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(Chest. 2001;119:714-719.)
© 2001 American College of Chest Physicians

Effectiveness and Safety of Salmeterol in Nonspecialist Practice Settings*

Anthony D. D’Urzo, MD; Kenneth R. Chapman, MD; André Cartier, MD; Frederick E. Hargreave, MB; Mark Fitzgerald, MB and David Tesarowski, PhD

* From the University of Toronto (Drs. D’Urzo and Chapman), Toronto, Ontario; the University of Montreal (Dr. Cartier), Montreal, Quebec; McMaster University (Dr. Hargreave), Hamilton, Ontario; the University of British Columbia (Dr. Fitzgerald), Vancouver, British Columbia; and Glaxo Wellcome Inc (Dr. Tesarowski), Mississauga, Ontario, Canada.

Correspondence to: Anthony D. D’Urzo, MD, Primary Care Lung Clinic, 1670 Dufferin St, Suite 107, Toronto, Ontario M6H 3M2, Canada


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings.

Design: A randomized, double-blind, 6-month, parallel-group study involving 253 centers.

Setting: Primarily nonspecialist practices (n = 232).

Patients: A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 µg; n = 455) or matching placebo twice daily (n = 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study.

Measurements and results: The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p = 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p = 0.028).

Conclusions: Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations.

Key Words: asthma control • effectiveness • exacerbation • safety • salmeterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The introduction of ß2-agonists into clinical practice has been accompanied by concerns that the long-term regular use of ß2-agonists worsens asthma control. Such fears have been prompted by laboratory-based studies1 2 3 4 5 showing modest tolerance to the bronchoprotective effect of either short-acting or long-acting ß2-agonists given on a scheduled basis. The clinical importance of this laboratory finding remains unclear, but several reports6 7 8 9 reassure that regular use of either short-acting or long-acting ß2-agonists does not result in loss of asthma control. Indeed, there is evidence of improved asthma con- trol with these agents. Two large multinational tri-als10 11 have reported that the addition of salmeterol to low-dose or moderate-dose inhaled corticosteroids (ICS) can produce greater improvements in peak flow and fewer symptoms than doubling the dose of ICS.

Studies of the role of salmeterol in asthma management have been conducted primarily in specialized centers or in preregistration trials that are associated with entry criteria that may not adequately reflect the real-life conditions of primary-care practice. Accordingly, the present study was undertaken to evaluate the effectiveness of salmeterol, 50 µg bid, vs placebo treatment in a large, primary-care population of asthmatics. All subjects were receiving an inhaled short-acting ß2-agonist on demand and were receiving regular anti-inflammatory asthma medication.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
An institutional committee on human research approved the study. Appropriate informed consent was obtained from all subjects. A total of 911 subjects (417 men; 494 women; mean ± SD age, 46.2 ± 16.3 years) were studied in 253 centers. Of this number, the vast majority of investigators were primary-care physicians (family physicians and general practitioners), with only 21 specialists (8% of total) recruiting 60 subjects. All subjects had a documented history of asthma according to the American Thoracic Society guidelines.12 There was no time restriction on the demonstration of reversibility of airflow obstruction as outlined in the American Thoracic Society guidelines. Current and former smokers were allowed to participate in order to reflect real-life conditions. Subjects were required to be using optimum (as defined by the investigator) doses of anti-inflammatory treatment while still requiring inhaled short-acting ß2-agonist therapy more than twice daily to control breakthrough symptoms. In the placebo group, 19.3%, 56.2%, and 24.6% of subjects received beclomethasone dipropionate (BDP) (or its equivalent) up to 500 µg/d; BDP, 500 to 1,000 µg/d; and BDP > 1,000 µg/d, respectively; in the salmeterol group, the percentage of subjects in these dose categories was 16.8%, 61.6%, and 21.3%, respectively.

The definition of optimal dose of ICS was left to the investigator in order to reflect (1) differences in the need for anti-inflammatory therapy among patients based on individual physician assessments, and (2) the recommendations for use of salmeterol as outlined in the product monograph. By utilizing this approach, we believe that patient selection and management during the trial would parallel the day-to-day management of asthmatics in primary care. All subjects gave their written informed consent before participating in the study.

Subjects were excluded from the study if they suffered from uncontrolled pulmonary or systemic disease or a psychological condition that, in the opinion of the investigator, precluded their entry into the study. There were no restrictions placed on concurrent asthma pharmacotherapy, including therapy for asthma exacerbations. Subjects receiving ß-blocker therapy were excluded.

Study Design
The study was a multicenter, randomized, double-blind, parallel-group design, in that salmeterol, 50 µg bid via metered-dose inhaler (MDI), was compared with placebo, bid via MDI. Both groups were allowed to take a short-acting ß2-agonist, salbutamol, as needed to control breakthrough symptoms. Randomization between the treatment groups was equal (1:1 ratio). The treatment period was 24 weeks in duration, with a follow-up visit 1 month after the last scheduled visit. During the treatment period, subjects visited the clinic monthly. The study was conducted according to World Medical Association Declaration of Helsinki as amended in Hong Kong, 1989. The study was approved by an established ethics review broad.

Potential subjects were screened at visit 1 to determine whether they met eligibility criteria, their histories were taken, and they underwent a physical examination. Patients were recruited from the practices of community-based primary-care physicians. In the majority of study centers, the primary-care physician was the principal investigator. All patients received instruction in the optimal MDI and Mini-Wright peak flowmeter use. At visits 2 through 8, peak flow and vital signs were measured and the patient was questioned carefully about possible asthma exacerbations (see below) and adverse events. At each visit, patients were encouraged to return to the clinic in the morning having refrained from the use of ß2-agonist medication before measurement of peak expiratory flow (PEF). Visit 7 was similar to the other visits with the exception that all subjects were instructed about a poststudy treatment plan. The poststudy treatment plan was established at the discretion of the investigator. At visit 8 (posttreatment), PEF was measured and a complete assessment of exacerbations and adverse events was undertaken.

Outcome Measures
The primary outcome variable was the proportion of subjects with serious asthma exacerbations, defined as an exacerbation requiring hospitalization, emergency department visit, or use of oral prednisone during the treatment period. Secondary variables included PEF, use of short-acting ß2-agonists, number of nighttime awakenings requiring rescue medication, number of days in hospital, days when prednisone was used for an asthma exacerbation, days when unscheduled visits were made to a physician because of asthma exacerbations, days requiring increased asthma medication, work or school days lost because of asthma exacerbations, and days when activities were limited because of asthma exacerbations. Blood eosinophil counts were measured on a subgroup of subjects experiencing asthma exacerbations.

Statistical Analysis
The proportion of subjects with serious asthma exacerbations was analyzed by logistic regression analysis with the subject’s age used as the covariate. The mean PEF, heart rate, and absolute blood eosinophil count were calculated for each patient and analyzed using analysis of covariance. The remaining secondary variables were analyzed using the Wilcoxon rank-sum test. The Hodges-Lehman method was used to estimate the treatment median difference and 95% confidence limits for the treatment medians.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 911 subjects were enrolled in the study (Table 1 ). All 911 subjects were included in the intent-to-treat population for analysis. A total of 199 subjects were withdrawn from the study after randomization (Table 1) . The withdrawal rates over the entire treatment period were 18% and 25% for the salmeterol and placebo groups, respectively (p < 0.05), with 11 subjects withdrawn in the placebo group for lack of efficacy compared to only 3 salmeterol-treated subjects.


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  		Table 1. Primary Reason for Withdrawal After Randomization: Intent-to-Treat Population*

 
Demographic characteristics of the intent-to-treat population are summarized in Table 2 . The baseline clinical history of the intent-to-treat population is summarized in Table 3 . There was no significant difference between groups for the unadjusted baseline PEF (378 L/min in the placebo group and 380 L/min in the salmeterol group), requirement for short-acting ß2-agonist (median value of four occasions per day for each group), or number of nighttime awakenings because of asthma requiring bronchodilator administration (median of one occasion during the week before the initial visit for each group).


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  		Table 2. Subject Demography: Intent-to-Treat Population*

 

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  		Table 3. Clinical History: Intent-to-Treat Population*

 
There were no differences between groups in the types of concomitant medications used during the study. For 93% of subjects, anti-inflammatory therapy was with ICS alone. Five percent of subjects used oral corticosteroids and ICS, while only 1% of subjects used oral corticosteroids exclusively. A handful of subjects used cromolyn or nedocromil. Sixteen percent used theophylline, and 16% used inhaled ipratropium.

During the study, the adjusted proportion of subjects with serious asthma exacerbations was not significantly different between salmeterol, 50 µg bid via MDI, and placebo, bid via MDI (20.8% vs 20.9%, respectively; p = 0.935). Postrandomization stratification (Table 4 ) showed that anti-inflammatory medication use was significantly associated with the proportion of subjects with serious asthma exacerbations (p < 0.001). The highest dosing of BDP (> 1,000 µg/d) was associated with a higher rate of exacerbation (33% vs 13% and 16% for subjects receiving BDP doses of < 500 µg/d and 500 to 1,000 mg/d) irrespective of the subject’s treatment group. Similarly, baseline PEF was also significantly associated with the proportion of subjects with serious asthma exacerbations (p = 0.011). For the > 80% of predicted PEF, the proportion was only 15%, whereby in the strata with PEF being 60 to 80% of predicted and < 60% of predicted, the proportions of subjects with exacerbations were each 25%. Finally, 11.6%, 6.5%, and 4.8% of subjects receiving BDP, > 1,000 µg/d, had PEF values of > 80% of predicted, 60 to 80% of predicted, and < 60% of predicted, respectively.


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  		Table 4. No. and Proportion of Subjects With Serious Asthma Exacerbations During the Treatment Period

 
The intent-to-treat population included subjects who had received at least one treatment of salmeterol or placebo. Therefore, the 199 subjects who did not complete the study were included in Table 4 . The PEF data in Table 4 compare the treatment groups and represent the mean of the visits for each patient and not just the end-of-treatment measurements that are often the case for most placebo-controlled trials. In our study, the data presented are adjusted to take into account the time subjects spent in the study. With respect to the serious asthma exacerbations data in Table 4 , the difference in withdrawal rates between the placebo group and the salmeterol group would tend to underestimate the proportion in the placebo group.

Salmeterol treatment was associated with a significant improvement in PEF as compared to placebo treatment (Tables 5 , 6 ). The adjusted mean PEF during treatment was 398 L/min and 386 L/min for salmeterol and placebo groups, respectively (p < 0.001). The adjusted PEF data for visits 2 through 7 are shown in Table 6 . Differences in PEF at visits 1 and 8 were not significant.


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  		Table 5. Secondary Variables: Median Values for Intent-to-Treat Population*

 

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  		Table 6. PEF Rate: Intent-to-Treat Population*

 
With respect to the other variables of interest, the need for short-acting ß2-agonist was less for salmeterol as compared to placebo treatment (median dose, two inhalations and three inhalations, respectively, during treatment; p < 0.001). The percentages of subjects who did not awaken because of their asthma, requiring rescue medication, were 74% and 68%, respectively, for the salmeterol and placebo groups (p = 0.028). There were no differences between salmeterol and placebo treatment for a number of secondary variables, as shown in Table 5 .

Heart rate was slightly but significantly higher in the salmeterol group (78 beats/min; 76 beats/min at baseline) compared to placebo (77 beats/min; unchanged from baseline; p < 0.05). In 75 subjects studied, there were no significant differences in the adjusted means for blood eosinophil count between salmeterol (0.22 x 109/L) and placebo (0.38 x 109/L) groups (p = 0.81).

During the course of the study, there were three deaths reported: two in the salmeterol group (one with congestive heart failure, and one of undetermined cause at autopsy, although the subject had a history of abdominal pain), and one in the placebo group (myocardial infarction leading to anoxic encephalopathy). All deaths were judged to be unrelated to the study medication.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study indicate that regular use of salmeterol over a 24-week period is not associated with a greater number of serious asthma exacerbations as compared to placebo treatment. Salmeterol use resulted in improved PEF and a reduction in the use of short-acting ß2-agonists and fewer nocturnal awakenings compared to placebo treatment. There were fewer withdrawals of subjects in the salmeterol-treated group compared to the placebo arm. Collectively, these findings suggest that regular use of salme-terol results in improved asthma control in subjects typically cared for by primary-care physicians.

Our study contributes to a growing body of literature on the long-term efficacy of salmeterol in the management of asthmatic subjects. In a 12-month study by Britton et al,13 regular salmeterol use was associated with improvements in morning PEF and daily symptoms and reductions in rescue ß2-agonist use and asthma exacerbations, as compared to regular salbutamol use. Similar findings are reported by Lundback et al7 in a 12-month study involving regular salmeterol and salbutamol use. Other studies14 15 of shorter duration report improved asthma control, including fewer exacerbations with salmeterol as compared to salbutamol use.

In the present study, subjects were required to be using optimum anti-inflammatory medication and be experiencing breakthrough symptoms requiring short-acting ß2-agonists more than twice daily before entry into the treatment period. The majority of subjects were using ICS as their anti-inflammatory treatment, with most subjects using > 500 µg/d of BDP or equivalent. A limitation of our study relates to the lack of specific definition of optimum dose of inhaled anti-inflammatory therapy among study centers. This makes is difficult to identify those patients who are most likely to benefit from treatment with a long-acting ß2-agonist like salmeterol. However, our finding that salmeterol did not increase severe exacerbations in this primary-care population is reassuring given concerns that have been raised in relation to regular ß2-agonist use.

The results of this study confirm those found in the largest randomized double-blind trial ever conducted in the United Kingdom (24,000 subjects). Castle et al16 found that 16 weeks of treatment with either salmeterol, 50 µg bid, or salbutamol, 200 µg qid, was not associated with a significant excess of asthma deaths and that overall asthma control was better in subjects receiving salmeterol. Our findings help to clarify the role of salmeterol in primary practice by showing that when it is used in conjunction with anti-inflammatory medication, asthma control improves and there is no associated increase in severe exacerbations.

In subjects using low-dose ICS who still have symptoms, it is current practice to increase the dose of ICS in an attempt to improve asthma control. The reports of Greening et al10 indicate that the addition of salmeterol, 50 µg bid, to low-dose ICS was not associated with more adverse effects or asthma exacerbations as compared to doubling the dose of ICS. Furthermore, salmeterol use was associated with significant improvement in PEF and other indexes of asthma control. Similar findings are reported by Woolcock et al,11 who compared the addition of salmeterol (50 µg or 100 µg bid) in subjects receiving BDP, 500 µg bid, to a group of asthmatics receiving 1,000 µg bid of BDP over a 24-week period. The latter study also reported no changes in bronchial hyperresponsiveness between study groups.

The reports of Pauwels et al17 indicate that the addition of formoterol (another long-acting ß2-agonist) to budesonide therapy is associated with improvements in asthma symptoms and in lung function without worsening of asthma control over a 1-year period. These investigators also reported that the addition of formoterol decreased the incidence of both severe and mild exacerbations. Our finding that the proportion of severe exacerbations was similar in the salmeterol and placebo groups may be related to differences in study design. For example, the study of Pauwels et al17 included a run-in phase in which all subjects received budesonide, 800 µg bid, for 4 weeks before randomization. This dose represented a twofold increase compared to the mean ICS dose at the beginning of the run-in phase. During the run-in phase, significant improvements in lung function were reported. It is difficult to speculate how such an improvement in asthma control during the run-in phase would influence outcomes throughout the remainder of that study. Because our study was designed to reflect day-to-day asthma care in primary practice, a run-in phase was not included. Therefore, it is not possible to directly compare the findings of Pauwels et al17 to those reported herein. It is also important to consider the possibility that our sample size, particularly of patients with moderate-to-severe airflow obstruction (Table 4) , was too small to detect any benefit of salmeterol use with respect to the proportion of severe exacerbations. Finally, variability of corticosteroid dose among patients in placebo and salmeterol groups may have been a relevant factor contributing to the outcome in this study.

In summary, the present study has shown that salmeterol use over a 24-week period in primary practice is not associated with a greater number of serious asthma exacerbations compared to placebo treatment. Salmeterol use improved lung function, reduced the use of short-acting ß2-agonist medication, and was associated with fewer nocturnal awakenings and withdrawals as compared to placebo treatment. If subjects are using regular anti-inflammatory medication and continue to experience breakthrough symptoms that require regular use of short-acting ß2-agonist therapy, primary-care physicians should consider the use of long-acting ß2-agonists as maintenance therapy in such subjects.


   Acknowledgements
 
The authors wish to thank the many investigators who participated in this trial. Special is given to D. K. D’Urzo, MSc, for her assistance throughout the trial and in the preparation of the article.


   Footnotes
 
Abbreviations: BDP = beclomethasone diproprionate; ICS = inhaled corticosteroids; MDI = metered-dose inhaler; PEF = peak expiratory flow

Supported by a grant from Glaxo Wellcome Inc, Canada.

Dr. D’Urzo was the largest recruiter for the study and the primary author of the article.

Drs. Chapman, Cartier, Hargreave, and Fitzgerald constituted an expert advisory panel who devised the study protocol, reviewed the study report, and contributed to the review and editing of this article.

Dr. Tesarowski was the clinical scientist at Glaxo Wellcome Inc responsible for the study, the coordination of the editorial reviews conducted by the other authors, and submission of the manuscript.

Received for publication February 10, 2000. Accepted for publication September 28, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Cockcroft, DW, McParland, CP, Britto, SA, et al (1993) Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 342,833-837[CrossRef][ISI][Medline]
  2. O’Connor, BJ, Aikman, SL, Barnes, PJ (1992) Tolerance to the nonbronchodilator effects of inhaled ß2-agonists in asthma. N Engl J Med 327,1204-1208[Abstract]
  3. Bhagat, R, Kalra, S, Swystun, VA, et al (1995) Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 108,1235-1239[Abstract/Free Full Text]
  4. 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]
  5. Cockcroft, DW, Swystum, VA, Bhagat, R, et al (1997) Salmeterol and airway response to allergen. Can Respir J 4,37-40
  6. Chapman, KR, Kesten, S, Szalai, P (1994) Regular vs as needed inhaled salbutamol in asthma control. Lancet 343,1379-1382[CrossRef][Medline]
  7. Lundback, B, Rawlinson, DW, Palmer, JBD (1993) A 12-month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic subjects. Thorax 48,148-153[Abstract]
  8. Devoy, MAB, Fuller, RW, James, BD, et al (1995) Are there any detrimental effects of the use of inhaled long-acting ß2-agonists in the treatment of asthma? Chest 107,1116-1124[Free Full Text]
  9. D’Urzo, AD (1997) Long-acting ß2-agonists: role in primary care asthma treatment. Can Fam Physician 43,1773-1777[ISI][Medline]
  10. Greening, AP, Ind, PW, Northfield, M, et al (1994) Added salmeterol versus higher-dose corticosteroid in asthma subjects with symptoms on existing inhaled corticosteroid. Lancet 344,219-224[CrossRef][ISI][Medline]
  11. Woolcock, A, Lundbach, B, Ringdal, N, et al (1996) Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 153,1481-1488[Abstract]
  12. . American Thoracic Society. (1987) Standards for the diagnosis and care of subjects with chronic obstructive pulmonary disease and asthma. Am Rev Respir Dis 136,225-244[ISI][Medline]
  13. Britton, MG, Earnshaw, JS, Palmer, JBD (1992) A 12-month comparison of salmeterol with salbutamol in asthmatic subjects. Eur Respir J 5,1062-1067[Abstract]
  14. D’Alonzo, GE, Nathan, RA, Henochowicz, S, et al (1994) Twice daily inhaled salmeterol as maintenance therapy for asthma. JAMA 271,1412-1416[Abstract]
  15. Pearlman, DS, Chervinsky, P, LaForce, C, et al (1992) A comparison of salmeterol with albuterol in the treatment of mild to moderate asthma. N Engl J Med 327,1420-1425[Abstract]
  16. Castle, W, Fuller, R, Hall, J, et al (1993) Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic subjects who require regular bronchodilator treatment. BMJ 306,1034-1037
  17. Pauwels, RA, Lofdahl, C-G, Postma, DS, et al (1997) Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 337,1405-1411[Abstract/Free Full Text]



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