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Effect of Long-term Salmeterol Therapy
Compared With As-Needed Albuterol
Use on Airway Hyperresponsiveness*
Richard R. Rosenthal, MD; William W. Busse, MD; James P. Kemp, MD, FCCP;
James W. Baker, MD; Christopher Kalberg, PhD; Amanda Emmett, MS; and
Kathleen A. Rickard, MD†
Study objectives: To determine the effect of long-term salmeterol aerosol therapy on airway
hyperresponsiveness measured by methacholine challenge.
Design: Randomized, double-blind, placebo-controlled, multicenter study.
Setting: Thirty-one clinical centers in the United States.
Patients: Four hundred eight asthmatic patients > 12 years of age with baseline FEV1 of > 70%
of predicted values. Patients were not using inhaled corticosteroids.
Interventions: Twice-daily salmeterol aerosol, 42 mg, or placebo via metered-dose inhaler for 24
weeks. Backup albuterol was available.
Measurements and results: Pulmonary function tests were performed before, during, and after
treatment. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow
(PEF) levels, and use of supplemental albuterol daily on diary cards. Methacholine challenges were
performed 10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days posttreatment. Over 24 weeks
of treatment, salmeterol provided significant (p < 0.001) protection against methacholine-induced
bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo
with no evidence for a progressive decrease in protection. A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol
treatment resulted in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and
an improvement of 26.2 L/min in morning PEF when compared to placebo (p < 0.001). The use of
salmeterol significantly reduced combined daytime asthma symptoms by 20% when compared to
placebo (p 5 0.005). A total of 34 and 48 exacerbations, respectively, were reported in the salmeterol
and placebo groups, and no evidence was present for a difference in the severity of asthma
exacerbations between groups. Adverse event profiles were similar for the salmeterol and placebo
groups.
Conclusions: Regular long-term use of salmeterol aerosol resulted in sustained improvements in
pulmonary function and asthma symptom control over the 24-week treatment period. There was no
increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen
following 4 weeks of therapy. There was no evidence of rebound airway hyperresponsiveness after
cessation of salmeterol treatment. Regular treatment with the long-acting b-agonist salmeterol does
not lead to clinical instability or vulnerability to unpredictable asthma attacks.
(CHEST 1999; 116:595–602)
Key words: asthma; bronchial hyperresponsiveness; methacholine challenge; salmeterol
Abbreviations: ANOVA 5 analysis of variance; MDI 5 metered-dose inhaler; PD20 5 provocative dose of methacholine
required to reduce the FEV1 by 20% from baseline; PEF 5 peak expiratory flow
*From the Johns Hopkins School of Medicine (Dr. Rosenthal),
Baltimore, MD; University of Wisconsin (Dr. Busse), Madison, WI;
Allergy and Asthma Medical Group and Research Center (Dr.
Kemp), San Diego, CA; Allergy Associates Research Center (Dr.
Baker), PC, Portland, OR; and Glaxo Wellcome, Inc (Drs. Kalberg
and Rickard, Ms. Emmett), Research Triangle Park, NC.
†A list of investigators is located in the Appendix.
This study was supported by a research grant from Glaxo
Wellcome, Inc., Research Triangle Park, NC.
Manuscript received July 14, 1998; revision accepted April 9, 1999.
Correspondence to: Richard R. Rosenthal, MD, 8318 Arlington
Blvd, Suite 308, Fairfax, VA 22031
CHEST / 116 / 3 / SEPTEMBER, 1999
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595
guidelines for the diagnosis and manageC urrent
ment of asthma recognize asthma as a chronic
inflammatory disease of the airways in which many
cells and cellular elements play a role. In particular,
mast cells, eosinophils, T lymphocytes, neutrophils,
and epithelial cells have been identified as important
contributors. Variable airway bronchoconstriction,
respiratory symptoms, and bronchial hyperresponsiveness characterize the disease.1 Early intervention
with inhaled corticosteroid therapy is emphasized for
patients with persistent asthma. For patients that
remain symptomatic while using inhaled corticosteroids, adding salmeterol, a long-acting bronchodilator, is recommended for long-term control of symptoms.1 Based on an extended duration of action of
. 12 h, salmeterol is classified as a controller medication in current asthma management guidelines.1
Clinical studies evaluating the combined use of
inhaled corticosteroids and salmeterol have shown
that this regimen is more effective in providing
overall improvement in pulmonary function and
symptom control when compared to doubling the
dose of inhaled corticosteroids.2,3
Previous studies have shown reduced bronchoprotective effects of salmeterol against methacholine
challenge in patients independent of the use of
inhaled corticosteroids.4 –7 The clinical relevance of
this effect is unclear, particularly as levels of bronchoprotection remained significantly above control
levels, and no loss of bronchodilatory effect or
control of asthma symptoms was observed with
regular salmeterol treatment. However, because the
studies showing reduced bronchoprotective effect of
salmeterol were conducted for no longer than 8
weeks, long-term studies are necessary to determine
whether a progressive reduction in bronchoprotection occurs and leads to clinical instability of patients’
asthma.
In this study, the effects of long-term regular use
of 42 mg inhaled salmeterol aerosol on bronchial
hyperresponsiveness were investigated during and
after treatment in patients with moderate persistent
asthma who were not using inhaled corticosteroids.
Additional clinical outcome measures included pulmonary function tests, symptom assessment, nocturnal awakenings, and supplemental albuterol use.
Materials and Methods
Study Design
Two identically designed, randomized, double-blind, placebocontrolled, parallel-group, multicenter studies involving 31 study
sites were conducted in parallel. All patients provided written,
informed consent prior to study entry. The protocol and consent
form were approved by an institutional review board at each
study site.
A run-in period lasting 15 to 30 days was conducted to
determine patient eligibility and collect baseline data. Baseline
was defined as the 7 days immediately prior to treatment
initiation. Following the run-in period, subjects who met all
eligibility criteria were randomly assigned to receive either
salmeterol aerosol, 42 mg twice daily, or placebo aerosol twice
daily via metered-dose inhaler (MDI). Subjects completed a
24-week treatment period followed by a 1-week posttreatment
evaluation period. Subjects were provided commercially available
albuterol MDI (Ventolin Inhalation Aerosol; Glaxo Wellcome
Inc; Research Triangle Park, NC) for relief of acute symptoms
during the run-in, treatment, and posttreatment periods.
During run-in, patients used the albuterol MDI as needed to
relieve asthma symptoms; additional asthma medications were
not allowed. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow (PEF), and use of supplemental albuterol daily on diary cards. Subjects measured PEF
using a hand-held, mini-Wright peak flowmeter (Clement Clarke
Inc.; Mason, OH). The study staff instructed the subjects in the
correct use of the flowmeter, and the subject tested the instrument before leaving the office at the end of the screening visit.
Each measurement during the study was performed in triplicate,
and the highest value was recorded. The morning determinations
were completed immediately after rising from bed and before the
subject took the first dose of the study drug (including supplemental albuterol). The evening measurements were completed
before taking the last dose of the study drug for the day. Daytime
asthma symptoms of wheezing, shortness of breath, and chest
tightness were rated using the following five-point scale: 0 5 no
symptoms; 1 5 some symptoms present but caused no discomfort; 2 5 symptoms that caused little discomfort and did not
interfere with normal daily activities; 3 5 symptoms that caused
discomfort and interfered with at least one normal daily activity;
and 4 5 symptoms that caused significant discomfort and prevented normal daily activity. The mean number of nighttime
awakenings due to asthma was evaluated according to the
following scale: 0 5 slept well; 1 5 awoke once; 2 5 awoke two
to three times; and 3 5 awoke more than three times. Patients
were required to demonstrate a defined response to methacholine challenge.
Following randomization, methacholine challenge tests were
performed after 4, 12, and 24 weeks of treatment, and at 3 and 7
days of posttreatment. The same standardized methacholine
challenge equipment and procedures were used at all investigational sites. Pulmonary function tests were performed on the
initial treatment day, after 4, 8, 12, 16, 20, and 24 weeks of
treatment, and at 3 and 7 days posttreatment. The use of the
blinded study drug was recorded daily on diary cards. Subjects
were instructed to administer two inhalations from their blinded
study inhaler each morning between 6:00 am and 9:00 am and
every evening between 6:00 pm and 9:00 pm. The use of spacers
was not allowed. The study drug was withheld for 10 to14 h prior
to pulmonary function and methacholine challenge testing, and
supplemental albuterol was withheld for at least 8 h prior to these
evaluations. Methacholine challenge tests were rescheduled if
any of the following occurred: influenza vaccination or respiratory
tract infection within 6 weeks, asthma exacerbation treated with
oral steroids within 2 weeks, or asthma exacerbation not requiring
oral steroids within 5 days.
Exacerbations were defined as asthma symptoms requiring treatment with medications other than albuterol MDI and the blinded
study drug. Patients were not allowed use of inhaled corticosteroids,
nedocromil, or cromolyn during the study. Subjects who required
parenteral corticosteroids or initiation of inhaled corticosteroids,
nedocromil, or cromolyn for treatment of exacerbations were withdrawn from the study. Theophylline, nebulized short-acting b-agonists, and oral corticosteroids (prednisone, $ 60 mg qd or equiva-
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Clinical Investigations
lent) were allowed for the treatment of exacerbations as long as
treatment duration was # 7 days.
Patients
Female and male patients $ 12 years of age with a diagnosis of
asthma were enrolled in the study. Patients were excluded if they
had any clinically significant disease other than asthma, had an upper
or lower respiratory infection within 6 weeks of the screening visit,
or were hospitalized for asthma within 3 months of the screening
visit. Patients were required to have a baseline FEV1 of $ 70% of
predicted values after asthma medications had been withheld.
Reversibility of disease was demonstrated by an increase in FEV1 of
at least 15% above baseline within 30 min after the inhalation of two
puffs (180 mg) of albuterol. The provocative dose of methacholine
required to reduce the FEV1 by 20% from baseline (PD20) was used
to assess bronchial hyperreactivity. During the run-in period, patients had to have demonstrated two PD20 values of # 55.5 cumulative dosage units (512 cumulative mg) of methacholine (equivalent
to a provocative concentration of methacholine necessary for a
$ 20% decrease in FEV1 from saline solution control value of 7.5
mg/mL of methacholine) that were within a threefold change of one
another. Each PD20 value was obtained at visits that were separated
by at least 3 days; patients were given three visits to obtain the
required PD20 values.
Methacholine Challenge Testing
All study sites used a standardized methacholine challenge procedure8 and methacholine challenge equipment consisting of a
spirometer (PDS Research; Louisville, CO), a breath-actuated dosimeter (PDS Research), and calibrated nebulizers (DeVilbiss
model 646; Sunrise Medical; Somerset, PA). The baffle and straw of
each nebulizer were fixed in place. Inhalation rates were held
constant at 0.5 L/s using a valve (Rosenthal Flow Regulator; PDS
Research) fitted to the inport of the nebulizer. Dosimeter actuation
was repeated at intervals of 0.6 s with 3 mL of solution in the
nebulizer bowl. Air supply was at a constant 30 pounds per square
inch, and inspiratory flow rate was fixed at 0.5 L/s. Under these
conditions, the output of all nebulizers was characterized to allow
calculation of the absolute amount (in micrograms) of the methacholine delivered to the patient. The methacholine concentration
sequence is provided in Table 1. Fresh solutions of methacholine
(Methapharm; Brantford, Ontario, Canada) were prepared daily in
preservative-free 0.9% inhalation saline solution. Challenges were
performed between 6:00 am and 9:00 am and before taking morning
study medications.
Prior to challenge testing, baseline pulmonary function levels
were determined using the highest FEV1 of three efforts.
Table 1—Methacholine Concentration Sequence
Stage
Concentration,*
mg/mL
No. of
Breaths
Cumulative Dosage
Units†
1
2
3
4
5
6
7
8
0.025
0.075
0.25
0.75
2.5
7.5
25.00
75.00
5
5
5
5
5
5
5
5
0.125
0.50
1.75
5.50
18.0
55.5
180.5
555.5
*In nebulizer.
†Cumulative dosage units 5 concentration of methacholine 3 number
to breaths summed for all stages.
Patients then inhaled five breaths of saline solution, and FEV1
was assessed 3 min after the last inhalation. Incremental concentrations of methacholine were administered in the same manner
using a concentration range of 0.025 to 75.0 mg/mL. Challenges
were stopped when the FEV1 from all three post-methacholine
challenge spirometry assessments for a particular concentration
decreased 20% from the highest post-saline solution inhalation
FEV1 baseline value. The PD20 was determined by linear
interpolation using software developed by PDS Research.
Analysis
Combined results are presented from two identically designed
studies that were run in parallel. All analyses were performed on
the intent-to-treat population using a two-sided statistical test. All
p values # 0.05 were considered statistically significant.
PD20 values were log10-transformed for analysis, and mean
PD20 values were expressed as the geometric mean by calculating
the antilog of the log10 PD20 values. Changes from baseline for
PD20 values obtained during treatment and posttreatment were
expressed as doubling concentration doses of methacholine using
the following formula:
[log10PD20 (treatment) 2 log10PD20 (baseline)]/log102
Analysis of variance (ANOVA) methods were used to determine treatment effects on PD20, FEV1, and PEF measurements.
Treatment group comparisons of change from baseline values for
symptom scores, nighttime awakenings, and supplemental albuterol use were performed using the van Elteren test. Study
withdrawal, exacerbation, and adverse event frequencies were
compared by treatment group using x2 methods.
Results
Patient Demographics and Disposition
A total of 202 and 206 subjects were randomized to
the salmeterol and placebo treatment groups, respecTable 2—Patient Characteristics, Pulmonary Function
at Screening, and Withdrawals from the Study*
Patient Characteristics
Sex, No.
Male
Female
Age, yr
FEV1
L
% of predicted
% reversibility
PEF, L/min
Morning
Evening
Supplemental albuterol, puffs/d
Patients with asthma $ 10 yr, %
PD20, cumulative mg
Patients withdrawn from the
study, No. (%)
Adverse event
Failed to return
Lack of efficacy
Other
Salmeterol
Group,
n 5 202
Placebo
Group,
n 5 206
114
88
29.3 (0.8)
127
79
28.7 (0.8)
3.29 (0.5)
84.15 (0.75)
19.89 (0.60)
3.28 (0.5)
84.30 (0.72)
21.56 (0.76)
457.0 (6.3)
479.9 (6.2)
2.98 (0.18)
66
53.92 (1.10)
456.9 (6.9)
480.3 (7.0)
2.83 (0.19)
63
43.58 (1.10)
1 (, 1)
4 (2)
5 (2)
24 (12)
4 (2)
11 (5)
8 (4)
30 (15)
*Data are presented as mean (SE) unless otherwise indicated.
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597
tively. Demographic characteristics, pulmonary function, and bronchial hyperresponsiveness to methacholine challenge were similar between groups at
screening (Table 2). A total of 87 subjects withdrew
from the study after randomization. Significantly fewer
patients withdrew from the salmeterol group than from
the placebo group (34 vs 53 patients, respectively;
p 5 0.03). Reasons for withdrawal included lack of
efficacy (salmeterol group, 5 patients; placebo group, 8
patients), adverse event (salmeterol group, 1 patient;
placebo group, 4 patients), and failure to return (salmeterol group, 4 patients; placebo group, 11 patients).
Additionally, 54 patients (salmeterol group, 24 patients;
placebo group, 30 patients) were withdrawn from the
study because of protocol violations or because they
were lost to follow-up.
Bronchial Hyperresponsiveness
The use of salmeterol significantly increased
(p , 0.001) PD20 values when compared to placebo
after 4, 12, and 24 weeks of treatment (Fig 1).
Change (SEM) from baseline was 1.05 (0.13), 1.03
(0.14), and 1.00 (0.14) doubling doses of methacholine after 4, 12, and 24 weeks of salmeterol treatment, respectively. In the placebo group, doubling
dose changes of 0.14 (0.14), 0.48 (0.15), and 0.40
(0.17) were observed. PD20 values obtained 3 and 7
days posttreatment remained above baseline levels in
both the salmeterol and placebo groups, and no significant differences were observed between groups.
PEF Measurements
Salmeterol significantly increased mean morning
PEF by 26.2 (2.5) L/min above baseline over weeks 1
through 24 when compared to an increase of 5.3 (2.0)
L/min for placebo (p , 0.001; Fig 2). Mean morning
PEF values over the posttreatment period remained
19.9 and 11.8 L/min, respectively, above baseline in the
salmeterol and placebo groups. Similarly, the use of
salmeterol significantly increased mean evening PEF
values by 18.7 (2.1) L/min above baseline when compared to an increase of 6.4 (2.0) L/min for treatment
with placebo (p , 0.001; Fig 2).
At baseline, mean evening to morning PEF variation was 23.9 (2.2) and 23.4 (2.6) L/min, respectively,
in the salmeterol and placebo groups. Over weeks 1
through 24, mean PEF variation was reduced significantly to 14.9 (1.6) L/min in the salmeterol group
compared with a mean increase to 24.8 (2.4) L/min
in the placebo group (p , 0.001).
Figure 1. Change from baseline in bronchial hyperresponsiveness during and after treatment from
methacholine challenge test. PD20 values are presented as geometric means. Treatment comparisons
are based on ANOVA on change from baseline, controlling for investigator. * 5 significant difference
from placebo.
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Clinical Investigations
Figure 2. Mean change from baseline in morning and evening PEF. Baseline is the average of the 7
days immediately prior to treatment day 1. Treatment comparisons are based on ANOVA on change
from baseline, controlling for investigator. * 5 significant difference from placebo.
Pulmonary Function Tests
Morning predose FEV1 values were increased
significantly over baseline in the salmeterol group at
all treatment assessments when compared to the
placebo group. With salmeterol, increases of 0.21,
0.23, 0.25, 0.23, 0.23, and 0.26 L above baseline were
observed after weeks 4, 8, 12, 16, 20, and 24,
respectively, when compared to placebo, where
change in FEV1 ranged from 20.03 L at week 4 to
0.08 L at week 24 (p , 0.001). In the salmeterol
group, FEV1 values obtained at posttreatment days 3
and 7 returned to near baseline levels (0.03 and 0.06
L, respectively, change from baseline) and were not
significantly different from placebo (0.07 and 0.04 L,
respectively, change from baseline).
Asthma Symptom Scores
For the overall treatment period (weeks 1 through
24), the use of salmeterol reduced mean symptom
scores for wheezing, shortness of breath, and chest
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599
tightness by 20%, 18%, and 16% from baseline when
compared to decreases from baseline of 3%, 3%, and
7% in the placebo group, respectively (Table 3). The
percentage change from baseline differences in
symptom scores for wheezing, shortness of breath,
and chest tightness for salmeterol compared with
placebo were significant (p # 0.042). The percentage of symptom-free days was increased significantly
(29%) from baseline in the salmeterol group when
compared to the placebo group (10%); (p , 0.001).
Nighttime Awakenings
At baseline, patients in both the salmeterol and
placebo groups reported that on 78% of the nights
they had no awakenings attributed to asthma symptoms. During the treatment period, use of salmeterol
significantly increased the percentage of nights with
no awakenings by 18% from baseline when compared to an 8% increase in the placebo group (Table
3).
Supplemental Albuterol Use
During the baseline period, patients in the salmeterol group used an average of 2.98 puffs per day of
supplemental albuterol compared with an average of
2.83 puffs per day in the placebo group (p 5 0.502).
Mean (SEM) daily use of supplemental albuterol
over treatment weeks 1 through 24 decreased by
51% to 1.48 (0.11) puffs per day in the salmeterol
group when compared with a 12% decrease to 2.47
(0.18) puffs per day in the placebo group (Table 3).
During the posttreatment week, supplemental albuterol use was not significantly different between the
treatment groups.
Exacerbations of Asthma
The treatments were not significantly different
with respect to the total number of subjects experi-
encing asthma exacerbations, defined as asthma
symptoms requiring treatment other than albuterol
MDI and the blinded study drug. During treatment,
25 subjects (12%) in the salmeterol group reported
31 exacerbations, and 33 subjects (16%) in the
placebo group reported 42 exacerbations. Respiratory tract infection was the most common suspected
cause of exacerbation and was cited for 68% and
52%, respectively, of the exacerbations in the salmeterol and placebo groups. During the posttreatment
period, three patients in the salmeterol group and six
patients in the placebo group experienced exacerbations. Oral steroids were used to treat 85% and 90%,
respectively, of exacerbations in the salmeterol and
placebo groups.
Clinical Adverse Events
A total of 149 patients (74%) in the salmeterol
group and 151 patients (73%) in placebo group
reported adverse events (Table 4). No significant
difference in the number of subjects reporting
adverse events was evident between treatments.
The most common adverse event for both treatments was upper respiratory tract infection. Other
adverse events occurring in $ 3% of the subjects
in the salmeterol group were common cold symptoms, sore throat, sinusitis, nasal sinus infection,
bronchitis, cough, influenza, headache, fever, back
pain, and myalgia. In the salmeterol group, adverse events requiring hospitalization were respiratory arrest because of an alcohol overdose, tonsillitis, mononucleosis, asthma exacerbation with
bronchitis, knee ligament tear, fractured leg, and
anaphylaxis to an acne treatment; one subject
receiving placebo was hospitalized because of
status asthmaticus associated with pneumonia.
None of the events was considered drug related by
the reporting physician.
Table 3—Mean Change From Baseline in Symptom Scores, Nighttime Awakenings, and Supplemental Albuterol Use
Over 24 Weeks of Treatment*
Salmeterol Group
Variables
Subject-rated symptoms
Wheezing
Shortness of breath
Chest tightness
Total
Symptom-free days, %
Nights with no
awakening, %
Supplemental albuterol
use, puffs/d
Placebo Group
Baseline
Change
Baseline
Change
p Value†
0.83 (0.05)
1.00 (0.06)
0.92 (0.06)
0.91 (0.05)
26.3 (2.4)
78.0 (2.2)
20.29 (0.04)
20.32 (0.04)
20.31 (0.04)
20.31 (0.04)
20.9 (2.1)
11.2 (1.7)
0.88 (0.05)
1.03 (0.05)
1.07 (0.05)
0.99 (0.05)
23.4 (2.2)
78.2 (2.0)
20.08 (0.04)
20.11 (0.04)
20.16 (0.04)
20.12 (0.03)
7.6 (1.9)
3.1 (1.3)
0.007
0.001
0.064
0.009
, 0.001
0.004
2.98 (0.18)
21.53 (0.15)
2.83 (0.19)
20.35 (0.13)
, 0.001
*Data are presented as mean (SEM).
†Based on a van Elteren test on change from baseline controlling for investigator.
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Table 4 —Most Common Adverse Events (> 3%)*
Salmeterol
Group
n 5 202
Adverse Events
Patients with any event
Patients with specific events
Upper respiratory tract infection
Cold symptoms
Bronchitis
Headache
Sore throat
Sinusitis
Nasal sinus infection
Cough
Myalgia(s)
Influenza
Fever
Back pain
149
37
20
14
14 (2)*
12 (2)*
12
9
7 (3)*
7
6
6
6
Placebo
Group
n 5 206
151
33
19
4
7 (2)*
14 (1)*
12
7
7 (5)*
2
5
4
3
*Data are presented as No. of patients, or as No. (possibly drugrelated).
Discussion
This study has shown that regular, long-term use
of salmeterol aerosol, 42 mg twice daily, in patients
with asthma results in sustained improvements in
pulmonary function and symptom control with no
evidence of an increase in bronchial hyperresponsiveness during or following treatment. The treatment groups were similar with respect to the number
of patients having asthma exacerbations during both
treatment and posttreatment, and no evidence suggested that the severity of exacerbations was different between groups. Most exacerbations were
treated either in a physician’s office or at home with
few patients requiring treatment in the emergency
department or resulting in hospitalization.
Methacholine challenges performed 10 to 14 h
postdosing showed a modest protective effect for
salmeterol of approximately one doubling dose of
methacholine after 4, 12, and 24 weeks of treatment.
These results are similar to previous results4 showing
protection against methacholine-induced bronchoconstriction of 0.6 to 1.2 doubling doses approximately 12 h postdosing over an 8-week treatment
period. Similarly, in a single-dose study, protection
against methacholine-induced bronchoconstriction
of approximately 1.5 doubling doses was shown 12 h
after a 50-mg dose of salmeterol.9
In this study, the twice-daily (morning and
evening) dosing schedule as stated in the prescription labeling for salmeterol was maintained with no
interruption. This was done to mimic the standard
conditions for use of salmeterol. Bronchial responsiveness was assessed at the end of the dosing period
when any development of underlying hyperrespon-
siveness would be most apparent. It is evident from
previous studies that the maximal or near-maximal
bronchoprotective effects of salmeterol obtained initially 1 h postdose are reduced with regular use.4,5,7
In these studies, reduced protection of approximately 1 to 2 doubling doses of methacholine was
observed 4 to 8 weeks after the first dose of salmeterol. However, a loss of protection was not observed
in all patients, possibly because of polymorphisms of
the human b2-receptor gene that are associated with
alterations in b2-receptor function.10 In addition, a
plateau in effect appeared between 4 and 8 weeks.
Because these studies were conducted over # 8
weeks, the protective effects of salmeterol were not
studied over a long-term treatment period. In the
current study, a 24-week treatment period was used
to demonstrate that regular, long-term salmeterol
use does not lead to a progressive loss of bronchoprotection from that seen following 4 weeks of
therapy.
If worsening bronchial responsiveness was masked
by the bronchodilating properties of salmeterol, an
increase in hyperresponsiveness would be expected
during the posttreatment period. In this study, mean
levels of bronchial responsiveness to methacholine
remained above baseline levels during the posttreatment period, providing no evidence for a rebound
increase in bronchial hyperresponsiveness after cessation of salmeterol therapy.
The effects of salmeterol use on asthma control
observed in the present study are consistent with
previous studies that have demonstrated sustained improvements in pulmonary function for up to 1 year with
no evidence of declining pulmonary function, increased
use of supplemental albuterol, or increased incidence
of asthma exacerbations.11–13 In this study, patients
receiving salmeterol reported fewer exacerbations than
placebo-treated patients during both treatment and
posttreatment, although the difference was not statistically significant. This reduction in exacerbations with
salmeterol is consistent with the results seen in the
year-long study by Britton et al,13 where the rate of
exacerbations in patients receiving salmeterol fell during the 12-month treatment period, suggesting that
regular salmeterol use is not associated with worsening
asthma. Additional indicators of worsening asthma,
including declines in PEF, increases in asthma symptoms, and increases in supplemental doses of albuterol,
were improved over baseline levels during the posttreatment period. The treatments were well tolerated,
with similar numbers of adverse events reported for
both treatments. In both treatment groups, cough was
the most common adverse event suspected of being
related to the study drug, with five cases in the placebo
group and three cases in the salmeterol group.
In contrast to reports by Sears et al14 and Taylor et
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al,15 recent reports by Drazen et al16 and Chapman
et al17 did not show deleterious effects of regular use
of albuterol on asthma control when compared to
as-needed use over either a 4- or 16-week treatment
period. It has been suggested however, that results
with short-acting inhaled b2-agonists cannot be generalized to the use of long-acting inhaled b2-agonists
such as salmeterol.18 The results of the present
study, however, show no deleterious effects of longterm salmeterol therapy and indicate that regular use
resulted in sustained improvements in pulmonary
function and asthma symptom control. Bronchial
hyperreactivity or progressive reduction in bronchoprotection did not increase following 24 weeks of
therapy compared with assessments following 4
weeks of therapy.
Patients in this study were not receiving inhaled
corticosteroids. In a steroid-naı̈ve population such as
this, deterioration from asthma, as indicated by increased use of short-acting b-agonists, would indicate
the necessity to institute treatment with inhaled corticosteroids. Combined use of long-acting b-agonists and
inhaled corticosteroids, as recommended in current
asthma management guidelines,1,19 has been shown to
provide effective control of both the inflammatory and
the bronchospastic components of asthma.
In summary, long-term use of a salmeterol aerosol
(42 mg twice daily) resulted in sustained improvements
in pulmonary function and asthma symptom control
with no increase in bronchial hyperreactivity or progressive reduction in bronchoprotection. No evidence
was present of a rebound increase in bronchial hyperresponsiveness or masking of deterioration from
asthma after cessation of salmeterol treatment. Salmeterol treatment does not lead to clinical instability or
vulnerability to unpredictable asthma attacks.
Appendix
The authors acknowledge the contributions of the following
clinical investigators and their patients: Robert Berkowitz, MD,
Atlanta, GA; Jonathan Bernstein, MD, Cincinnati, OH; Edwin
Bronsky, MD, Salt Lake City, UT; Paul Chervinsky, MD, North
Dartmouth, MA; Arthur Degraff, MD, Hartford, CT; Robert
Dockhorn, MD, Lenexa, KS; Thomas Edwards, MD, Albany, NY;
Linda Ford, MD, Papillion, NE; Jay Grossman, MD, Tucson, AZ;
William Howland, MD, Austin, TX; Phillip Korenblat, MD, St.
Louis, MO; Craig LaForce, MD, Raleigh, NC; Richard Lockey,
MD, Tampa, FL; Rogelio Menendez, MD, El Paso, TX; Dominick Minotti, MD, Seattle, WA; Nicholas Nayak, MD, Normal, IL;
Harold Nelson, MD, Denver, CO; David Pearlman, MD, Aurora,
CO; Paul Ratner, MD, San Antonio, TX; Howard Schwartz, MD,
Cleveland, OH; Allen Segal, MD, Dallas, TX; Gail Shapiro, MD,
Seattle, WA; D. Loren Southern, MD, Princeton, NJ; Sheldon
Spector, MD, Los Angeles, CA; John Weiler, MD, Iowa City, IA;
Steven Weinstein, MD, Huntington Beach, CA; Stephen
Weisberg, MD, Minneapolis, MN; and James Wolfe, MD,
San Jose, CA.
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Clinical Investigations