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Combination Therapy in Asthma - Fixed or Variable Dosing in Different Patients?

Posted on: Friday, 7 January 2005, 03:00 CST

Key words: Budesonide * Fluticasone * Formoterol * Inhaled corticosteroids * Long-acting β^sub 2^-agonists * Salmeterol

SUMMARY

The introduction of combination products, for the co- administration of an inhaled corticosteroid (ICS) with a long- acting β^sub 2^-agonist in a single inhaler, has greatly simplified asthma therapy. The two combination inhalers currently available, Symbicort* (budesonide/formoterol in a single inhaler) and Seretidet (salmeterol/fluticasone), comply with Step 3 of international guidelines that recommend the addition of a long- acting β^sub 2^-agonist to ICS in patients who are inadequately controlled on ICS alone. Importantly, combination inhalers ensure that patients cannot neglect their ICS maintenance therapy in favour of the long-acting β^sub 2^-agonist - which may improve adherence and overall asthma control. In vitro experiments suggest that ICS and long-acting β^sub 2^-agonists may interact beneficially when they are administered via one inhaler. The efficacy and tolerability of budesonide/formoterol and salmeterol/ fluticasone have been demonstrated. There are currently two approaches for treating asthma using combination therapy - fixed and adjustable dosing. Fixed dosing with budesonide/ formoterol or salmeterol/fluticasone provides effective asthma control in line with guideline goals. However, given the inherent variability of asthma, there is increasing evidence that adjusting the dose of ICS according to fluctuations in symptoms is beneficial. Findings from a series of studies comparing fixed and adjustable symptom-guided dosing regimens demonstrate that adjustable dosing may improve asthma control at an overall lower steroid dose. Ultimately, if adjustable dosing proves to be an effective treatment option, it may be possible to use budesonide/formoterol for both maintenance therapy and symptom relief, thereby overcoming the need for a separate reliever inhaler. This is because formoterol has a more rapid onset and greater dose-related effects than salmeterol in salmeterol/fluticasone. Given that all patients are different, with different disease severities and treatment preferences, both fixed and adjustable dosing strategies are likely to be important in the long-term management of asthma. It is possible that different treatment options will be used for different patients, depending on their disease severity, personality and ability to adhere to therapy.

Introduction

Asthma is a chronic disorder of the bronchial airways, characterised by episodic exacerbations of coughing, wheezing, chest tightness and breathing difficulties. Inflammation of the airways is recognised as critical in the pathogenesis of asthma, and inflammatory processes are apparent at all levels of disease severity1,2. Chronic inflammation in asthma leads to long-term bronchial hyper-responsiveness and airway remodelling3. Hyper- responsiveness to stimuli, such as tobacco smoke, dust, allergens and exercise, causes bronchoconstriction, mucus production and further inflammation, which in turn lead to airway obstruction. Asthma is classified as mild intermittent, mild persistent, moderate persistent or severe persistent depending on the frequency and severity of symptoms. The severity of asthma among individuals can change in a given individual over time. Patients with all severities of asthma may suffer exacerbations that can be mild, moderate or severe in intensity.

Given the variability of asthma, successful long-term control requires flexible and tailored management. Currently, inhaled corticosteroids (ICS) represent the cornerstone of asthma therapy, effectively controlling inflammation and stabilising symptoms. ICS are recommended for all patients with persistent asthma. Regular treatment with ICS should begin at an early stage of the disease in order to reduce the risk of irreversible airway remodelling4-6

Current guidelines recommend a stepwise approach to therapy based on asthma severity7'8. Initial treatment strategies for gaining control of asthma vary. Some physicians aim to gain rapid control of asthma by using a high initial dose of ICS that is down-titrated once control is achieved, while others prefer to start with a level of ICS considered appropriate based on the patient's asthma severity, only increasing the dose when necessary. Whichever strategy is employed, it is recommended that the dose of ICS should be increased if control is not achieved and sustained, and decreased if control is sustained for at least 3 months7. Once asthma is under control, it is recommended that ICS should be down-titrated to the minimum effective dose in order to avoid potential side effects associated with long-term ICS use7. In practice, however, evidence suggests that this is not always implemented8, which means that some well-controlled asthma patients are to a degree over-treated with ICS whereas others may be under-treated. Perhaps more importantly, asthma in many patients is not well controlled because of poor adherence to the prescribed treatment regimen9.

The development of combination therapies containing an ICS together with a long-acting β^sub 2^-agonist in a single inhaler provides an opportunity to simplify treatment, which may improve adherence and overall asthma control. Two combination products are currently available: Symbicort*, which contains budesonide and formoterol, and Seretide[dagger], which comprises salmeterol and fluticasone. There are some differences in the pharmacology of both the ICS and the long-acting β^sub 2^- agonist components of these two products, perhaps making them suitable for different therapeutic approaches. This review will focus primarily on the role of the long-acting β^sub 2^- agonist components used for additional therapy to ICS in current asthma management and how these can influence the therapeutic approach.

Long-acting β^sub 2^-agonists

Inhaled long-acting β^sub 2^-agonists, such as formoterol and salmeterol, represent important advances in the management of asthma, providing effective bronchodilation and long-term improvement in lung function when given on a regular basis. The beneficial effects of both formoterol and salmeterol as regular treatment for asthma in combination with ICS are well accepted7,10,11. Addition of either formoterol" or salmeterol10 to ICS improves lung function to a greater degree than a higher dose of ICS. The addition of formoterol to a low dose of ICS is as effective at reducing the incidence of asthma exacerbations as a fourfold increase in ICS11. Thus, current evidence generally argues that adding a long-acting β^sub 2^-agonist to a low dose of an ICS is preferable to increasing the ICS dose in the management of asthma7. Monotherapy with long-acting β^sub 2^-agonists is not recommended.

Onset of Action and Duration of Effect of Long-Acting β^sub 2^-Agonists

Like the short-acting β^sub 2^-agonists, formoterol provides a bronchodilating effect within minutes of inhalation12,13. Three minutes after dosing, formoterol resulted in a significantly greater increase in forced expiratory volume in l s (FEVJ than salmeterol ( p < 0.05) (Figure l(a))12. The effects of both formoterol and salmeterol have been shown to be sustained for > 12 h (Figure l(b))12,14. In fact, 24 h after a single dose of formoterol or salmeterol, the effects of both of these drugs can still be observed15 (J Ltvall, unpublished observation). Less is known about the duration of effect of regular treatment with long-acting β^sub 2^-agonists, but it is likely that this will depend on the concentration of drug in the airway microenvironment. The half- life of the airway effect of both salmeterol and formoterol seems to be approximately 16h-24h. Based on this assumption, a steady state for this effect should be found after 4-5 elimination half-lives of the drug, and it would also take this amount of time for any airway effect to wear off after stopping regular treatment. One large clinical study in patients with mild to moderate asthma evaluated the rate of decline of morning peak expiratory flow (PEF) after ceasing regular formoterol treatment16. The effect of formoterol disappeared slowly and PEF returned to baseline values over a 3-day period (Figure 2(a)). A similar effect has been observed with salmeterol (Figure 2(b))17. These studies, therefore, lend strength to the argument that longacting β^sub 2^-agonists accumulate in the airways during regular treatment and a beneficial effect may be observed for several days after treatment ceases, as the drugs are eliminated slowly from the airway tissues.

Figure 1. Change in mean forced expiratory volume in l s (FEV^sub 1^; % over baseline) after inhalation of single doses of formaterol (6 g, 12g or 24 g), salmeterol (50 g) or placebo: (a) over the first 60 min and (b) up to 12 h after inhalation12. Permission granted by: European Respiratory Society Journals Ltd

Pharmacology of Formoterol and Salmeterol

There are some clear clinical and pharmacological differences in the effects of formoterol and salmeterol, including the previously mentioned differences in the onset of action. The faster onset of effect of formoterol12 may, at least in part, be explained by differences in the speed of diffusion of the two drugs through the airway microenvironment to the smooth mu\scle β^sub 2^- adrenoceptor18. After inhalation, the drug is deposited on the surface of the airway epithelial lining fluid, where it dissolves. The drug must then diffuse through the epithelium and submucosa to reach the smooth muscle before bronchial smooth muscle relaxation and subsequent bronchial widening can be induced. Salmeterol is more lipophilic than formoterol and consequently has a greater propensity to enter cell membranes in the bronchial wall than formoterol. A drug that is present in cell membranes is likely to diffuse more slowly through the tissues than a drug that dissolves in the epithelial lining fluid. Salmeterol will thus reach the smooth muscle in sufficient concentrations to induce bronchodilation at a later time than a water-soluble β^sub 2^-agonist. Conversely, as formoterol is less lipophilic than salmeterol, and even though some formoterol will enter cell membranes, a greater proportion of formoterol will remain in the interstitium, diffusing more rapidly into the smooth muscle18. This simple difference in chemistry may, therefore, explain why formoterol has a more rapid onset of action than salmeterol.

The lipophilicity of both formoterol and salmeterol may also contribute to their long duration of effect. Because high concentrations of these drugs stay in cell membranes in and around the smooth muscle for a prolonged time, these drugs are available in the vicinity of the β^sub 2^-adrenoceptors for at least 12h12,18. It has been proposed that the slower onset of action of salmeterol may be due to the drug entering the bronchial smooth muscle cell membrane before diffusing into the active receptor site18. It has also been suggested that salmeterol may have a second high-affinity binding site within the β^sub 2^-adrenoceptor, which may contribute further to its long duration of action19. Regardless of which mechanisms are responsible, there is currently no evidence for a clinical difference in the duration of effect of formoterol and salmeterol.

Figure 2. (a) Mean morning peak expiratory flow (PEF) in 125 patients with mild to moderate asthma during treatment with formaterai 18 g twice daily (delivered dose) and after 3 days of washout. Reproduced from'6 with permission from the BMJ Publishing Group, (b) Mean PEF rates SEM in 12 patients with stable asthma during 13 days of treatment with salmeterol (50 g twice daily) or salbutamol (200 g four-times daily) and during 6 days of washout17. With permission from American Lung Association

In vitro pharmacological studies using smooth muscle cell preparations from animals and humans have demonstrated that formoterol has a higher pharmacological efficacy than salmeterol20. Thus, strongly contracted smooth muscle relaxes to a lesser extent when salmeterol is added compared with formoterol, indicating that salmeterol is a partial agonist at the β^sub 2^-adrenoceptor site relative to formoterol20.

Clinically, the difference in maximal effect between formoterol and salmeterol has only recently been established. High doses of formoterol were shown to provide greater protection against methacholine-induced bronchoconstriction in patients with asthma compared with salmeterol21. Increasing the pre-treatment dose of formoterol up to 120 g (measured dose) caused a 4.6-doubling dose shift in methacholine responsiveness, whereas the maximal effect of salmeterol (500 g measured dose) was approximately 2.7-doubling doses (Figure 3)21. This supports the hypothesis that formoterol can be used to reverse acute severe bronchoconstriction and indicates that the effects of formoterol are dose-dependent and that additional clinical effects may be observed by increasing the dose of formoterol. In fact, formoterol (90 μg delivered dose) has been shown to be as effective as terbutaline 10 mg at reversing airflow obstruction in patients admitted to the emergency ward with acute asthma (Figure 4)22. In contrast, salmeterol shows no clear dose-dependent effect over the 50 g dose and has a slower onset of effect. Salmeterol should, therefore, only be used as a maintenance treatment for asthma.

Figure 3. Mean (plusmn;SD) shift in the provocative dose of methacholine producing a 20% fall (PD^sub 20^) in the forced expiratory volume in 1 s (FEV) following inhalation of increasing doses of formaterai (FORM) or salmeterol (SALM). Values were corrected for the corresponding placebo day values. There was no significant difference in the shift in PD^sub 20^ at the lowest concentration of each drug (p = 0.07). At the two higher doses, however, formaterai caused a significantly greater shift in PD^sub 20^ compared with salmeterol (p = 0.0021 and p = 0.0001, respectively)21. With permission from American Lung Association

Figure 4. Geometric mean forced expiratory volume in l s (FEV1) values after administration of formaterai (cumulative dose 90 g) or terbutaline (cumulative dose 10 mg) in patients attending an emergency room, with acute asthma. Study drugs were administered at Omin, 30min, 60min, 120min, 150min and 180min (indicated by dotted lines). At 90min after the first inhalation of study drug, patients also received methylprednisolone 40 mg intravenously (indicated by solid line)22. Permission granted by: European Respiratory Society Journals Ltd

Formoterol as Reliever Medication

In patients with mild to moderate asthma, the onset of action of formoterol is comparable with that of the classical reliever medication salbutamoln. In patients where bronchoconstriction is induced with methacholine, formoterol provided rapid and effective bronchodilation, again comparable with that of traditional reliever medications23,24. The rapid onset of effect and high pharmacological efficacy of formoterol suggest a role for this agent as a reliever medication in patients with asthma. Evidence supporting this use came initially from a doubleblind study by Tattersfield and co- workers25. Adult patients with moderate to severe asthma who used formoterol 4.5 g on an as-needed basis up to 12 times daily showed better asthma control and had a greater probability of remaining free from a severe exacerbation than those using the short-acting β^sub 2^-agonist, terbutaline 0.5mg25. More recently, the effectiveness of formoterol as reliever medication was confirmed in the very large, but open, RELIEF study26. In this worldwide, parallel-group study, 18124 patients (4-91 years of age) were randomised to receive either formoterol 4.5 g/inhalation or salbutamol 200 g/inhalation as reliever medication for 6 months. Patients receiving formoterol experienced fewer asthma exacerbations, irrespective of asthma severity, than those receiving salbutamol26. Furthermore, formoterol as reliever therapy was found to be as safe as salbutamol in patients of all ages and across all asthma severities27. Formoterol is approved in the European Union for regular use in patients with steroid-treated asthma, and additional doses for symptomatic relief are allowed up to a maximum total daily dose of 54 g (i.e. 12 inhalations of 4.5 g/inhalation).

Safety of Long-Acting β^sub 2^-Agonists

Although both short- and long-acting β^sub 2^-agonists are very safe, systemic effects such as increased heart rate and skeletal muscle tremor may develop when high doses are taken. The risk of adverse cardiac effects may be greater in patients with myocardial disease. One study in patients suffering from chronic obstructive pulmonary disease (COPD) with pre-existing cardiac arrhythmias and hypoxaemia showed a greater incidence of superventricular or ventricular premature beats after a single dose of formoterol 24 g than after single doses of formoterol 12 g or salmeterol 50 g28. Another study in patients with chronic congestive heart failure concluded that oral salbutamol (6 mg four-times daily) may cause serious arrhythmias in patients predisposed to developing arrhythmias29.

Despite the long duration of effect in the airways, both salmeterol and formoterol have surprisingly few systemic effects. If the dose is increased, however, classical β^sub 2^-agonist- mediated effects will develop. These may be experienced when extra formoterol is given for immediate symptom relief. The duration of formoterol's systemic effects (measured as changes in serum potassium) have been shown to be similar to those of salbutamol at equieffective doses30. Compared with salmeterol, formoterol at high doses causes more pronounced systemic effects, in parallel with its greater efficacy in the airways21. One study has implied that the systemic effects of formoterol may be of slightly shorter duration than those of high doses of salmeterol31.

Formoterol given at a cumulative dose of 90 g over a 3-h period to patients with acute bronchoconstriction (mean baseline FEV1 33% of predicted normal) has been shown to be quite well tolerated22. Changes in serum potassium levels, pulse rate and ECG variables were not significantly different from those observed in patients receiving a cumulative dose of terbutaline 10 mg over the same time period.

Monotherapy with long-acting β^sub 2^-agonists is not recommended. In a large safety study, black American patients taking salmeterol without ICS had an increased risk of asthma-related death32. Other randomised studies have found that patients switched from combination therapy with ICS and salmeterol to monotherapy with salmeterol alone experienced a clinically significant loss of asthma control33.

Development of Tolerance to β^sub 2^-Agonists

Regular use of a short-acting β^sub 2^-agonist has been associated with the induction of tolerance in patients with asthma. This is often not apparent when evaluating bronchodilating effects before and after a period of regular treatment, whereas pronounced tolerance to side effects usually develops during regular treatment. Daily treatment with long-acting β^sub 2\^-agonists also results in the development of some tolerance. This is not usually measurable as reduced bronchodilation, however, but is more apparent for the protective effect against bronchial challenges. For example, regular treatment with salmeterol or formoterol has been shown to decrease their protective effects against methacholine-34, exercise- 35 and allergen-3G induced bronchoconstriction. Importantly, however, Boulet and colleagues34 reported that the development of tolerance was not associated with loss of asthma control. Furthermore, several large long-term studies have shown that regular formoterol treatment reduces the number of asthma exacerbations11- 37. Therefore, tolerance induced by regular use of long-acting β^sub 2^-agonists is not likely to be clinically important and is outweighed by the benefits in asthma control that can be achieved.

Combination therapy

ICS and Long-Acting β^sub 2^-Agonists in Separate Inhalers

The addition of a long-acting β^sub 2^-agonist, e.g. formoterol or salmeterol, has been shown to be an effective alternative to higher doses of ICS in patients whose symptoms persist despite treatment with low-dose ICS10,11,37,38. Lemanske and co-workers39 reported that the addition of salmeterol (42g twice daily) to triamcinolone therapy allowed for a substantial (50%) reduction in triamcinolone dose, without loss of asthma control. Total elimination of triamcinolone therapy was not recommended, however, as this resulted in a significant deterioration in asthma control.

In the early study by Greening and colleagues10, patients receiving twice-daily salmeterol 50 g plus beclomethasone 200 g showed significantly greater improvements in morning PEF - apparent within 1 week and maintained throughout the 6-month treatment period - compared with patients receiving twice-daily beclomethasone 500 g10. Woolcock and co-workers38 found similar results with twice- daily salmeterol 50g or 100 g plus beclomethasone 500 g compared with twice-daily beclomethasone 1000 g. As no differences were observed between the two doses of salmeterol, this suggests that maximal effects are attained with salmeterol 50 g twice daily38.

In a 12-month study in 852 adult patients with moderate to severe asthma, Pauwels and colleagues11 compared the effect on lung function and asthma control of formoterol (12g twice daily) with a low or high dose of budesonide (100g or 400 g twice daily). Morning PEF increased with the addition of formoterol irrespective of budesonide dose. Moreover, the addition of formoterol to the low dose of budesonide was more effective than a fourfold higher dose of budesonide alone. Interestingly, in contrast to the studies by Greening and co-workers10 and Woolcock and colleagues38 where there was no difference between increasing the dose of beclomethasone or adding salmeterol to a lower dose of beclomethasone on asthma exacerbation rates, a higher dose of budesonide or the addition of formoterol significantly reduced the rate of both mild and severe exacerbations11. This was confirmed recently in a study by O'Byrne and co-workers37 where the addition of formoterol (9 g/day) to a low dose of budesonide (200 g/day) was more effective at increasing the number of asthma control days and reducing the risk of severe exacerbations than doubling the budesonide dose in steroid- dependent asthmatics. In steroid-naive patients with mild asthma, however, the addition of formoterol provided no further improvement in either the number of asthma control days or the risk of having a severe exacerbation compared with budesonide alone37. This led the authors to conclude that additional therapy with formoterol was only of benefit if optimal control was not achieved with ICS alone.

Concerns that addition of long-acting β^sub 2^-agonists to low doses of ICS may mask underlying airway inflammation have been largely alleviated by Kips and colleagues40. Analysis of sputum markers of airway inflammation before and during a 4-week run-in (budesonide 800 g twice daily) and after 1 month, 2 months, 3 months, 6 months, 9 months and 12 months showed no significant differences between twice-daily budesonide 400 g or twice-daily budesonide 100 g plus formoterol 12 g. This study indicates that there was no loss of control of airway inflammation in patients receiving low-dose ICS with formoterol, compared with those receiving a fourfold higher dose of ICS. However, if ICS are discontinued during treatment with long-acting β^sub 2^- agonists, signs of worsened inflammation and reduced asthma control can be found in sputum41.

Interactions Between ICS and Long-Acting β^sub 2^-Agonists

Several studies indicate that long-acting β^sub 2^-agonists and ICS may interact to produce a synergistic effect on airway function. For example, in vitro and in vivo animal data suggest that long-acting β^sub 2^-agonists may have some antiinflammatory effect42, while other evidence suggests that regular ICS use may prevent cytokine-induced downregulation of β^sub 2^-agonist receptors, thereby protecting against the development of tolerance to β^sub 2^-agonists43. In vitro studies have shown that glucocorticoids, acting via the glucocorticoid receptor, can induce β^sub 2^-adrenoceptor gene transcription and increase the number of β^sub 2^-adrenoceptors44. Conversely, in vitro studies have also demonstrated that β^sub 2^-agonists are potent activators of the glucocorticoid adrenoceptor45. Several other in vitro studies suggest that long-acting β^sub 2^- agonists provide additional anti-inflammatory effects to ICS, which may be a mechanism facilitating improved asthma control. Patients with asthma show an increased production of cytokines such as granulocyte macrophage colonystimulating factor (GM-CSF), interleukin (IL)-S, IL-6 and IL-8 in the airways, which are believed to contribute to airway inflammation. Addition of formoterol and budesonide to cultured human bronchial epithelial cells inhibits GM- CSF secretion in response to tumour necrosis factor-α to a greater extent than either compound alone46. Similar results with IL- 8 were observed in cultured human airway smooth muscle cells using combinations of dexamethasone and fluticasone with salbutamol or salmeterol47. These effects are believed to be β^sub 2^- adrenoceptor-mediated46.

Although evidence from in vitro studies suggests that the interaction between long-acting β^sub 2^-agonists and ICS is synergistic, this is difficult to demonstrate in vivo because one treatment group has to be maintained on long-acting β^sub 2^- agonists alone. These patients may show a worsening of their asthma due to withdrawal of ICS therapy, while patients receiving both long- acting β^sub 2^-agonists and ICS may show an improvement in asthma control that is greater than that given by the two treatments alone; this may be interpreted as synergy between the two drugs. This was illustrated in a recent study by Shapiro and co-workers48 in 349 patients (aged ≥ 12 years) with asthma that was not controlled by ICS alone. Combination therapy with salmeterol 50 g and fluticasone 250g twice daily for 12 weeks provided significantly better asthma control and greater improvements in lung function than either of the individual treatments. However, many of the patients in the salmeterol-only group showed either no improvement or worsening of asthma control as a result of discontinuing their ICS at randomisation. Overall, it is evident that long-acting β^sub 2^-agonists do not provide clinically significant anti-inflammatory effects on their own, and any synergy between ICS and long-acting β^sub 2^-agonists seems difficult to prove in a clinical study design.

Figure 5. Change in morning peak expiratory flow rate during 12 weeks of treatment (0 days-90 days) with either budesonide/ formoterol 80pg/4.5 g twice daily or budesonide 200 g twice daily in adults with asthma not fully controlled on low-dose inhaled corticosteroids alone. All patients received inhaled budesonide 100g twice daily during the run-in period (Day -10 to Day 0)53

Figure 6. Mean adjusted morning peak expiratory flow (PEF standard error of the mean) rates in symptomatic patients with moderate to severe asthma treated with salmeterol/fluticasone (50 g/ 250g) or budesonide (800 g) twice daily for 24 weeks. Values shown at each timepoint were adjusted for age, sex, country and baseline value. *p < 0.001 vs budesonide. Reprinted from54, with permission from Elsevier

Fixed Combinations of ICS and Long-Acting ≥^sub 2^- Agonists in a Single Inhaler

Asthma therapy has been greatly simplified by the introduction of single inhalers which co-administer ICS and long-acting β^sub 2^-agonists. Currently, two fixed combination single inhaler products are available for the treatment of asthma: Seretide Diskus (GlaxoSmithKline, UK) containing salmeterol and fluticasone (50 g/ 100 g; 50 g/250 g or 50 g/500 g) and Symbicort Turbuhaler (AstraZeneca, Sweden) comprising budesonide and formoterol (80 g/ 4.5 g; 160 g/4. g or 320 g/9 g). Studies have shown both combination products to be at least as effective as the monoproducts given concurrently via separate inhalers49-52.

Figure 7. Percentage change in forced expiratory volume in I s (FEV^sub 1^) up to 15 min and 3 h after single inhaled doses of budesonide/formoterol 160 g/4.5 g (1 or 2 inhalations), salmeterol/ fluticasone 50 g/250 g (1 inhalation), or placebo. Reprinted from57, with permission from Elsevier

The efficacy and safety of salmeterol/fluticasone and budesonide/ formoterol have been clearly demonstrated in a number of studies. Results indicate that the combination of ICS and a long-acting β^sub 2^-agonist provides effective asthma control with a lower overall steroid dose compared with budesonide or fluticasone alone. I\n adult patients with mild to moderate asthma, budesonide/ formoterol 80 g/4.5 g twice daily for 12 weeks increased morning and evening PEF significantly more than a higher dose of budesonide alone (200 g twice daily) (Figure 5)53. This confirms previous findings by Greening and co-workers10, who compared the effect of high-dose beclomethasone with a lower dose plus salmeterol10. In addition, the percentage of symptom-free days and overall asthma control days was also significantly increased, while the risk of an asthma exacerbation was reduced by 26% compared with budesonide alone53. In a 6-month study in adult and adolescent patients with moderate to severe asthma, salmeterol/fluticasone 50 g/250 g twice daily was shown to be more effective than a threefold higher dose of budesonide (800 g twice daily)54 (Figure 6). This study also found that treatment with salmeterol/fluticasone was more cost-effective than high-dose budesonide55. Other studies have shown that salmeterol/fluticasone 50 g/100 g and 50 g/250 g are more cost- effective than the corresponding dose of fluticasone alone56.

Comparisons between budesonide/formoterol and salmeterol/ fluticasone indicate that the onset of bronchodilation is more rapid with budesonide/ formoterol than with salmeterol/fluticasone (Figure 7)57. This is attributed to the formoterol component of budesonide/ formoterol, which has a more rapid onset of effect than salmeterol12. Formoterol also has a steeper dose-response curve compared with salmeterol, as discussed previously21. These properties of formoterol potentially provide Symbicort with wider therapeutic applications compared with Seretide. For example, increasing the dose of Symbicort may provide additional bronchodilation when asthma worsens, owing to formoterol's high pharmacological efficacy and rapid onset of effect. Importantly, there is no evidence of any clinically significant difference in effect between budesonide/formoterol and salmeterol/fluticasone when either is given as regular doses in the morning and evening.

Figure 8. Adjusted changes in mean morning peak expiratory flow (PEF) rate in patients with asthma following 12 weeks of treatment with salmeterol (50 g) and fluticasone 100 g twice daily either via a single inhaler (Seretide) or separate inhalers. *p < 0.05 vs separate inhalers49

Benefits of Asthma Treatments in a Single Inhaler

Combining an ICS and a long-acting β^sub 2^-agonist in a single inhaler confers a number of benefits for both the patient and physician. Firstly, combination treatments ensure that patients get a regular dose of ICS along with the long-acting β^sub 2^- agonist. This is important for controlling the underlying inflammation during maintenance therapy, but may also be important when patients have an exacerbation. Providing both products in a single inhaler, therefore, means that patients are unable to neglect their ICS in favour of the symptom-relieving long-acting β^sub 2^-agonist, which may be important in view of the recent data suggesting that patients taking salmeterol without ICS have poorer asthma control32,33.

Secondly, there is some suggestion that inhaling an ICS and a long-acting β^sub 2^-agonist together through the same device may confer a small additional benefit on lung function over their delivery through separate inhalers. The mechanism or mechanisms responsible for any such synergy are unknown. In a study by Zetterstrm and colleagues52, patients receiving budesonide/ formoterol (160 g/4.5 g, 2 inhalations twice daily) showed a more rapid improvement in morning and evening PEF and asthma symptom scores during the first 30 days of treatment than those receiving the same drugs in separate inhalers. Similarly, Bateman and co- workers'19 found that patients who received twice-daily salmeterol/ fluticasone 50 g/100 g showed numerically greater improvements in morning and evening PEF at all timepoints than the concurrent monoproducts administered in separate inhalers (Figure 8)49. Theoretically, this slight numeric improvement could be due to increased adherence to the ICS in the group treated with the combination inhaler, although more studies are required to investigate this further. It could also be hypothesised that, because the ICS and long-acting β^sub 2^-agonist administered via a combination inhaler are deposited in the same areas of the lungs, the concentration of both drugs in the bronchial wall could be optimised for molecular interactions.

Another advantage of fixed combination treatment is the simplicity offered by such a regimen. Complicated treatment regimens (frequent doses, multiple inhalers) are believed to contribute to poor adherence to asthma therapy58-60. Patients receiving budesonide and formoterol are known to prefer to take their treatment in a single inhaler rather than in separate inhalers61. In a 12-month, open, randomised, parallel-group study61, significantly fewer patients receiving budesonide/formoterol in a single inhaler withdrew from the study compared with those receiving the same treatment via separate inhalers (9% vs 19%; Figure 9), which may indicate better adherence to treatment.

Providing fixed combination treatments in a single inhaler may also improve their cost-effectiveness compared with the same drugs given in separate inhalers. During a 12-month open study, Rosenhall and colleagues61 observed no differences between budesonide/ formoterol and the corresponding doses of budesonide and formoterol given via separate inhalers in terms of efficacy and safety, but showed that the single inhaler treatment was more cost-effective than using separate inhalers in this selected patient group. A recent study has also reported that treatment with salmeterol/ fluticasone 50 g/250 g was more cost-effective than budesonide (1600 g) and formoterol (12 g) in separate inhalers62. One should, however, be cautious when drawing conclusions about cost- effectiveness and, in this case, it should be noted that the budesonide dose used was excessively high, which contributed to an unusually high cost of the separate-inhaler treatment.

Figure 9. Proportion of patients withdrawing from the study during 12 months of treatment with budesonide/formoterol (Symbicort) 160 g/4.5 g 2 inhalations twice daily or corresponding doses of the monocomponents via separate inhalers. **p < 0.01 vs budesonide + formaterol61

A clinical problem with combination inhalers, however, is that it becomes tedious or perhaps even difficult to step down the treatment ladder. Thus, an asthma patient in whom treatment with a combination inhaler has been initiated would have to change inhaler and obtain a new prescription in order to stop using the long-acting β^sub 2^-agonist and start treatment with ICS alone. This approach may result in over-treatment in patients receiving a combination of ICS and long-acting β^sub 2^-agonist who may be fully controlled on an ICS alone.

Dosing regimens with combination therapies

There are currently two approaches for treating asthma using combination therapy. The first approach is for the ICS and long- acting β^sub 2^-agonist to be taken morning and evening as a regular fixed maintenance dose, either in a single inhaler or in separate inhalers. This approach is in line with Step 3 of the asthma management guidelines7 and numerous studies have demonstrated the success of such an approach in providing effective asthma control, as shown by improved lung function, fewer exacerbations and reduced reliever medication use10,11,37,38,52-54. For many patients this is the preferred approach to treatment. Fixed dosing regimens have been successfully used with both budesonide/formoterol and salmeterol/ fluticasone in many patients. The pharmacology of salmeterol allows regular, but not increased, dosing. Hence, salmeterol/fluticasone can only be used in fixed dosing regimens because it has a flat dose-response curve. The fluctuations in asthma severity in some patients may, however, mean that a fixed dosing regimen may result in under-treatment during periods of asthma worsening and over-treatment during periods of good asthma control. This is one reason for the clinical testing of an adjustable dosing regimen using the combination of formoterol and budesonide available in Symbicort. Current guidelines recommend that patients should receive the minimum effective maintenance dose of ICS when asthma control is good, but during periods of asthma worsening the dose of ICS should be increased until control is regained. There is now growing evidence implying that, in some patients, it may be beneficial to titrate the dose of ICS according to the severity of asthma symptoms.

Adjusting the Dose of Inhaled Steroids

Many studies have shown dose-related improvements in lung function with ICS, although the dose-response curve for most asthma outcome measures is relatively flat63. For example, Busse and co- workers64 demonstrated that 12 weeks of treatment with budesonide 200 g/day, 400 g/day, 800 g/day or 1600 g/day in adult patients with moderate to severe asthma resulted in significantly greater improvements in morning PEF and FEV^sub 1^ compared with placebo, but the difference in effect (mean change from baseline in PEF and FEV^sub 1^) between the lowest and highest dose was small compared with the difference seen between the placebo and lowest ICS dose group. A recent meta-analysis of the dose-response relationship of inhaled fluticasone propionate in > 2300 adult and adolescent patients with asthma concluded that most of the therapeutic benefit is achieved with a total daily dose of 100 g-250 g, with a maximal effect at a dose of around 500 g/day65. In contrast, adrenal suppression increases linearly with ICS doses up to 2000 g/day66, which explains why doses above 1000 g/day should only be used when clinically required.

Figure 10. Oral corticosteroid use inpatients with symptomatic moderate persistent asthma during 6 months of treatment with either budesonide 400 g twice daily plus placebo four-times daily for 7 days in the case of asthma worsening, budesonide 100 g twice daily plus budesonide 200 g four- times daily for 7 days in the case of asthma worsening or budesonide 100 g twice daily plus placebo four- times daily for 7 days in the case of asthma worsening. All patients received budesonide 800 g twice daily during a 4-week run-in period. ***p < 0.001 vs budesonide 100 g + placebo67

A more pronounced dose-response effect for ICS is observed in the prevention and treatment of asthma exacerbations. In a 12-month study by Pauwels and colleagues11, adult patients with moderate to severe asthma receiving a high maintenance dose of budesonide (800 g/ day) had fewer mild and severe exacerbations compared with patients receiving budesonide 200 g/day. Foresi and co-workers67 demonstrated that in patients receiving low maintenance doses of ICS, stepping up the dose at the earliest indication of asthma worsening was as effective as a high maintenance dose at controlling asthma exacerbations. In their study, 213 adults with moderate persistent asthma who were already receiving ICS (500 g/day-1000 g/day) were treated with budesonide 800 g twice daily for 4 weeks before being randomised to receive budesonide 100 g or 400 g twice daily for 6months. Patients in the low-dose budesonide group were further randomised to receive either placebo or a high dose of budesonide (200 g four-times daily) for 7 days if their asthma worsened. At the end of the study, patients receiving the low dose of budesonide had similar lung function and symptom control to those receiving the high maintenance dose. Furthermore, early intervention with a short- term increase in the dose of budesonide at the onset of an asthma exacerbation was shown to be as effective as a high maintenance dose of budesonide in terms of the number of days with exacerbations and the need for oral corticosteroids (Figure 10)67.

These studies indicate that it can be beneficial to titrate the dose of ICS according to the severity of asthma symptoms. Systemic effects are minimised by downtitrating to the minimum effective dose during periods of good asthma control, whereas increasing the dose of ICS during periods of asthma worsening is beneficial in controlling exacerbations.

Evidence suggests, however, that there is a widespread problem with patient adherence to ICS therapy. A systematic literature review of patient compliance with ICS estimated that the percentage of under-use days ranged between 24% and 69%68. In a study involving 2803 adults and children in Europe, Rabe and colleagues9 found that only 27.6%, 22.7% and 25.4% of adult patients with mild, moderate or severe persistent asthma, respectively, reported using ICS in the past month. There are many reasons for non-compliance with asthma therapy60,69,70. In a study conducted by Buston and Wood70, apart from forgetfulness, the most common reason given by patients for poor adherence to the prescribed therapy was a perception that the medication was not effective. As ICS have a slow onset of action, while reliever medication quickly improves symptoms, many patients do not appreciate the need to also take regular anti-inflammatory medication to con-trol the underlying inflammation and instead tend to over-rely on their reliever medication. Overuse of reliever medication, however, may mask airway remodelling and, as a consequence, may not alert patients to potentially life-threatening situations71. Conversely, the correct use of ICS could potentially reverse or prevent airway remodelling72,73. Several studies have shown that patients receiving ICS are at significantly less risk of hospitalisation with a fatal or near-fatal asthma attack, compared with those relying on reliever medication74-76. In a study of patient compliance with antibiotic courses, Pechre77 found that mothers giving antibiotics to children were most likely to adhere to the dosing regimen, while working adults were the least compliant. Working adults were also the least likely group to take all daily doses of medication, highlighting the importance of a convenient dosing regimen. Combination products containing long-acting β^sub 2^-agonists with ICS in a single inhaler have the advantage of ensuring regular intake of ICS while simultaneously providing bronchodilation and thus subjective symptom relief. This should improve adherence to therapy thus resulting in better asthma control, which is an obvious reason for the popularity of combination inhalers.

Adjusting the Dose of Combination Treatments

One potential problem with combination products in a single inhaler is their lack of flexibility when the ICS dose needs to be adjusted78. In the same way that adding a long-acting β^sub 2^- agonist overcomes the need to increase the dose of ICS when asthma is not adequately controlled, one way of stepping down the level of medication when patients have achieved good asthma control is to remove the longacting β^sub 2^-agonist. This is particularly easy in patients using two separate inhalers for administering the ICS and the long-acting β^sub 2^-agonist. In patients using single-inhaler products, however, this may require a new prescription of the ICS alone, which if not filled may result in overtreatment. Several studies have shown that steroid-dependent patients with mild or moderate asthma achieve better asthma control with budesonide and formoterol than with a two-fold higher dose of budesonide alone11,37.

Whether adjusting a fixed combination of budesonide and formoterol in a single inhaler provides additional benefit to asthma patients is currently under active investigation. This approach may be possible with this combination product since Symbicort is approved in Europe for administration 1-4 times daily. Adjusting the dose of both ICS and the long-acting β^sub 2^-agonist according to asthma severity is, however, an approach that challenges current guidelines. Recently presented data imply that some additional control may be achieved with the 'flexible dosing' regimen with budesonide/formoterol79,80. When comparing combination products containing the long-acting β^sub 2^-agonists formoterol and salmeterol, only those containing formoterol are likely to be successful since the dose-response relationship is much clearer with formoterol than with salmeterol, although no direct comparative study has been performed.

A series of recent studies has tested whether adjusting the maintenance dose of budesonide/formoterol according to the level of symptoms is an effective way of gaining and maintaining asthma control compared with fixed dosing regimens81-83. Patients allocated to the adjustable dosing regimen received a physician-guided action plan that advised them to step up their dose of budesonide/ formoterol by taking additional inhalations from the same inhaler if, on 2 consecutive days, they required reliever medication ≤ 3 times daily and had night-time awakenings due to asthma. They were advised to step down the dose if, in the previous week, they required reliever medication on ≤ 2 days and had no night- time awakenings due to asthma. Patients on the fixed dosing regimen received twice-daily doses of budesonide/formoterol throughout. Both groups used the short-acting bronchodilator, terbutaline, as needed. Adjustable and fixed dosing were found to produce similar improvements in symptom severity over a 12-week treatment period81,82. Compared with patients on the fixed dosing regimen, however, patients on adjustable dosing took 15% fewer inhalations of budesonide/formoterol and significantly less reliever medication81. These results have been confirmed in a subsequent study conducted over a 6-month period83. In this extended study, patients assigned to the adjustable dosing regimen with budesonide/formoterol had fewer exacerbations (defined as use of oral steroids for asthma worsening, treatment at a medical care unit for asthma, an asthma- related serious adverse event, or withdrawal owing to a need for non- study asthma medication), compared with those on a fixed dosing regimen (p < 0.05: Figure 11 (a)), despite using 40% fewer inhalations (p < 0.001: Figure 11 (b))83. Consequently, total asthma- related healthcare costs were lower in the adjustable dosing group (p < 0.001)84. It is possible that patients on the adjustable dosing regimen experienced fewer exacerbations because they responded to increased doses of medication at the onset of worsening symptoms, which may enable asthma control to be regained faster. It is important, however, to point out that these adjustable dosing studies were open, and differences in the way the two treatment groups were managed may have contributed to the effects seen. It remains to be demonstrated whether patients using adjustable dosing in a real-life situation will achieve the levels of control observed in these studies or whether they will end up either over- or under- treated.

Further ongoing studies are investigating whether the combination of budesonide and formoterol can be used for both maintenance treatment as well as for relief medication in patients, thereby removing the need for a separate reliever inhaler. This concept has evolved primarily because of the rapid onset of action of formoterol and its dose-response effects12,21,57,85. Using a model of severe bronchoconstriction, it has been shown that patients given the combination of budesonide and formoterol get faster improvements in lung function and more rapid relief from subjective dyspnoea - within 1 min - compared with those using the combination of fluticasone and salmeterol85,86. In real-life situations, some patients already use budesonide/formoterol on demand to relieve symptoms, because they subjectiv\ely sense rapid relief of asthma symptoms. Thus, it may prove possible for asthma patients to use the combination of formoterol and budesonide - or any other combination product containing formoterol - for both maintenance therapy as well as for reliever use. Clearly, the most attractive argument for this approach would be that patients taking this combination containing the rapid-acting formoterol, as reliever medication, are also guaranteed to receive the controller medication with every inhalation. Patients receiving combination treatment with ICS and long-acting β^sub 2^-agonists as regular morning and evening maintenance therapy, perhaps via separate inhalers, may sometimes only take the bronchodilator medication for rapid symptom relief. Although this approach will not be applicable to all patients with asthma, especially not to those known to be bronchodilator overusers, it seems an interesting approach to test in different populations of patients with asthma. Clinical studies investigating the safety, efficacy and cost-effectiveness of this approach are urgently awaited.

Figure 11. Effect of 6 months of treatment with either fixed or adjustable dosing with budesonide/formoterol on asthma control in 1034 patients with asthma. Patients on the fixed dosing regimen received budesonide/formoterol 2 inhalations twice daily while those on the adjustable dosing regimen received I or 4 inhalations twice daily depending on symptoms and morning peak expiratory flow. (a) Proportion of patients experiencing ≥ I exacerbation, (b) Mean number of daily inhalations of study medication. *p < 0.05; ***p < 0.001 vs fixed dosing. Reprinted from83, with permission from Blackwell Publishing

Conclusions

Current guidelines state that patients who are inadequately controlled on ICS alone should be treated with the addition of an inhaled long-acting β^sub 2^-agonist. Combination products that co-administer ICS and long-acting β^sub 2^-agonists in a single inhaler are popular and convenient treatments in the clinical setting, and have been proven effective in many patients with asthma. A major advantage of combination inhalers is that they guarantee the patient receives the controller medication - the ICSalong with the symptom-relieving long-acting β^sub 2^- agonist.

Two fundamentally different treatment strategies are currently being marketed for combination inhalers. Both salmeterol/ fluticasone and budesonide/formoterol can be administered twice daily in the morning and evening, as fixed maintenance doses. This regimen works well in many patients, and evidence from prospective blinded studies supports this approach in large population studies. Nevertheless, as treatment is not altered in response to fluctuations in disease severity, this dosing regimen may result in some patients becoming under-treated during periods of worsening, while others may be over-treated during periods of low asthma activity.

As asthma is a disease that varies over time, adjusting treatment in an individual patient according to symptom severity holds potential benefits. Support for adjustable dosing with budesonide/ formoterol has come from a series of recently presented studies, in which total steroid load was reduced, while the frequency of asthma exacerbations was unchanged or even reduced in comparison with a fixed dosing regimen81-83. Furthermore, although ICS represent the cornerstone of asthma therapy, adherence is often poor, possibly because the effects of these drugs are not immediately apparent. Therefore, combination products containing the long-acting β^sub 2^-agonist formoterol with an ICS in a single inhaler may increase the use of the controller medication while simultaneously providing rapid bronchodilation. In the longer term, this could overcome the need for a separate short-acting reliever inhaler in some patients, as the combined medication dose may be safely increased during times of asthma worsening.

These fundamentally different strategies for treating asthma with the combination of an ICS and a long-acting β^sub 2^-agonist are likely to be suitable for different patient groups, with different types of asthma, different personalities and different preferences. Understanding how these different approaches may influence the long-term control of asthma in a real-life situation warrants careful scientific and clinical evaluation. We should remember that patients with asthma are a very heterogeneous group, and, therefore, a single treatment strategy may not be appropriate in all cases.

Acknowledgement

Over the last 5 years, Jan Ltvall has received support for clinical research, fees for presentations at symposia and consulting fees from several pharmaceutical and biotech companies, including GlaxoSmithKline, AstraZeneca, Resistentia, Merck Sharpe and Dohme, and Schering Plough.

Publication support for this manuscript has been covered by a grant from AstraZeneca.

* Symbicort Turbuhaler is a registered trademark of AstraZeneca, Sweden

[dagger] Seretide Diskus are both registered tradenames of GlaxoSmithKline, UK

* Symbicort Turbuhaler is a registered trademark of AstraZeneca, Sweden

[dagger] Seretide Diskus are both registered tradenames of GlaxoSmithKline, UK

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