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* From Dartmouth Medical School (Dr. Mahler), Lebanon, NH; University of North Carolina (Dr. Donohue), Chapel Hill, NC; Arizona Medical Center (Dr. Barbee), Tucson, AZ; University of California (Dr. Goldman), Los Angeles, CA; Hines VA Hospital (Dr. Gross), Hines, IL; and Glaxo Wellcome Inc (Drs. Wisniewski, Rickard, and Anderson, and Messrs. Yancey and Zakes), Research Triangle Park, NC. Supported by Glaxo Wellcome Inc, Research Triangle Park, NC.
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial.
Setting: Multiple sites at clinics and university medical centers throughout the United States.
Patients: Four hundred eleven symptomatic
patients with COPD with FEV1 
65% predicted and no
clinically significant concurrent disease.
Interventions: Comparison of inhaled salmeterol (42 µg twice daily), inhaled ipratropium bromide (36 µg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks.
Results: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments.
Conclusions: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.
Key Words: chronic obstructive pulmonary disease • dyspnea • inhaled ß2-agonists • ipratropium • salmeterol
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both inhaled ß2-agonists and anticholinergic medications are considered as initial bronchodilator therapy for patients with COPD.1 ,4 Randomized clinical trials have demonstrated that these medications can improve lung function and reduce the severity of breathlessness in such patients.5 ,6 ,7 Most clinical experience with inhaled ß2-agonists has been with short-acting agents whose actions last 4 to 6 h. Salmeterol xinafoate is a long-acting preparation with a 12-h duration of action that has been used effectively in the treatment of asthma. Twice daily administration of salmeterol (42 µg) is the optimum dosing regimen for patients with mild-to-moderate reversible airways obstruction.8
Although several studies have shown modest bronchodilation and/or reduction in dyspnea with salmeterol in patients with COPD, these investigations were all short term and involved only small numbers of patients.9 ,10 ,11 ,12 In a 16-week European trial, salmeterol (42 or 84 µg) inhaled twice daily produced improvement in daytime and nighttime symptom scores, dyspnea ratings following the 6-min walk (6MW) test, use of additional bronchodilators, patient/physician assessment, number of exacerbations, and days unable to perform work compared with placebo.13 No differences were observed between the two doses of salmeterol. Jones and Bosh14 found that salmeterol at a dose of 42 µg taken twice daily led to a modest improvement in lung function in patients with COPD and an associated clinically significant gain in health and well-being over 4 months compared with placebo.
The purpose of the present study was to compare the efficacy and safety of salmeterol (42 µg) twice daily vs ipratropium four times a day vs placebo in the treatment of COPD. FEV1 and dyspnea ratings were considered as primary outcome measures. To our knowledge, this multicenter study is the first comprehensive comparison of salmeterol, a long-acting ß2-agonist, vs ipratropium, an anticholinergic bronchodilator, in the treatment of COPD.1
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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200 mL and 12% in the baseline FEV1. All other
patients were considered "nonresponsive."
During a 14- to 21-day baseline period, pulmonary function, dyspnea and
other symptoms, 6MW distance, and HRQL were measured. Patients returned
for evaluations at 2-week intervals during the treatment period.
Treatment with theophylline and short-acting bronchodilators was
stopped 36 and 6 h, respectively, prior to initiating study
treatment. However, albuterol was allowed for acute symptomatic relief.
During the treatment period, patients on a stable regimen of oral
( 10 mg prednisone [or equivalent] per day) or inhaled
corticosteroids continued these regimens.
Study Patients
Inclusion criteria were as follows: 35 years of age; a
10 pack-year history of smoking; a diagnosis of COPD as defined by
the American Thoracic Society1
; a baseline
FEV1 of > 0.70 L and 65% of the predicted normal
values (or, if < 0.70 L, 40% of predicted normal
value)15
; an FEV1/FVC ratio of 70%; and a
baseline severity of breathlessness of grade 1 (shortness of breath
when hurrying on the level or walking up a slight hill) or higher on
the modified Medical Research Council dyspnea scale. Exclusion criteria
included the following: unstable respiratory status within the previous
4 weeks; a known history of asthma or chronic respiratory disease other
than COPD; any clinically significant concurrent disease; oxygen
therapy other than nocturnal use; a change in medications for COPD
within 4 weeks prior to the screening visit; and inability to
discontinue treatment with theophylline, ipratropium bromide, or oral
ß-agonist therapy after the screening visit.
Efficacy Evaluations
Pulmonary function and dyspnea ratings were the primary efficacy
measures. Area under the 12-h curve for FEV1
(FEV1 AUC) was calculated from the pretreatment measurement
for each time interval from 0 to 12 h by the trapezoidal method
and summed for each of the four 12-h visits. Pulmonary function was
measured at weeks 0 (following first administration of study drug), 4,
8, and 12. The severity of dyspnea was measured at week 0 with the
multidimensional baseline dyspnea index (BDI), and changes in the
severity of dyspnea were assessed every 2 weeks with the transition
dyspnea index (TDI).16
The 6MW was conducted on alternate
visits (weeks 2, 6, and 10) within 4 h of the morning dose of
study medication, and patients rated their intensity of breathlessness
on the Borg dyspnea scale17
(a 0 to 10 scale with 0 = no
breathlessness and 10 = maximal breathlessness) before and after the
6MW. Other efficacy measures included spirometric measures over 12
h (FEV1, FVC), patient self-rating of symptoms (daytime
symptom scores ranging from 0 = no symptoms to 4 = symptoms so
severe you were not able to do most daily activities; nighttime symptom
scores ranging from 0 = no symptoms to 4 = symptoms so severe that
you did not sleep), nighttime awakenings, supplemental albuterol use,
and time to first COPD exacerbation.
Any patient who experienced worsening of symptoms during the washout or baseline periods was withdrawn from the study. An individual remained in the study if the exacerbation could be treated successfully using an oral antibiotic and/or up to 14 days of an oral or parenteral corticosteroid. Anyone who required more than two courses of such treatment was withdrawn from the study.
HRQL Evaluations
HRQL was assessed at weeks -2, 0, 2, 6, 8, and 12 weeks using
the chronic respiratory disease questionnaire (CRDQ), a 20-item,
interviewer-administered, disease-specific questionnaire that considers
the domains of dyspnea, fatigue, emotional function, and
mastery.18
Safety Evaluations
The following safety data were collected: adverse events and
vital signs at 2-week intervals; clinical laboratory evaluations,
physical examinations, and medical history at screening and end of
treatment; a 12-lead ECG at weeks -2, 0, 4, 8, and 12; and continuous
ambulatory ECG for 24 h at approximately half the study sites at
weeks -2, 0, 4, 8, and 12.
Statistical Analysis
Statistical comparisons among treatment means were performed
using analysis of variance, except for Borg dyspnea scores (van Eltern
test) and clinical laboratory data (Wilcoxon sign rank test).
Comparisons among treatment groups were performed using
Cochran-Mantel-Haenszel test except for adverse events (Fisher's Exact
Test), and time to exacerbation was compared using the Kaplan-Meier
test. Analyses were performed on three groups of patients: all
patients, responsive, and nonresponsive strata.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dyspnea Ratings
The mean BDI scores for the placebo, salmeterol, and
ipratropium groups were 6.3, 5.9, and 6.0, respectively, indicating a
moderate level of dyspnea for all patients at the start of the study.
The mean TDI scores demonstrated a greater improvement in patients
treated with either salmeterol or ipratropium compared with placebo
(Fig 2 ).
For all patients, statistically significant improvements for salmeterol
and ipratropium vs placebo were observed at weeks 2, 4, 8, and 10, and
for ipratropium vs placebo also at weeks 6 and 12. For responsive
patients, improvements in TDI scores were similar to those obtained in
the total population; for the nonresponsive strata, there were no
significant treatment differences except for ipratropium vs placebo at
week 8.
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Patient Self-assessment
Mean baseline daytime symptom scores (shortness of breath, chest
tightness, and cough) were not significantly different among treatment
groups in the total group or in either stratum (responsive and
nonresponsive). Mean daytime symptom scores in all three treatment
groups decreased (improved) over the 12-week treatment period. With the
exception of ipratropium vs placebo for shortness of breath in the
responsive stratum, there were no significant differences between
ipratropium or salmeterol and placebo. However, paired comparisons
(baseline vs subsequent weeks) for nighttime shortness of breath showed
significantly greater improvement in the salmeterol group
(0.59 ± 0.07 to 0.46 ± 0.07) than in the placebo (0.59 ± 0.07
to 0.59 ± 0.07; p = 0.042) and ipratropium groups (0.434 ± 0.07
to 0.39 ± 0.06; p = 0.037) from weeks 5 to 8, and there was a
trend toward significance (p = 0.087) over the 12 weeks of treatment.
Comparison between groups for nighttime shortness of breath showed that
salmeterol was statistically superior to ipratropium (p = 0.043) over
the entire 12-week period. Results for daytime and nighttime cough and
chest tightness were similar for all three treatment groups.
Supplemental Albuterol Use
At baseline, there was no significant difference among the
three treatment groups in the daytime use of supplemental albuterol:
4.3 ± 0.3, 4.6 ± 0.3, and 4.5 ± 0.3 puffs per day for placebo,
salmeterol, and ipratropium, respectively. There was a significant
decrease in mean puffs per day of albuterol (to 2.0 ± 0.3 and
2.4 ± 0.3 puffs per day, respectively) in the salmeterol
(p < 0.001) and in the ipratropium (p < 0.047) groups compared
with placebo at every interval. Similar findings were observed in the
responsive stratum. There were no significant differences in albuterol
use in the nonresponsive subgroup among treatment groups.
COPD Exacerbations
The percentages of patients experiencing one or more exacerbations
over the 12-week treatment period were 32.9%, 20.7%, and 30.8% for
the placebo, salmeterol, and ipratropium groups, respectively. Analysis
of the time to first COPD exacerbation demonstrated salmeterol to have
a delayed onset of exacerbations compared with placebo (p = 0.0052)
and ipratropium (p = 0.0411) (Fig 3
).
More patients in the placebo group (n = 21) experienced their first
exacerbation during week 1 than did patients in the salmeterol
(n = 7) and ipratropium (n = 7) groups.
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10 points in
overall score (the minimum change indicative of an important
difference)18
was significantly higher at week 12 in the
salmeterol (46%, p = 0.002) and ipratropium (39%, p = 0.041)
groups than in the placebo group (27%). Both salmeterol and
ipratropium showed a progressive increase from weeks 2 to 12 in the
proportion of patients achieving an overall increase of 10 in the CRDQ
score, which is reflected in both strata. Both salmeterol and
ipratropium demonstrated a statistically higher proportion of patients
who achieved an increase of 10 points in overall CRDQ score in the
nonreversible stratum at week 12. In the responsive stratum,
statistical significance was observed only for salmeterol.
Safety
No major differences were seen in the incidence of adverse events
across treatment groups (Table 4
).
There was a significantly reduced incidence of bronchitis in both the
ipratropium (p = 0.037) and salmeterol (p = 0.037) groups compared
with placebo. Twenty-three patients reported an adverse event
considered related to the study drug (10 placebo, 6 salmeterol, 7
ipratropium). There were no significant differences between treatment
groups by body system or individual events. A total of 16 patients
withdrew from the study due to adverse events (8 placebo, 1 salmeterol,
and 7 ipratropium). There were no deaths during the study.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At the present time, ipratropium bromide is considered first-line therapy for the treatment of continuous symptoms due to COPD.1 ,4 However, in this double-dummy, parallel group investigation, a single administration of salmeterol produced greater sustained bronchodilation over 12 h as measured by the FEV1AUC than two administrations of ipratropium given four times a day. It is unlikely that the slightly higher baseline FEV1 percent predicted in the salmeterol group influenced these results. Rather, this effect appeared to be due to the longer duration of action of salmeterol because the peak responses for salmeterol and ipratropium were similar. Although higher doses (four to six puffs) of ipratropium have been used in clinical practice, we studied the recommended starting dose (two puffs [36 mg]) given four times a day. The bronchodilator activity of salmeterol was maintained throughout the 12-week study period; in fact, mean FEV1 levels on each of the testing days remained elevated in the morning as a result of the doses administered 12 h earlier (Fig 1 ). There was no evidence of the development of tolerance to the bronchodilator activity of salmeterol over the 12-week period.
Any improvement in airflow in patients with moderate-to-severe COPD may be of important clinical benefit. We observed similar reductions in breathlessness (higher TDI scores) with both salmeterol and ipratropium that were evident at 2 weeks and were generally sustained over the entire 12-week period (Fig 2 ). The improvement in dyspnea throughout the study was supported by the observed significant decrease in supplemental albuterol use with both salmeterol and ipratropium. The relief of dyspnea may be due in part to the reduced resistive work of breathing due to even modest bronchodilation. In addition, the known effects of bronchodilators in reducing end-expiratory lung volume12 ,19 would be expected to lead to a decrease in the inspiratory elastic work of breathing.20 Thus, both bronchodilation and/or decreased hyperinflation may contribute to the clinical benefits of salmeterol and ipratropium.
Despite these clinical benefits, neither medication altered the 6MW distance or led to a decrease in prewalk or postwalk Borg dyspnea ratings. A timed walking test is a measure of functional exercise capacity that is clearly dependent on the effort of the individual.21 Although the patients who received salmeterol or ipratropium had less dyspnea with daily activities (as observed with the BDI/TDI), this benefit may not result in an increase in walking distance unless the patient was motivated to walk faster during the test. Furthermore, some patients with COPD are limited in their exercise capacity by leg discomfort and general fatigue rather than by breathlessness.22 Therefore, bronchodilator therapy may not alter a timed walking test. Although dyspnea ratings increased after completion of the walking test in all three groups, there were no differences among the treatment groups. Previous studies of bronchodilator therapy in COPD have shown similar improvements in lung function and reductions in dyspnea, but no significant change in walking distance or peak exercise performance.19 ,23 ,24
Our results confirm a previous report that salmeterol improves HRQL in patients with COPD. Jones and Bosh14 reported that salmeterol at a dose of 50 µg twice a day was associated with significant increases in the "total" and "impact" scores for the St. George's Respiratory Questionnaire, a disease-specific instrument, compared with placebo. We used the CRDQ, a different disease-specific instrument focused on four domains (dyspnea, fatigue, emotional function, and mastery) that affect patients with COPD. Benefits in quality of life were achieved with both salmeterol and ipratropium compared with placebo in both responsive and nonresponsive strata. However, direct comparisons showed that salmeterol provided greater improvements in mean CRDQ overall scores than those observed in the ipratropium group. Furthermore, the time to first COPD exacerbation was significantly longer with salmeterol than with either placebo or ipratropium bromide. Whether prolonged bronchodilation with salmeterol or another mechanism contributed to this benefit is unclear.
In summary, salmeterol was significantly better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week period. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; and this improvement was associated with reduced use of supplemental albuterol. As provided in this study, patients should use a short-acting ß-agonist, such as albuterol, as a rescue medication. The safety profile of salmeterol was similar to ipratropium and placebo in this trial. Compared with ipratropium, salmeterol exhibited a significantly lower COPD exacerbation rate and led to significantly greater improvements in HRQL. Furthermore, the twice-daily dosing schedule of salmeterol should enhance compliance. These collective data support the use of salmeterol as first-line therapy for the long-term treatment of airflow obstruction in patients with COPD.
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Acknowledgements |
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Footnotes |
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Abbreviations: AUC = area under the curve; BDI = baseline dyspnea index; CRDQ = chronic respiratory disease questionnaire; HRQL = health-related quality of life; 6MW = 6-min walk; TDI = transition dyspnea index
Received for publication June 30, 1998. Accepted for publication November 13, 1998.
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