THE STEP 3 DILEMMA FOR MODERATE PERSISTENT ASTHMA

To the Editor :

I read the recent study from Calhoun and colleagues (1) showing significant superiority of fluticasone-salmeterol combination compared with montelukast monotherapy, but wondered what was the actual clinical relevance of these findings for everyday practice. These patients had an average FEV₁ of 67% predicted at screening, and at baseline were using their albuterol as a mean of five puffs per day, in keeping with persistent asthma of moderate severity.

According to current guidelines at step 3, the use of montelukast on its own without inhaled corticosteroid would clearly be inappropriate as initial maintenance therapy for moderate persistent asthma (2). Nonetheless, it was evident that even in these type of patients, montelukast as monotherapy exhibited significant improvements in objective and subjective efficacy variables over the 12 weeks.

Although the fluticasone-salmeterol combination produced a 23% mean improvement in the primary outcome variable of FEV₁, it should be noted that this may have been biased because of a requirement for an increase of at least 12% in FEV₁ in response to albuterol as one of the inclusion criteria. In other words, patients had been selected so as to demonstrate a bronchodilator response to the salmeterol moiety of the combination inhaler. Consequently, it can hardly be a surprise to find that two drugs are better than one.

Finally, this study measured objective changes in lung function, but did not evaluate any surrogate inflammatory markers. In this respect, the addition of montelukast, but not salmeterol, to inhaled corticosteroid results in sustained improvements in airway reactivity to adenosine monophosphate as well as suppression of blood eosinophils (3).

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

1. Calhoun WJ, Nelson HS, Nathan RA, Pepsin PJ, Kalberg C, Emmett A, Rickard KA, Dorinsky P. Comparison of fluticasone propionate- salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting ₂-agonists alone. Am J Respir Crit Care Med 2001; 164: 759-763 [Abstract/Free Full Text].

2. National Institutes of Health. Highlights of the expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health (National Heart, Lung, and Blood Institute); 1997. p. 1-50. NIH Publication No. 97-4051A.

3. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001; 119: 1021-1026 [Abstract/Free Full Text].

From the Author :

We respond to the inquiries from Dr. Lipworth regarding our recent work comparing montelukast to the fluticasone-salmeterol combination (1). The question of asthma severity is correctly outlined: these patients had predominantly moderate persistent asthma, per the U.S. Guidelines (2). The question of relevance for everyday practice is, ironically, entirely backwards. In a fully guideline-compliant world, monotherapy with montelukast would not generally be offered to these patients. The world of everyday practice is quite different. Despite considerable educational efforts, physicians still fail to recognize asthma severity, and hence treat asthma patients with insufficient controller agents. Many patients, like those we studied, are treated in everyday practice with single agent therapeutic regimens, so our findings are at the very least applicable to everyday practice, if not in fact to an ideal situation. It is important to note that the prescribing information for montelukast is unqualified, and states that montelukast "is indicated for the treatment of chronic persistent asthma" (3). The pivotal trials for montelukast were conducted in a patient population very similar to the one used in our study. Malmstrom and colleagues (4), evaluated symptomatic patients previously treated with inhaled short-acting ₂-agonists alone who had a mean FEV₁ at baseline of 65% of predicted normal (entry criteria allowed for patients with an FEV₁ range of 50 to 85% of predicted). We agree that montelukast monotherapy, even in these more moderately severe patients, had some benefit in our study. The question we addressed, however, was the relative benefit of montelukast versus fluticasone-salmeterol combination; for the outcomes studied in our patients, fluticasone-salmeterol combination consistently outperformed montelukast.

We reject the validity of the suggestion of subject bias, due to a requirement for a 12% increase in FEV₁ after albuterol inhalation; there is no bias. This requirement, very simply, is part of the definition of asthma (5). Were our subjects not to have met this requirement, they would not have met the consensus physiologic definition for asthma. We chose to study asthma, rather than some other less well-defined respiratory disease.

The question of inflammatory markers in asthma is critically important, and it is correct that our study did not address these matters. These will be important studies to conduct in the future. However, I know of no data which demonstrate that bronchial responsiveness to adenosine monophosphate is a validated measure of airway inflammation (6). Peripheral blood eosinophil counts may reflect the development of allergic responses (6), but are entirely unhelpful as a measure of airway inflammation. Invasive sampling of the airway (7, 8), not blood or urine surrogates, will remain the gold standard for quantifying airway inflammation.

Dr. Calhoun discloses that the study cited in Reference 1 was funded in part by GlaxoSmithKline.

University of Pittsburgh, Pittsburgh, Pennsylvania

1. Calhoun WJ, Nelson HS, Nathan RA, Pepsin PJ, Kalberg C, Emmett A, Rickard KA, Dorinsky P. Comparison of fluticasone propionate- salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting ₂-agonists alone. Am J Respir Crit Care Med 2001; 164: 759-763 .

2. National Institutes of Health. Highlights of the expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health (National Heart, Lung, and Blood Institute); 1997. p. 1-50. NIH Publication No. 97-4051A.

3. Singulair7 (montelukast sodium). Product Information. Merck & Co. West Point, PA. February 1998.

4. Malmstrom K, Guillermo RG, Guerra J, Villaran C, Pineiro A, Wei LX, Seidenberg BC, Reiss TF. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med 1999; 130: 487-495 [Abstract/Free Full Text].

5. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-244.

6. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001; 119: 1021-1026 .

7. Calhoun WJ, Lavins BJ, Minkwitz MC, Evans R, Gleich GJ, Cohn J. Effect of zafirlukast (Accolate) on cellular mediators of inflammation: Bronchoalveolar lavage fluid findings after segmental antigen challenge. Am J Respir Crit Care Med 1998; 157: 1381-1389 [Abstract/Free Full Text].

8. Jarjour NN, Peters SP, Djukanovic R, Calhoun WJ. Investigative use of bronchoscopy in asthma. Am J Respir Crit Care Med 1998; 157: 692-697 [Free Full Text].