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(Chest. 1999;115:666-673.)
© 1999 American College of Chest Physicians

Nocturnal Asthma*

Effect of Salmeterol on Quality of Life and Clinical Outcomes

Richard F. Lockey, MD, FCCP; Lawrence M. DuBuske, MD; Bruce Friedman, MD; Virginia Petrocella; Fred Cox, PhD and Kathleen Rickard, MD

* From the Division of Allergy and Immunology (Dr. Lockey), University of South Florida College of Medicine, Tampa, FL; Allergy and Arthritis Family Treatment Center (Dr. DuBuske), Gardner, MA; Allergy, Asthma, Bronchitis and Immunology Associates (Dr. Friedman), Fountain Valley, CA; and Glaxo Wellcome Inc (Ms. Petrocella, and Drs. Cox and Rickard), Research Triangle Park, NC.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate the effect of salmeterol on asthma-specific quality of life in patients experiencing significant nocturnal symptoms.

Design: Randomized, double-blind, placebo-controlled, multicenter clinical trial.

Setting: Allergy/respiratory care clinics.

Patients: Nonsmokers >= 12 years of age with nocturnal asthma symptoms on at least 6 of 14 days during screening and >= 15% decrease in peak expiratory flow (PEF) from baseline on nocturnal awakening at least once during screening.

Interventions: Salmeterol, 42 µg, or placebo twice daily. Patients were allowed to continue theophylline, inhaled corticosteroids, and "as-needed" albuterol.

Measurements and results: Outcome measures included Asthma Quality of Life Questionnaire (AQLQ) global and individual domain scores, FEV1, PEF, nighttime awakenings, asthma symptoms, and supplemental albuterol use. Mean change from baseline for the global and domain AQLQ scores was significantly greater (p <= 0.005) with salmeterol compared with placebo. At week 12, salmeterol significantly (p < 0.001 compared with placebo) increased mean change from baseline in FEV1, morning and evening PEF, percentage of symptom-free days, percentage of nights with no awakenings due to asthma, and the percentage of days and nights with no supplemental albuterol use. Significant improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline (p < 0.05).

Conclusions: These results provide evidence that validates the role of salmeterol in improving quality of life in patients with moderate persistent asthma who exhibited nocturnal asthma symptoms and supports the efficacy of salmeterol compared with that of placebo (ie, "as-needed" albuterol).

Key Words: asthma • nocturnal • pharmacoeconomics • quality of life • randomized controlled trial • salmeterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Patients with nocturnal asthma who are clinically stable have been found to have poorer daytime cognitive performance and poorer subjective and objective sleep quality compared with normal, healthy patients.1 Currently, there is no cure for asthma; thus, it is important to utilize drug therapies that minimize the impact of the disease on daily functioning and well-being, thereby enhancing quality of life. Because conventional clinical outcomes alone do not directly reflect quality-of-life considerations, the assessment of quality-of-life parameters through validated questionnaires has been included in clinical trials with increasing frequency to evaluate the full impact of treatment interventions.

Treatment of nocturnal asthma symptoms has focused on sustained-release oral ß2-agonists, theophylline, anti-inflammatory medications, and more recently the long-acting, inhaled ß2-agonist bronchodilators, such as salmeterol xinafoate. Since salmeterol xinafoate produces effective bronchodilation for 12 h after a single inhaled dose in addition to reducing nocturnal and daytime symptoms of asthma, it is an attractive alternative for the treatment of nocturnal asthma symptoms.2 ,3 ,4 ,5 ,6 Salmeterol has also demonstrated significant improvements in overall quality of life assessments compared with albuterol or placebo in patients with asthma7 ,8 ,9 ,10 ,11 ,12 ; however, several of these studies involved small numbers of patients in each treatment arm, used crossover study designs, or focused on a broad range of asthma severity within the same study.

This is the first randomized, double-blind, placebo-controlled study conducted in the United States to evaluate the effect of salmeterol, 42 µg twice daily, on asthma-specific quality of life in a large number of patients experiencing significant nocturnal symptoms associated with moderate persistent asthma. Efficacy and safety evaluations were also conducted to confirm the results of previous studies2 ,3 ,4 ,6 and to correlate objective and subjective efficacy measurements with quality-of-life assessments.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
Patients were nonsmokers, at least 12 years of age, who had asthma (defined in accordance with American Thoracic Society criteria13 ) that was treated with the daily use of a bronchodilator for at least 6 weeks prior to the study. All patients had a FEV1 of 40 to 80% of predicted normal values for age, sex, and height.14 ,15 Reversibility of airway obstruction was demonstrated by a >= 15% increase in FEV1 over baseline within 15 min after two puffs of albuterol (within 12 months prior to study enrollment). Patients must have demonstrated nocturnal asthma symptoms on at least 6 of 14 days during the screening period and a >= 15% decrease in PEF from baseline on nocturnal awakening at least once.

Patients were excluded from the study for any of the following reasons: pregnancy or lactation; significant concurrent illness; immunotherapy requiring a change in dosage regimen within 2 months prior to the study; use of oral ß-adrenergic agonists, methylxanthines requiring a change in dosage regimen within 6 weeks prior to the study, other inhaled ß-adrenergic agonists (long-acting), hydroxyzine hydrochloride, inhaled anticholinergics, inhaled cromolyn or nedocromil, inhaled corticosteroids requiring a change in dosage regimen within 6 weeks prior to the study, astemizole, or oral corticosteroids.

Study Design
Two randomized, double-blind, placebo-controlled, parallel-group studies were conducted at 49 clinical centers throughout the United States. All patients gave written informed consent, and the protocol was approved by the appropriate Institutional Review Board for each clinical center. Washout periods were required prior to pulmonary function testing at each visit for the following drugs: inhaled short-acting ß-adrenergic agonists (>= 8 h), anticholinergic eye drops (>= 24 h), or antihistamines (>= 48 h).

Patients were allowed to use theophylline during the treatment period. Patients were stratified based on theophylline use (therapeutic range, 10 to 20 µg/mL [55 to 110 µmol/L]); however, prior to screening, patients withheld theophylline to obtain baseline pulmonary function measures (theophylline concentration < 5 µg/mL [28 µmol/L]).

At the screening visit prior to the 2-week run-in period, patients were instructed to measure peak expiratory flow (PEF) in the mornings and evenings using a Mini-Wright peak flowmeter (Clement Clark, Inc; London, England) in accordance with specific instructions explained by the study staff. Patients tested peak flowmeters before leaving the clinic. Previous short-acting inhaled bronchodilator therapy was replaced with albuterol aerosol to be used only as needed to relieve breakthrough symptoms. Patients were instructed to record daytime and nighttime use of albuterol aerosol and the number of nocturnal awakenings due to asthma on diary cards, and to rate symptoms of chest tightness, shortness of breath, and wheezing (0 = none, 1 = mild symptom that caused little or no discomfort, 2 = moderate symptom that caused some discomfort but did not affect normal daily activities, 3 = severe symptom that caused significant discomfort and interfered with one or more of your normal daily activities). Compliance was calculated from the patient diary record of doses taken.

Eligible patients were randomly assigned to receive one of the following inhaled treatments via metered dose inhaler for 12 weeks: salmeterol, 42 µg (two inhalations; each actuation delivers 21 µg of salmeterol xinafoate from the actuator) twice daily, or placebo (two inhalations) twice daily. Inhaled albuterol was continued on an as-needed basis. Patients were allowed to continue theophylline and inhaled corticosteroids. Patients who experienced asthma exacerbations (asthma requiring treatment beyond study medication) were treated as deemed appropriate by the investigator. All concurrent medications (and changes in dose) were recorded in the case report form. Diary card data during the period of treatment intervention for an exacerbation were included in the intent-to-treat analyses.

Patients returned to the clinic every 4 weeks. At each clinic visit, diary card information was assessed and pulmonary function tests were performed. Efficacy measures included FEV1, morning and evening PEF, patient-rated daytime and nighttime symptoms, nighttime awakenings, and supplemental albuterol use. Safety was assessed by physical examinations, vital signs, number of exacerbations, and adverse event reports. Investigators determined whether or not adverse events were potentially drug-related (possibly, probably, or almost certainly related to study drug).

Quality of Life Assessments
The primary study objective was to assess the impact of salmeterol on asthma-specific quality of life as compared with placebo (as-needed albuterol). Each patient completed a Asthma Quality of Life Questionnaire8 (AQLQ) at the screening visit prior to treatment on study day 1, week 4, week 8, week 12, and at the point of withdrawal if the patient was withdrawn from the study for any reason. The AQLQ is a 32-item, self-administered, asthma-specific instrument that assesses quality of life over a 2-week time interval. Each item is scored using a scale from 1 to 7, with lower scores indicating greater impairment and higher scores indicating less impairment in quality of life. Items are grouped into four domains: Activity Limitation (assesses the amount of limitation of individualized activities that are important to the patient and are affected by asthma); Asthma Symptoms (assesses the frequency and degree of discomfort of shortness of breath, chest tightness, wheezing, chest heaviness, cough, difficulty breathing out, fighting for air, heavy breathing, difficulty getting a good night's sleep); Emotional Function (assesses the frequency of being afraid of not having medications, concerned about medications, concerned about having asthma, frustrated); and Environmental Exposure (assesses the frequency of exposure to and avoidance of irritants such as cigarette smoke, dust, and air pollution). Individual domain scores and a global score are calculated. A change of ± 0.5 (for both global and individual domain scores) represents the smallest difference that patients perceive as meaningful.

Statistical Analysis
The target enrollment size of 300 patients per treatment arm was chosen to provide 80% power of detecting differences in efficacy variables at a significance level of 0.05. A target enrollment size of approximately 80 patients per treatment arm was necessary to detect a clinically significant difference of 0.5 in AQLQ scores at a significance level of 0.05. Efficacy (including quality of life) and safety analyses were based on data from the intent-to-treat population, comprising all patients exposed to the study drug. By-visit analyses were performed only on data from patients remaining in the study at that specific visit.

Demographic and baseline disease characteristics were summarized and tested for group differences using the Cochran-Mantel-Haenszel and F tests for nonparametric and parametric variables, respectively, each controlling for investigator. For parametric variables such as pulmonary function test and quality-of-life data, within-group differences were analyzed by t tests, paired by patient; between-group differences were analyzed by analysis of variance F tests on change from baseline, controlling for investigator. For nonparametric variables such as symptoms, between-group comparisons of differences from baseline were analyzed by the van Elteren test,16 controlling for investigator. Analyses of patient-rated PEF and symptoms were based on 7-day averages within subjects that were then averaged over treatment groups. The incidence of adverse events was tabulated by treatment group and analyzed for treatment differences using Fisher's exact test. A p value <= 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 474 patients were randomly assigned to treatment. Randomization resulted in comparable treatment groups at baseline with respect to patient demographics (except for sex; 59% of subjects in the salmeterol group were female, compared with 50% in the placebo group; p = 0.035), pulmonary function measurements (except for FEV1 percent predicted; p = 0.013), and number of patients receiving either theophylline or corticosteroids (Table 1 ). The disposition of patients is shown in Table 2 .


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  		Table 1. Patient Demographics and Baseline Characteristics*

 

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  		Table 2. Patient Disposition*

 
AQLQ Scores
At baseline, the AQLQ domain and global scores were not significantly different between treatment groups (Fig 1 ). At weeks 4, 8, and 12, both treatment groups showed significant improvements from their baseline domain and global scores (p <= 0.001). However, the improvement in all domains (and global score) was significantly greater in the salmeterol group (p <= 0.005) compared with placebo (ie, as-needed albuterol). Fig 1 shows the mean score change from baseline to week 12 for the two treatment groups.



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  		Figure 1. Mean change from baseline in AQLQ scores at week 12.

 
The salmeterol group met the reported criteria for clinically significant improvements (ie, small change = 0.5; moderate change = 1.0; large change = 1.5) in all domains (and global), first evident at week 4 and continuing through week 12 (mean score range, 0.79 to 1.63; Fig 1 ). By week 4, the placebo group scores met the criteria for a small change for only the Asthma Symptoms domain. However, by week 12, the placebo group scores had also met the criteria for a small change from baseline for all domains (mean score range, 0.27 to 0.86; Fig 1 ). The difference between treatment groups for mean score change from baseline was also at least 0.5 points greater (range, 0.50 to 0.89) for salmeterol at all assessment points except at week 4 and week 8 for the Environmental domain.

Pulmonary Function
Morning PEF, evening PEF, and morning/evening differential PEF were similar in both treatment groups at baseline. Salmeterol significantly improved morning, evening, and morning/evening differential PEF measurements compared with placebo at weeks 4, 8, and 12 (p <= 0.002). By week 12, a 13% improvement from baseline morning PEF was observed in the salmeterol group, whereas morning PEF in patients treated with placebo was essentially unchanged (Table 3 and Fig 2 ). Similarly, by week 12, diurnal variation in PEF decreased 18 L/min (60% improvement from baseline) in salmeterol-treated patients; diurnal variation in PEF increased by 1 L/min (3% change from baseline) in placebo-treated patients.


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  		Table 3. Baseline and Mean Change (SEM) From Baseline in Pulmonary Function

 


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  		Figure 2. Mean morning PEF throughout 12 weeks of treatment.

 
Values for FEV1 were similar in both treatment groups at baseline (except for percent predicted FEV1; p = 0.013). FEV1 measurements in patients treated with salmeterol were significantly improved compared with those observed in patients treated with placebo at treatment week 8 and week 12 (p <= 0.004); these changes represented 8 and 16% improvements from baseline with placebo and salmeterol, respectively, at week 12 (Table 3 ).

Nighttime Awakenings
Salmeterol significantly increased the percentage of nights with no awakenings due to asthma from 28 to 77% by week 12, compared with an increase from 28 to 49% in patients treated with placebo (p < 0.001; Fig 3 ).



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  		Figure 3. Mean percentage of nights with no awakenings due to asthma during weeks 1 to 4, 5 to 8, and 9 to 12.

 
Asthma Symptoms
Salmeterol significantly reduced patient-rated mean daytime symptom scores (combined symptoms of wheezing, chest tightness, and shortness of breath) compared with placebo after each week of treatment (p < 0.05). By week 12, salmeterol reduced scores by 50% from baseline, compared with a 26% reduction in scores in the placebo group (p < 0.001). The percentage of symptom-free days significantly increased after 12 weeks in patients treated with salmeterol (from 9 to 48%; p < 0.001) compared with patients treated with placebo (from 9 to 26%).

Supplemental Albuterol Use
Salmeterol significantly reduced daytime and nighttime supplemental albuterol use from baseline at week 12 by 60 and 69%, respectively (p < 0.001), compared with placebo, which reduced albuterol use by 24 and 17% in the daytime and nighttime, respectively. Similarly, salmeterol significantly increased the percentage of days (from 12 to 49%) and nights (from 35 to 82%) with no supplemental albuterol use over the 12-week treatment period compared with placebo (p < 0.001).

Theophylline Users vs Nonusers
Approximately one fourth of patients in each treatment group were concurrently using theophylline. Mean change from baseline in morning PEF was analyzed separately in theophylline users and nonusers (Fig 4 ). Salmeterol significantly improved morning PEF compared with placebo at every week throughout the study regardless of theophylline use (p <= 0.013). PEF values in patients treated with placebo were similar in both theophylline users and nonusers. All other efficacy measures and AQLQ assessments improved significantly over 12 weeks of treatment with salmeterol compared with placebo in patients not treated with theophylline (p < 0.05); significant improvements with salmeterol compared with placebo were also noted in all other efficacy measures (nighttime awakenings, supplemental albuterol use) in patients treated with theophylline, except for FEV1 at week 4 and week 12, morning/evening PEF differential, and combined symptom scores.



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  		Figure 4. Mean change from baseline in morning PEF, theophylline users and nonusers throughout 12 weeks of treatment.

 
Safety
Salmeterol was well tolerated throughout the 12 weeks of treatment. No clinically significant differences were noted between treatment groups in physical examination findings and vital signs. The number of patients with exacerbations was significantly higher (p = 0.02) in patients treated with placebo (n = 70 [30%]) compared with patients treated with salmeterol (n = 49 [20%]). At least one third of all exacerbations were associated with respiratory infection.

The number of patients withdrawn because of adverse events was similar in each treatment group (placebo, 6%; salmeterol, 4%). During the study, 15 patients in the placebo group (6%) and 19 patients in the salmeterol group (8%) experienced at least one adverse event that was considered to be potentially related to treatment. The most commonly reported adverse events (>= 2% incidence) considered by the investigator to be potentially related to treatment were insomnia (salmeterol, 2%; placebo, 0%) and headache (salmeterol, 2%; placebo, 0%). There were no significant differences between treatment groups in the number of serious adverse events. Five patients developed serious adverse events considered by the investigator to be potentially related to treatment. Two patients treated with placebo experienced status asthmaticus; two patients treated with salmeterol experienced status asthmaticus and one patient treated with salmeterol experienced tongue/uvular swelling. All serious adverse events resolved after discontinuation of the study drug.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study confirm the effectiveness of salmeterol in improving patients' quality of life as well as clinical outcomes in the treatment of nocturnal (and daytime) asthma symptoms. In this study, patients with nocturnal asthma symptoms who were treated with salmeterol had significant quality-of-life improvements from baseline at each clinic visit. These improvements were noted in each of the AQLQ domains (activity limitation, asthma symptoms, emotional function, and environmental exposure) as well as in global scores. Significant improvements in AQLQ scores were observed with salmeterol (compared with placebo) at the first visit (week 4) following randomization to treatment, and were maintained throughout the 12-week study period. Similar improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline.

The AQLQ was chosen to evaluate quality-of-life parameters in this study because it is a reliable, valid, and responsive asthma-specific quality-of-life instrument.8 ,10 ,17 The magnitude of change in AQLQ scores that corresponds to a minimally important clinical difference has been previously ascertained (changes >= 0.5 = minimal; changes >= 1.0 = moderate; changes >= 1.5 = large).18 Although minimal improvements (> 0.5) in quality of life were observed with placebo in the current study, treatment with salmeterol was associated with moderate to large improvements. The small improvements observed in patients treated with placebo are most likely related to increased compliance in a study situation, in which patients perceive that the level of care from health-care practitioners is higher than normal and that management of their disease is better. Thus, the AQLQ results in the current study confirm that treatment with salmeterol confers physical, emotional, and social benefits to patients with nocturnal asthma symptoms. The AQLQ results with salmeterol in this population of patients with nocturnal asthma are similar to those reported in other study populations (mild to moderately severe asthma).10 ,11 ,12

After 12 weeks of treatment, salmeterol significantly improved mean change from baseline measurements in FEV1, morning and evening PEF, morning/evening PEF differential, asthma symptom scores, percentage of symptom-free days, and percentage of nights with no awakenings; it also reduced the need for supplemental albuterol compared with placebo (as-needed albuterol). These improvements are consistent with the improvements in PEF and symptom scores observed in other studies.2 ,3 ,4 ,6

Based on the improvements observed in clinical measures evaluated in the present study, tolerance to the bronchodilator effects did not occur. Several studies using methacholine or exercise challenges have shown that the bronchoprotective effects of salmeterol may decrease with regular use in some patients.19 ,20 ,21 ,22 ,23 However, the clinical significance of these laboratory findings is unclear because to date there have been no studies that associate tolerance to salmeterol's bronchoprotective effect with a decrease in asthma morbidity. Numerous long-term studies have demonstrated that salmeterol use is not associated with a loss of asthma control and that tolerance to its bronchodilatory effect does not occur.3 ,4 ,24 ,25 ,26 ,27 ,28 ,29 ,30

The most recent NIH guidelines for the treatment of asthma31 suggest adding long-acting bronchodilators, such as salmeterol, to the treatment regimen of patients with moderate persistent asthma who are already receiving anti-inflammatory medications and who continue to have persistent daytime or nighttime symptoms. The improvements observed in the quality of life and clinical outcomes from this study, in which 62 to 67% of all patients received inhaled corticosteroid therapy, demonstrate the effectiveness of salmeterol in patients with moderate persistent asthma who also experience nocturnal symptoms. In addition to the significant improvements observed in traditional clinical outcome measurements after treatment with salmeterol, patients in this study also perceived that treatment with salmeterol greatly enhanced their ability to carry on daily activities without the fears associated with asthma instability, thereby confirming the importance of considering quality-of-life measurements and the role of salmeterol in determining an effective treatment plan in patients with asthma.


   Acknowledgements
 
Dr. Lockey provided significant input into the design, analysis, data collection, and interpretation of data in this study and also in the manuscript review process. Dr. DuBuske and Friedman participated in data collection and in the manuscript review process. We wish to acknowledge the contributions of all the investigators who participated in this study. We would also like to thank Marty Johnson for management and conduct of the study, Amanda Emmett for statistical analyses, and Kim Poinsett-Holmes (a Glaxo Wellcome medical writer) for drafting and revising this manuscript.


   Footnotes
 
Preliminary results were presented at the American Academy of Allergy, Asthma and Immunology meeting in San Francisco, CA, February 19–25, 1997.

Supported by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC.

Correspondence to: Richard F. Lockey, MD, FCCP, Division of Allergy and Immunology, University of South Florida College of Medicine, c/o Veterans Administration Hospital, 13000 B.B. Downs Blvd, Tampa, FL 33612

Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; PEF = peak expiratory flow

Received for publication April 16, 1998. Accepted for publication September 10, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  21. Kalra, S, Swystun, VA, Bhagat, R, et al (1996) Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 109,953-956[Abstract/Free Full Text]
  22. Ramage, L, Lipworth, BJ, Ingram, CG, et al (1994) Reduced protection against exercise-induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 88,363-368[CrossRef][ISI][Medline]
  23. Simons, FER, Gerstner, TV, Cheang, MS, et al (1997) Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 99,655-659[Abstract/Free Full Text]
  24. Faurschou, P, Engel, AM, Haanaes, OC (1994) Salmeterol in two different doses in the treatment of nocturnal bronchial asthma poorly controlled by other therapies. Allergy 49,827-832[ISI][Medline]
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  27. Greening, AP, Ind, PW, Northfield, M, et al (1994) Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 344,219-224[CrossRef][ISI][Medline]
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S. R. Salpeter, T. M. Ormiston, and E. E. Salpeter
Meta-Analysis: Respiratory Tolerance to Regular {beta}2-Agonist Use in Patients with Asthma
Ann Intern Med, May 18, 2004; 140(10): 802 - 813.
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 Eur Respir JHome page
E.F. Juniper, M.E. Wisniewski, F.M. Cox, A.H. Emmett, K.E. Nielsen, and P.M. O'Byrne
Relationship between quality of life and clinical status in asthma: a factor analysis
Eur. Respir. J., February 1, 2004; 23(2): 287 - 291.
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 PediatricsHome page
M. J. Coffey, B. Wilfond, and L. F. Ross
Ethical Assessment of Clinical Asthma Trials Including Children Subjects
Pediatrics, January 1, 2004; 113(1): 87 - 94.
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