INITIAL THERAPY IN CLINICAL ASTHMA STUDIES OFTEN DOES NOT EQUAL THERAPY FOR MILD, PERSISTENT ASTHMA

To the Editor :

I have noticed a disturbing trend in recently published studies comparing two treatments in patients who have the diagnosis of asthma and are symptomatic on -agonists alone (1, 2). Both studies have shown the superiority of the aerosol medication (either a combined steroid and long acting -agonist or steroid alone) to an oral leukotriene modifier. Although the methodology and results of both studies appear valid, the interpretations and conclusions are erroneous. Both studies imply that the use of a leukotriene modifier, particularly montelukast, will lead to inferior results in the treatment of mild persistent asthma. Calhoun states in his introduction "this is the first study to compare the efficacy and safety . . . as initial maintenance therapy in patients with persistent asthma who were uncontrolled on short-acting 2-agonists alone" (1). In the discussion section, he states "clearly, there are patients with mild persistent asthma for whom monotherapy with a single maintenance treatment such as a low dose of an inhaled corticosteroid would be sufficient."

However, if one looks carefully at the inclusion/exclusion criteria for this study, it is clear that patients with mild, persistent asthma are actually being excluded from this study. Patients needed an FEV₁ between 50 and 80% of predicted normal range to be randomized. Furthermore, patients had to have a minimum number of daily symptoms to be included in the study. Patients in both groups were using approximately five puffs of albuterol per day. There were approximately 6% of days during the study in which they required no use of albuterol, and two to three nights per week in which they awoke with asthma symptoms. In other words, these patients had moderate persistent asthma, not mild persistent asthma (3). It is unclear to me why the authors chose to examine this group of patients, as leukotriene modifiers clearly have not been recommended as monotherapy in this group of patients. The authors attempt to address this design flaw by dividing the patients in more and less severe groups, with an FEV₁ cutoff of 70% predicted, but they are still only examining two groups of moderate asthmatics.

Thus, studies that attempt to compare therapies as initial controller therapy in patients who are symptomatic on short-acting 2-agonists alone should include mild persistent asthmatics in their selection criteria. Studies such as this one, which specifically exclude such patients, should be discounted.

State University of New York, Stony Brook, Stony Brook, New York

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. Busse W, Raphael GD, Galant S, Kalberg C, Goode-Sellers S Sr. ebro S, Edwards L, Rickard K. Low dose fluticasone proprionate compared with montelukast for the first-line treatment of persistent asthma: a randomized clinical trial. J Allergy Clin Immunol 2001; 107: 461-468 [Medline].

3. 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.

Dr. Ilowite discloses that he serves on the Speakers Bureau for Merck, Novartis, Glaxo, and Boehringer, and that he has served as a principal investigator for studies involving asthma for these companies and also for Genentech and AstraZeneca.

From the Author :

Dr. Ilowite asserts that our interpretations and conclusions in our paper (1) are erroneous, a position with which we most vigorously disagree. I believe that he is confused about the nature of our study and the clinical presentation of patients with asthma. He accurately quoted our description of the study as evaluating "initial maintenance therapy," but it was he, not us, who added the qualifier "mild" to the description of "persistent asthma" in our population. The subjects in our study predominantly had moderate persistent asthma by the NIH Guidelines (2), as reflected by both symptom frequency and pulmonary function criteria. Not all patients appropriate for initial maintenance therapy have mild persistent asthma. Patients on short-acting -agonists alone do present to physicians with moderate, or even severe persistent asthma. It is therefore a valid scientific and clinical question to evaluate initial maintenance therapy in such patients.

We do not advocate montelukast monotherapy as optimal therapy for patients with moderate persistent asthma. However, it is absolutely and unequivocally not a design flaw (and it is fallacious to suggest that it is) to include such patients in a trial. We chose montelukast as a comparison drug because it is indicated for treatment of (unqualified) persistent asthma (3). Furthermore, the pivotal trials for montelukast evaluated a similar patient population (entry criteria allowed for patients with an FEV₁ range of 50 to 85% of predicted) (4).

We stand by our assertion that there are patients with mild persistent asthma for whom single controller agent therapy would be appropriate. There was no implication in our paper that we were referring to our study population, and perhaps Dr. Ilowite was confused on this point also.

Finally, including mild persistent asthma patients in clinical studies is often problematic because subjects with normal lung function may fail to show a diagnostic bronchodilator response (5), and therefore fail to have an established diagnosis of asthma. Dr. Ilowite asserts that our study should be discounted because it failed to include a particular population of interest to him, but acknowledges that our methodology and factual results are sound. I view his conclusion as being logically unsound, and would suggest that the scientific method requires that opinions not based in scientific fact be discounted.

Dr. Calhoun discloses that the study cited in reference 1 was funded 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.