Download Salmeterol Powder Provides Significantly Better Benefit Than

Salmeterol Powder Provides
Significantly Better Benefit Than
Montelukast in Asthmatic Patients
Receiving Concomitant Inhaled
Corticosteroid Therapy*
James E. Fish, MD, FCCP; Elliot Israel, MD, FCCP; John J. Murray, MD, PhD;
Amanda Emmett, MS; Rebecca Boone, BS; Steven W. Yancey, MS; and
Kathleen A. Rickard, MD
Study objectives: Comparison of inhaled salmeterol powder vs oral montelukast treatment in
patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids.
Design: Randomized, double-blind, double-dummy, parallel-group, multicenter trials of 12-week
duration.
Setting: Outpatients in private and university-affiliated clinics.
Patients: Male and female patients > 15 years of age with a diagnosis of asthma (baseline FEV1 of 50
to 80% of predicted) and symptomatic despite receiving inhaled corticosteroids.
Interventions: Inhaled salmeterol xinafoate powder, 50 ␮g bid, or oral montelukast, 10 mg qd.
Measurements and results: Treatment with salmeterol powder resulted in significantly greater
improvements from baseline compared with montelukast for most efficacy measurements, including
morning peak expiratory flow (35.0 L/min vs 21.7 L/min; p < 0.001), percentage of symptom-free days
(24% vs 16%; p < 0.001), and the percentage of rescue-free days (27% vs 20%; p ⴝ 0.002). Total
supplemental albuterol use was decreased significantly more in the salmeterol group compared with
the montelukast group (ⴚ 1.90 puffs per day vs ⴚ 1.66 puffs per day; p ⴝ 0.004) and nighttime
awakenings per week decreased significantly more with salmeterol than with montelukast (ⴚ 1.42 vs
ⴚ 1.32; p ⴝ 0.015). Patients treated with inhaled salmeterol were significantly more satisfied with
their treatment regimen and how well, how fast, and how long it worked than were patients who were
treated with oral montelukast. The safety profiles for the two treatments were similar.
Conclusion: In patients with persistent asthma who remain symptomatic while receiving inhaled
corticosteroids, adding inhaled salmeterol powder provided significantly greater improvement in
lung function and asthma symptoms and was preferred by patients over oral montelukast.
(CHEST 2001; 120:423– 430)
Key words: asthma; leukotriene receptor antagonist; long-acting ␤2-agonist; montelukast; peak expiratory flow; salmeterol;
xinafoate
Abbreviations: LABA ⫽ long-acting ␤-agonist; PEF ⫽ peak expiratory flow
elucidation of the basic physiologic
A lthough
mechanisms of asthma continues to be one target
of biomedical research, it is recognized that asthma
*From the Jefferson Medical College (Dr. Fish), Philadelphia,
PA; Brigham & Women’s Hospital (Dr. Israel), Boston, MA;
Vanderbilt Medical Center (Dr. Murray), Nashville, TN; and
Glaxo Wellcome Inc (Mss. Emmett and Boone, Mr. Yancey, and
Dr. Rickard), Research Triangle Park, NC.
This work was funded by Glaxo Wellcome Inc, Research Triangle
Park, NC.
Manuscript received July 12, 2000; revision accepted February 6,
2001.
Correspondence to: James E. Fish, MD, FCCP, Jefferson Medical
College, 1025 Walnut St, Suite 805, Philadelphia, PA 19107-5083;
e-mail: [email protected]
is the result of a variety of complex interactions
among inflammatory cells, mediators, and other cells
and tissues in the airway.1 The study of these
interactions has led to the knowledge that inflammation is an early and persistent component of asthma,2
and current asthma therapy is focused toward longterm control of the underlying inflammation. Due to
their broad actions on the inflammatory process,
inhaled corticosteroids are now recognized as providing effective long-term control for persistent asthma.1 Although the precise mechanism by which
inhaled corticosteroids provide clinical benefit in
asthma is uncertain, their beneficial clinical effects
CHEST / 120 / 2 / AUGUST, 2001
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423
may in part be mediated by mechanisms that include
reducing inflammation in the airways,3 reducing
cellular infiltrates, decreasing subepithelial fibrosis,
and increasing ciliated epithelial cells, some of which
appear to be implicated in airway remodeling.4,5
Inhaled corticosteroids are considered first-line
treatment for persistent asthma and have become
the cornerstone of asthma care.6
Although inhaled corticosteroids are effective in
controlling symptoms in many patients, some may
remain symptomatic despite inhaled corticosteroid
therapy. In these patients, the options are to increase
the dosage of inhaled corticosteroids or add a second
controller medication. There are only limited data to
help select a second controller medication from
those available, although several studies7–11 have
shown that the combination of an inhaled corticosteroid with a long-acting ␤-agonist (LABA) is more
effective than increasing the dosage of inhaled corticosteroids. Adding long-acting bronchodilators to a
regimen of inhaled corticosteroids may lead to a
decrease in asthma exacerbations with no change in
the ability to detect worsening asthma.12–14 Studies15–17 with a combined formulation of the inhaled
corticosteroid, fluticasone propionate, and salmeterol have shown that this regimen offers significant
clinical advantages over either of the products alone.
Compounds that block either the synthesis or
receptor activity of cysteinyl leukotrienes have been
shown18 –23 to be efficacious in the treatment of
asthma. Although published data comparing leukotriene modifiers with other established long-term
control therapies are limited, leukotriene modifiers
have been used as monotherapy in patients with mild
asthma and as add-on therapy with inhaled corticosteroids or an existing asthma treatment regimen in
patients with persistent asthma.24 The present study
compares the long-acting bronchodilator salmeterol
with the leukotriene receptor antagonist montelukast
as add-on therapy for patients who remain symptomatic while receiving low to intermediate dosages of
inhaled corticosteroids.
Materials and Methods
Study Design and Patients
Two multicenter, randomized, double-blind, parallel-group
clinical trials were conducted to compare the efficacy and safety
of inhaled salmeterol xinafoate (Serevent; Glaxo Wellcome Inc;
Research Triangle Park, NC), 50 ␮g bid, via a multidose powder
inhaler (Diskus; Glaxo Wellcome, Inc), with oral montelukast
(Singulair; Merck & Co, Inc; West Point, PA), 10 mg qd, over a
12-week treatment period in patients with persistent asthma. The
studies were conducted at 71 clinical centers in the United States
and Puerto Rico.
Eligible patients underwent screening assessments including
medical history, physical examination, and pulmonary function
testing including FEV1 reversibility. All patients provided written
informed consent, and institutional review boards approved the
study at each respective center.
Male patients and nonpregnant, nonlactating female patients
ⱖ 15 years old were eligible if they had a diagnosis of asthma as
defined by the American Thoracic Society25 for at least 6 months
and were symptomatic despite receiving inhaled corticosteroids
for at least 6 weeks prior to screening, and at a constant dosage
for 30 days prior to screening. Patients had a baseline FEV1 of 50
to 80% of predicted26,27 after withholding bronchodilator therapy
for 6 h and had at least a 12% increase in FEV1 30 min following
inhalation of 180 ␮g of albuterol. Predicted FEV1 values were
race adjusted for African Americans.28 After a 7-day to 14-day
run-in period to assess symptoms, diary card completion, and
patient proficiency with inhaler use, patients whose FEV1 remained within 50 to 80% of predicted normal values were eligible
for enrollment. Patients were also required to meet one or more
of the following criteria during the 7 days prior to randomization:
use of an average of ⱖ 4 puffs per day of albuterol, a symptom
score of ⱖ 2 on ⱖ 3 days, and ⱖ 3 nights when the patient
awakened due to asthma symptoms.
At enrollment, patients were supplied with albuterol inhalers
(albuterol sulfate; Ventolin; Glaxo Wellcome Inc) for relief of
breakthrough symptoms. Use of all other inhaled or oral bronchodilators, systemic corticosteroids, cromolyn, nedocromil, ipratropium, or leukotriene modifiers was prohibited. Concurrent use of
theophylline during the study or use of any medication that could
potentially interact with sympathomimetic amines or montelukast
was not allowed (ie, ␤-blockers, polycyclic antidepressants, monoamine oxidase inhibitors, phenobarbital, and rifampin).
Patients used a hand-held peak flowmeter (Astech; Center
Laboratories; Port Washington, NY) to measure daily morning
and evening peak expiratory flow (PEF), recording the highest of
three forced exhalations prior to taking study medications. Patients also recorded nighttime awakenings due to asthma, daytime and nighttime supplemental albuterol use, ratings of asthma
symptoms, and use of blinded study drug on daily diary cards.
Daytime asthma symptoms of wheezing, chest tightness, and
shortness of breath were rated on a 5-point scale: 0 ⫽ no
symptoms, 1 ⫽ symptoms present but caused no discomfort,
2 ⫽ symptoms caused discomfort but did not interfere with
normal daily activities, 3 ⫽ symptoms caused discomfort and
interfered with at least one normal daily activity, 4 ⫽ symptoms
caused discomfort and interfered with two or more activities, and
5 ⫽ symptoms that caused discomfort and prevented normal
daily activities. Patients returned to the clinic for adverse event
assessments after 1, 4, 8, and 12 weeks of treatment. A satisfaction with treatment questionnaire was completed after 12 weeks
of treatment. Each item on the questionnaire was scored on a
scale of 0 to 6, with higher scores indicating greater satisfaction
with therapy.
Asthma exacerbations were defined as any worsening of asthma
symptoms requiring treatment beyond the use of blinded study
drug and/or supplemental albuterol. Patients who experienced an
asthma exacerbation were withdrawn from the study.
Statistical Analysis
The primary efficacy measure was morning PEF at end point. A
sample size of 440 patients per treatment arm provided ⬎ 80%
power to detect a significant difference of 15 L/min from baseline in
morning PEF measurements between the two treatment groups
based on a two-sample, two-sided t test at a significance level of 0.05.
Other efficacy measures included evening PEF, daytime asthma
symptom score, supplemental albuterol use, and nighttime awakenings. Asthma exacerbation information and patient-rated satisfaction
with study medication were also assessed.
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Clinical Investigations
Descriptive and inferential analyses of the PEF data were
performed comparing the two treatment groups at each treatment week, across each 4-week treatment period, across the
entire 12-week treatment period, and at end point. End point was
defined as the last available treatment week mean. Mean changes
in PEF from pretreatment baseline were assessed, and the two
treatment groups were compared using analysis of covariance
controlling for investigator and baseline. Supplemental albuterol
use and nighttime awakenings per week were analyzed in the
same manner.
Inferential analyses comparing treatment groups based on
change from baseline values for daytime asthma symptom scores,
percentage of symptom-free days, percentage of rescue-free
days, and number of nights per week with awakenings were
performed using a van Elteren test29 controlling for investigator.
Asthma exacerbation and adverse event frequencies between the
two treatment groups were summarized by frequency of event.
Frequencies of treatment satisfaction scores were compared by
treatment group using a Cochran-Mantel-Haenszel test30 controlling for investigator differences.
Results
Demographics
A total of 476 patients received inhaled salmeterol
and 472 patients received oral montelukast. The
treatment groups had similar demographic and disease characteristics at baseline (Table 1).
PEF
Mean baseline morning PEF was comparable
between the two groups (371.0 L/min vs 370.2 L/min
in the salmeterol and montelukast groups, respectively). During the 12-week treatment period, patients in the salmeterol group had significantly
greater increases in mean morning PEF (35.0 L/min)
compared with montelukast (21.7 L/min; p ⬍ 0.001).
Significantly greater improvements in morning PEF
(Fig 1, top, A) and evening PEF (Fig 1, bottom, B)
were noted in the salmeterol group within the first
week of treatment, and the superior bronchodilating
properties of salmeterol remained significantly
greater than montelukast over all treatment weeks.
Asthma Symptom Scores, Supplemental ␤-Agonist
Use, and Nighttime Awakenings
Mean symptom scores at end point and supplemental albuterol use and nighttime awakenings over
the 12-week study are shown in Table 2. Patients in
the salmeterol group experienced a significantly
greater increase in the percentage of symptom-free
days than did patients in the montelukast group
(24% vs 16%; p ⬍ 0.001). Although symptom scores
were low at baseline, the daytime scores for all
symptoms combined decreased by 39% in the salmeterol group compared with a 31% decrease for
montelukast (p ⫽ 0.039). Symptom scores for chest
tightness and shortness of breath decreased by 42%
and 38%, respectively, in the salmeterol group compared with 31% and 29% in the montelukast group
(p ⫽ 0.008 and p ⫽ 0.044, respectively). Wheezing
Table 1—Demographics and Disease Characteristics at Baseline
Treatment Groups
Variables
Age, yr
Mean (SE)
Range
Gender, No. (%)
Female
Male
Ethnic origin, No. (%)
White
Black
Asian
American hispanic
Other
Asthma duration, No. (%)
⬍ 10 yr
ⱖ 10 yr
Mean (SE) FEV1 before bronchodilation, L
Mean (SE) percent predicted FEV1
Mean (range) inhaled corticosteroid use, ␮g
Fluticasone
Triamcinolone
Beclomethasone
Budesonide
Flunisolide
Salmeterol
(n ⫽ 476)
Montelukast
(n ⫽ 472)
39.9 (0.6)
15–83
39.5 (0.6)
15–82
288 (61)
188 (39)
292 (62)
180 (38)
413 (87)
29 (6)
5 (1)
25 (5)
4 (⬍ 1)
393 (83)
42 (9)
9 (2)
28 (6)
0 (0)
114 (24)
362 (76)
2.33 (0.03)
68.1 (0.4)
120 (26)
352 (74)
2.34 (0.03)
68.6 (0.4)
468 (44–1,320)
548 (200–1,600)
269 (84–672)
714 (400–1,200)
1,117 (250–2,000)
497 (176–1,760)
557 (100–1,600)
261 (84–672)
588 (84–800)
1,036 (800–1,500)
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425
Figure 1. Mean change from baseline in morning (AM; top, A) and evening (PM; bottom, B) PEF values
for treatment week 1 through treatment week 12. “Overall” indicates the comparison of treatment groups
at end point. * ⫽ statistically significant difference between treatment groups (p ⱕ 0.032).
decreased by 39% in the salmeterol group and 31%
in the montelukast group (p ⫽ 0.403).
In the salmeterol group, daytime and nighttime
supplemental albuterol use decreased by 42% and
51%, respectively, from baseline compared with
decreases of 35% and 40%, respectively, in the
montelukast group. Both differences between treatment groups were significant (p ⱕ 0.012). The in-
crease in the percentage of days with no rescue
albuterol use in the salmeterol group was also significantly greater than in the montelukast group (27%
vs 20%; p ⫽ 0.002).
Over 12 weeks of treatment, patients receiving
salmeterol experienced significantly greater reductions in nighttime awakenings per week compared
with the montelukast group (1.42 vs 1.32; p ⫽ 0.015)
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Clinical Investigations
Table 2—Baseline and Mean Change From Baseline in Symptom Scores, Supplemental Albuterol Use, and Nighttime
Awakenings Over 12 Weeks of Treatment*
Treatment Groups
Salmeterol
(n ⫽ 452)
Variables
Subject-rated daytime symptoms†
Wheezing
Shortness of breath
Chest tightness
All symptoms
Percentage of symptom-free days†
Percentage of rescue-free days†
Total supplemental albuterol use, No. of puffs‡
Daytime supplemental albuterol use, No. of
puffs‡
Nighttime supplemental albuterol use, No. of
puffs
Nighttime awakenings per week, No.‡
Nights per week with awakenings, No.†
Montelukast
(n ⫽ 448)
Baseline
Change
Baseline
Change
p Value
1.21 (0.04)
1.55 (0.05)
1.42 (0.04)
1.40 (0.04)
8 (0.8)
10 (1.0)
4.37 (0.12)
3.62 (0.10)
⫺ 0.47 (0.05)
⫺ 0.59 (0.05)
⫺ 0.60 (0.05)
⫺ 0.55 (0.04)
24 (1.5)
27 (1.6)
⫺ 1.90 (0.10)
⫺ 1.51 (0.08)
1.19 (0.04)
1.51 (0.05)
1.34 (0.05)
1.34 (0.04)
10 (1.0)
9 (1.0)
4.66 (0.13)
3.79 (0.10)
⫺ 0.37 (0.04)
⫺ 0.44 (0.05)
⫺ 0.42 (0.05)
⫺ 0.41 (0.04)
16 (1.3)
20 (1.4)
⫺ 1.66 (0.11)
⫺ 1.31 (0.09)
0.403
0.044
0.008
0.039
⬍ 0.001
0.002
0.004
0.010
0.76 (0.05)
⫺ 0.39 (0.04)
0.88 (0.05)
⫺ 0.35 (0.04)
0.012
2.62 (0.18)
2.02 (0.11)
⫺ 1.42 (0.13)
⫺ 1.06 (0.08)
3.00 (0.19)
2.25 (0.12)
⫺ 1.32 (0.15)
⫺ 0.93 (0.09)
0.015
0.007
*Data are presented as mean (SE). Baseline is an average for the 7 days immediately prior to randomization.
†p values are based on a van Elteren test on change from baseline controlling for investigator.
‡p values are based on an analysis of covariance on change from baseline controlling for investigator and baseline.
and a larger decrease in the number of nights per
week with awakenings (2.42 vs 2.06, respectively;
p ⫽ 0.078).
Patient Satisfaction With Treatment
Analysis of surveys of overall satisfaction with
treatment favored salmeterol over montelukast
(p ⫽ 0.021; Table 3). Analysis of domains of satisfaction was significantly greater for salmeterol for how
well (p ⫽ 0.006) and how fast (p ⬍ 0.001) medication worked compared with montelukast. There was
no significant difference between groups in satisfaction with how long medication worked (p ⫽ 0.102).
Patients in the salmeterol group were more likely to
use study medication again compared with patients
in the montelukast group (p ⫽ 0.004).
Asthma Exacerbations
Six percent (26 of 476) of patients in the salmeterol group experienced a total of 27 asthma exacerbations compared with 5% (23 of 472) of patients in
the montelukast group who experienced 24 asthma
exacerbations during the 12-week treatment period.
The most common suspected causes of exacerbation
in both treatment groups were respiratory infection,
allergens, or unknown etiology. Most exacerbations
were treated in the clinician’s office (54%), while
others were treated at home (25%) or in the emergency department (11%).
Adverse Events
The percentages of patients reporting at least one
drug-related adverse event were comparable in the
two treatment groups (7% in the salmeterol group
compared with 6% in the montelukast group). The
most frequently reported drug-related adverse
events in the salmeterol and montelukast groups
were headache (1% in each group) and insomnia (1%
in the salmeterol group). All other drug-related
events occurred in ⬍ 1% of patients in each group.
Ten serious adverse events were reported. In the
salmeterol group, three patients experienced acute
asthma exacerbations related to concurrent illnesses
(respiratory tract infection, acute bronchitis, and
chicken pox), one patient experienced a syncopal
episode, and one patient experienced chest tightness
and aches/numbness in the elbows. In the montelukast group, one patient experienced chest pain,
one patient had pneumonia, one patient experienced
migraine headache, one patient experienced appendicitis, and one patient had a spontaneous abortion.
None of these events were considered drug related.
Twenty-six patients were withdrawn from the study
due to adverse events (13 patients in each treatment
group).
Discussion
The results from these well-controlled, multicenter studies show that the addition of inhaled
salmeterol powder to inhaled corticosteroid therapy
provides significantly greater improvement in lung
function and control of asthma symptoms compared
with oral montelukast in patients who remain symptomatic while receiving low or intermediate dosages
of inhaled corticosteroids. Our findings are consisCHEST / 120 / 2 / AUGUST, 2001
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427
Table 3—Patient Satisfaction With Treatment
and Use*
Treatment Groups
Variables
Overall satisfaction
Dissatisfied
Neutral
Satisfied
How well it works
Dissatisfied
Neutral
Satisfied
How fast it works
Dissatisfied
Neutral
Satisfied
How long it works
Dissatisfied
Neutral
Satisfied
Use of study medication again
Yes, I would ask my doctor
for them
Yes, if my doctor thought I
should
Not sure, I might or might
not
No, even if my doctor
thought I should
No, I would ask for
something else
Salmeterol Montelukast
(n ⫽ 400) (n ⫽ 386) p Value†
0.021
23 (6)
40 (10)
337 (84)
43 (11)
36 (9)
306 (79)
27 (7)
35 (9)
336 (84)
47 (12)
42 (11)
297 (77)
24 (6)
91 (23)
284 (71)
53 (14)
90 (23)
243 (63)
24 (6)
68 (17)
307 (77)
48 (12)
47 (12)
291 (75)
145 (36)
116 (30)
186 (47)
182 (47)
47 (12)
48 (12)
8 (2)
8 (2)
14 (4)
31 (8)
0.006
⬍ 0.001
0.102
0.004
*Data are presented as No. (%).
†Treatment comparisons are based on a Cochran-Mantel-Haenszel
test controlling for investigator.
tent with those of Condemi and colleagues,11 who
found that salmeterol added to a regimen of fluticasone propionate increased morning PEF by 47
L/min, and those reported by Laviolette et al,31 who
found a 10-L/min increase in PEF when montelukast
was added to a regimen of beclomethasone, 200 ␮g
bid. It is unlikely that our results would have been
different had we used different doses of either
montelukast or salmeterol. Others8 have shown salmeterol at 100 ␮g bid had no greater effect than 50
␮g bid in reducing nocturnal symptoms in symptomatic patients receiving inhaled corticosteroids. Moreover, dose-ranging studies32,33 with montelukast indicate that optimal improvement in asthma control
variables is achieved at the 10-mg/d dosage. It is also
important to note that these results are obtained at
the nadir of the effect of salmeterol (immediately
prior to the morning dose) but near the apex of the
effect of montelukast based on once-daily dosing in
the evening.34
These findings are important since there is little
published information comparing the effects of these
two classes of controller medications. Busse and
colleagues35 found that salmeterol provided significantly greater improvement in asthma control
(morning and evening PEF, percentage of symptomfree days, percentage of days with no supplemental
albuterol, greater relief in asthma signs and symptoms) than the oral leukotriene receptor antagonist,
zafirlukast, in a population in which most, but not all,
patients were concurrently receiving inhaled corticosteroids. To our knowledge no other well-controlled studies comparing salmeterol and montelukast have been
published to date.
The mechanisms by which an inhaled corticosteroid and a long-acting bronchodilator provide clinical
benefit in asthma have not been fully elucidated.
Clearly, however, asthma is a disease of two components: bronchoconstriction and inflammation. Thus,
it is likely that the combination of a long-acting
bronchodilator and an inhaled corticosteroid provide
benefit via complementary bronchodilatory and antiinflammatory modes of action.36 –38 In vitro studies39
have suggested that there may be a complementary
interaction. Li and colleagues39 showed a significant
fall in the number of eosinophils in the lamina
propria of asthmatic patients when salmeterol was
added to a regimen of inhaled corticosteroids but not
when the inhaled corticosteroid dosage was increased. A concurrent improvement in clinical status
also occurred in these patients.
Several mechanisms have been proposed for this
complementary action. Corticosteroids are believed
to inhibit cytokine production and prevent ␤2-adrenergic receptor downregulation, allowing ␤2-adrenergic agonists to be more effective.36 Corticosteroids
have also been shown to increase ␤2-receptor synthesis40 and to decrease ␤2-receptor desensitization.41 LABAs have been reported to prime the
glucocorticoid receptor for steroid-dependent activation.42 These mechanisms may lead to increased
responsiveness to steroids,43 increased potency or
activity of the combination compared with either
drug alone,44,45 or a broader range of pharmacodynamic activity than using either a LABA or corticosteroid alone.46 These proposed mechanisms are
derived from in vitro data and are therefore speculative. Nevertheless, they are of potential clinical
significance, insofar as Kraft et al47 have reported
that glucocorticoid binding affinity and pharmacodynamic activity are reduced at night in patients with
nocturnal asthma compared to those without nocturnal asthma, and other clinical trials7–11 have demonstrated improvements in measures of asthma control
with combined LABA and corticosteroid therapy.
Although it has been suggested that patients prefer oral medications to inhaled medications,48 Balsbaugh and colleagues49 found that patients do not
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Clinical Investigations
have strong preferences regarding route of administration and that route of administration is not an
important feature of a controller medication. Patients treated with inhaled salmeterol in our study
were significantly more satisfied with their treatment
regimen and with how well, how fast, and how long
it worked than were patients treated with montelukast. These findings suggest that efficacy of the
treatment regimen may be a more important determinant of patient compliance than route of administration.
In summary, we have demonstrated that the addition of salmeterol to a regimen of inhaled corticosteroids provides significantly greater improvement in
lung function and asthma symptoms than the addition of montelukast in patients with mild-to-moderate persistent asthma. These clinical results support
a growing body of in vitro and in vivo scientific
evidence that the combination of a long-acting bronchodilator and an inhaled corticosteroid has complementary modes of action addressing both the bronchospastic and inflammatory components of asthma.
Further studies are needed to assess whether these
treatment-related differences persist for a longer
period of time and whether either LABAs or leukotriene antagonists have a bearing on the natural
history of asthma.
ACKNOWLEDGMENT: The authors thank Larry E. East for
his assistance in the writing and editing of this article.
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Clinical Investigations