Correspondence

Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma

N Engl J Med 1998; 338:1071-1073April 9, 1998

Article

To the Editor:

Pauwels et al. (Nov. 13 issue)1 found that in patients with persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial. Three features of the study design may have helped increase the size of the effect seen and reduce its generalizability to clinical practice. First, the high rate of exacerbations of asthma in the group given low-dose budesonide is not surprising. In this group, the mean dose of inhaled corticosteroids was similar to that in the other groups (range, 818 to 856 μg daily) before the study. Second, most exacerbations of asthma were defined in terms of clinical measures. Only 27 percent of severe exacerbations were associated with a fall in the peak expiratory flow rate of more than 30 percent on two successive days. Few clinicians would initiate prednisone therapy for patients who had a peak expiratory flow rate in the range of 70 to 100 percent of the predicted value. The current consensus regarding treatment, although not proved,2 would be to double the dose of inhaled corticosteroids and try to prevent a more severe exacerbation requiring prednisone. The study design most likely did not allow changes in the maintenance dose of inhaled corticosteroids, and this again would amplify the differences between the groups. Third, the importance of the high-dose induction phase is unclear, and again this would not usually be used in clinical practice.

J. Mark FitzGerald, M.D.
Vancouver Hospital and Health Sciences Center, Vancouver, BC V5Z 3J5, Canada

2 References

1. 1

   Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-1411
   Full Text | Web of Science | Medline

2. 2

   Ernst PP, FitzGerald JM, Spier S. Canadian asthma consensus conference: summary of recommendations. Can Respir J 1996;3:89-100
   

To the Editor:

Airway hyperresponsiveness, which is one of the hallmarks of asthma, has been shown to be increased after long-term or regular use of β₂-agonists. This is one of the major reasons for the controversy associated with the regular use of β₂-agonists in the management of asthma. Pauwels et al. mentioned this in their introduction but did not address this issue in their study. The only outcomes monitored were changes in lung functions, extent of symptoms, and the need for rescue medications. Drazen et al.1 have shown that although regular use of β₂-agonists was not associated with worsening of symptoms, worsening of lung function, or an increased need for rescue medication, it increased bronchial hyperresponsiveness significantly during the treatment period, and this increase was associated with a greater variability in peak flow and an increased requirement for rescue medication when the medications were withdrawn. Pauwels et al. did not include a withdrawal period in their study. How might the patients who were regularly receiving formoterol have fared once this medication was stopped after one year?

Sundeep Salvi, M.D.
University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom

1 References

1. 1

   Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996;335:841-847
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: There are several reasons why we did not measure bronchial responsiveness. Although bronchial hyperresponsiveness is an important characteristic of asthma, it is only an intermediate outcome. Bronchial responsiveness to a direct agonist such as histamine is poorly related to clinical outcomes.1 There is still debate as to whether bronchial responsiveness to a direct or an indirect agonist is a better correlate of disease activity.2 Furthermore, most studies have shown a decrease but not a loss of protective activity for bronchoconstrictor agonists during prolonged treatment with long-acting β₂-agonists. We therefore decided that it was more important to look at clinically important outcome measures such as severe and mild exacerbations, symptoms, and use of rescue medication.

FitzGerald suggests that the severe exacerbations, defined in terms of clinical variables, did not justify treatment with oral glucocorticoids. We have compared symptom scores, changes in peak expiratory flow, and use of rescue medication in the days preceding the course of oral glucocorticoids in the patients with severe exacerbations that were identified on the basis of clinical judgment and on the basis of peak-expiratory-flow criteria and found that the changes were similar in both groups. No patients with a peak expiratory flow that was 70 to 100 percent of the predicted value were defined as having a severe exacerbation of asthma, as suggested by FitzGerald. In fact, we added the peak-expiratory-flow criteria to protect patients who were unaware that they had had a significant decrease in their lung function from having a life-threatening exacerbation. Our study therefore confirms that clinical judgment is in most instances an adequate means to identify severe exacerbations of asthma.

We cannot make a definitive statement about the influence of the high-dose induction phase on the long-term effects of the various treatments, since no control group was included. The principal reason for the high-dose induction phase was to exclude patients whose asthma could not be controlled with a very high dose of inhaled budesonide and who were therefore at greater risk when randomly assigned to the low dose. The use of this phase may have contributed to the long-term effect. A study with a similar design showed that the effects of a high-dose induction phase on measures of airway inflammation were maintained for one year of therapy with lower doses of inhaled glucocorticoids.3 The high-dose induction phase has been recommended in guidelines on the treatment of asthma.4

Romain A. Pauwels, M.D.
University Hospital, B9000 Ghent, Belgium

Anne E. Tattersfield, M.D.
City Hospital, Nottingham NG5 1PB, United Kingdom

Claes-Göran Löfdahl, M.D.
University Hospital, S-221 85 Lund, Sweden

4 References

1. 1

   Josephs LK, Gregg I, Mullee MA, Holgate ST. Nonspecific bronchial reactivity and its relationship to the clinical expression of asthma: a longitudinal study. Am Rev Respir Dis 1989;140:350-357
   CrossRef | Web of Science | Medline

2. 2

   Pauwels R, Joos G, Van der Straeten M. Bronchial hyperresponsiveness is not bronchial hyperresponsiveness is not bronchial asthma. Clin Allergy 1988;18:317-321
   CrossRef | Medline

3. 3

   Kips JC, O'Connor BJ, Svensson K, Pauwels RA, O'Byrne PM. Low dose budesonide plus formoterol versus high dose budesonide in asthma therapy: effects on markers of airway inflammation. Eur Respir J 1997;10:Suppl 25:1s-1s abstract.
   CrossRef | Web of Science

4. 4

   British Thoracic Society. The British guidelines on asthma management. Thorax 1997;52:S1-S21
   CrossRef | Web of Science | Medline