(Chest. 2002;121:334-337.)
© 2002
American College of Chest Physicians
Marginal Utility of Montelukast for Persistent Asthma*
David A. Mathison, MD, and
James A. Koziol, PhD
*
From the Division of Allergy, Asthma and Immunology (Dr. Mathison), Scripps Clinic, and the Department of Molecular and Experimental Medicine (Dr. Koziol), The Scripps Research Institute, La Jolla, CA.
Correspondence to: David A. Mathison, MD, Scripps Clinic, Division of Allergy, Asthma and Immunology, 10666 North Torrey Pines Rd, 205W, La Jolla, CA 92037;
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Abstract
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Background: The efficacy of a new pharmacologic agent
for asthma, in this instance the leukotriene receptor antagonist
montelukast, is determined in controlled trials in research subjects.
The utility of a new drug is determined by multiple uncontrollable
factors in individual patients.
Objective: To assess
the utility of montelukast in the management of persistent asthma.
Design: Observational, retrospective.
Setting: Suburban multispecialty medical clinic.
Methods: From April 1998, montelukast was prescribed for
110 patients with persistent but controlled asthma, primarily for the
corticosteroid-sparing effect. Outcomes after 1 year were determined
from audits of medical records and responses to questionnaires.
Results: At least 56% of patients continued receiving
montelukast for the entire year. However, compared to those
patients who had discontinued montelukast therapy, those who continued
receiving it had no difference in the use of inhaled or systemic
corticosteroid or inhaled ß2-agonist therapy.
Conclusion: Montelukast had marginal utility in the
management of these adult patients with controlled persistent
asthma.
Key Words: antiasthmatic agents • asthma • leukotriene antagonists • montelukast • outcomes assessment • patient
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Introduction
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Prescription
by physicians for a newly approved medication for asthma, in this
instance the leukotriene receptor antagonist montelukast (Singulair;
Merck & Co, Inc; West Point, PA), is based on evidence of efficacy in
short-term, blinded, and controlled trials in selected and uniform
cohorts of large numbers of compensated research
subjects.1
2
The utility of a new medication depends on
individual patient characteristics (eg, severity of disease,
cultural background, economic capabilities, adherence to prescribed
regimen, dose route and frequency, palatability, and tolerability for
side effects) in the aggregate, perceptions of benefit, and value
leading to continued or discontinued use. This is a report on the
utility of montelukast for persistent asthma based on observations of
and by a series of 110 patients. As gauged by continued use
after 1 year, > 56% of these patients found montelukast to have
utility in the management of their asthma. As gauged by the concomitant
use of other medications, montelukast had a marginal, if any, effect.
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Materials and Methods
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Over a 1-year period starting from it availability in April
1998, montelukast was prescribed for 110 patients with persistent
asthma who were under continuing care by a single asthma specialist in
a multispecialty physician group. Patients met the following
criteria: they had persistent asthma, which was defined as the ongoing
use of long-term control medication (eg, corticosteroid,
salmeterol, cromolyn/nedocromil, and/or theophylline); their disease
was under control in terms of symptom control, optimal pulmonary
function, and activity levels3
; and they were motivated to
undertake a trial of new pharmacotherapy frequently by the wish to
reduce corticosteroid usage. The majority of patients resided in
outer-city and suburban San Diego, CA (women, 57%; men, 43%) with an
age range of 11 to 88 years (median age, 53.5 years). More than ninety
percent of patients had received a confirmation of their asthma by
spirometric measurements of a response to an inhaled albuterol
bronchodilator (mean FEV1 rise, 29%) or to a
methacholine bronchoconstrictor (mean FEV1 fall,
32%), 84% of patients were atopic, as determined by positive
responses to cutaneous or in vitro tests for IgE (pollen,
70%; house-dust mites, 54%; cats, 50%; mold, 45%; dogs, 35%;
cockroach, 14%), and 15% of patients were aspirin-sensitive
(ie, had positive results to an oral challenge or a typical
history).
On prescription (ie, study entry) for montelukast (10 mg
daily, except doses of 5 mg daily for four patients under age 15
years), patients were instructed to continue individualized current
programs of avoidances, immunotherapy, and medications.3
At follow-up contacts, patients who had continued to control their
asthma, as indicated by no increase in the use of a rescue ß-agonist
inhaled bronchodilator and/or stable or improved
FEV1 values, were instructed to reduce
corticosteroid use by approximately 20%.
One year after the initiation of montelukast therapy, medical records
were audited by technicians for medication usage, including
montelukast, and questionnaires sent to 103 patients (7 were lost to
follow-up) were returned by 75 (73%) with responses relating to
insurance coverage, perceived benefits, and side effects of the
therapy. Patient anonymity was assured, and no experimental
investigation was undertaken so that approval of the study by the Human
Subjects Committee was not required. Inhaled corticosteroid use was
quantitated in "fluticasone 220 equivalent puffs," as noted in
Table 1
, and was calculated on the basis of individual use, as reported by the
patient at their last visits for the years immediately preceding and
subsequent to montelukast prescription. Systemic corticosteroid use was
expressed as the average (including episodes of rescue use) daily dose
of prednisone or its equivalent, as calculated for the years before and
after entry. The use of short-acting and long-acting inhaled
bronchodilators, cromolyn/nedocromil, and theophylline was noted for
the last visits in the years before and after study entry. The details
of our methods have been reported previously.4
View this table:
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Table 1.. Estimated Comparative Doses of Inhaled
Corticosteroids Based on 1997 Guidelines for the Diagnosis and
Management of Asthma*
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Drug usage was summarized as the mean ± SE. Comparisons in drug usage
between the two study cohorts (ie, continued vs discontinued
montelukast usage) at corresponding time points were made with Wilcoxon
tests for discrete data and standard two-sample t tests for
continuous data. Comparisons within study cohorts of the amount of
change (ie, differences in drug usage over the course of the
1-year observation period) were made with Wilcoxon signed-rank
(discrete data) and paired-comparison t tests (continuous
data). Observed two-sided p values of < 0.05 were taken to be
indicative of statistical significance.
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Results
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As displayed in Table 2
, 62 patients (or at least 56% of the patients) continued montelukast
therapy and 37% discontinued montelukast therapy at 1 year (7% were
lost to follow-up). The groups that continued and discontinued therapy
did not differ for atopy/nonatopy, aspirin sensitivity, or insurance
coverage for medications (patients continuing therapy, 96%; patients
discontinuing therapy, 82%; p = 0.20). Side effects reported by
seven patients included hives, dry mouth, and unspecified side effects.
Six of the seven patients discontinued montelukast therapy.
The medication usage is summarized in Table 2
. There were no
statistically significant differences between the group that continued
montelukast therapy and the group that discontinued montelukast therapy
relating to therapy with inhaled ß2-agonists,
inhaled salmeterol, inhaled corticosteroids, or systemic
corticosteroids, either in the year preceding study or following study
entry, or in the amount of change (ie, the difference in
drug usage) over the 1-year period of observation. There was a
statistically significant decline in inhaled
ß2-agonist usage only in the group that
continued montelukast therapy. On the other hand, inhaled
corticosteroid usage declined only in the group that discontinued
montelukast therapy, and both groups experienced statistically
significant declines in systemic corticosteroid usage.
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Discussion
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The National Asthma Education and Prevention Program3
placed leukotriene-modifying drugs under consideration for the
long-term control of mild, persistent asthma "although their position
in therapy is not fully established." The results of subsequent
reports of direct comparisons of oral leukotriene receptor antagonists
with inhaled corticosteroids5
6
and with inhaled
long-acting ß2-agonist
salmeterol7
8
suggest greater efficacy for the latter two
agents, at least for adults. Nonetheless, one report9
suggested that montelukast therapy added to the control of asthma in
subjects whose conditions were uncontrolled with low-dose
beclomethasone therapy, and another report10
found that
montelukast therapy, when compared to placebo, allowed a greater
reduction in inhaled corticosteroid use in patients with chronic asthma
who were receiving high doses of an inhaled corticosteroid. These
reports1
2
5
6
7
8
9
10
reflect the results of pharmaceutical
company-sponsored controlled trials of large numbers of highly selected
research subjects. For example, Reiss et al2
enrolled 681
patients in order to have 95% power to detect a mean difference
between treatment groups of 5.4 percentage points in
FEV1 (in terms of the percentage change from
baseline). The extrapolation of results from such studies to
individual patients cared for by physicians on a continuing basis
requires monitoring and outcome audits for utility.
The differences between the results of this observational study
and those of controlled trials lie in methodology, patient selection,
and statistical power. The parameter of utility in patients with
controlled asthma differs from measurements of asthma control outcomes
in placebo or comparison controlled trials in research subjects with
partially controlled asthma. The reductions of therapy with
short-acting inhaled ß2-agonists and systemic
corticoids coincident to the continuation of montelukast therapy over 1
year, compared to the discontinuation of montelukast therapy in this
group of 110 patients, are modest. Prospectively, > 500 patients
would need to be observed in order to ensure that differences of this
magnitude would be found to be statistically significant with a power
of 0.90 at the two-sided 0.05 significance level. The results presented
here are consistent with the results of the direct comparisons of
therapy with leukotriene modifiers to inhaled corticosteroids and
salmeterol. Unlike therapy with inhaled corticosteroids and salmeterol,
the utility of therapy with montelukast has not been established as
a long-term control medication for patients with persistent asthma.
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Footnotes
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This research was supported by grants from The Ruth Church McKay
Foundation.
Received for publication April 4, 2001.
Accepted for publication August 22, 2001.
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References
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Altman, LC, Munk, Z, Seltzer, J, et al (1998) A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. J Allergy Clin Immunol 102,50-56[CrossRef][ISI][Medline]
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Reiss, TF, Chervinsky, P, Dockhorn, RJ, et al (1998) Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial; Montelukast Clinical Research Study Group. Arch Intern Med 158,1213-20[Abstract/Free Full Text]
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National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis, and management of asthma. Bethesda, MD: National Institute of Health, April 1997; Publication No. 97–4051
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Mathison, DA, Koziol, JA (2000) Persistent asthma: patient characteristics, courses of asthma, and utility of salmeterol. J Asthma 37,441-450[ISI][Medline]
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Malmstrom, K, Rodriguez-Gomez, G, Guerra, J, et al (1999) Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial; Montelukast/Beclomethasone Study Group. Ann Intern Med 130,487-495[Abstract/Free Full Text]
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Stempel, DA, Meyer, JW, Stanford, RH, et al (2001) One-year claims analysis comparing inhaled fluticasone propionate with zafirlukast for the treatment of asthma. J Allergy Clin Immunol 107,94-98[CrossRef][ISI][Medline]
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Busse, W, Nelson, H, Wolfe, J, et al (1999) Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 103,1075-1080[CrossRef][ISI][Medline]
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Nelson, HS, Busse, WW, Kerwin, E, et al (2000) Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 106,1088-1095[CrossRef][ISI][Medline]
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Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma: Montelukast/Beclomethasone Additivity Group. Am J Respir Crit Care Med 1999; 160:1862–1868
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Lofdahl, CG, Reiss, TF, Leff, JA, et al (1999) Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 319,87-90[Abstract/Free Full Text]
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Abstract
Introduction
