© 2005 American Thoracic Society
The GOAL Study Designed to Favor a Long-acting ß2-Agonist?To the Editor:Bateman and colleagues (1) have demonstrated that a fluticasone propionate/salmeterol combination (FP/SM) conferred superiority on guideline-derived asthma control when compared with an increased dose of FP alone. Exacerbation rates and overall health outcomes were also significantly better with the use of FP/SM in patients with suboptimally treated asthma. While their findings are impressive, there are a number of points to consider. For example, the median reversibility to inhaled short-acting ß2-agonist at baseline was greater than 20%. This finding biases the study heavily in favor of FP/SM, with the long-acting ß2-agonist moiety having "plenty of room" to exert its effects in terms of relaxation of bronchial smooth muscle. In other words, SM was able to maximally dilate the airways in patients who had been shown to have great potential to do so. Consequently, it is of little surprise that patients randomized to receive FP/SM fared significantly better than those who received FP alone. It is also curious that only the median reversibility to inhaled short-acting ß2-agonist is shown, when mean data were otherwise expressed at baseline. Furthermore, such a high degree of reversibility could hardly be representative of the general asthmatic population that primary and secondary care physicians frequently encounter on a daily basis. The authors also failed to evaluate bronchial hyperresponsiveness or any surrogate inflammatory biomarkers, such as airway eosinophils. These in turn are the ultimate driving force behind symptoms, the disability of asthma, and longer term sequelae, such as airway remodeling. Indeed, endpoints such as symptoms and lung function favor drugs that act on bronchial smooth muscle, and provide little information about the pathophysiologic hallmarks of the asthmatic inflammatory process. Despite the increasing popularity of combination inhalers, there are few data comparing their effects to inhaled corticosteroids in terms of airway remodeling. In a study by Ward and colleagues (2), significant reductions in basement membrane thickness did not occur until after 3 months of high-dose inhaled corticosteroid treatment. Moreover, Reddel and colleagues (3) demonstrated that patients starting with 3,200 µg/day of budesonide had greater normalization in bronchial hyperresponsiveness and fewer exacerbations than patients starting with 1,600 µg/day of budesonide. It is therefore important to ensure that untoward long-term sequelae do not occur at the expense of short-term superior bronchodilation with the use of combination inhalers such as FP/SM. Further prospective studies incorporating surrogate inflammatory biomarkers and parameters reflecting airway remodeling are therefore required to fully evaluate their effects. A large multicenter study by Bjermer and colleagues (4) demonstrated that the addition of montelukast, in patients with asthma whose symptoms remain uncontrolled by FP alone, provides equivalent clinical control as add-on SM. Moreover, doing so confers significantly superior effects on surrogate inflammatory markers and bronchial hyperresponsiveness (4, 5). Indeed, potentiation of the effects of inhaled corticosteroids by long-acting ß2-agonists has largely been confined to in vitro studies (6) and has not been mirrored in vivo (5, 7). While Bateman and colleagues (1) have succinctly highlighted the pharmacologic properties of SM in terms of maximally bronchodilating patients with asthma with impaired lung function and significant potential reversibility of greater than 20%, it is uncertain whether these findings can be extrapolated into the typical patient with asthma. Moreover, it remains to be seen whether the use of FP/SM confers "real-life" superiority over inhaled corticosteroids plus treatment with a leukotriene CysLT1-receptor antagonist.
a Aberdeen Royal Infirmary Aberdeen, United Kingdom FOOTNOTES Conflict of Interest Statement: G.P.C. has been paid by GlaxoSmithKline in 2004 for giving lectures amounting £300; D.K.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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