The Role of Inhaled Long-Acting Beta-2 Agonists in the Management of Asthma. Clinical Use of LABAs

Posted by James

The LABAs are approved for chronic maintenance therapy of asthma, chronic obstructive pul¬monary disease and exercise-induced bronchospasm (EIB). Numerous trials have demonstrated the superiority of maintenance therapy with an inhaled LABA (administered twice daily) to maintenance therapy with an inhaled short-acting beta-2 agonist (administered four times daily). Therapy with LABAs improves lung function, bronchial hyperre-sponsiveness and symptom control during chronic administration. The LABAs also provide superior control of asthma with fewer adverse effects than sustained-release theophylline. However, the LABAs are less effective than low-dose inhaled corticosteroids as monotherapy for persistent asthma, particularly in preventing asthma exacerbations. In the studies comparing monotherapy with LABAs to inhaled corticosteroids, no improvement in bronchial hyperresponsiveness compared to placebo was noted, and one 12-month trial in children reported a decrease in lung function and increase in bronchial hyperresponsiveness for LABA therapy. However, there was no placebo group and the differences between active treatments were similar to those seen in the other studies that showed no difference in these outcomes from the placebo control group. This suggests the changes were most likely a result of patients not receiving the inhaled corticosteroid as opposed to the putative effect of LABAs on worsening asthma.

In contrast, the Salmeterol Multicenter Asthma Research Trial (SMART), which began in 1996 to evaluate the safety of salmeterol, suggests that LABAs may adversely affect the outcome of patients with asthma. The SMART trial was initiated as a 28-week safety trial of salmeterol or placebo added to existing prescribed therapy evaluating pri¬mary endpoints of the number of respiratory-related deaths and life-threatening experiences. A planned interim analysis of the initial 25,858 enrolled showed no difference in the primary endpoint, but it revealed an increased risk of asthma-related, life-threatening events (including death) in the salmeterol arm in the African-American population (19 versus four, relative risk = 4.6) but not others by subgroup analysis. Of note, the rate of concomitant inhaled corticosteroids was very low (46%) overall in the entire study population and only 39% in African Americans. Due to the interim analysis findings, the low rate of primary outcomes and the difficulty in recruiting, the study was halted. Of interest, the Arg/Arg 16 genotype occurs more frequently in African Americans. While this may have contributed to the findings in this study, the African Americans in the study had more severe asthma at baseline and fewer received inhaled corticosteroid therapy than the Caucasians. In addition, asthma-related deaths were more frequent overall in those patients not receiving inhaled corticosteroids. Although the study was not powered to detect differences in subsets of African Americans receiving and not receiving inhaled corticosteroids, these findings underscore the importance of the use of inhaled corticosteroids in patients with more severe asthma. This may suggest that LABAs should not be used as monotherapy for asthma.

Like the short-acting inhaled beta-2 agonists, the LABAs effectively prevent EIB. Following a single dose of a LABA, protection against EIB lasts up to 12 hours, diminishing slightly over that time. The tolerance to beta-2-agonist stimulation from chronic therapy with a LABA is hardly apparent when exercise testing is repeated one hour after a single dose, but the protection against EIB is significantly reduced six hours later. Thus, patients may still require preventative use of a short-acting beta-2 agonist just prior to exercise if it has been at least four hours since their last dose of a LABA.
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