Asthma is characterized by airway hyperresponsiveness

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1 Long-Acting Bronchodilator or Leukotriene Modifier as Add-on Therapy to Inhaled Corticosteroids in Persistent Asthma?* Graeme P. Currie, MD; Daniel K. C. Lee, MD; and Prasima Srivastava, MD Despite the widespread use of inhaled corticosteroids, many asthmatic patients experience persistent symptoms. In such individuals, the addition of a long-acting 2 -agonist (LABA) is frequently more effective than doubling the dose of inhaled corticosteroid. However, the role of additional therapy with a leukotriene receptor antagonist (LTRA) as an alternative to an LABA has been the focus of attention in recent studies. In order to determine the overall efficacy of the pharmacologic armamentarium used in asthma, it is imperative that a combination of end points, including lung function, airway hyperresponsiveness, effects on underlying inflammation, symptoms, and more long-term sequelae such as exacerbations, are assessed. This evidence-based systematic review outlines the pharmacologic properties of LABAs and LTRAs and the importance of evaluating end points in addition to lung function when assessing these drugs. We also highlight the results of all published studies that have performed direct comparisons of both LABAs and LTRAs as add-on therapy to inhaled corticosteroids. (CHEST 2005; 128: ) Key words: asthma; formoterol; inflammation; leukotriene receptor antagonist; long-acting 2 -agonist; montelukast; salmeterol; zafirlukast Abbreviations: AHR airway hyperresponsiveness; CSS Churg-Strauss syndrome; LABA long-acting 2 -agonist; LTRA leukotriene receptor antagonist; PEF peak expiratory flow Asthma is characterized by airway hyperresponsiveness (AHR) 1 with consequent reversible airflow obstruction orchestrated by an array of inflammatory cells and cytokines. Inhaled corticosteroids are crucial in attenuating the underlying inflammatory process, with additional second-line preventive therapy being instituted for patients with persistent symptoms. 2,3 The use of concomitant second-line therapy has become increasingly important as the dose-response effect (in terms of airway caliber) for inhaled corticosteroids such as fluticasone propionate is relatively flat at daily doses 500 g in *From the Department of Respiratory Medicine (Drs. Currie and Srivastava), Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland; and Department of Respiratory Medicine (Dr. Lee), Ipswich Hospital, Ipswich, England, UK. Dr. Currie has received funding from Merck, Sharp, and Dohme and GlaxoSmithKline for attending postgraduate educational meetings; he has also received an honorarium from GlaxoSmith- Kline and AstraZeneca for giving talks. Manuscript received February 25, 2005; revision accepted April 22, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Graeme P Currie, MD, Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN Scotland, UK; graeme.currie@ nhs.net adults. Indeed, most benefit in this study was observed with a fluticasone dose of 100 to 250 g/d. 4 Moreover, there is a greater propensity for systemic adverse effects with increasing doses of inhaled corticosteroids, 5 while patients may express a preference for treatment that avoids an excessive corticosteroid burden. From a pathophysiologic point of view, asthma treatment is directed toward the airway to effectively suppress inflammation, attenuate AHR, and optimize lung function. Ideally, this in turn should translate into benefits in terms of symptom control, prevention of exacerbations, optimizing quality of life, along with patient satisfaction and minimal inconvenience. In most individuals, this can be achieved with an inhaled corticosteroid alone. When symptoms persist despite the use of inhaled corticosteroids in low-to-moderate doses (400 to 800 g/d of beclomethasone dipropionate or equivalent), it is important to firstly assess compliance and inhaler technique along with instructing patients to use a device that facilitates optimum delivery of antiinflammatory therapy to the endobronchial tree. 2 It is important to note that fluticasone is considered twice as potent as beclomethasone and budesonide (on a microgram basis), which in turn is reflected in the 2954 Reviews

2 way these drug are prescribed in clinical practice. 2,3 When these factors have been addressed and patients remain symptomatic, clinicians should consider the addition of concomitant second-line therapy: the so-called step 3 of the asthma treatment escalator. Current UK guidelines propose that in the first instance, a therapeutic trial with a long-acting 2 -agonist (LABA) should be considered, while the addition of a leukotriene receptor antagonist (LTRA) is advocated only after the former option is tried unsuccessfully or if symptoms persist (ie, at step 4). 2 Other guidelines suggest that in moderate persistent asthma, an LABA is added to a low-to-medium dose of inhaled corticosteroid with the addition of an LTRA being a suitable alternative. 3 Considerable debate has emerged concerning the exact positioning of LTRAs in the stepwise management of asthma. Moreover, following the publication of UK guidelines, 2 several large-scale studies 6,7 have directly evaluated the comparative effects of adding LABAs vs LTRAs in symptomatic patients using inhaled corticosteroids alone (ie, at step 3). This evidence-based review outlines the pharmacologic and clinical effects of both drugs (LABAs and LTRAs) in the management of asthma and the importance of assessing a variety of end points when doing so. We also highlight the results of all randomized placebo-controlled trials that have performed head-to-head comparisons of both treatments as therapeutics adjuncts to inhaled corticosteroids. Pharmacology LABAs Salmeterol and formoterol are currently the most commonly used LABAs in clinical practice. Both bind to smooth-muscle 2 -adrenoceptors and demonstrate a bronchodilating effect in excess of 12 h after a single inhalation. 8 Salmeterol is a partial agonist and has a slower onset of action, whereas formoterol is a full agonist and demonstrates a quicker onset of bronchodilation. This pharmacologic property can be exploited, allowing formoterol to be used on an as-needed basis. 9,10 LABAs are potent bronchodilators and demonstrate an airwaystabilizing effect on exposure to an acute bronchoconstrictor stimulus. 11 It is important to be aware that LABAs do not exhibit in vivo antiinflammatory activity 12,13 and as a consequence are not advocated for use as monotherapy. Considerable concern has been focused on the use of LABAs and the masking of underlying airway inflammation. Theoretically, patients may use such drugs for instant bronchodilation and adhere less stringently to inhaled corticosteroid therapy. This may result in persisting chronic mucosal inflammation of which the patient is unaware. In a study by McIvor et al, 14 the use of salmeterol controlled symptoms and maintained airway caliber, although an increase in sputum eosinophils was observed when inhaled corticosteroids were tapered in 13 asthmatic patients. However, it is important to note that large-scale studies with greater relevance to real-life conditions have generally dispelled such concerns. For instance, in a year-long study 15 incorporating 60 moderate asthmatics, no significant differences in sputum markers of airway inflammation were observed between budesonide at 100 g plus formoterol bid compared to a higher dose of budesonide (400 g bid). Moreover, in a case-control study 16 evaluating the safety of LABAs, no adverse effects on mortality with medium-to-long term use were observed. Potentially important critical interactions have been observed between LABAs and inhaled corticosteroids. For example, a synergistic effect on transcription factors and an inhibitory effect on smoothmuscle cell proliferation have been observed when both moieties have been administered concurrently, 17 while salmeterol enhanced the activation of the glucocorticoid receptor in primary human lung fibroblasts and vascular smooth-muscle cells in another study. 18 Moreover, concomitant treatment with an LABA has shown a significant reduction in blood vessel density in lamina propria following direct histologic assessment. 19 However, whether these in vitro observations extrapolate into clinically relevant effects in real life has not been substantiated to any great degree of relevance. 20,21 Genetic polymorphisms of the 2 -adrenoceptor have been identified, where substitution of glycine for arginine at codon 16 (occurring in approximately 40% of the UK population) enhances the susceptibility to down-regulation. In other words, due to prolonged receptor occupancy, the 2 -adrenoceptor becomes internalized and degraded. As a result, an attenuated bronchoprotective response can be observed with different types of inhaled stimuli. 22,23 In the clinical setting of an acute asthma attack occurring in patients receiving LABAs, this may translate into failure to derive benefit from even high doses of inhaled salbutamol. 24 The administration of corticosteroids and LABAs in a single inhaler device is gaining widespread popularity. 25 Currently, salmeterol can be conveniently administered with fluticasone propionate in a single inhaler, and formoterol has been formulated with budesonide. This has the potential advantage of improving patient compliance in view of fewer inhalations and inhaler devices required, while the quick onset of bronchodilation provides patients with a CHEST / 128 / 4/ OCTOBER,

3 relatively instant improvement in airway caliber (especially with formoterol). However, the main drawback is that adjusting the inhaled corticosteroid dose becomes less straightforward, with the potential consequence that patients may receive an unnecessary or insufficient dose for a prolonged period of time. Use of LABAs in Asthma It has become increasingly recognized that the addition of an LABA is frequently superior to increasing the dose of inhaled corticosteroids For example, Woolcock et al 27 randomized 738 asthmatics not controlled on beclomethasone dipropionate, 1,000 g/d, to receive either double their inhaled corticosteroid dose or the addition of two different doses of salmeterol. Exacerbation rates were similar in all three groups, although patients who were treated with either dose of salmeterol experienced fewer symptoms and demonstrated a greater peak expiratory flow (PEF). In a metaanalysis 28 of nine parallel group trials, the addition of salmeterol to a low or moderate dose of fluticasone propionate was superior to at least doubling the dose of the latter in terms of lung function and symptoms. It is relevant to point out that despite no individual study conferring a significant reduction in exacerbations, there was a 2.4% reduction (p 0.03) in moderate-tosevere exacerbations on pooling the data. In patients with more severe asthma, an adequate dose of antiinflammatory therapy should be administered on a regular basis, prior to institution of an LABA. For example, 30 optimizing the inhaled corticosteroid dose to 800 g/d of budesonide and then adding formoterol resulted in a significantly reduced number of severe exacerbations compared to adding formoterol to 200 g/d of budesonide (49% vs 26% reductions, respectively). In a recent landmark study, 10 the use of a combined corticosteroid plus LABA inhaler was evaluated in terms of its use on a regular plus intermittent basis. In this parallel-group study, 10 2,760 asthmatics were randomized to receive terbutaline for as required use along with either 80 g bid of regular budesonide plus 4.5 g of formoterol, or budesonide, 320 g bid. A further group of patients was randomized to receive budesonide, 80 g bid, plus formoterol, 4.5 g, with the same inhaler being used intermittently for acute relief of symptoms. The latter treatment prolonged the time to first severe exacerbation (p 0.001), resulting in a 45 to 47% lower exacerbation risk vs the other treatments. Moreover, using budesonide plus formoterol for both maintenance and relief also prolonged the time to the first, second, and third exacerbations requiring medical intervention (p 0.001), reduced severe exacerbation rates, and improved symptoms and lung function vs both fixed dosing regimens. This simplified approach may in fact reflect what patients do in real life in terms of increased use of treatment according to symptoms. Although not substantiated by the study, concerns would obviously exist regarding over usage of inhaled corticosteroids on a dayto-day basis, especially in those with persistent symptoms. Adverse Effects Inhaled LABAs are generally well tolerated, although adverse effects such as fine tremor and palpitations are occasionally troublesome. These agents should also be used with caution in those with cardiovascular disease, in patients who are at risk for prolongation of the QT interval, and where concomitant drug administration may increase the risk of serious hypokalemia. 31 Pharmacology LTRAs The cysteinyl leukotrienes (C 4,D 4, and E 4 ) are lipid mediators involved in the pathogenesis of asthma, and are produced from an arachidonic acid precursor following a series of enzymatic steps. They exert their effects (Table 1) following activation of specific receptors located on cell membranes of pulmonary smooth muscle and macrophages. Knowledge of the effects of cysteinyl leukotrienes in asthma was therefore instrumental in the development of designer drugs. Despite treatment with even high-dose oral corticosteroids, cysteinyl leukotrienes are found in the airways of asthmatics, in turn suggesting that the addition of an LTRA may provide more complete attenuation of the inflammatory process. 32 Moreover, in a mouse model, parameters reflecting airway remodeling were significantly reduced with the addition of an LTRA. 33 Two LTRAs are licensed for clinical use in the United Kingdom, United States, and Europe (montelukast and zafirlukast), while pranlukast is licensed for use in Japan. Table 1 Effects of Cysteinyl Leukotrienes Actions of Cysteinyl Leukotrienes in Asthma Bronchoconstriction Mucous hypersecretion Enhanced vascular permeability Decreased mucociliary clearance Recruitment of eosinophils to the airway Proliferation of airway smooth muscle 2956 Reviews

4 LTRAs demonstrate bronchodilator and antiinflammatory properties in addition to an ability to attenuate AHR. 34 This in turn suggests that they are perfectly suited to deal with intrinsic components of the asthmatic inflammatory process. A further therapeutic benefit is that LTRAs exert their effects following single doses and are orally active. This latter property may enhance compliance especially in children, adolescents, and the elderly, in whom technical difficulties associated with and dislike of inhaled medication may occur. Furthermore, unlike LABAs, tolerance to their bronchoprotective effects has not been demonstrated. Use of LTRAs in Asthma Clinical trials 35 have shown LTRAs to confer beneficial effects across a range of asthma severities. They can be used as monotherapy, especially in patients with mild asthma and with troublesome exercise-induced symptoms. 36 However, when compared to inhaled corticosteroids as monotherapy, they are inferior in both antiinflammatory and clinical outcome measures. 37,38 Numerous studies 39 have shown LTRAs to demonstrate efficacy as add-on therapy to inhaled corticosteroids (step 3 of UK guidelines). For example, in a study 40 of 642 persistent asthmatics (mean FEV 1, 72% predicted), the addition of montelukast, 10 mg/d, to inhaled beclomethasone dipropionate, 400 g/d, conferred additional asthma control compared to inhaled beclomethasone dipropionate alone. Benefits were observed on lung function, peripheral blood eosinophils, and symptoms. In a further randomized, double-blind, parallel-group, 16-week study, 41 the effects of montelukast, 10 mg/d, administered concomitantly with a constant dose of budesonide (from 400 to 1,600 g/d) were evaluated. Subjects (mean FEV 1, 81%) were symptomatic despite receiving inhaled corticosteroids. Those receiving active treatment experienced 35% fewer asthma exacerbation days along with a 56% increase in asthma-free days when compared to placebo. Concomitant treatment with an LTRA plus an inhaled corticosteroid also conferred benefit in patient-orientated end points including fewer nocturnal awakenings and shortacting 2 -agonist use. There are also data demonstrating that LTRAs have a positive impact in individuals with aspirin-sensitive asthma. 42 Use of LTRAs in Asthmatics With Concomitant Allergic Rhinitis Successful treatment of allergic rhinitis features of which can be found in up to 40% of asthmatics has been shown to confer benefit in asthma control. 43,44 It is increasingly appreciated that LTRAs are of some benefit in patients with allergic rhinitis, albeit less so than the gold standard treatment of nasal corticosteroids. 45 For example, patients with both asthma and concomitant allergic rhinitis were randomized to receive 400 g/d of orally inhaled budesonide plus 200 g/d of intranasal budesonide or 10 mg of montelukast plus 10 mg of oral cetirizine. 46 Both treatments were equally effective in terms of improving lung function, symptoms, and inflammatory markers. In another study 47 of patients with asthma and allergic rhinitis, montelukast was as effective as orally inhaled and intranasal budesonide on lower airway parameters, with both treatments conferring benefit on symptoms of allergic rhinitis. In a multicenter study 48 incorporating 831 patients with symptomatic allergic rhinitis plus asthma, montelukast conferred significant improvement compared to placebo across a variety of upper- and lower-airway parameters. Perhaps asthmatics with concomitant allergic rhinitis requiring additional second-line therapy should preferentially be initially commenced on an LTRA, which in turn may confer a positive effect on both the upper and lower airways. Adverse Effects As a class of drug, LTRAs are generally well tolerated, although adverse effects such as abdominal pain, rashes, headaches, angioedema, pulmonary eosinophilia, and arthralgia have been reported. Due to lack of data, their use in pregnancy is not advised. Concerns have been raised regarding the development of Churg-Strauss syndrome (CSS) and administration of LTRAs. Many, although not all, of the documented cases of CSS have been in patients in whom concomitant LTRA treatment has permitted a reduction in dose of inhaled corticosteroid. This in turn suggests that latent CSS may have been unmasked by a reduction in antiinflammatory therapy delivered to the lungs. 49 Outcome Measures of Asthma Control When assessing the effects of asthma treatment, it is important to incorporate a variety of end points. Indeed, common sense suggests that clinicians should evaluate not only lung function but effects on AHR, biomarkers of inflammation, symptoms, and exacerbations. For example, end points such as lung function tend to favor drugs that act on smooth muscle but provide little information about the underlying inflammatory process or extent of AHR. Moreover, in many studies evaluating the effects of LABAs, 29 an exquisitely high degree of reversibility to inhaled bronchodilator in FEV 1 can be found, CHEST / 128 / 4/ OCTOBER,

5 even as high as of 23%. This in turn may bias results heavily in favor of drugs that relax smooth muscle. In contrast, if only antiinflammatory end points are measured, inhaled corticosteroids will consistently appear superior to bronchodilators. Despite no change in lung function, it is also possible that positive effects on other intrinsic features of the asthmatics inflammatory process occur with pharmacologic intervention. For example, in a study of mild-to-moderate persistent asthmatics, the addition of montelukast to fluticasone propionate plus salmeterol in combination resulted in no additional improvement in FEV 1 or PEF, although additive effects were observed on AHR and inflammatory biomarkers. 21 In a study by Pauwels et al, 30 there was a disconnection between lung function and exacerbations. In other words, despite a significant reduction in exacerbations, FEV 1 and PEF were unchanged when comparing budesonide, 200 g/d, vs budesonide, 800 g/d. This all indicates that when optimizing the dose of inhaled corticosteroid, lung function is relatively distant from the underlying inflammatory process, and despite no change in value, further beneficial clinical effects may actually occur. While classical of asthma, reversibility of at least 12% to inhaled bronchodilator is not always possible to demonstrate in everyday life, especially in patients with normal or near-normal lung function. Indeed, many asthmatics particularly those at the milder end of the spectrum exhibit normal lung function and individuals frequently included in clinical trials may not be reflective of the asthmatic population at large. Indeed, in persistent asthmatics with essentially normal lung caliber, it is likely that underlying inflammation and AHR are the driving forces behind subsequent perception of symptoms and exacerbations. It is also pertinent to consider that when evaluating relatively mild asthmatics, there is frequently no discernable room for improvement in lung function and alternative measures of efficacy of treatment are required. As a consequence, combinations of end points are vital in the overall assessment of efficacy of LABAs and LTRAs in asthmatics of all severities. Materials and Methods A computerized search was carried out using MEDLINE, Clinical Evidence, Cochrane library, and EMBASE databases to extract trials where the add-on effects of LTRA vs LABA were compared in asthmatics all maintained on a constant dose of inhaled corticosteroid. All authors carried out the search by checking for suitable trials as evident from the title and abstract independently of one another. All trials were required to be of a randomized controlled design in which investigators were blinded to treatment, to be ethically approved, and to have results clearly available from the text. Studies were included irrespective of whether they were supported by the pharmaceutical industry. The following key words were used in the search: asthma, long-acting 2 -agonist, leukotriene receptor antagonist, inflammation, lung function, exacerbations, salmeterol, formoterol, montelukast, zafirlukast, and pranlukast. Relevant fully published articles were then selected and the following data extracted: study design, number of patients, length of study, mean inhaled corticosteroid dose, which randomized treatments were used, effects on the primary end point, and effects on FEV 1, PEF, symptoms or quality of life, inflammatory biomarkers, AHR, and exacerbations were measured. Following statistical consultation, it was determined that there was too much heterogeneity (in terms of different primary end points, variable time of measurements after dosing, different delivery devices, different LTRA used, and different salmeterol doses) between the trials to proceed to a formal metaanalysis. Results Nine trials were identified that evaluated the effects of LTRAs vs LABAs as add-on therapy to inhaled corticosteroids (Table 2). In all of these, patients were receiving constant doses of inhaled corticosteroids, although in one study no mean dose was documented. No significant differences in serious adverse effects were found between treatments, and both were well tolerated. Exacerbations Six trials evaluated effects on exacerbations. In four of these 6,7,53,55 including the two of longest duration and greatest number of patients no significant differences were observed between randomized treatments. In the other two studies 50,51 (where effect on exacerbations was a secondary end point), the addition of salmeterol was superior compared to montelukast. However, in one of these studies 50 incorporating 447 randomized patients, as few as 4 patients (2%) in the salmeterol-treated group vs 13 patients (6%) in the montelukast-treated group experienced an exacerbation (p for the difference). Lung Function and Symptoms In most trials, the addition of an LABA conferred superiority over add-on LTRA in terms of lung function (FEV 1 and PEF). In one study, 52 no difference was observed in lung function between randomized treatments, although salmeterol improved FEV 1 and PEF compared to placebo, while montelukast only improved the PEF compared to placebo. Quality of life and symptoms were the primary outcomes in none of the studies identified. In most trials (five of nine studies), 6,21,50,52,54 no significant differences were observed between add-on LABA or LTRA in terms of symptoms or quality of life. In one 2958 Reviews

6 Table 2 Studies Comparing Effects of LABAs vs LTRA as Add-on Therapy to Inhaled Corticosteroids Sourcee Design Randomized Subjects, No. Duration, wk Treatment ICS, g FEV 1 PEF Inflammatory Biomarker AHR Exacerbations Quality of Life or Symptoms Fish et al 53 PG SM vs ML 606 NA LABA * NA NA NSD LABA Bjermer et al 6 PG 1, SM vs ML 200 LABA LABA LRTA NA NSD* NSD Ilowite et al 7 PG 1, SM vs ML 220 LABA LABA LRTA NA NSD* LABA Currie et al 21 XO 22 8 SM vs ML 466 NSD LABA LRTA LRTA * NA NSD Nelson et al 50 PG SM vs ML 200 LABA LABA * NA NA LABA NSD Wilson et al 52 XO 20 6 SM vs ML 800 NSD NSD LRTA NSD* NA NSD (median) Ringdal et al 51 PG SM vs ML 200 LABA LABA * NA NA LABA LABA Storms et al 54 PG SM vs ML 200 LABA * NA NA NA NA NSD Nelson et al 55 PG SM vs ZL NA LABA LABA * NA NA NSD LABA *ICS mean daily inhaled corticosteroid dose at study entry (unless specified); SM salmeterol; ML montelukast; PG parallel group; XO crossover; LABA significant superiority vs LTRA; LTRA significant superiority vs LABA; NSD no significant difference between randomized treatments; * primary end point, NA not documented or measured. of the largest trials 7 shown in Table 2, in which add-on salmeterol was statistically superior to that of montelukast, this difference did not reach a clinically meaningful level. 56 Inflammation and AHR Four trials evaluated the effects of treatment on inflammatory biomarkers (peripheral blood eosinophils and exhaled nitric oxide). In all of the trials, add-on LTRA was significantly superior to LABA. In one study, 6 a subgroup analysis revealed a significant reduction in induced-sputum eosinophils in montelukast-treated patients. In another study, 21 in which the primary end point was AHR to adenosine monophosphate, add-on montelukast conferred superiority over salmeterol. In a further 4-week study 52 in which AHR was assessed, montelukast (but not salmeterol) significantly attenuated the adenosine monophosphate threshold concentration compared to placebo after both first and last doses. Conclusions Inhaled corticosteroids exhibit potent antiinflammatory properties in asthma and, as a consequence, most patients can be satisfactorily controlled using these drugs as monotherapy. Nonetheless, many patients continue to have symptoms and exacerbations with the implication that additional pharmacotherapy is frequently required. Ideal add-on therapy should be able to deal with the pathophysiologic components of the asthmatic inflammatory and bronchospastic processes and, in turn, alleviate symptoms, maximize quality of life, reduce exacerbations, and prevent airway remodeling. The studies highlighted in this review article have shown that the addition of an LTRA to an inhaled corticosteroid is generally as effective at reducing exacerbations as adding an LABA. In particular, in the two largest and longest studies 6,7 in which the primary end point was effect on exacerbations, the difference between either treatment was statistically and clinically nonsignificant. The addition of an LABA was consistently superior to an LTRA in improving lung function, while the latter treatment conferred antiinflammatory effects and attenuated AHR to a greater extent. In most of the studies, there were no significant differences in quality of life or symptoms, although in four out of nine studies, 7,51,53,55 the addition of an LABA was more favorable than that of an LTRA. It is not surprising that the addition of an LABA conferred consistent superiority in terms of improving airway caliber (FEV 1 and PEF) in all but one of the studies in Table 2. LABAs are the most potent bronchodilators used in the treatment of asthma. However, especially in patients with moderate-tosevere asthma, it is important to note that optimizing the inhaled corticosteroid dose is vital prior to the introduction of an LABA. As mentioned earlier, the addition of formoterol to 200 g/d of budesonide was significantly inferior to a fourfold increase in budesonide in terms of reducing exacerbations. 30 In the same study, these benefits on exacerbations were observed without any significant change in lung function. This in turn suggests that serial monitoring of lung function alone may fail to expose potential long-term benefits when adjusting inhaled corticosteroid therapy. In the clinical setting of an acute asthma attack, it may be relevant that a blunted response to inhaled salbutamol occurs with chronic treatment with LABAs. 24 This is in contrast to LTRAs that have been shown to have some benefit in patients with CHEST / 128 / 4/ OCTOBER,

7 Figure 1. Suggested algorithm guiding clinicians as to whether an LABA or LTRA should be used as additional second-line therapy in patients with persistent asthma using a low-to-moderate dose of inhaled corticosteroid. acute asthma. 57,58 A study by Storms et al 54 evaluated the effects of montelukast or salmeterol on the response to short-acting 2 -agonist following exercise-induced bronchoconstriction. In patients receiving montelukast, significantly greater protection from an exercise-induced decrease in FEV 1 than those receiving salmeterol was observed (p 0.001). Moreover, the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol (p 0.001). Thus, compared to salmeterol, montelukast permitted a greater and more rapid rescue bronchodilation with short-acting 2 - agonist and provided consistent protection against exercise-induced bronchoconstriction. Whether these observations are of clinical significance in the context of an acute exacerbation of asthma requires prospective evaluation. Our results illustrate that both LABAs and LTRAs confer favorable effects on different aspects of the asthma syndrome. What is the evidence that using both modalities together with inhaled corticosteroids provides further benefit? Despite being advocated in current guidelines, 2,3 there are actually few data specifically evaluating this important question. In a randomized, placebo-controlled study 59 involving 100 patients with chronic persistent asthma, add-on montelukast failed to provide further benefits in patients receiving inhaled corticosteroids plus additional second-line therapy (mostly LABAs). It is noteworthy that in this 4-week study, 59 the primary outcome was PEF, and since the patients were likely to have been maximally bronchodilated, no further improvements in airway caliber could have been expected. Moreover, the short duration of the study would have precluded any demonstrable differences in exacerbations rates compared to placebo. Another randomized, placebo-controlled study 21 in patients with mild-to-moderate persistent asthma evaluated the effects of add-on montelukast to daily fluticasone propionate, 500 g, plus salmeterol. No additional effects were observed on FEV 1 or PEF (as expected), although improvements in AHR and inflam Reviews

8 matory biomarkers did occur. As a consequence, clinicians should bear in mind that treatment with an LTRA may not always confer improvements in airway caliber (especially when patients are using LABAs) although beneficial effects on inflammatory biomarkers, and AHR may in fact translate into reductions in exacerbations. The national montelukast survey 60 evaluated the effects of LTRAs across a range of asthma severities (1,351 patients). Montelukast was observed to be an effective and welltolerated treatment in everyday life in as many as 66% of individuals, including symptomatic individuals already receiving inhaled corticosteroids plus LABAs. In conclusion, whether future asthma guidelines acknowledge that addition of an LTRA at step 3 is as effective as adding an LABA in reducing exacerbations remains to be seen. It appears reasonable that at step 3, patients with persistent asthma and impaired FEV 1 should continue to proceed to a trial of LABA as add-on therapy. However, perhaps those step 3 patients with essentially normal lung function (especially those with symptomatic allergic rhinitis) who are therefore less likely to benefit from the bronchodilator effects of an LABA should preferentially be started on an LTRA (Fig 1). This in turn would deal with the dual components of persistent inflammation and AHR, which are likely to be the driving forces behind symptoms and exacerbations. Large-scale trials are required in step 3 patients with and without both persistent allergic rhinitis and significant airflow limitation in order to establish which second-line controller therapy provides greatest all-round benefit. Moreover, further studies are also required to prospectively evaluate whether any differences are apparent in parameters of airway remodeling according to which add-on treatment patients receive over a prolonged period of time. References 1 Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness in asthma matter? 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