Long-Acting 2 -Agonists in Management of Childhood Asthma: A Critical Review of the Literature

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1 Pediatric Pulmonology 29: (2000) State of the Art Long-Acting 2 -Agonists in Management of Childhood Asthma: A Critical Review of the Literature Hans Bisgaard, MD, Dr Med Sci* Summary. This review assesses the evidence regarding the use of long-acting 2 -agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled salmeterol or formoterol cause prolonged bronchodilatation (>12 h) and extended bronchoprotection against exercise-induced bronchoconstriction in children, some children achieving full protection for more than 12 h. Heterogeneity in bronchoprotection has been observed, and individual dose-titration may be attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting 2 -agonists are used as regular treatment, including cross-tolerance to short-acting 2 -agonists. Regular treatment with salmeterol in children with or without corticosteroids provides statistically significant bronchodilatation, but the degree of improvement in lung function or bronchoprotection against exercise and nonspecific irritants is small with regular use. There is no evidence of anti-inflammatory effects from inhaled long-acting 2 -agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting 2 - agonists as monotherapy, nor does it support their general use as regular add-on therapy. In conclusion, long-acting 2 -agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting 2 -agonists as an as needed rescue medication instead of short-acting 2 -agonists for pediatric asthma management. Pediatr Pulmonol. 2000; 29: Wiley-Liss, Inc. Key words: formoterol; salmeterol; asthma; long-acting 2 -agonists; children; treatment; randomized controlled trials. INTRODUCTION Anti-inflammatory treatment with topical corticosteroids is essential for the treatment of asthma, but bronchodilator therapy remains an indispensable complementary treatment. Various bronchodilators exist, and by far the most widely used are inhaled 2 -agonists. Inhaled 2 -agonists are commonly divided into two groups: those with a short duration of action (2 6 h) and those with a longer duration (>12 h). Two inhaled long-acting 2 - agonists, formoterol and salmeterol, are approved for use in children, providing pediatricians with a choice of therapies. This review investigates published, controlled, clinical studies performed with inhaled formoterol and salmeterol in children. The available published English literature on randomized controlled, double-blind studies on the effects of formoterol and salmeterol in children (including adolescents) with asthma was identified using a computerized citation search (MEDLINE 2000 Wiley-Liss, Inc. EMBASE and CURRENT CONTENTS) and a nonsystematic review of the asthma literature up to Only peer-reviewed, full articles on the clinical outcome in children were included; reports in abstract form were not. Thirty reports were identified fulfilling these criteria As supportive evidence, the in vitro properties of longacting 2 agonists are discussed briefly, and issues not studied in children are addressed based on a nonsystematic review of adult studies. The objective of this review is to develop a consensus Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark. *Correspondence to: Professor Hans Bisgaard, M.D., Dr. Med. Sci., Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@rh.dk Received 11 February 1999; Accepted 18 June 1999.

2 222 Bisgaard based on the published reports on the effects of salmeterol and formoterol in children with asthma. Based on this review, the present positioning and possible future repositioning of inhaled long-acting 2 -agonists in the management of childhood asthma are discussed. PHARMACOLOGY OF LONG-ACTING 2 -AGONISTS Mechanism of Action The exact mechanisms by which salmeterol and formoterol exert prolonged bronchodilation remain unknown. The exosite binding hypothesis suggests that, as salmeterol has a long aliphatic side chain, it may anchor the catechol end of the molecule to a structure distinct from (but adjacent to) the 2 -adrenoceptor (the exosite or exoceptor). 31 This allows the active saligenin head of the molecule to detach and reattach repeatedly to the active site of the 2 -adrenoceptor. This would account for salmeterol s long duration of action and ability to reassert relaxation after 2 -adrenoceptor blockade. Problems with this hypothesis do exist, as preincubation of guinea pig trachea with analogues of the salmeterol side-chain does not prevent the occurrence of reassertion relaxation. This suggests that the salmeterol molecule interacts with the receptor via a different mechanism. In contrast, the prolonged duration of action of formoterol may be associated with its lipophilic binding tendency and interaction with membrane lipid bilayers (plasmalemma diffusion microkinetic model). 32 The plasmalemma acts as a depot for 2 -agonists with moderate or high lipophilic binding tendency. Formoterol has moderate lipophilic binding tendencies, and is retained within the plasmalemma and can diffuse slowly to activate the 2 - adrenoceptor over an extended period. Moreover, formoterol is also available in the aqueous phase, which allows it to diffuse rapidly to the receptor, accounting for its rapid onset of action. This hypothesis can also be used Abbreviations BDP Beclomethasone dipropionate BID Twice daily CI Confidence interval DD Doubling doses DPI Dry powder inhaler ECG Electrocardiogram EIB Exercise-induced bronchospasm FEV 1 Forced expiratory volume in 1 second FVC Forced vital capacity NO Nitric oxide OD Once daily PC 20 Provocative concentration required to produce a 20% decrease in FEV 1 from baseline PEF Peak expiratory flow PMDI Propellant-driven pressurized metered dose inhalers to explain the mechanism of action of salmeterol, which is highly lipophilic. Salmeterol enters quickly into the lipid plasmalemma, where it diffuses relatively slowly to the receptor, accounting for its slow onset and long duration of action. The plasmalemma hypothesis has some experimental support. 33,34 It seems that a high topical concentration of formoterol is needed for accumulation in the plasmalemma and subsequent long duration of action. This may explain the longer duration of action of formoterol via the inhaled rather than the oral route, since local concentrations within the lung will be higher when inhaled than when the drug is taken orally Agonism Salmeterol and formoterol differ with respect to potency, efficacy and selectivity. 31 Formoterol has a higher affinity for 2 -adrenoceptors than salmeterol. Also, the efficacy of formoterol is higher than that of salmeterol, the former being a full 2 -agonist, while the latter is only a partial 2 -agonist. In principle, partial 2 -agonists may prevent more efficacious 2 -agonists from working. Experiments performed with guinea pig tracheal strip preparations have shown that salmeterol acts as a competitive antagonist and reduces the bronchodilating capacity of the short-acting 2 -agonist, salbutamol. 36 Salmeterol has the highest 2 -selectivity of any 2 - agonist. It is claimed that a higher 2 -adrenoceptor selectivity will reduce the occurrence of side effects associated with the stimulation of 2 -adrenoceptors per se, particularly on the human heart. However, this does not appear to be the case in practice, and it has been shown that the cardiostimulating effects of 2 -agonists are largely due to 2 -adrenoceptors and not 1 - or 3 - adrenoceptors. 37,38 Delivery Devices A number of different delivery devices are available for both formoterol and salmeterol. Each has distinct deposition characteristics, which affect the therapeutic potency of the drug. 39 Doses are given as metered dose, delivered dose, or labeled (or nominal) dose, making dose comparisons between devices difficult. The metered dose is the dose that leaves the dosing unit, while the delivered dose is the amount of drug that leaves the mouthpiece, and the labeled (or nominal dose) is the dose specified on the product label. To facilitate comparisons in the present review, the metered dose is emphasized (i.e., 4.5 g delivered dose from Turbuhaler is equal to 6 g metered dose, and 9 g delivered dose is equal to 12 g metered dose). Traditionally, both compounds have been administered using propellant-driven pressurized metered dose inhalers (PMDIs). These are problematical and require a

3 Long-Acting 2 -Agonists in Asthma 223 high degree of coordination to use correctly. Many children fail to use these devices properly, and their use is not recommended in pediatrics. 39 The more recently developed dry powder inhalers (DPIs) eliminate most of the problems associated with using PMDIs. Salmeterol is available in an aerosol formulation administered via a PMDI or DPI Diskhaler or Diskus (Accuhaler ). Studies in children have shown comparable efficacy between these different formulations. In a randomized, doubleblind study involving 162 children (aged 4 16 years) with symptomatic asthma, comparable values of peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV 1 ) and daytime and night-time symptom scores were reported with salmeterol (50 g bid) administered from PMDI or DPI Diskhaler for 2 weeks. 17 Formoterol is available as PMDI (Foradil ) and DPI (Aerolizer and Oxis Turbuhaler ). Suitability of the Aerolizer for children has been questioned due to excessive flow-dependent effects on lung deposition. 8 According to in vitro estimates, Turbuhaler provides a lung dose approximately twice that of the PMDI. 39 The recommended dose from Oxis Turbuhaler in children (>6 years) is currently 6 12 g (od/bid). SINGLE-DOSE EFFECTS Sixteen, peer-reviewed, randomized, double-blind, controlled pediatric trials have assessed the effects of single doses of long-acting 2 -agonists: eight trials with formoterol, 1 8 and eight trials with salmeterol responses can show considerable variation and some patients can reach a plateau with maximum bronchodilation at relatively low doses, whereas others may benefit from doses above the usual recommended dose. The high therapeutic ratio (efficacy:safety) with formoterol allows individually increased dosing if required. Therefore, it has been suggested that the dose should be titrated according to effect. 40 Two single-dose comparison studies of salmeterol have reported a trend towards a dose-related improvement in pulmonary function in the dose range from g. 9,15 In a randomized, double-blind, crossover study in 20 children, single doses of salmeterol 50 g PMDI provided significantly better bronchoprotection against methacholine than salmeterol 25 g, from 30 min to 12 h. 9 The 12-h serial lung function in 243 asthmatic children showed consistently higher lung function from single doses of 50 g salmeterol than from 25 g salmeterol PMDI, though this was not statistically significant. 15 Two single-dose studies on the bronchoprotective effect of inhaled salmeterol (Diskhaler ) on exerciseinduced bronchoconstriction (EIB) found no significant differences between the protection offered by single doses of 25 g or 50 g of salmeterol, although there was a trend to greater protection from 50 g. 13,14 The recommended dosage of salmeterol for children 4 years of age is 50 g (bid). For patients aged >12 years, a dosage of 100 g (bid) may be considered in cases of severe airway obstruction. Bronchodilatation, Single Dose Dose-Finding Formoterol exhibited a dose-related effect at doses of 6 54 g in children. 1,4 Cumulative doses of formoterol (6 g, 18 g, and 54 g) and salbutamol (100 g, 300 g, and 900 g) were given from a PMDI to nine children with stable asthma (aged 7 13 years) at hourly intervals in a double-blind, crossover study. 4 Substantial improvements in FEV 1, PEF, and forced vital capacity (FVC) were observed after the first application of both drugs, while subsequent doses gave only minor additional improvement. The authors suggested that formoterol at 6 24 g can be recommended for schoolchildren and that higher doses are not required to produce the desired therapeutic effect. In a controlled study of the 12-h bronchodilatory and bronchoprotective effects of formoterol PMDI, 24 g were more effective than 12 g, which was again more effective than placebo and salbutamol 200 g. 1 The recommended dosage of formoterol for children >6 years is 6 g (nominal dose) bid, which is probably at the steep part of the dose-response curve of formoterol in children with asthma. It should be noted that individual Onset and Duration of Action Inhaled formoterol has a rapid onset of action (3 min) and a maximum effect at 30 min to 1 h after inhalation in asthmatic children, similar to the effect of the shortacting 2 -agonist, salbutamol. 1 3 Inhaled salmeterol has a relatively slow onset of action, with a significant effect reported min after inhalation of a single 50 g dose; 12 this dose is comparable to the effect of salbutamol after 30 min. 9 Because of its slow onset and partial agonist property, it is recommended not to use salmeterol for the treatment of acute asthma symptoms including EIB, or in the treatment of patients with rapidly deteriorating asthma. It has been recommended that patients prescribed salmeterol should have a short-acting 2 - agonist available at all times for the treatment of breakthrough symptoms. 41 Formoterol causes a sustained, significant bronchodilation over 12 h. 1 3 Similarly, salmeterol 50 g results in significant bronchodilation compared with placebo for up to 12 h, 9 and one study has reported a residual effect that approaches significance at 24 h after administration. 11

4 224 Bisgaard TABLE 1 Single-Dose Studies of Long-Acting 2 -agonist in Exercise-Induced Asthma 1 Reference Drug Device Concomitant treatment with inhaled steroid Henriksen et al., 1992 (5) Formoterol PMDI via spacer 3 out of 12 3 h 3h 8h Time of last exercise N Treatment 12 Pl Su F12 Boner et al., 1994 (6) Formoterol PMDI None 12 h 15 Pl Su 200 F12 Daubjerg et al., 1996 (7) Formoterol DPI aerolizer 9 out of h 16 Pl Su 400 F12 Nielsen et al., 1997 (8) Formoterol DPI aerolizer 14 out of h 16 Pl F12 Green and Price, 1992 (10) Salmeterol PMDI via spacer 7 out of 13 9 h 13 Pl S50 Carlsen et al., 1995 (13) Salmeterol DPI diskhaler 18 out of h 23 Pl S25 S50 De Benedictis et al., 1996 (14) Salmeterol PMDI Not reported 12 h 12 Pl S25 S50 Nielsen et al., 1998 (16) Salmeterol DPI diskus 14 out of h 18 Pl S50 Simon et al., 1997 (25) Salmeterol PMDI 14 out of 14 9 h 14 Pl S50 Mean max % fall in FEV 1 Significance 39 ± ± ± 7 F vs. PI: P < ± ± 25 8 ±11 37 ± ± ± ± 13 Fvs.Su: P <0.01 F vs. PI: P <0.001 Fvs.Su: P <0.01 F vs. PI: P < ± 19 F vs PI: P < ± 12 4 ±4 S50vsPI: P < (95% Cl, 23 36) 19 (95% Cl, 12 25) 18 (95% Cl, 12 25) 31 ± ± ± ± 14 S25 vs PI: P <0.001 S50 vs PI: P <0.001 S25 vs PI: P <0.05 S50 vs PI: P < ± 11 S50 vs PI: P < ± ± 6 S50 vs PI: P < All trials double-blind, randomized crossover designs. DPI, dry powder inhaler; PMDI, pressurized metered dose inhaler; Pl, placebo; S, salmeterol; Su, salbutamol; F, formoterol. 2 Indicates dose given. Bronchoprotection, Single-Dose Methacholine Challenge The single-dose protective effects of long-acting 2 - agonists have been assessed in children, using bronchial provocation tests and measuring changes in the provocative concentration required to produce a 20% decrease in FEV 1 from baseline (PC 20 ). The protection offered against methacholine challenge by formoterol, salbutamol, and placebo was determined in a double-blind, randomized, crossover study in stable asthmatic children aged 6 12 years. 1 On 4 treatment days, patients were given placebo, salbutamol 200 g or formoterol PMDI 12 g or 24 g. The FEV 1 and PC 20 were then measured repeatedly over 12 h. After salbutamol inhalation, the mean PC 20 was increased significantly for only 3 h, whereas, after treatment with formoterol 12 g or 24 g, mean PC20 was increased significantly for 12 h. Moreover, the magnitude of protection offered by both doses of formoterol at 12 h was equivalent to that offered by salbutamol at 3 h. Hence, formoterol provided significantly better and longer bronchoprotection than salbutamol. The single-dose bronchoprotective effect of salmeterol 50 g provided significant bronchoprotection for up to 24 h in 20 children (aged 9 16 years) with mild to moderate asthma. 11 In this study, the maximum protective effect was reached 1 h after inhalation (average 3.7 doubling doses (DD) and gradually decreased, being 3.0 DD at 12 h and 1.3 DD at 24 h. Fifteen out of the 20 children reported clinically relevant protection 24 h after inhalation, i.e., more than 1 DD above baseline. Two other pediatric studies have demonstrated that salmeterol at 25 g or 50 g provides protection against methacholineinduced bronchoconstriction, which lasts for up to 12 h, contrasting the 3-h protection afforded by 200 g salbutamol. 9,22 In agreement with these pediatric studies of formoterol and salmeterol, comparative studies of formoterol and salmeterol in adults have shown similar bronchoprotection in adults undergoing methacholine challenge. 42 Exercise challenge Exercise is a frequent trigger of asthma exacerbations in children. Measuring lung function before and after a standardized treadmill exercise can assess this. The percentage protection can be calculated from the percentage reduction in FEV 1 with placebo minus the percentage reduction in FEV 1 after treatment, divided by the decrease with placebo, times 100. A 50% protection is generally considered clinically important. Nine single-dose studies have assessed the protective effect of long-acting 2 -agonists in asthmatic children prone to develop EIB (Table 1), four on inhaled formoterol, 5 8 and five on inhaled salmeterol. 10,13,14,16,25 All studies were designed as double-blind, placebocontrolled, randomized crossover studies, including children who had at least a 15% reduction in FEV 1 after

5 Long-Acting 2 -Agonists in Asthma 225 This could offer an opportunity to study possible disease heterogeneity. Interestingly, leukotriene modifiers protect against EIB in both children 43 and adults with similar variability. 44 In conclusion, single doses of formoterol and salmeterol provide maximal and long-lasting bronchodilatation (>12 h) as well as prolonged protection against EIB and other challenges, with some children achieving full protection for more than 12 h after a single dose. Individual differences in response to a single dose were observed, and individual dose-titration according to effect may be attempted. The onset of action of formoterol was comparable to salbutamol, while salmeterol had a slower onset. Fig. 1. Maximum change in FEV 1 after exercise performed 8 12 hafterasingledoseofformoterol(5,6,7,8)orsalmeterol(10, 13, 14, 16). standardized submaximal exercise on a treadmill. The last exercise challenge was performed 8 12 h after a single dose of salmeterol or formoterol. It is quite clear from these nine studies that, on average, children benefit clinically useful protection against EIB for at least 12 h after single-dose inhalation of salmeterol or formoterol. On the other hand, it is also clear that there is heterogeneity to the bronchoprotective effect of long-acting 2 - agonists (Fig. 1). A considerable percentage of patients did not receive clinically relevant protection against EIB at the last exercise challenge, while others were fully protected. The protective effect of formoterol 12 g from a DPI (Aerolizer ) 12 h after drug administration in 32 children was assessed in two studies, 7,8 and showed a median protection of 40%. Four studies tested the effect of salmeterol in 68 children 12 h after drug administration from DPIs. 6,13,14,16 The median protection was 42%, i.e., not all the children were well protected from salmeterol or formoterol against EIB 12 h after dosing. The individual responses to exercise in all nine studies are depicted in Figure 1, showing a large group of children who have clinically important EIB 8 12 h after receiving salmeterol or formoterol. The reason for this heterogeneity is unclear. It may partly reflect that the bronchoprotective effect is less than 12 h. However, a similar scatter in the level of protection was revealed in the studies challenging at 8 9 h post-dose. This heterogeneity may be ascribed to unreliable drug delivery to the lung from inefficient devices, 8 to heterogeneity of the disease, or to 2 -receptor heterogeneity. Future studies should focus on the group of patients with apparently poor bronchoprotection from long-acting 2 -agonists. EFFECTS OF REGULAR TREATMENT Fourteen peer-reviewed reports on randomized, double-blind, controlled pediatric trials have assessed the effects on lung function following regular treatment with salmeterol (Table 2), while no such reports have been published on formoterol. Bronchodilatation Monotherapy in Steroid-Naive Children Four peer-reviewed studies have reported on the longterm bronchodilatory effect of salmeterol as monotherapy in corticosteroid naive asthmatic children (Table 2) ,26 In each study, subjects were randomly assigned to receive either salmeterol 50 g (bid) or a comparator (placebo or beclomethasone dipropionate (BDP)). Verberne et al. (1996) compared the effects of salmeterol 50 g (bid) with salbutamol bid during a 12-week study period in 30 corticosteroid-naive children. 22 At no time, either after the first dose was given or during the treatment period, were there any significant changes in FEV 1 within or between the two treatment groups measured 12 h after the last dose. In a subsequent 12-month study, Verberne et al. (1997) compared the effects of salmeterol with inhaled BDP 200 g (bid) on lung function and symptoms (Table 2). 23 Sixty-seven children with mild to moderate asthma (not treated with inhaled corticosteroids in the previous 6 months, and aged 6 16 years) were randomized to treatment for a 1-year period. After 1 year, the FEV 1 measured h after study drug had increased significantly in the children treated with BDP; however, in the salmeterol group, there was a reduction of 4.5% in predicted values for FEV 1 (95% confidence interval (CI ), ) in the prebronchodilator FEV 1 and a similar decrease in the postbronchodilator FEV 1. The differences between the groups were 14.2% in predicted (P < ) and 7% in

6 226 Bisgaard TABLE 2 Long-Term Effect of Salmeterol on Airway Caliber in Pediatric Studies 1 Reference Design Device Anti-inflammatory treatment Duration N Treatment Verberne et al., 1996 (22) P-G Diskhaler DPI None 12 weeks 30 SALM 50 SALBU Verberne et al., 1997 (23) P-G Diskhaler DPI None 12 months 67 SALM 50 BDP Simons, 1997 (24) P-G Diskhaler DPI None 12 months 241 SALM 50 BDP Weinstein et al., 1998 (26) P-G Diskhaler DPI None 12 weeks 207 SALM 50 Meijer et al., 1995 (18) P-G Diskhaler DPI All on inhaled steroid 16 weeks 40 SALM 50 Russell et al., 1995 (19) P-G Diskhaler DPI All on inhaled steroid 12 weeks 210 SALM 50 Hewer et al., 1995 (20) P-G Diskhaler DPI All on inhaled steroid 8 weeks 23 SALM 100 Lenney et al., 1995 (21) P-G Diskhaler DPI or pmdi Von Berg et al., 1998 (28) Zarkovic et al., 1998 (27) P-G C-O 55% on inhaled steroid 3 months 847 SALM 50 SALM 25 SALBU Diskhaler DPI 52% on inhaled steroids 12 months 426 SALM 50 Diskhaler DPI 80% on inhaled steroids 6 months 91 SALM 50 Change from baseline 2.5% pred 3.9% pred 4.5% pred +10% pred +10% pred +10% pred +5% pred +5.8% pred +2.2% pred +0.2 L 0.2 L +13% pred +11% pred FEV 1 Difference from comparator NS P < P <0.001 P <0.001 NS P <0.05 P <0.05 Change from baseline +49L/min +61 L/min +41 L/min +35 L/min +25 L/min +25 L/min +13 L/min +8.2% pred +4.9% pred +26L/min 35 L/min +28 L/min +22 L/min +15 L/min +56L/min +44 L/min +16 L/min +8 L/min Morning PEF Difference from comparator NS P <0.001 P <0.05 P <0.001 P <0.05 P <0.05 P <0.05 P <0.05 P < P-G, parallel groups; PI-C, placebo-controlled; C-O, cross-over; DPI, dry powder inhaler; NS, not significant;, placebo; SALM, salmeterol bid. NS predicted (P 0.007) values for FEV 1 for pre- and postbronchodilator responses, respectively. Simons reported on a study of 241 children (mean age, 9.3 years) with clinically stable asthma and less than 1 month of prior corticosteroid use. The children were randomized to receive BDP 200 g (bid), salmeterol 50 g (bid), or placebo for 1 year. 24 BDP and salmeterol were equally efficient in improving FEV 1 measured at 12 h post-dose compared to placebo (FEV 1 : +10% (salmeterol); +10% (BDP); +5% (placebo) compared with baseline). Weinstein et al. (1998) reported on 207 children (aged 4 11 years), comparing salmeterol and placebo for 12 weeks (Table 2). 26 The 12-h serial PEF and FEV 1 exhibited a significant improvement after 12 weeks of treatment. In addition, a statistically significant (albeit clinically small) increase in morning PEF (25.1 ± 2.3 L/min vs ± 2.5 L/min), evening PEF (20.0 ± 2.5 L/min vs ± 2.5 L/min) and reduction in the use of rescue medication ( 0.8 ± 0.2 puffs/day vs. 0.3 ± 0.1 puffs/ day) were noted with salmeterol treatment, compared with placebo. Add-On to Inhaled Corticosteroid Treatment Three studies have investigated the effect of long-acting 2 -agonists as add-on therapy to inhaled corticosteroid in the treatment of childhood asthma. In addition, three studies have addressed the effect of salmeterol in mixed groups of children, the majority of whom were on concomitant anti-inflammatory treatment (Table 2). 21,27,28 Addition of salmeterol to inhaled corticosteroid treatment provided a small benefit in FEV 1 over 4 months of treatment in 40 asthmatic children (aged 7 15 years). 18 The initial response more strongly favored salmeterol over placebo, but the difference was not significant after 4 months of treatment (5.8% ± 2.6% for salmeterol vs. 2.2 ± 2.1 for placebo, P 0.3). In a multicenter, double-blind study of 210 children (aged 4 16 years), already receiving inhaled BDP (mean dose 750 g), additional salmeterol (50 g bid) or placebo were given over a 12-week treatment period. 19 A maintained (yet small) improvement in mean morning PEF was seen with added salmeterol compared with placebo (8.2% vs. 4.9%; P < 0.05), and there was a significant improvement in evening PEF after 4 weeks but not thereafter. The number of symptom-free days was also significantly increased with salmeterol (P < 0.05). In 23 adolescents (aged years) with difficult to manage asthma, salmeterol dry powder (100 g bid) significantly improved morning and evening PEF and FEV 1 when compared with placebo. 20 Importantly, the children had previously been symptomatic despite maintenance treatment with high-dose inhaled corticosteroids. Three studies evaluated children with and without concurrent anti-inflammatory treatment. 21,27,28 Two separate studies were compiled into one report on the effect of salmeterol vs. salbutamol (no placebo control) in children, 55% of whom were on regular inhaled corticoste-

7 Long-Acting 2 -Agonists in Asthma 227 roids. 21 A total of 847 children were treated with salmeterol 50 g vs. salmeterol 25 g vs. salbutamol 200 g, all given bid from either PMDI or Diskhaler. At 3 months, the adjusted mean changes from baseline in morning PEF were 9.5%, 7.4%, and 5.3%, respectively, all greater than after 1 week of treatment. Salmeterol 50 g was significantly superior to salmeterol 25 g and salbutamol 200 g with regard to morning and evening PEF, irrespective of corticosteroid treatment, though the improvements in evening PEF with both doses of salmeterol were similar. 21 Von Berg et al. (1998) reported on 426 children (aged 5 15 years) randomized to receive salmeterol or placebo over a 12-month period. 28 Concurrent anti-inflammatory treatment (inhaled corticosteroid, cromoglycate, or nedocromil) was used by 76% of the children. Throughout the study, the mean change in morning PEF relative to baseline was slightly but significantly higher with salmeterol than with placebo. At the end of the study, the improvement in PEF was +56 L/min (salmeterol) compared to +44 L/min (placebo), which is of minor clinical importance. The effect of salmeterol 50 g bid was compared to placebo over 6 months in a cross-over, within-patient comparison study. 27 Eighty percent of the study population was receiving inhaled corticosteroid therapy. An unusual failure rate may have biased this study: 153 children were enrolled, of whom 91 were randomized and 68 completed the study. Salmeterol failed to improve lung function. The increase in PEF on salmeterol was +16 L/min and placebo 8 L/min. Symptoms showed a statistically significant improvement, though of little clinical importance (median symptom-free days for salmeterol was 85% compared with 76% for placebo). In summary, the improvement in lung function from regular treatment with salmeterol 50 g bid in asthmatic children, although usually statistically significant, is of limited clinical significance (Table 2). Changes in FEV 1 ranged in the best case from 5% increases over placebo treatment, 24 and in the worst case to a 4.5% loss from baseline over a 1-year period. 23 One study with 23 children reported a 61 L/min advantage in peak flow from salmeterol over placebo. 20 The remaining reports show either less or no change in FEV 1. PEF improved between 8 L/min and 16 L/min from regular treatment with salmeterol compared with salbutamol or placebo in five studies comprising 1,812 children. 21,24,26 28 Most studies have indicated that regular treatment with salmeterol in pediatric asthma with or without concomitant corticosteroid treatment provides statistically significant bronchodilatation, but the improvement is of limited clinical significance. Such evidence does not support a general recommendation of salmeterol as regular add-on therapy, though it may be of benefit to individual patients. There are no reports on formoterol, but a different outcome is not expected. Comparison of Adding a Long-Acting -2 Agent to Increasing the Dose of Inhaled Corticosteroid Studies in adults suggested that the addition of salmeterol to existing corticosteroid therapy may be more efficient in controlling asthma symptoms and lung function compared with doubling the dose of inhaled corticosteroid The effect of add-on therapy with salmeterol vs. an increased dose of inhaled corticosteroid was studied in 177 children. 29 The children, who received inhaled corticosteroids, were randomized into three treatment groups. Children received either BDP (200 g bid) with or without salmeterol (50 g bid), or a higher dose of BDP (400 g bid) alone for 1 year. At the end of the 1-year treatment period, there was no significant difference in symptom scores, exacerbation rate, PEF measurements, FEV 1, or airway hyperresponsiveness between the treatment groups. All groups improved significantly, probably as a reflection of improved compliance to treatment during the study. Since no difference was found between 400 and 800 g daily doses of BDP, it appears that the flat part of the corticosteroid doseresponse curve had already been reached for this group of children. From this study, we cannot conclude anything regarding the relative benefits of increased doses of inhaled corticosteroids vs. the addition of salmeterol in children. Bronchoprotection Tolerance Downregulation of the 2 -adrenoceptor as a consequence of regular receptor stimulation with 2 -agonists is well established. Regular treatment with short-acting 2 - agonists causes a reduction of its bronchoprotective effect against methacholine-induced bronchospasm 48 and increases airway responsiveness during allergen challenge. 49,50 This has been considered a possible mechanism for the epidemiological evidence of loss of asthma control from regular use of short-acting 2 -agonists. 51,52 There is no reason to suggest that such unwanted effects of regular therapy with short-acting 2 -agonists would not be seen with long-acting 2 -agonists. Cheung et al. (1992) in a parallel group study compared the effects of salmeterol 50 g bid and placebo given for a period of 8 weeks to adults with mild asthma. 55 The protection to methacholine PC 20 dropped from 3.3 DD after the first dose to 1.0 DD after 4 and 8 weeks of continuous treatment with salmeterol, despite well-maintained bronchodilatation. There is now a growing body of evidence in adults to show that regular use of long-acting 2 -agonists results in increased airway responsiveness to allergen

8 228 Bisgaard TABLE 3 Long-Term Effect of Salmeterol on Bronchial Reactivity in Pediatric Studies 1 Reference Design Device Anti-inflammatory treatment Duration N Treatment Verberne et al., 1996 (22) P-G Diskhaler DPI None 12 w 30 SALM 50 SALBU Verberne et al., 1997 (23) P-G Diskhaler DPI None 12 m 67 SALM 50 BDP Meijer et al., 1995 (18) P-G Diskhaler DPI All on inhaled steroid 16 w 40 SALM 50 Zarkovic et al., 1998 (27) C-O Diskhaler DPI 80% on inhaled steroids 6 m 91 SALM 50 Simons (24) P-G Diskhaler DPI None 12 m 241 SALM 50 BDP Bronchial reactivity Difference from comparator 52 g 25 g 0.73 DD DD +1.2 DD +0.8 DD 42 g 43 g na na P P 0.05 P < NS NS NS P < P-G, parallel groups;, placebo-controlled; DPI, dry powder inhaler; w, week; m, month; na, not available; ns, not significant;, placebo; SALM, salmeterol bid. challenge 53,54 and reduced protective effect against nonspecific bronchoconstrictors Tolerance to bronchoprotection occurs more readily than for bronchodilator effects. 58,60,61 This disparity between tolerance to bronchodilatation and bronchoprotection is poorly understood. The rapid development of tolerance to regular salmeterol has been reported as early as after two doses of salmeterol when used as monotherapy. 57 Tolerance has been attributed to subsensitivity of 2 -receptors, as it is associated with a significant reduction in lymphocyte 2 -adrenoceptor density. 62 Corticosteroids have a facilitatory effect on 2 -receptor function, probably because of their effects in increasing 2 - adrenoceptor transcription and expression, 63 and should therefore counteract this downregulation. Systemic corticosteroids did in fact seem to attenuate or reverse subsensitivity, as evaluated by the systemic response in asthmatic adults. 64 However, subsensitivity as evaluated from the airway response in asthmatics was not affected by the addition of inhaled corticosteroids ,61,65 The effects of frequency and dose on bronchoprotection by formoterol compared to regular terbutaline were assessed in a randomized, parallel-group, double-blind study in 72 adult patients. 61 Patients received formoterol 6 g (bid), 24 g (bid), or 12 g (od), terbutaline 500 g (qid), or placebo. It was found that tachyphylaxis was not related to dose frequency during the day or the total daily dose, and the residual degree of protection after 2 weeks of treatment with formoterol was comparable to that observed with regular terbutaline. The development of tolerance to salmeterol also caused tolerance to the short-acting 2 -agonist, salbutamol, i.e., the development of cross-tolerance from regular add-on treatment to rescue treatment. 57,59,60,62 In a recent pediatric study, regular treatment with inhaled salmeterol 50 g (bid) modified the dose-response curve of the inhaled, short-acting 2 -agonist terbutaline, such that higher doses of terbutaline were required to produce the same degree of bronchodilation. 30 Methacholine Challenge The effect of regular salmeterol treatment on bronchial reactivity has been reported in five pediatric studies (Table 3); no such reports are available for formoterol. Verberne et al. (1996) initially reported on a 4-month study in 30 asthmatic children, in whom salmeterol provided a significant and continued protection against methacholine challenge 12 h after the last dose compared with baseline and salbutamol. 22 The protective effect during chronic treatment, however, was significantly less than the effect after the first dose of salmeterol (0.6 ± 0.3 DD and 1.7 ± 0.3 DD, respectively). This tolerance to the protective effect of salmeterol occurred early on, with no indication of progression. The same Dutch research group 23 pursued these observations in a subsequent 1-year study. This time they reported a significant deterioration of bronchial responsiveness in a group of children treated with salmeterol as monotherapy for 12 months, with a mean decrease in PC 20 of DD (95% CI, ). A parallel group of asthmatic children on regular BDP had an improved bronchial reactivity of DD (95%CI, ). The median PD 20 values were 7 g and 58 g for the salmeterol and BDP treated groups, respectively, after 1 year of treatment. Meijer et al. (1995) showed significant initial bronchoprotection from salmeterol at 8 h after an initial dose, but a subsequent loss of protection after 1 week of regular use of salmeterol, and overall no sustained protection in a 16-week study in 40 children. 18 Similarly, Zarkovic et al. (1998) failed to find any sign of bronchoprotection following 6 months of treatment with salmeterol in a cross-over study of 91 asthmatic children. 27 The effect of long-term treatment on airway responsiveness was reported from a 1-year study of 241 children, 24 in which regular salmeterol treatment was compared with BDP and placebo. Bronchial reactivity improved following BDP treatment with more than doubling of the PC 20 value, but there was no difference between salmeterol

9 Long-Acting 2 -Agonists in Asthma 229 and placebo treatment on PC Von Berg et al. (1998) reported on a subgroup of children from a multicenter comparison of salmeterol vs. placebo. 28 The protection was small ( DD) and apparently not different from placebo treatment, although a statistical comparison was not reported. There was no evidence in any of these pediatric studies of rebound deterioration in bronchial responsiveness after stopping treatment with long-acting 2 -agonists, 18,24 nor in adult studies. 55 Exercise Challenge EIB may be considered an important and clinically relevant measure of bronchial hyperreactivity. Tolerance to the protective effect of salmeterol on EIB was consistently reported in the three available studies, 25,56,66 including one study in adolescents. 25 Twelve adults with EIB were treated with salmeterol (bid) for a month in a double-blind, crossover trial. Salmeterol produced significant protection against EIB at 6 and 12 h after the first dose in comparison with placebo, whereas there was no significant attenuation of EIB after 4 weeks of regular treatment with salmeterol despite continued bronchodilatation. 56 In another study in 20 adult asthmatics, the morning dose of salmeterol attenuated the degree of bronchoconstriction after exercise 30 min following a dose, with no significant change through 4 weeks regular treatment (decrease in FEV 1 on day 1, 5 ± 2%; on day 29, 9 ± 3%; P 0.1). However, the duration of protection from salmeterol fell with prolonged use, and the benefit recorded 9 h after dosing diminished significantly by the second week. Although salmeterol was initially better than placebo, there was no difference at the 9-h time-point after 4 weeks of treatment. The mean additional fall in FEV 1 between the half-hour and 9-h exercise challenge was 6 ± 2% on day 1, and 14 ± 3% on day 29 (P 0.003). 66 Simons et al. showed significant initial protection against EIB from the administration of once daily adminstration of salmeterol 50 g in adolescents (aged years) on regular inhaled corticosteroids. 25 However, after 28 days of continuous treatment, the bronchoprotective effect was markedly reduced and was only significantly greater than placebo at 1 h post-administration but not 9 h after drug administration, despite concomitant use of inhaled corticosteroid, and use of salmeterol only once daily. These consistent observations in adults and adolescents, that tolerance becomes apparent by the end of the time-response curve, probably reflects that tolerance is more easily revealed when the drug effect is marginal. In conclusion, regular treatment with salmeterol in asthmatic children does not maintain prolonged bronchoprotection against nonspecific irritants, including EIB. No reports on formoterol are available, but a different outcome is not expected. Tolerance develops if longacting 2 -agonists are used as regular treatment with or without concomitant corticosteroid treatment, and crosstolerance to short-acting 2 -agonists also appears to be present. The clinical significance of long-acting 2 agonists in protecting against EIB is not yet clear. It is possible that tolerance from regular use of long-acting 2 - agonists may contribute to less effective control of asthma. In clinical practice, tolerance may translate into reduced bronchoprotection against irritants, exercise, and other asthma triggers, with an increased clinical vulnerability to unpredictable attacks, while maintaining normal baseline lung function between such attacks. DISEASE CONTROL Long-Term Effects Early data indicated some anti-inflammatory properties of long-acting 2 -agonists in vitro. 32 However, there are no clinical data to support this observation. Recent clinical studies demonstrated that salmeterol has no effect on eosinophil airway inflammation, as reflected by eosinophilia in sputum or bronchoalveolar lavage fluid, 67,68 nor does it affect the alleged inflammatory marker nitric oxide (NO) in exhaled air. 30 On the contrary, the bronchodilating and symptomrelieving effects of salmeterol can mask increasing inflammation and delay awareness of worsening of asthma. In a recent controlled clinical trial using a steroidreduction model to induce exacerbations in adult asthmatics, salmeterol controlled symptoms and PEF for a longer period before an inflammatory exacerbation (increased eosinophils in sputum) became clinically evident, masking the increasing inflammation preceding an exacerbation. 69 That this is not merely a theoretical concern is illustrated by the pediatric study by Verberne et al. 23 Symptoms improved during regular monotherapy with salmeterol, while lung function and bronchial hyperresponsiveness significantly deteriorated. This shows that a reduction in symptoms may occur during salmeterol treatment, with a concomitant deterioration in airway responsiveness. Such worsening of bronchial reactivity may reflect uncontrolled airway inflammation. Exacerbations In the study by Verberne et al., 23 asthma exacerbations requiring oral corticosteroid were more frequent (17 vs. 2), as were the numbers of withdrawals due to exacerbations (6 vs. 1) in the salmeterol group compared to the control group treated with inhaled corticosteroids. Four other pediatric studies have reported on the incidence of asthma exacerbation during regular treatment with salmeterol. Exacerbation rates on salmeterol and placebo treatment were 62% and 53% per 12 months in the larg-

10 230 Bisgaard est controlled report on pediatric exposure, 28 the difference showing a borderline significance ( 2 test, P 0.05). Similar trends were reported in the three other available reports. 20,21,27 Lack of asthma control, as reflected by unchanged or increased bronchial reactivity and an increased rate of asthma exacerbation, is an important marker for inadequate asthma control. Regular treatment with longacting 2 -agonists may mask the severity of the disease and allow ongoing inflammation. 69 If long-acting 2 - agonists are used as regular treatment, concomitant antiinflammatory treatment should be emphasized. In conclusion, there is no evidence of an anti-inflammatory effect from inhaled long-acting 2 -agonists. These drugs leave underlying inflammation uncontrolled, which might be expected to result in increased bronchial hyperreactivity and higher rates of exacerbation. The available pediatric reports seem to support such impression of loss of asthma control, though this is in contrast to studies on moderately to severe asthmatic adults. 47 In conjunction with appropriate anti-inflammatory treatment, regular add-on treatment with long-acting 2 -agonists may be of less concern. TOLERABILITY AND SAFETY Formoterol and salmeterol are generally well tolerated without clinically important side-effects. Similar to other 2 -agonists, inhaled formoterol or salmeterol are associated with some cardiovascular and other nonpulmonary side effects, including tremor, palpitations, and changes in blood glucose and plasma potassium concentrations. In the clinical studies mentioned in this review, both formoterol and salmeterol were associated with the occurrence of minimal side effects. The most commonly reported adverse events were disease-related. The tolerability of formoterol at high doses has been demonstrated in adults. Twenty standard doses of formoterol (total 120 g) and 20 standard doses of terbutaline (total 10 mg) were administered from a Turbuhaler to adult asthmatic patients over 3 consecutive days. 70 The effects on serum potassium, heart rate, blood pressure, and ECG were compared. Terbutaline had a statistically significantly greater effect than formoterol on heart rate, PR-interval, QT-interval, QTc, and serum potassium concentrations. The systemic effects had the same short duration with formoterol as with the shortacting 2 -agonists. The same number of standard dose inhalations of formoterol elicited fewer systemic responses than the same number of standard dose inhalations of terbutaline. In children, single-dose studies found no difference in systemic side-effects between high-dose formoterol (48 78 g) and salbutamol. 4 These studies demonstrated good tolerance of formoterol and have shown that, in contrast to its bronchodilating effects, the systemic effects of formoterol are short-lasting and similar to those observed with short-acting 2 -agonists. If formoterol was utilized as rescue medication, there would be no safety implications. This has important implications for future therapeutic applications of formoterol. Similar to formoterol, the use of inhaled salmeterol in adults is associated with some cardiovascular and other nonpulmonary effects, including tremor, palpitations, and changes in blood glucose and plasma potassium concentrations. In general, the development of clinically significant nonpulmonary effects in children was minimal, and the increase in mean heart rate and other cardiac effects were not clinically significant. 41 Headache, which is a pharmacologically predictable effect of 2 -agonists, was reported in 21 of 99 children receiving salmeterol 50 g bid, but only 9 out of 107 children receiving placebo. 19 Headache was also the most commonly reported drug-related adverse event (4% of those treated with salmeterol) in a 1-week study of salmeterol in 243 children. 15 In other studies, headache was reported as frequent 29 or less frequent 23 in children on salmeterol as compared to the comparator group. The most commonly reported adverse events were found to be diseaserelated. 21,28 In conclusion, formoterol and salmeterol are welltolerated drugs, even after long-term use, with an adverse effect profile comparable with that of short acting 2 - agonists. ROLE OF LONG-ACTING 2 -AGONISTS IN PEDIATRIC ASTHMA MANAGEMENT Individual countries have produced detailed guidelines for the management of childhood asthma 71 and international guidelines have been published, e.g., The Global Initiative for Asthma. 72 Although there are slight differences between the individual documents, overall they are remarkably similar. Treatment is generally directed against airway inflammation to prevent long-term sequelae. This strategy is reflected in the strong emphasis placed on the early use of inhaled corticosteroid therapy. It is suggested that long-acting 2 -agonists can be added to inhaled corticosteroids in patients with persistent asthma, whose symptoms are not well-controlled on moderate doses of inhaled corticosteroids. When to start therapy remains a difficult decision, and the minimal dose of corticosteroid at which regular treatment with a long-acting 2 -agonists can be initiated remains subjective. In the opinion of the author, if a child is wellcontrolled on 400 g/day or less of inhaled budesonide (or the equivalent with other corticosteroids), initiation of add-on therapy is not required. However, if a child has

11 Long-Acting 2 -Agonists in Asthma 231 pronounced symptoms despite such treatment (e.g., nocturnal awakening), or is regularly using short-acting 2 - agonists, and has worsening asthma and decline in lung function, further therapy is required. In such cases, initiating long-acting 2 -agonist therapy or leukotriene modifiers should be considered according to the present guidelines. It is of concern that children who are treated with lower doses of corticosteroids, together with regular use of a long-acting 2 -agonist, may suffer an increase in airway inflammation and hyperresponsiveness. The clinical symptoms could be masked by the use of regular 2 -agonist and the child s underlying asthma may deteriorate, increasing the chance of a severe exacerbation. Hence, regular long-acting 2 -agonist use should always be combined with adequate anti-inflammatory therapy in children. ROLE OF LONG-ACTING 2 -AGONISTS IN FUTURE PEDIATRIC ASTHMA MANAGEMENT The regular use of short-acting 2 -adrenergic stimulants has been discouraged in most guidelines. One reason is that tolerance to bronchoprotective efficacy develops as a result of regular long-term treatment with 2 - stimulants, as referenced above. This has been suggested to have a negative effect on asthma control and mortality The current positioning of long-acting 2 - agonists as regular add-on treatment, therefore, seems to contradict this notion. The bronchodilating effect gained from regular treatment in most studies is small and likely of little clinical importance, and the induced tolerance reduces the advantage of prolonged protection against EIB, which is of major importance to children. Therefore, it may be time for a reappraisal of the positioning of the use of long-acting 2 -agonists in pediatric asthma. In future treatment strategies, prescription of long-acting 2 -agonists may be suggested instead of a short-acting 2 -agonists, for use as-required. Hence, such irregular treatment would be less prone to result in development of tolerance, and less likely to mask the development of symptoms. Instead, the benefit of 12-h bronchodilatation and bronchoprotection may be gained. Naturally, the number of inhalations per day will need to be monitored closely, and children will need to be encouraged to continue their anti-inflammatory medication even if they feel that it is not necessary. The as needed use of long-acting 2 -agonists may still be a useful indication that there is a need for adjustment in the dose of corticosteroids. Among the presently available longacting 2 -agonists only formoterol seems to have the rapid onset of action required for use as a rescue medication. Other similar long-acting bronchodilators with rapid onset of action are likely to become available in the future. Considering the good safety profile, it is generally difficult to argue the case for short-term relief when longterm relief is available. The need for long-term relief is particularly evident in the case of the young asthmatic child and in the case of EIB in children. Young children rely on the caretaker for symptomatic treatment. The toddler is often cared for during the day in institutions by people not observant or experienced in detecting asthma-related symptoms. In this particular group of asthmatics, long-acting 2 - agonists could play an important role as as needed treatments with whole-day protection. During symptomatic periods, the mother could give the child one treatment in the morning to ensure effective symptomatic relief throughout the day when the child is away from home. This potential usefulness of long-acting 2 - agonists in young asthmatics should certainly be explored in future studies. EIB is a common expression of pediatric asthma. Physical activity is essential for the social and physical development of a child. EIB is the most important symptom to treat from the child s perspective. The present guidelines emphasize the use of rescue, short-acting 2 - agonists for EIB. However, this is insufficient for most children. Typically, children do not have a scheduled life with exercise planned ahead. Instead, exercise is engaged in spontaneously. Therefore, the recommendation to use short-acting 2 -agonist preferably 15 min before exercise may be valid for adults but is seldom of use to the child. Long-term coverage is definitely preferred to protect the child from EIB. Inhaled corticosteroids can be used to treat exerciseinduced asthma and provide full-time coverage, but high doses are generally required to provide more than mere control of symptoms and baseline lung function. 73 The benefits of long-acting 2 -agonists on EIB are convincing in single-dose studies, and they protect against exercise and other challenges significantly longer than do the short-acting 2 -agonists. Combined with exceptional tolerability following multiple doses, long-acting 2 - agonists may be recommended for use as-required. This will provide the child with an effective treatment for EIB while avoiding the disadvantage of regular treatment with 2 -stimulants. This approach may eventually prove more successful for the management of childhood asthma than current treatment options. To achieve such reappraised positioning of long-acting 2 -agonists, future studies should assess the potential of these agents as rescue medication. Also, their potential as steroid-sparing drugs should be further explored. Longterm studies are required, and it is essential to investigate the potential additive effects of formoterol and salmeterol on low doses of inhaled corticosteroids. Additional issues that must be addressed include the effects of for-