Affiliations: GlaxoSmithKline Research Triangle Park, NC
GlaxoSmithKline Uxbridge, UK,
St. Joseph/McMaster University Hamilton, ON, Canada
Correspondence to: Stephen B. Shrewsbury, MB ChB, FCCP, Director, Clinical Development and Product Strategy, GlaxoSmithKline Research and Development, Five Moore Dr, PO Box 13398, Research Triangle Park, North Carolina 27709-3398; e-mail: email@example.com
We read with interest Dr. Sears’ editorial (May 2001)1 on the deleterious effects of β2-agonists. We were pleased to see the subheading: “short-acting and long-acting agents differ,” but still had a few comments about the text that we wished to make.
Dr. Sears states that our meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA)2work did not show a “substantive reduction of exacerbations.” It is erroneous to draw this conclusion without mentioning that this meta-analysis of nine studies including 3,685 patients investigated the addition of salmeterol in comparison to at least doubling the dose of inhaled corticosteroids (ICS). We did not look at whether the absolute reduction in exacerbations from baseline in both groups were significant, only the differences between the two treatment groups. Compared with increased doses of inhaled steroids, the addition of salmeterol was not only superior in controlling asthma symptoms but also resulted in a lower incidence of exacerbations. A recent study by Matz et al3 reported similar findings in 925 patients whose asthma was not controlled with low-dose fluticasone propionate (FP). Patients receiving salmeterol plus fluticasone had a significantly lower rate of exacerbations compared with more than double the dose of FP. In addition, significantly greater improvements in lung function and asthma symptom scores were observed in the 2 weeks following an exacerbation.
Lastly, in the final paragraph, Dr. Sears states that “long-acting β2-agonists have the potential to mask the clinical effects of increasing eosinophilic airway inflammation when the steroid dose is insufficient” and refers to the article by McIvor et al.4 In this study, 13 patients were rapidly withdrawn from inhaled steroids until an asthma exacerbation occurred and, in many of the patients, ICS were removed altogether. We believe that the reduction in exacerbation rates seen in the study by Matz et al3 and MIASMA with the combination of salmeterol and ICS would not be expected to occur without effective control of the underlying disease by both products. Two trials5–6 examining airway inflammation via lung biopsy and BAL have shown no increase in eosinophils with the addition of long-acting β2-agonists to low-dose ICS compared to higher doses of ICS in symptomatic asthma. In addition, improvement in clinical outcomes (ie, lung function, reduction in exacerbations) were seen in both studies. These combined observations,3,5–6 along with MIASMA2 support the view that addition of long-acting β2-agonists to low-dose ICS provide better overall asthma control than higher-dose ICS.
I thank Drs. Shrewsbury and Pyke of GlaxoWellcome for their comments on my editorial about short- and long-acting β- agonists. Their comments highlight one of the major limitations of their meta-analysis1in assessing the effects of salmeterol on exacerbations, namely that the studies included had not been specifically designed to address that end-point. The minimal and nonsignificant reduction in exacerbations associated with use of salmeterol (2.73% for any exacerbation and 2.42% for severe exacerbations) was in comparison with at least doubling the dose of inhaled corticosteroid, as they correctly point out. A comparable study to the Formeterol and Corticosteroids Establishing Therapy Study,2which assessed the effect on exacerbations of adding formoterol to a fixed dose of corticosteroid, was not available for salmeterol. Likewise, the study of Matz et al3(which was available only as an abstract when the editorial was written) compares treatment with salmeterol plus low-dose fluticasone with treatment with higher-dose fluticasone. Hence, this study does not specifically address the question of whether addition of salmeterol to a constant dose of corticosteroid reduces exacerbations. A very recently published Canadian study by D’Urzo et al4 did address the issue of exacerbations with addition of salmeterol to inhaled corticosteroid and found no reduction in exacerbations, despite the expected improvement in symptoms and pulmonary function indexes. Evidence that use of salmeterol reduces exacerbations of asthma when added to a constant dose of corticosteroid is awaited.
The study of McIvor et al,5 of which I was senior author, was a concept study designed to determine whether use of a long-acting β-agonist could mask the development or persistence of eosinophilic inflammation if the dose of corticosteroid was insufficient. The answer was yes, as the mean level of sputum eosinophils, 1 week before a clinically recognizable exacerbation (or total withdrawal of corticosteroid), was 19.9% in the group receiving salmeterol vs 9.3% in those receiving the placebo (p = 0.006). The greater reduction in corticosteroid dose during salmeterol treatment had allowed inflammation to increase, with no warning increase in symptoms or fall in pulmonary function. We have never suggested that salmeterol increased inflammation. Rather, we have emphasized that the use of a long-acting β-agonist for its obvious benefits on symptoms and lung function (which are only two components of control) must be combined with an adequate dose of an inhaled corticosteroid to provide other aspects of disease control.
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