Clinical Use in Adults

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Addition of LABA to ICS Therapy

Inhaled corticosteroids are established as the most effective initial antiinflammatory treatment for asthmatics with persistent symptoms. The use of LABA monotherapy instead in such patients leads to a loss of asthma control, e.g., there is increased airway inflammation and exacerbation rates for patients treated with salmeterol monotherapy compared to ICS mono-therapy (100). An alternative strategy is to use LABA as an additional therapy in patients who are symptomatic despite taking ICS. Additional LABA therapy in this context has been shown to improve lung function and reduce exacerbations (58,101,102). Before the introduction of LABA, it was common for the dose of ICS to be increased in such patients. However, this can have disappointing results as the dose-response curve for these drugs is relatively flat for the linear segment (103). Using LABA as additional therapy offers advantages over increasing the dose of ICS; LABA provide an alternative mechanism of action (sustained smooth muscle relaxation), which can improve symptoms, and may also allow increased ICS delivery to the peripheral airways. Furthermore, it is possible that LABA and corti-costeroids have synergistic anti-inflammatory effects in vivo.

The value of adding a LABA instead of increasing the ICS dose has been investigated in several landmark clinical studies. Greening and coworkers studied 429 mild-asthmatic patients who had persistent symptoms after a run-in period on beclomethasone dipropionate (BDP) 400 mg/day (104). Patients were randomized to receive either an increased steroid dose (1000 mg/day), or the addition of salmeterol (100 mg/day) for six months. While lung function, use of relief medication, and symptoms improved in both groups, the salmeterol group demonstrated the greatest improvements (Fig. 7). A similar study by Woolcock and coworkers (105) involved more severe asthma patients who were symptomatic while being treated with

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Figure 7 Significant improvements in lung function in asthma patients taking salmeterol with inhaled beclomethasone dipropionate (BDP) compared to doubling the BDP dose without salmeterol. Source: From Ref. 104.

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Figure 7 Significant improvements in lung function in asthma patients taking salmeterol with inhaled beclomethasone dipropionate (BDP) compared to doubling the BDP dose without salmeterol. Source: From Ref. 104.

BDP 1000 mg/day. Subjects were randomized to one of three treatment arms: addition of salmeterol 100 mg/day, addition of salmeterol 200 mg/day, or a doubling of BDP to 2000 mg/day. Again, the groups receiving LABA therapy had significantly greater improvements in lung function, relief medication use, and symptoms. There was no difference between the effects of the two doses of salmeterol used, as these two salmeterol doses are at the top of the dose-response curve for bronchodilator and bronchoprotective effects

The introduction of long-term regular treatment with LABA raised concerns about the possible loss of asthma control in some patients. The basis for this concern was that LABA improve symptoms, which may lead to inadequate doses of ICS being prescribed to control airway inflammation. This has been called "masking" of airway inflammation, and assumes that the effect of LABA is purely bronchodilator in nature, with no syner-gistic anti-inflammatory activity in conjunction with ICS. This possibility has been investigated during ICS reduction in severe asthmatics; the addition of salmeterol improved lung function and ICS reduction faster compared to placebo, but this was associated with increased sputum eosinophilia (106). However, this phenomenon was not observed in a study involving the reduction ofbudesonide 1600 to 800 mg daily or 200 mg daily plus formoterol (107). Lung function improved in the formoterol group and overall clinical asthma control and sputum eosinophilia did not differ between the groups. Biopsy studies have also reassuringly demonstrated that LABA therapy in conjunction with ICS does not predispose to worsening airway inflammation (87,94).

The benefits of add-on LABA therapy on asthma control was further investigated in two important studies using formoterol. First, the FACET

study investigated the effect of formoterol add-on therapy on exacerbation rates over 12 months (108). The length of this study allowed exacerbation rates to be properly investigated. Symptomatic moderate asthmatics were given budesonide 1600 mg/day for a four-week run-in period, and then randomized to one of four treatments: (i) budesonide 200 mg/day, (ii) budesonide 200 mg and formoterol 18 mg/day, (iii) budesonide 800 mg/day plus placebo, or (iv) budesonide 800 mg and formoterol 18 mg/day. First, the addition of formoterol to either dose of budesonide reduced severe exacerbation rates, and second, the budesonide 800 mg/day group had less severe exacerbations than the budeso-nide 200 mg/day group (Fig. 8). Lung function over the 12 months showed the greatest improvements in the groups taking both ICS and formoterol, with the greatest increase observed in the budesonide 800 mg/day plus formoterol group. In summary, this study showed that the addition of formoterol to either a low- or medium-ICS dose reduced exacerbations in moderate asthmatics. Optimum control in these patients was achieved with the use of formoterol plus the higher dose of ICS.

A second study assessed the use of add-on formoterol therapy in asthmatics with milder disease taking budesonide 200 mg/day (64). The addition of formoterol improved control with fewer exacerbations compared to doubling the ICS dose, but again the maximal reduction in exacerbations was achieved by doubling the dose of budesonide and adding in formoterol. A meta-analysis of the use of salmeterol in mild to moderate asthma has

Figure 8 FACET study. Severe exacerbation rates in asthma patients treated with budesonide (200 or 800 mg/day) with and without formoterol for one year. Increasing the budesonide dose and using formoterol both significantly reduced exacerbations (p < 0.05). Source: From Ref. 108.

confirmed that the introduction of this LABA instead of doubling the ICS dose also reduces exacerbations (109). These studies have changed the use of LABA in asthma; after establishing symptomatic patients on ICS, the next step in pharmacotherapy is now the addition of LABA rather than doubling the dose of ICS.

The Optima study (64) was the first to provide information on the potential benefits in mild asthma in addition to low-dose ICS. This has been further investigated in recent studies; the addition of salmeterol to 200 mg fluticasone propionate per day in comparison to doubling the dose of ICS provides (i) a greater benefit to lung function and symptoms (110,111) (ii) a long-term steroid-sparing effect (112), and (iii) a reduction in exacerbation rates (113). Similarly, the addition of formoterol to budesonide 160 mg/day causes a greater increase in lung function and a reduction in exacerbations compared to doubling the ICS dose (114). While ICS at low doses improve AHR in mild asthma, there may be little effect on pulmonary function (115). The superior clinical effects of combined low-dose ICS/LABA in these patients is due both to a greater improvement in AHR and an increase in pulmonary function. It is interesting to speculate that combined low-dose ICS/LABA may ultimately prove to be the best form of initial pharmacotherapy for patients with symptomatic, persistent asthma. There is evidence of superiority in lung function and symptoms for this approach compared to ICS alone (116), although further studies are required to confirm the potential benefits of this strategy.

LABA Used "As Needed''

The fast onset of action of formoterol (similar to SABA) (27) has led to its use as an ''as needed'' reliever medication, with the advantage of a long duration of action. Salmeterol, with its slow onset of action, cannot be used for this purpose. Furthermore, formoterol has better dose-response properties than salmeterol, which may be important during repeated dosing when cumulative therapeutic effects may be of clinical benefit.

It is important to consider the safety profile of formoterol as an ''as needed'' medication, since this may involve cumulative doses that are greater than those given during regular dosing (the maximum dose of for-moterol is usually 24 mg as a single dose). The systemic effects of formoterol at higher doses (cumulative doses up to 90 mg) appear to be of similar duration and no worse than for SABA (117).

In a study in asthmatics needing significant SABA therapy (over three inhalations per day) despite regular ICS use, patients randomized to use formoterol ''as needed'' had fewer severe exacerbations and an improved quality of life score compared to terbutaline (101). Formoterol is also safe and effective when used ''as needed'' in addition to ICS and regular LABA therapy twice daily (118). The practical advantage of using fewer inhalers, coupled with the long duration of action compared to SABA, may lead to increased usage of formoterol for ''as needed'' symptom relief in the future. However, data in the context of clinical trials need to be replicated in everyday clinical practice, as there is a potential for patients to take too much formoterol unless appropriately instructed.

Formoterol may also be a useful treatment for acute asthma in the emergency room. High-dose SABA have traditionally been the mainstay of initial bronchodilator treatment in this setting, with inhaled anticholinergics used either concurrently or as second-line treatment. However, formoterol 15 mg repeated to a cumulative dose of 90 mg over three hours produces similar improvements in lung function compared to inhaled terbutaline in acute severe asthma, and has a similar safety profile (119). Additionally, formoterol (cumulative dose 54 mg over one hour) caused a greater increase in lung function than albuterol (cumulative dose 2400 mg), albeit with a greater decrease in serum potassium levels (120). Although these studies suggest that formoterol is potentially an effective bronchodilator for acute severe asthma, further large studies are needed to define the patient group that would respond best to treatment with formoterol, and the doses that can be safely and effectively prescribed.

Single-Inhaler LABA and Corticosteroid Therapy

The increased use of LABA in conjunction with ICS has led to the introduction of ''combination'' inhalers containing both of these drugs. The currently licensed formulations are salmeterol combined with fluticasone propionate and formoterol with budesonide. There are predictable differences in the onset of bronchodilation of these combination therapies due to the pharmacological properties of the LABA components, i.e., the budesonide/formoterol combination has a faster onset than the fluticasone proprionate/salmeterol combination (121). Combination inhalers provide better asthma control compared to using either the LABA or the ICS component alone. This has been demonstrated for salmeterol across a range of fluticasone doses from 200 to 1000 mg/day (122-124). In symptomatic patients already treated with ICS, the introduction of a LABA using individual component inhalers is known to be a more effective strategy for increasing lung function and reducing exacerbations compared to doubling the dose of ICS (64,104,105,108,109). Using a combination inhaler for LABA introduction provides similar results (114,125). In addition, combination formulations may have greater pharmacological effects compared to the individual components given in separate inhalers, which may be due to ''codeposition'' in the lungs, thus increasing synergistic effects (126). There are also practical advantages for patients using combination treatments. First, patients receiving long-term treatment may prefer to take one rather than two inhalers. This may explain why fewer patients who were taking a combination inhaler withdrew from a six-month study compared to those taking the individual components (127). Second, combination inhalers improve compliance by ensuring that patients take both medications rather than just the LABA component.

During an exacerbation of asthma, treatment should be intensified. However, there is frequently a delay in the initiation of additional treatment, as many patients seek medical consultation before changing their therapy. The effectiveness of early self-management during an exacerbation using written action plans has been assessed using the budesonide/formoterol combination. The formoterol component allows flexibility in the dosing regime and a rapid onset of bronchodilation. Furthermore, the molecular interactions of ICS and LABA may increase anti-inflammatory activity. Early self-management using an adjustable dosing regime reduces exacerbations compared to fixed dosing LABA/ICS regimes (128,129). The successful implementation of this strategy in clinical practice will depend on adequate patient education, so that patients are able to confidently and effectively vary their own treatment as required.

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