukast to fluticasone, including pulmonary function, symptoms, and rate of asthma exacerbations. 35. Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy 2004, 59:469–478. 36. Bateman ED, Boushey HA, Bousquet J, et al.: Can guidelinedefined asthma control be achieved? The Gaining Optimal Asthma ControL Study. Am J Respir Crit Care Med 2004, 170:836–844. 37. Buhl R, Creemers JPHM, Vondra V, et al.: Once-daily budesonide/ formoterol in a single inhaler in adults with moderate persistent asthma. Respir Med 2003, 97:323–330. 38. FitzGerald JM, Sears MR, Boulet L-P, et al.: Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a fivemonth multicenter Canadian study. Can Respir J 2003, 10:427–434. 39. Ind PW, Haughney J, Price D, et al.: Adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients: the ASSURE study. Respir Med 2004, 98:464–475. 40. Boonsawat W, Charoenratanakul S, Pothirat C, et al.: Formoterol (Oxis) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma. Respir Med 2003, 97:1067–1074. 41. Pauwels RA, Sears MR, Campbell M, et al.: Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Resp J 2003, 22:787–794.