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Clinical Investigations: ASTHMA |

Effect of Long-term Salmeterol Therapy Compared With As-Needed Albuterol Use on Airway Hyperresponsiveness* FREE TO VIEW

Richard R. Rosenthal, MD; William W. Busse, MD; James P. Kemp, MD, FCCP; James W. Baker, MD; Christopher Kalberg, PhD; Amanda Emmett, MS; Kathleen A. Rickard, MD
Author and Funding Information

Affiliations: *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.

Correspondence to: Richard R. Rosenthal, MD, 8318 Arlington Blvd, Suite 308, Fairfax, VA 22031



Chest. 1999;116(3):595-602. doi:10.1378/chest.116.3.595
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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 μg, 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 = 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-actingβ -agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Figures in this Article

Current guidelines for the diagnosis and management 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.1Clinical 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.23

Previous studies have shown reduced bronchoprotective effects of salmeterol against methacholine challenge in patients independent of the use of inhaled corticosteroids.47 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 μg 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.

Study Design

Two identically designed, randomized, double-blind, placebo-controlled, 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 μg 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 = no symptoms; 1 = some symptoms present but caused no discomfort; 2 = symptoms that caused little discomfort and did not interfere with normal daily activities; 3 = symptoms that caused discomfort and interfered with at least one normal daily activity; and 4 = 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 = slept well; 1 = awoke once; 2 = awoke two to three times; and 3 = 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 β-agonists, and oral corticosteroids (prednisone, ≥ 60 mg qd or equivalent) 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 μg) 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 μg) 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. 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:

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 usingχ 2 methods.

Patient Demographics and Disposition

A total of 202 and 206 subjects were randomized to the salmeterol and placebo treatment groups, respectively. 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 = 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).

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 −0.03 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 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 = 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 experiencing 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.

This study has shown that regular, long-term use of salmeterol aerosol, 42 μg 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-μg 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 hyperresponsiveness 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.45,7 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 β2-receptor gene that are associated with alterations in β2-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.1113 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 al14and Taylor et al,15recent reports by Drazen et al16and Chapman et al17did 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 inhaledβ 2-agonists cannot be generalized to the use of long-acting inhaled β2-agonists such as salmeterol.18 The results of the present study, however, show no deleterious effects of long-term 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-naïve population such as this, deterioration from asthma, as indicated by increased use of short-acting β-agonists, would indicate the necessity to institute treatment with inhaled corticosteroids. Combined use of long-actingβ -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 μg 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.

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.

Abbreviations: ANOVA = analysis of variance; MDI = metered-dose inhaler; PD20 = provocative dose of methacholine required to reduce the FEV1 by 20% from baseline; PEF = peak expiratory flow

This study was supported by a research grant from Glaxo Wellcome, Inc., Research Triangle Park, NC.

Table Graphic Jump Location
Table 1. Methacholine Concentration Sequence
* 

In nebulizer.

 

Cumulative dosage units = concentration of methacholine × number to breaths summed for all stages.

Table Graphic Jump Location
Table 2. Patient Characteristics, Pulmonary Function at Screening, and Withdrawals from the Study*
* 

Data are presented as mean (SE) unless otherwise indicated.

Figure Jump LinkFigure 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. * = significant difference from placebo.Grahic Jump Location
Figure Jump LinkFigure 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. * = significant difference from placebo.Grahic Jump Location
Table Graphic Jump Location
Table 3. Mean Change From Baseline in Symptom Scores, Nighttime Awakenings, and Supplemental Albuterol Use Over 24 Weeks of Treatment*
* 

Data are presented as mean (SEM).

 

Based on a van Elteren test on change from baseline controlling for investigator.

Table Graphic Jump Location
Table 4. Most Common Adverse Events (≥ 3%)*
* 

Data are presented as No. of patients, or as No. (possibly drug-related).

National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and treatment of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 97–4051.
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol vs higher-dose corticosteroid in asthma patients with symptoms on existing inhaled cortisteroid.Lancet1994;344,219-224. [PubMed] [CrossRef]
 
Woolcock, A, Lundback, B, Ringdal, N, et al Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids.Am J Respir Crit Care Med1996;153,1481-1488. [PubMed]
 
Booth, H, Fishwick, K, Harkawat, R, et al Changes in methacholine-induced bronchoconstriction with the long-acting β2-agonist salmeterol in mild to moderate asthmatic patients.Thorax1993;48,121-124
 
Kalra, S, Swystun, VA, Bhagat, R, et al Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.Chest1996;109,953-956. [PubMed]
 
Baghat, R, Lalra, S, Swystun, VA, et al Rapid onset of tolerance to the bronchoprotective effect of salmeterol.Chest1996;106,1235-1239
 
Cheung, D, Timmers, MC, Zwinderman, AH, et al Long-term effects of a long-acting β2adrenoreceptor antagonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med1992;327,1198-1203. [PubMed]
 
Chai, H, Farr, RS, Froelich, LA, et al Standardization of bronchial inhalation challenge procedures.J Allergy Clin Immunol1975;56,323-327. [PubMed]
 
Derom, EY, Pauwels, RA, Van Der Straeten, MEF The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.J Allergy Clin Immunol1992;89,811-815. [PubMed]
 
Green, SA, Turki, J, Hall, IP, et al Implications of genetic variability of human β2-adrenergic receptor structure.Pulm Pharmacol1995;8,1-10. [PubMed]
 
D’Alonzo, GE, Nathan, RA, Henochowicz, S, et al Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma.JAMA1994;271,1412-1416. [PubMed]
 
Pearlman, D, Chervinsky, P, LaForce, C, et al A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med1992;327,1420-1425. [PubMed]
 
Britton, MG, Earnshaw, JS, Palmer, JBD A 12-month comparison of salmeterol with salbutamol in asthmatic patients.Eur Respir J1992;5,1062-1067. [PubMed]
 
Sears, MR, Taylor, DR, Print, CG, et al Regular inhaled β-agonist treatment in bronchial asthma.Lancet1990;336,1391-1396. [PubMed]
 
Taylor, DR, Sears, MR, Herbison, GP, et al Regular inhaled β-agonist in asthma: effects on exacerbations and lung function.Thorax1993;48,134-138. [PubMed]
 
Drazen, JM, Israel, E, Boushey, HA, et al Comparison of regularly scheduled with as-needed use of albuterol in mild asthma.N Engl J Med1996;335,841-847. [PubMed]
 
Chapman, KR, Kesten, S, Szalal, JP Regular vs as-needed inhaled salbutamol in asthma control.Lancet1994;343,1379-1382. [PubMed]
 
O’Byrne, PM, Kerstjens, HAM Inhaled β2-agonists in the treatment of asthma [editorial].N Engl J Med1996;335,886-888. [PubMed]
 
Global Initiatives for Asthma. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Bethesda, MD: National Institutes of Health, 1995; National Heart, Lung and Blood Institute Publication No. 95–3659.
 

Figures

Figure Jump LinkFigure 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. * = significant difference from placebo.Grahic Jump Location
Figure Jump LinkFigure 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. * = significant difference from placebo.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Methacholine Concentration Sequence
* 

In nebulizer.

 

Cumulative dosage units = concentration of methacholine × number to breaths summed for all stages.

Table Graphic Jump Location
Table 2. Patient Characteristics, Pulmonary Function at Screening, and Withdrawals from the Study*
* 

Data are presented as mean (SE) unless otherwise indicated.

Table Graphic Jump Location
Table 3. Mean Change From Baseline in Symptom Scores, Nighttime Awakenings, and Supplemental Albuterol Use Over 24 Weeks of Treatment*
* 

Data are presented as mean (SEM).

 

Based on a van Elteren test on change from baseline controlling for investigator.

Table Graphic Jump Location
Table 4. Most Common Adverse Events (≥ 3%)*
* 

Data are presented as No. of patients, or as No. (possibly drug-related).

References

National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and treatment of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 97–4051.
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol vs higher-dose corticosteroid in asthma patients with symptoms on existing inhaled cortisteroid.Lancet1994;344,219-224. [PubMed] [CrossRef]
 
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