The Role of Inhaled Long-Acting Beta-2 Agonists in the Management of Asthma. LABAs as Adjunctive Therapy

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The various guidelines have defined the role of LABAs as adjunctive, given concurrently with an inhaled corticosteroid, and the combination is now considered preferred therapy for moderate and severe persistent asthma. This is supported by a large body of evidence that adding a LABA to the inhaled corticosteroid in patients poorly controlled on just the inhaled corticosteroid is superior to doubling the dose of the inhaled corticosteroids. These studies have been extensively reviewed elsewhere. Most were of short duration (12-24 weeks) and, while virtually all demonstrated greater improvements in symptom control and lung function with combination therapy than with inhaled corticosteroid monotherapy at the same or increased dosage, their short duration precluded definitive analysis of effects on rates of asthma exacerbation. When the studies were grouped together and subjected to meta-analysis, however, these studies collectively suggested that the combination of a LABA and an inhaled corticosteroid decreased the rate of asthma exacerbations overall.

The question as to whether the combination indeed decreases the rate of asthma exacerbations at one time assumed major importance. This was driven by the concern that the addition of a LABA produced improvement in lung function and symptom control simply through their bronchodilating action, possibly masking underlying worsening of bronchial inflammation, hyperresponsiveness and the tendency to exacerbations. Thus, the results from two yearlong clinical trials of the addition of formoterol to various doses of budesonide became very important, as they prospectively evaluated the effect of combi¬nation therapy on asthma exacerbation as their primary endpoints. The FACET study evaluated the effect of adding formoterol to low dose budesonide (200 mg daily) and to higher-dose budesonide (800 mg daily) in patients with moderate-to-severe persistent asthma. Compared to the increasing the dose of budesonide, formoterol produced greater improvement in lung function. More importantly, formoterol decreased the rate of severe exacerbations whether added to low- or higher-dose budesonide. While the increased dose of budesonide produced a greater decrease in exacerbation rate than did the low-dose budesonide/formoterol combination, the exacerbation rate was lowest with the high-dose budesonide/formoterol combination. The character of the onset, severity and duration of the exacerbations did not differ between combination therapy and inhaled corticosteroid monotherapy, suggesting that formoterol did not mask worsening of the underlying inflammation. This suggestion was supported by the subgroup of study subjects, showing that sputum eosinophilia was not different between the combination or inhaled corticosteroid monotherapy. This has recently been supported by a three-month comparison of fluticasone propionate 1,000 mg daily versus fluticasone propionate 400 Lig plus salmeterol 50 mg daily. The investigators obtained bronchial biopsies, bronchial washings and bronchoalveolar lavage before and after treatment and found no increase in airway inflammation in the salmeterol group.

The OPTIMA trial assessed combination therapy with formoterol and low-dose budesonide (200 |ig daily) and medium-dose budesonide (400 |ug daily) in patients with mild-to-moderate asthma. These investigators found an improvement in lung function but no decrease in exacerbation rate when adding formoterol to low-dose budesonide in patients with mild asthma. They did report, however, in patients with moderate asthma who had previously received inhaled corticosteroids, that the addition of formoterol produced both a greater improvement in lung function and a greater reduction in exacerbations than did doubling the dose of inhaled corticosteroids. More recently, a large multicenter trial designed to determine if patients with persistent asthma could obtain control as defined by the GINA and NIH guidelines reported that the majority of patients regardless of severity could achieve control. Control of asthma occurred more rapidly and at a lower inhaled corticosteroid dose with combination therapy (salmeterol and fluticasone propionate) than monotherapy with fluticasone propionate.

Taken together, these trials confirm the existing guidelines that low-dose inhaled corticosteroid monotherapy is likely adequate in many patients with mild persistent asthma, although greater improvement in lung function may be expected from the addition of an LABA. However, in those patients with moderate asthma, the LABA/inhaled-corticos-teroid combination provides superior efficacy than medium-dose inhaled corticosteroid. In addition, those patients not achieving guideline-defined control escalation of the corticosteroid dosage can be expected to produce further improvement, but the addition of an LABA should be attempted first. Furthermore, the reduction in severe exacerbations has been shown to offset the cost of adding LABAs and, in some cases, produce a cost savings by reducing other healthcare resource use. Maintaining a lower dose of inhaled corticosteroid also reduces the potential for systemic effects of the inhaled corticosteroid, particularly in children. Finally, in those patients with severe asthma, both an increase in inhaled corticosteroid dose and the addition of the LABA is warranted. Some have been concerned that following the introduction of a LABA that patients would become less compliant with their inhaled corticosteroid, leading to loss of control and asthma exacerbations. However, studies have actually reported improved compliance with the inhaled corticosteroid when a LABA is added, even when administered as two separate inhalers.

Only a few trials have compared the efficacy of the combination of an inhaled corticosteroid and another adjunctive therapy, like theophylline or a leukotriene modifier to the LABA/inhaled-corticos-teroid combination. Three showed that adding a LABA to an inhaled corticosteroid to be more effective than adding either zafirlukast or montelukast to the same inhaled corticosteroid. Other studies have shown that the addition of theophylline to low-dose inhaled corticosteroid is no more effective than doubling the dose of inhaled corticosteroid, and comparative trials of adding either a LABA or theophylline to patients already receiving inhaled corticosteroid found the addition of LABAs to provide superior control of asthma. Buy imitrex online

In conclusion, the primary role of formoterol and salmeterol in asthma is as adjunctive therapy to low-to-medium dose inhaled corticosteroid in moderate and severe persistent asthma. They should not be used as monotherapy without inhaled corticosteroids. The combination produces improved outcomes compared to all other alternatives, including increased doses of the inhaled corticosteroids or the addition of other controller medications. There is no evidence for masking or worsening of inflammation with the addition of LABAs. In fact, clinical and biopsy studies suggest no increase in airway inflammation with lower doses of inhaled corticosteroids in combination with LABAs. Thus, the combination of LABA and inhaled corticosteroid should continue to be considered the preferred therapy of moderate-to-severe persistent asthma.