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Communications to the Editor |

Lost in the Labyrinth of End Points FREE TO VIEW

Brian J. Lipworth, MD
Author and Funding Information

Asthma Allergy Research Group, Ninewells Hospital and Medical School Dundee, Scotland

Correspondence to: Brian J. Lipworth, MD, Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee DDI 9SY, Scotland; e-mail: b.j.lipworth@dundee.ac.uk



Chest. 2001;120(1):323-324. doi:10.1378/chest.120.1.323-a
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To the Editor:

We feel that the attack on our article in CHEST (October 2000)1by Kass and Bartter in their editorial2is unjustified on the basis of the data that have been presented. If they had taken care to read the“ Materials and Methods” section carefully, they would have clearly seen that the primary outcome variable was the effect on bronchial hyperresponsiveness to adenosine monophosphate challenge, which is a suitable surrogate for mast cell-mediated airway inflammation. On the basis of this end point, there was significant superiority of monotherapy with budesonide over formoterol after 4 weeks, amounting to a 2.5-fold difference. A 1 doubling dilution shift (ie, twofold) in bronchial hyperresponsiveness is usually taken as being a clinically relevant effect. Likewise, there was also a significant difference when comparing these two therapies in the suppression of exhaled nitric oxide, which is another airway inflammatory surrogate. We did not show any difference between combination therapy and budesonide monotherapy for either of these surrogate inflammatory markers, suggesting that any improvements in control with combination therapy are simply due to bronchodilatory activity. For Kass and Bartter to concentrate their editorial on end points of lung function such as FEV1 and peak expiratory flow, which are insensitive in patients with mild-to-moderate asthma, and which clearly were not chosen as the a priori primary efficacy variable, is to miss the whole rationale of the study, even though we clearly stated the emphasis on the inflammatory markers in the title and in the introduction. Indeed, it has been shown previously that the dose response for inhaled budesonide is much steeper for effects on bronchial hyperresponsiveness than on lung function in patients with mild-to-moderate asthma.3 To properly evaluate the effects on lung function would require hundreds of patients with more severe asthma, as has already been done in pharmaceutically sponsored multicenter studies.

It was interesting that our patients preferred the treatment regimens that contained formoterol, perhaps suggesting that they had acquired a taste for its rapid effect on airway caliber. We believe that this response may lull patients into a false sense of security, especially if they receive a suboptimal dose of an inhaled steroid before considering adding in the long-acting β2-agonist. It was evident from a multicenter study that optimizing the dose of budesonide alone to 800 μg/d had a significantly greater impact on severe exacerbations than did the addition of formoterol to budesonide, 200 μg/d (ie, a 49% vs 26% reduction).4

This is especially pertinent as two different fixed-dose combination therapy inhalers (fluticasone-salmeterol and budesonide-formoterol) will soon be available in the United States. These are being aggressively marketed for use in patients with all grades of asthma when there is ample evidence to show that a low-to-medium dose of an inhaled steroid will suffice in most cases of mild-to-moderate asthma. While there is convincing independent evidence to support the use of long-acting β-agonists as steroid-sparing agents in cases of more severe persistent asthma, these studies had a duration of only 6 to 12 months and have not evaluated bronchial biopsy, especially over a longer period of several years to see whether using a lower dose of inhaled steroid is associated with irreversible airway damage due to putative airway remodeling. Until such long-term data are available, it makes more sense to use long-actingβ 2-agonists on a as-required basis rather than on a regular basis, once the dose of inhaled steroid has been optimized, perhaps using bronchial hyperresponsiveness in addition to other control markers to titrate the dose, as suggested by the study of Sont et al.5 We never intended to make sweeping implications on the basis of our small study, but we hope it will make prescribers appraise their choices for each individual patient more carefully.

References

Aziz, I, Wilson, AM, Lipworth, BJ (2000) Effects of once daily formoterol and budesonide given alone or in combination on surrogate inflammatory markers in asthmatic adults.Chest118,1049-1058. [CrossRef]
 
Kass, JE, Bartter, T The labyrinth of asthma therapy: lost in the choices [editorial].Chest2000;118,891-893. [CrossRef]
 
Wilson, AM, Lipworth, BJ Dose response evaluation of the therapeutic index for inhaled budesonide in patients with mild to moderate asthma.Am J Med2000;108,269-275. [CrossRef]
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma.N Engl J Med1997;337,1405-1411. [CrossRef]
 
Sont, JK, Willems, NA, Bel, AH, et al Clinical control and histopathological outcome of asthma when using airway hyperresponsiveness as an additional guide to long term treatment.Am J Respir Crit Care Med1999;159,1043-1051. [CrossRef]
 

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References

Aziz, I, Wilson, AM, Lipworth, BJ (2000) Effects of once daily formoterol and budesonide given alone or in combination on surrogate inflammatory markers in asthmatic adults.Chest118,1049-1058. [CrossRef]
 
Kass, JE, Bartter, T The labyrinth of asthma therapy: lost in the choices [editorial].Chest2000;118,891-893. [CrossRef]
 
Wilson, AM, Lipworth, BJ Dose response evaluation of the therapeutic index for inhaled budesonide in patients with mild to moderate asthma.Am J Med2000;108,269-275. [CrossRef]
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma.N Engl J Med1997;337,1405-1411. [CrossRef]
 
Sont, JK, Willems, NA, Bel, AH, et al Clinical control and histopathological outcome of asthma when using airway hyperresponsiveness as an additional guide to long term treatment.Am J Respir Crit Care Med1999;159,1043-1051. [CrossRef]
 
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