BUDESONIDE DOSE-RESPONSE IN MILD PERSISTENT ASTHMA

To the Editor :

I read with interest the results of the OPTIMA trial that showed differential effects of add-on therapy with formoterol to budesonide in patients with mild persistent asthma, depending on prior treatment with corticosteroids (1). In Group B patients who were taking inhaled corticosteroids before enrollment, there was no significant difference on severe exacerbations when comparing budesonide at 200 µg/day versus 400 µg/day, in contrast to a significant difference when adding formoterol. This is perhaps not surprising because these patients would already be near the plateau of the steroid dose-response curve before randomization, which would tend to minimize any subsequent response to randomized treatment with low-dose budesonide. Consequently, this would always bias the results towards showing a significant effect of formoterol as add-on therapy compared with doubling the budesonide dose. This was clearly evident in the steroid-naive Group A, where there was a significant effect of budesonide at 200 µg/day as monotherapy versus placebo, but without any further significant add-on effect of formoterol. Moreover, in Group A, no evaluation was made of doubling the dose of budesonide as compared with adding formoterol. Comparing the prebronchodilator FEV₁ % predicted values along with morning peak expiratory flow, there appears to be no clinically relevant difference in the degree of asthma severity between Groups A and B.

Clinicians are subject to increasing commercial pressure from the pharmaceutical industry to use combination inhalers at an earlier stage for persistent asthma, whereas the available evidence suggests that for most patients, monotherapy with low- to medium-dose inhaled steroid alone will achieve adequate control. Indeed, at step 3 in moderate persistent asthma, optimizing the budesonide dose had a significantly greater impact on severe exacerbations than adding formoterol to low-dose budesonide (2). In the United Kingdom, there are also considerable differences in direct costs of drug therapy, with budesonide 200 µg bid costing 135.05 GBP per year, as compared with budesonide 200 µg/formoterol 4.5 µg bid costing 231.17 GBP per year.

University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland

1. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose inhaled budesonide and formoterol in mild persistent asthma: The OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392-1397 [Abstract/Free Full Text].

2. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405-1411 [Abstract/Free Full Text].

From the Authors:

We thank Dr. Lipworth for his interest in our recent publication (1).

Dr. Lipworth is correct in stating that the patients studied in Group B (patients with mild persistent asthma taking a low dose of inhaled corticosteroids) were likely close to the top of their dose responses for inhaled corticosteroids. However, the question that the study was asking was whether this population of patients with mild persistent asthma would benefit from the addition of the long acting inhaled ₂-agonist, formoterol, to low doses of inhaled corticosteroids. The answer that the study provided was that they did benefit, particularly as measured by a reduction in severe and mild asthma exacerbations. This is new information for patients with mild persistent asthma, and we do not understand how the fact that they were at the top of the inhaled corticosteroid dose-response biased this result. Any recommendation on a change in treatment strategy, as this recommendation for mild asthma is, needs to be supported by large randomized control trials, where the treatment strategy is evaluated, as this study was.

We agree with Dr. Lipworth's view that many patients with mild persistent asthma will not require combination therapy to optimally control their asthma. Indeed, this is consistent with the findings in this study in Group A (patients with mild persistent asthma not taking inhaled corticosteroids) and our comments about this patient population in the article's discussion.

McMaster University, Hamilton, Ontario

Peter J. Barnes

Imperial College, London, United Kingdom

Roberto Rodriguez-Roisin

University of Barcelona, Barcelona, Spain

Thomas Sandstrom

University of Umea, Umea, Sweden

Anne Tattersfield

City Hospital, Nottingham, United Kingdom

1. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose inhaled budesonide and formoterol in mild persistent asthma: The OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392-1397 .