MONTELUKAST ADDED TO INHALED BECLOMETHASONE IN TREATMENT OF ASTHMA

To the Editor :

Laviolette and coworkers (1) state that their primary objective was to determine whether montelukast provides clinical benefits when added to a regimen of inhaled beclomethasone. Their conclusion of "additional asthma control" is not supported by the results reported. Daytime symptom scores improved by 6%, morning FEV₁ by 5%, morning PEFR by 2.5% and evening PEFR by 1.4%. The first three are statistically different but have questionable clinical significance. Furthermore, the patients' own global assessment of asthma control is not statistically altered with combination therapy. Laviolette and colleagues have confirmed the earlier study of Malmstrom (2) that demonstrates the superiority of beclomethasone compared with montelukast as initial monotherapy for asthma.

The lack of clinical significance for the above combination should not imply that add-on therapy in asthma is not effective. In fact, studies that assess the addition of long-acting bronchodilators to a regimen of inhaled corticosteroids (3, 4) demonstrate threefold greater improvement in FEV₁, morning and evening PEFR, and symptom scores than noted in this present report. Busse and coworkers (5) compared the addition of salmeterol or zafirlukast to a regimen of inhaled corticosteroids and found significantly greater improvement in lung function and symptom control with the addition of the long-acting bronchodilator as compared with a leukotriene modifier. Greater improvement in clinical outcomes is noted whether salmeterol or formoterol (6) is added as a long-acting bronchodilator to a regimen including any of the following inhaled corticosteroids: fluticasone, beclomethasone, or budesonide. In addition, the combination of montelukast and beclomethasone protected against a rise in the total eosinophil count but did not cause a reduction. Laviolette and colleagues confuse the importance of statistical findings in the absence of significant clinical results.

Virginia Mason Medical Center, Seattle, Washington

1. Laviolette, M., K. Malmstrom, S. Lu, P. Chervinsky, J.-C. Pujet, I. Peszek, and T. F. Reiss. 1999. Montelukast added to inhaled beclomethasone in treatment of asthma. Am. J. Respir. Crit. Care Med. 160: 1862-1868 [Abstract/Free Full Text].

2. Malmstrom, K., G. Rodriguez-Gomez, J. Guerra, C. Villaran, A. Piñeiro, L. X. Wei, B. C. Seidenberg, and T. F. Reiss. 1999. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann. Intern. Med. 130: 487-495 [Abstract/Free Full Text].

3. Condemi, J. J., S. Goldstein, C. Kalberg, S. Yancey, A. Emmett, and K. Rickard. 1999. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann. Allergy Asthma Immunol. 82: 383-389 [Medline].

4. Baraniuk, J., J. J. Murray, R. A. Nathan, W. E. Berger, M. Johnson, L. D. Edwards, S. Srebro, and K. A. Rickard. 1999. Fluticasone alone or in combination with salmeterol vs triamcinolone in asthma. Chest 116: 625-632 [Abstract/Free Full Text].

5. Busse, W., H. Nelson, J. Wolfe, C. Kalberg, S. W. Yancey, and K. A. Rickard. 1999. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J. Allergy Clin. Immunol. 103: 1075-1080 [Medline].

6. Pauwels, R. A., C. G. Löfdahl, D. S. Postma, A. E. Tattersfield, P. O'Bryne, P. J. Barnes, and A. Ullman. 1997. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 337: 1405-1411 [Abstract/Free Full Text].

From the Authors:

In our article (1), the conclusion that montelukast provides clinical benefit compared with beclomethasone alone was based on the response across multiple clinically important endpoints, including not only symptoms and measurement of airways obstructions but also outcomes (e.g., asthma exacerbations were decreased by 25%). A change of 5% in FEV₁ was clinically significant in this patient population with moderate asthma (mean baseline FEV₁ predicted ± 72%), while studies that have reported larger increases in FEV₁ were conducted in patients with more severe asthma (2). Further evidence for the complementary effect seen in this study comes from the fact that in vivo studies indicate that inhaled steroids do not have any effect on LTD₄ (3). The additional effect of montelukast on eosinophil counts emphasizes its effect on parameters of asthmatic inflammation. This supports the clinical importance of the combination of inhaled steroids and an antileukotriene agent.

Additional support for this additive benefit is found in a study of patients with severe persistent asthma (aspirin-intolerant) (4). In this 4-wk trial, patients (~ 90%) were treated with oral, inhaled, or a combination of inhaled and oral corticosteroids; the same improvement across multiple endpoints compared with placebo was observed in lung function, symptoms, and asthma exacerbation. The complementary benefit has also been demonstrated in a recent study (5) of the ability to taper inhaled corticosteroids when inhaled corticosteroids and antileukotrienes are given concomitantly.

Although the long-acting -agonist trials cited show additive benefit on airway function such as FEV₁, it is widely believed that long-acting -agonists have no effect on inflammation. In addition, there is evidence of a loss of the protective effect against bronchoconstriction due to exercise with -agonists, which was not seen with montelukast (6). Long-term studies measuring appropriate asthma outcomes and complementary effects on parameters of inflammation as primary endpoints are required to resolve head-to-head comparisons of clinical benefit.

MICHEL LAVIOLETTE

Centre de Pneumologie de l'Hôpital Laval

Québec, Canada

KERSTIN MALMSTROM

THEODORE F. REISS

Department of Pulmonary/Immunology

Merck Research Laboratories

Rahway, New Jersey

1. Laviolette, M., K. Malmstrom, S. Lu, P. Chervinsky, J.-C. Pujet, I. Peszek, and T. F. Reiss. 1999. Montelukast added to inhaled beclomethasone in treatment of asthma. Am. J. Respir. Crit. Care Med. 160: 1862-1868 .

2. Condemi, J. J., S. Goldstein, C. Kalberg, S. Yancey, A. Emmett, and K. Richard. 1999. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann. Allergy Asthma Immunol. 82: 383-389 .

3. Dworski, R., G. A. Fitzgerald, J. A. Oates, and J. R. Sheller. 1994. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am. J. Respir. Crit. Care Med. 149: 953-959 [Abstract].

4. Kuna, P., K. Malmstrom, S. E. Dahlen, E. Nizankowska, M. Kowalski, D. Stevenson, J. Bousquet, B. Dahlen, C. Picado, W. Lumry, S. Holgate, R. Pauwels, A. Szczeklik, A. Shahane, and T. F. Reiss. 1997. Montelukast (MK-0476), A CysLT, receptor antagonist, improves asthma control in aspirin-intolerant asthmatic patients (abstract). Am. J. Respir. Crit. Care Med. 155: A975 .

5. Lofdahl, C. G., T. F. Reiss, J. A. Leff, E. Israel, M. J. Noonan, A. F. Finn, B. C. Seidenberg, T. Capizzi, S. Kundu, and P. Godard. 1999. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. Brit. Med. J. 319: 87-90 [Abstract/Free Full Text].

6. Edelman, J. M., J. A. Turpin, E. A. Bronsky, J. Grossman, J. P. Kemp, A. F. Ghannam, P. T. DeLucca, G. J. Gormley, and D. S. Perlman. 2000. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Ann. Inter. Med. 132: 97-104 [Abstract/Free Full Text].