A twelve-week comparison of salmeterol and salbutamol in the treatment of mild-to-moderate asthma: A Canadian multicenter study

A twelve-week comparison of salmeterol and salbutamol in the treatment of mildto-moderate asthma: A Canadian multicenter study Louis-Philippe Boulet, MD, a Michel Laviolette, MD, a Serge Boucher, MD, b Allan Knight, MD, c Jacques Hdbert, MD, d Kenneth R. Chapman, MD e Sainte-Foy, Quebec, and Toronto, Ontario, Canada Background: A long-acting inhaled bronchodilator that is both well tolerated and effective could allow for improved control of both daytime and nighttime symptoms in patients with asthma who use frequent as-needed short-acting bronchodilators despite antiinflammatory treatment. Objective and methods: We compared the efficacy and safety of inhaled salmeterol, 50 lag twice daily, with inhaled salbutamol, 200 lag four times daily, delivered through a metereddose inhaler for 3 months in a multicenter, randomized, double-blind, parallel-group study of 228 patients (aged 12 to 76 years) with mild-to-moderate asthma. Results: A single morning dose of salmeterol produced improvement in F E V 1 that was significantly greater (p <- 0.012) than that produced by two doses of salbutamol (taken 6 hours apart) when patients were assessed 3 to 6 hours and 10 to 12 hours after the dose. This greater bronchodilation was present on day 1 of the study and after 4, 8, and 12 weeks of regular treatment. Over the 12 weeks, compared with salbutamol, salmeterol treatment was associated with a greater mean improvement in morning peak expiratory flow (35 L/min vs - 3 L/min, p < 0.001), a higher percentage of days with no symptoms (29% vs 15%; p = 0.012), and a higher percentage of nights with no awakenings (14% vs - 1 % ; p < 0.001). Adverse events were similar for both treatments. Conclusions: In this study salmeterol, 50 tag twice daily, was well tolerated and more effective than salbutamol, 200 tag four times daily, in improving symptoms and lung function in patients with mild-to-moderate asthma. (J Allergy Clin Immunol 1997;99:13-21.) Key words: Asthma, salmeterol, salbutamol, [3e-agonists

The pharmacologic properties and therapeutic effects of salmeterol have been reviewed previously. 1-3 Salmeterol xinafoate is a selective, long-acting 132-adrenoreceptor agonist with a duration of bronchodilator action of at least 12 hours in patients with asthma c o m p a r e d with 4 to 6 hours for salbutamol. 4 Salmeterol is a highly effective bronFrom aCentre de Pneumologie, H6pital Laval, Sainte-Foy; bH6pital du St-Sacrement, Sainte-Foy; cSunnybrook Health Science Centre, Toronto; dCentre Hospitalier de L'Universit6 Laval, Sainte-Foy; and eToronto Hospital-Western Division, Toronto. Supported by a grant from Glaxo Wellcome Canada, Inc. Received for publication July 12, 1995; revised Jan. 18, 1996; accepted for publication June 6, 1996. Reprint requests: Louis-Philippe Boulet, MD, Centre de Pneumologie, H6pital Laval, 2725 Chemin Sainte-Foy, SainteFoy, Qu6bec, Canada GIV 4G5. Copyright © 1997 by Mosby-Year Book, Inc. 0091-6749/97 $5.00 + 0 1/1/75641

Abbreviations used MDI: Metered-dose inhaler PEF: Peak expiratory flow

chodilator with no evidence of clinically significant tolerance to this effect? In addition, salmeterol protects against bronchoconstriction induced by a wide variety of stimuli in both adults and children. 6-15 In contrast to short-acting [32-agonists, salmeterol protects against both early and late asthmatic responses and against the increased bronchial hyperresponsiveness induced by allergen exposure?4, 16 A dose of 50 ixg given twice daily has been shown to be both safe and highly effective in the treatment of mild-to-moderate asthma17-23; a 13

14

B o u l e t et al.

J ALLERGYCLIN IMMUNOL JANUARY 1997

dose of 100 Ixg given twice daily was of benefit to patients with m o r e severe disease. 24 T h e p u r p o s e of this study was to further characterize the efficacy and safety of inhaled salmeterol, 50 txg twice daily, in c o m p a r i s o n with the efficacy and safety of salbutamol, 200 txg four times daily, in adolescent and adult patients with mild-tom o d e r a t e asthma over a 12-week t r e a t m e n t period by using sequential 12-hour serial p u l m o n a r y function testing and 24-hour continuous electrocardiography.

METHODS Patients Three hundred patients were recruited from 14 Canadian centers. After meeting all entry criteria, 228 patients were randomized to one of the two treatments. All patients were 12 years of age or older and had a medical history of mild-to-moderate asthma that had required daily pharmacotherapy for at least 6 months. To be included in the study, patients had to have a baseline FEV 1 of 50% to 80% of their predicted normal value25.26 after bronchodilators had been withheld for at least 8 hours; an increase in FEV 1 of 15% or greater over baseline after inhalation of 200 ~g of salbutamol; and symptoms of asthma on 4 of the last 7 days of the prerandomization period. Patients using [3z-agonists other than the study medications or patients unable to withhold methylxanthines, inhaled anticholinergics, or oral corticosteroids were excluded. Patients receiving inhaled and intranasal corticosteroids, inhaled sodium cromoglycate, antihistamines, or immunotherapy could be enrolled provided that treatment had been initiated at least 1 month previously and that the dose remained constant throughout the study. This study, conducted in accordance with the Declaration of Helsinki, was approved by the ethics committees of each participating center. Written informed consent was provided by each patient or guardian before participation.

Study design This was a multicenter, randomized, double-blind, parallel-group study of 15 weeks' duration. The 12-week treatment period was preceded by a 2-week prerandomization assessment period and was followed by a 1-week posttreatment period. Eligible patients were randomized to receive either salmeterol, 50 ~g twice daily, or salbutamol, 200 p~g four times daily, delivered through a metered-dose inhaler (MDI) for 12 weeks. Doubleblinding of treatments was achieved through the use of two matching inhaler combinations, the first delivering salmeterol, 25 ~g per actuation, and placebo and the second delivering salbutamol 100 ~g/actuation each time. The drug was self-administered four times daily with the patients taking 2 puffs from one inhaler at approximately 6:00 AM and 4:00 PM each day and 2 puffs from the other inhaler at approximately 11:00 AM and

9:00 PM each day. For those patients receiving salmeterol treatment, active drug was administered in the first and third daily doses. Open-labeled salbutamol MDIs were provided to all patients as "rescue" medication to be used on an as-needed basis for the relief of acute asthma symptoms. FEV1 was assessed on arrival at each clinic visit, and 12-hour serial FEV1 measures were taken on treatment day 1 and at clinic visits at the ends of weeks 4, 8, and 12. During these 12-hour visits, doses were administered between 7:00 and 9:00 AM. FEV1 measures were conducted 30 minutes before dosing, immediately before dosing (time 0), and at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6 (before the second dose of study drug), 7, 8, 9, 10, 11, and 12 hours (before the third dose of study drug). Peak expiratory flows (PEFs) were measured with a mini-Wright peak flow meter (Clement Clarke, U.K.) and were recorded by the patient twice daily on a diary card, in the morning before the first daily dose of study medication and in the evening before the last dose. Patients also recorded daily scores of respiratory symptoms (chest tightness, wheezing, shortness of breath, and coughing), the number of times they awoke during the night because of asthma (including awakening earlier than usual), and use of rescue salbutamol. Adverse events were monitored throughout the study. Twelve-lead electrocardiograms were recorded during the prerandomization period, immediately before randomization, and at the ends of weeks 4, 8, and 12. Blood and urine samples were collected for routine hematologic, biochemical, and urinalysis determinations at these same clinic visits. In three centers resting electrocardiograms were supplemented by 24-hour Holter monitoring.

Statistical methods All 228 randomized patients were included in the analysis. The study data were analyzed by using SAS software (version 6.07, SAS Institute Inc.). 27 The level of significance was set at e~ = 0.05, two-tailed, for all effects with the exception of the treatment-by-center effect, which was considered statistically significant atp -< 0.10. The primary measure of efficacy was FEV1; all other measures of efficacy were considered secondary. This study was calculated to have a power greater than 80% to detect an FEV1 difference of 0.25 L between the two treatments. For the 12-hour serial FEV1 data, betweentreatment differences were analyzed with repeated-measures analysis of variance on the change from baseline (the mean of the two predose values on treatment day 1). This analysis of variance was performed by using treatment, center, and treatment-by-center interaction as factors in the model. Within-treatment tests were conducted by using paired t tests for each patient by comparing individual postdose time point data with baseline data on pairs of visits. In addition, treatments were compared with respect to change from baseline (average of the 7 days immediately preceding treatment day 1) for morning PEF, evening PEF, and the morning/

J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 1, PART 1

B o u l e t et al.

15

TABLE I. Patient characteristics Group Variable

Sex (male/female ratio) Age (yr, mean - SD) Smoking status, n (%) Never smoked Ex-smoker Asthma duration, n (%) 7 mo to 5 yr 6 to 10 yr >10 years Inhaled corticosteroid use, n (%) FEV 1 (L, mean --_ SD)* FEV1, predicted (L; mean % +_ SD)* Morning PEF (L/min, mean ___SD)t Evening PEF (L/rain, mean + SD)t Morning/evening PEF difference (L/min, mean -+ SD)t Symptom-free days (mean % -+ SD)t Nights with no awakenings (mean % -+ SD)t Rescue salbutamol use, puffs/day (mean --_ SD)t

Salmeterol (n = 113)

Salbutamol (n = 115}

p value

63/50 37 -+ 16

65/50 40 _+ 16

0.91 0.16

71 (63%) 42 (37%)

76 (66%) 39 (34%)

0.6•

21 (18.5%) 22 (19.4%) 70 (61.9%) 81 (71.7%) 2.36 _ 0.78 66 _+ 10 393 _+ 84 419 _+ 85 26 + 30 5 --- 12 76 -+ 30 3.6 _+ 2.4

28 (24.3%) 14 (12.1%) 73 (63.4%) 87 (75.7%) 2.31 -+ 0.73 66 -+ 10 389 -+ 83 417 -+ 82 28 -+ 36 7 -4- 15 80 +--30 3.4 - 2.6

0.29 0.13 0.81 0.50 0.62 0.77 0.72 0.86 0.65 0.27 0.31 0.55

*Baseline is the average of the -0.5 hour and the 0 hour FEV 1 measurements on treatment day 1. tBaseline is the average of the 7 days immediately preceding treatment day 1. evening PEF differential by using the PROC REG procedure on the SAS program; between-treatment differences were tested by using the van Elteren test and within-treatment differences with the Wilcoxon signedr a n k test. 27-29 The percentage of days with no symptoms, percentage of nights with no awakenings, and use of rescue medication were also compared. RESULTS Patient characteristics

O f the 228 patients, 113 were randomized to the salmeterol treatment group and 115 to the salbutamol treatment group. The two groups did not differ with respect to baseline demographic, treatment, or pulmonary function characteristics (Table I). Similar numbers of patients were withdrawn from the study from each group after randomization: 11 (9.7%) from the salmeterol group and 10 (8.7%) from the salbutamol group. Three patients failed to return to the clinic (one in the salmeterol group and two in the salbutamol group), four patients (two in each group) withdrew because of adverse events, and four patients (two in each group) did not meet the inclusion criteria and were subsequently withdrawn. Patients taking salbutamol were withdrawn because of exacerbations of asthma (two patients), noncompliance (one patient), or drop-out (one patient); patients taking salmeterol were withdrawn because of elevated

liver enzymes (two patients), drop-out (two patients), vacation (one patient), or protocol violation (one patient). FEV1 m e a s u r e m e n t s

Within treatments. On treatment day 1, changes from baseline were significant (p < 0.001) at every postdose time point for each of the treatment groups. On each of the subsequent 12-hour days, changes from baseline FEV1 were significant (p --< 0.012) at every postdose time point for the salmeterol treatment group. However, within the salbutamol group, postdose F E V 1 measures were not significantly different (p > 0.05) from baseline at hours 6 and 12 in week 4; at hours 5, 6, and 12 in week 8; and at hours 5, 6, 11, and 12 in week 12. The relatively sustained bronchodilator effect of salmeterol over the 12-hour assessment period versus the biphasic response to the two doses of salbutamol is shown in Fig. 1 (Fig. 1) for both the first and last days of treatment. On treatment day 1, a m e a n peak improvement in F E V 1 to 3.08 L was achieved at 3 hours after the dose (33.8% improvement over baseline) in the salmeterol group. A 25.2% improvement in FEV1 over baseline was still present at 12 hours after the last dose. In comparison, a mean p e a k improvement in FEV1 to 2.99 L (a 31.6% improvement over base-

16

Boulet et al.

J ALLERGYCLIN IMMUNOL JANUARY 1997

Salmeterol

3.1

I

-

•

*

Day 1

W~ck 4 w~8

I

I

Salbutamol ~

3.1

2.9

2.9

~ 2.7-

2.7-

2.5-

2.5-

2.3 !

2.3 .I

2.1

2.1_

WcekWc148 ckDayII

----o---- Week 12

Firstdose

Seconddose

/

/

Hours

Hours

FIG. 1. M e a n 12-hour serial FEV 1 values f o r the t r e a t m e n t g r o u p s on first and last (at 12 weeks) days o f t r e a t m e n t and at 4 and 8 weeks. Base = a v e r a g e of the - 0 . 5 h o u r and 0 h o u r FEV 1 m e a s u r e m e n t s on t r e a t m e n t day 1.

line) was noted in the salbutamol group at 1 hour after the dose, which declined to a 12.1% improvement over baseline by hour 6. After the second dose of salbutamol, a similar peak improvement in FEV1 to 2.98 L (a 32.2% improvement over baseline) at 1 hour after the dose (hour 7) was observed, which declined to a 13.0% improvement over baseline by hour 12. At the end of treatment week 12, a mean peak improvement in FEV 1 to 2.83 L at 3 hours after the dose (a 24.6% improvement over baseline) was recorded in the salmeterol group. A 15.8% mean improvement in FEV1 over baseline was still present 12 hours after the dose. Between treatments. On treatment day 1 (Fig. 1), the between-treatment comparison shows that salbutamol-treated patients had a significantly greater (p = 0.005) increase in FEVa from baseline than did salmeterol-treated patients at only 0.5 hour after the dose; this effect was not observed on any of the subsequent 12-hour assessment days. The mean improvement with salmeterol treatment was significantly greater than that with salbutamol treatment from hours 3 to 6 (p < 0.001) and hours 10 to 12 (p -< 0.012). This effect was maintained throughout the study. At each of the subsequent 12-hour visits (data not shown), salmeterol treatment resulted in a significantly greater (p --- 0.012) mean improvement in FEV a compared with salbutamol treatment from hours 3 to 6 and hours 10 to 12. As shown in Fig. 1, a trend (p -< 0.05) of similar magnitude was observed toward a downward shift in the mean postdose changes in FEV1 over the course of the study for both salmeterol and salbutamol treatments. The average FEV~ decreased 8.1% for salmeterol-treated patients, from 2.98 L

on day 1 to 2.74 L at week 12; an average decrease of 9.7% was observed for salbutamol-treated patients, from 2.79 L on day 1 to 2.52 L at week 12. Secondary

efficacy variables

For both treatment groups, there was no difference between the week 12 and week 1 changes from baseline for morning and evening PEF, percentage of nights with no awakenings, and use of rescue salbutamol. The morning/evening PEF difference decreased with both treatments over time. However, the decrease observed for the salmeterol group (from 6% at week 1 to - 3 % at week 12) was approximately twice that observed for the salbutamol group (from 13% at week 1 to 9% at week 12). Over the 12 weeks (Figs. 2 and 3), salmeterol treatment was significantly better (p < 0.02) than salbutamol treatment for all secondary efficacy variables with the exception of rescue salbutamol use (p whereas an average decrease of 3 L/rain was observed for salbutamol-treated patients (p < 0.001). The average improvement in evening PEF was 34 L/min for salmeterol-treated patients and 6 L/min for salbutamol-treated patients (p < 0.001). This resulted in a substantially smaller mean morning/evening PEF difference for salmeterol-treated patients (25 L/rain) as compared with salbutamoltreated patients (37 L/min) (p = 0.019). Salmeterol treatment was associated with a higher percentage of symptom-free days and nights. The average percentage increases in symptom-free days were 29% and 15% for the salmeterol and salbutamol treatment groups, respectively (p = 0.012). The average percentage increase in the number of nights with no awakenings was 14%

J ALLERGYCLIN IMMUNOL VOLUME 99, NUMBER 1, PART 1

B o u l e t et a[.

17

--B--Salmeterol - pm PEFR ]

480

[]

Satbutamol- pm PEFRI Salmeterol - am PEFR O Salbutamol - am PEFR|

470 460 450 c

"F= 440 LL 430 Ill

13.

~ 420 I11 410 400 1

390 380

0

1

,~

,

,

I

I

I

I

I

I

I

I

2

3

4

5

6

7

8

9

10

11

12

W e e k s After First Dose FIG. 2. M e a n m o r n i n g and e v e n i n g PEF v a l u e s f o r t h e t r e a t m e n t g r o u p s f r o m w e e k 1 t h r o u g h w e e k 12. Differences in m e a n m o r n i n g and e v e n i n g PEF v a l u e s are s i g n i f i c a n t (p < 0.001, s a l m e t e r o l vs s a l b u t a m o l . PEFR, Peak e x p i r a t o r y f l o w rate.

for salmeterol-treated patients, whereas salbutamoltreated patients experienced a decrease of 1% (p < 0.001). Safety parameters

Both treatments were well tolerated. A similar number of patients in each group experienced adverse events that were assessed by the investigator as being possibly, probably, or almost certainly treatment-related: 22 salmeterol-treated patients (19.5%) and 23 salbutamol-treated patients (20.0%). The adverse event most frequently assessed as being treatment-related was headache, which occurred in 10.6% of patients receiving salmeterol and in 7.0% of patients receiving salbutamol, followed by palpitations (in 1.8% and 5.2% of the salmeterol and salbutamol groups, respectively). The most commonly reported adverse event in both groups was headache, which occurred in 33 patients (29.2%) in the salmeterol groups and 23 patients (20.0%) in the salbutamol group, followed by upper respiratory tract infections (29.2% and 19.1% in the salmeterol and salbutamol groups, respectively). Thirty-five patients experienced one or more exacerbations of asthma (defined as a worsening of asthma symp-

toms that required treatment beyond the use of study drug and rescue salbutamol): 18 patients (15.9%) in the salmeterol group experienced 22 exacerbations; 17 patients (14.8%) in the salbutamol group experienced 19 episodes. Two patients from each treatment group were withdrawn because of adverse events. One salmeterol-treated patient experienced nausea, tremor, sleep disturbance, and cognitive impairment; the other experienced diaphoresis, vertigo, headache, and weakness. One patient receiving salbutamol experienced palpitations, and another was withdrawn because of an upper respiratory tract infection. Additional withdrawals include two salbutamol-treated patients who had an exacerbation of asthma and two salmeterol-treated patients who had a transient elevation in liver enzymes. Three salbutamol-treated patients had abnormal 12-lead electrocardiographic readings that were assessed as being possibly drug-related. Thirty-four patients (18 receiving salmeterol, 16 receiving salbutamol; age, 38 _+ 17 years [mean + SD]) underwent 24-hour continuous electrocardiography. Under the conditions of this study, there was no evidence that either therapeutic intervention resulted in cardiac arrhythmias.

18

B o u l e t et al.

J ALLERGY CLIN IMMUNOL JANUARY 1997

40-

35-

~-~;

30-

~'//~

1///

r-

~////

y/~ / / / /

////

0 15-

''''

V//Z ~////

***

p < o.ool

//// / / / / / / / i z l / /

z,-,-/, ////,

*

p <0.05

/, /~/ ,/ ~

///~

i / / / / / / / /..'.1/

5-

I

. F I . i / / /

//// ii/i I

PEFR am

Y/l× V/l×

/ / i / / / / / / / / /

i

**'k

/ / / /

/ / / / . /i.'/

////

i//i

-5-

/ / / /

/ / / / / / / /

/ / / /

// I/ // //

¢--

o

////

i / / / i / / i

/ t / / z/// / / / /

10-

Salmeterol

////

"/ /"/"/ "

2o-

I~ Yr

1 / / /

i/## 1/11

t-

Salbutamol

/ / / /

i i i i

25-

D

'

PEFR pm

''

Symptom-free days

'1

Nights with no awakening

K///M

'

Rescue use

-10

FIG. 3. Mean percent change from baseline in secondary efficacy parameters from week 1 through week 12. Difference in mean percent change was significant (p < 0.02) for salmeterol versus salbutamol for all parameters except the use of rescue salbutamol (p = 0.063). PEFR, Peak expiratory flow rate.

DISCUSSION Our results demonstrate that salmeterol, 50 ~g twice daily, is well tolerated and more effective than salbutamol, 200 Ixg four times daily, in controlling asthma symptoms and lung function in adolescent and adult patients with mild-to-moderate asthma. Salmeterol treatment was superior to salbutamol treatment for all primary and secondary efficacy measures with the exception of use of rescue salbutamol. A single morning dose of salmeterol resulted in sustained bronchodilation over the 12-hour observation period; FEV1 measures were statistically significantly greater than baseline for every postdose time point on each of the 12-hour days. The peak bronchodilator effect was seen within 3 to 4 hours, and a decrease of only 9% from that peak occurred 12 hours after salmeterol inhalation. The mean improvement in FEV~ with salmeterol was significantly greater than that observed from salbutamol from hours 3 to 6 and hours 10 to 12, and these effects were maintained over the 12-week treatment period. Although a reduction in the response to bronchodilator occurred during the study with both salbutamol and salmeterol, the improvement in FEV1 remained clinically significant throughout the dosing interval, even after 12 weeks of treatment. Clinic-based spirometry, repeated at monthly intervals over the 12-week treatment period, showed a small but significant downward shift in

the 12-hour profile of the mean FEV1 response to both salmeterol and salbutamol treatments. Such tolerance to 132-agonists after long-term regular administration has been described previously,3°' 31 although other studies have not confirmed these results. 3 Most of this decrease in bronchodilator efficacy occurred early in the regular treatment with salmeterol and salbutamol, with more than 90% of the bronchodilator benefit seen initially still present at the end of the 12 weeks. Because this reduction in the mean FEV 1 response at 12 weeks for both treatment groups was small and not associated with any increase in asthma symptoms or fall in PEFs, these findings are unlikely to be of clinical importance. Nevertheless, in seeking an explanation of the decrease in the mean FEV 1 response over the 12 weeks, a few issues can be considered. First, this observation cannot be attributed to dropouts or to data-replacement techniques used on the intent-to-treat population (i.e., all patients randomized to treatment) for analyses, because results for the per-protocol population (i.e., all patients having a full complement of data, excluding those who dropped out) show a similar downward shift in FEV1 over time. Second, in keeping with the most recent recommendations on the management of asthma, 3z 71.7% of salmeterol-treated patients and 75.7% of salbutamol-treated patients were receiving con-

J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 1, PART 1

comitant inhaled corticosteroid therapy throughout this study. Because inhaled steroids may counteract the desensitization of the [~2 receptors, 33' 34 our study with high concomitant inhaled steroid use would be even less likely to demonstrate any sign of induced tolerance of the [32-receptors. Unfortunately, the small number of patients not receiving corticosteroids in this study did not allow for statistically valid comparisons with the group receiving corticosteroids. In previous studies there was no difference between patients using corticosteroids and those using only bronchodilators with regard to the improvement in pulmonary function, although a reduction in the bronchodilator response with time was not observed. 19,23 Most importantly, because of the absence of a placebo control group, we might have failed to detect an independent confounding factor responsible for the apparent decrease in bronchodilator effect. For example, compliance with inhaled corticosteroids might have fallen over the course of this trial. In the two similar studies mentioned above, both of which included placebo controls, no decrease in F E V 1 was observed over a 12-week treatment period5 9,23 In fact, this effect has not been observed in any other clinical trial with salmeterol. 17-24 Furthermore, because the salbutamol comparative group served as an active control in this study and because the downward shift of mean F E V 1 over time is approximately the same for both treatments, the observed downward shift is most likely a trial effect unique to this study. If one considers a shortened duration of action to be a more sensitive index of tolerance than maximal bronchodilation, 35 our results may suggest that desensitization occurred; however, at the given dose and dosing interval for salmeterol, the improvement in FEV~ remained clinically significant throughout the dosing interval and for the entire duration of the study. Some previous studies of long-term scheduled use of 132-agonists have reported poorer control of asthma when compared with as-needed use of these agents, 36, 37 The occurrence and clinical relevance of this phenomenon remain controversial, and more than one study has failed to detect differences in asthma control between scheduled and as-needed dosing regimens. 38, 39 Our study was not designed to address this controversy directly because we compared two scheduled [32-agonist regimens. However, to the extent that there is a greater theoretic concern about a more potent and longer-acting [3z-agonist given on a scheduled ba-

Boulet et al.

19

sis, our results were reassuring; there was no difference in the number of asthma exacerbations or in the number of treatment-related adverse events between the salmeterol-treated and salbutamol-treated patients. One unexpected finding in our study was that there was no difference between salmeteroltreated patients and salbutamol-treated patients in rescue salbutamol use, despite significant differences in objective outcome measures. Two factors may account for this discordance between asthma symptoms and rescue bronchodilator use. In the recent past, for example, it was usual to prescribe inhaled [32-agonists on a scheduled basis, and many patients automatically used an inhaled bronchodilator at certain times even in the absence of symptoms. Indeed, the prophylactic use of rescue salbutamol before exercise is a reasonable bronchodilator strategy, but it could have confounded our study. Similarly, the routine use of rescue salbutamol before the inhalation of corticosteroids is also a common practice that could have contributed to the persistence of open-label rescue salbutamol use that we observed. Second, we relied on the patients' self-reports to quantify rescue salbutamol use, and thus we cannot rule out the possibility that reported use and actual use may have been significantly different. In summary, salmeterol, 50 p,g twice daily, is well tolerated and more effective than salbutamol, 200 ~g four times daily, in the bronchodilator management of mild-to-moderate asthma in adolescents and adults. The prolonged bronchodilatory effect of salmeterol offers clinically significant benefits, particularly to those patients with a diurnal variation in asthma severity that leads to reduced lung function on awakening and to patients requiring additional protection against regular breakthrough symptoms. We express our gratitude to all of the participating study teams and to the subjects for their cooperation. Participating study teams include: Drs. R. Amyot and L. Passerini, H6tel-Dieu de Montr6al, Montr6al, Qu6bec; Drs. A. Lavoie and P. M. B6dard, Centre Hospitalier de L'Universit6 Laval, Sainte-Foy, Qu6bec; Dr. F. Plante, Centre Hospitalier de Verdun, Verdun, Qu6bec; Drs. M. Lapointe and F. Corbeil, Trois-Rivi6res, Qu6bec; Drs. A. Cartier and J. L. Malo, H6pital du Sacr6-Coeur, Montr6al, Qu6bec; Drs. P. Warren, S. Sharma, and S. Mink, University of Manitoba Respiratory Hospital, Winnipeg, Manitoba; Drs. J. Mazza and W. Moote, Victoria Hospital, London, Ontario; Dr. S. Kesten, Toronto Hospital - Western Division, Toronto, Ontario; Drs. R. Grossman, A. Day, and M. Balter, Mount Sinai

20

B o u l e t e t al.

Hospital, Toronto, Ontario; Drs. R. H. Hyland and C. K. N. Chan, The Wellesley Hospital, Toronto, Ontario; Dr. V. Hoffstein, St. Michael's Hospital, Toronto, Ontario; and Dr. K. Binkley, Sunnybrook Health Science Centre, Toronto, Ontario. W e thank Cornelia Borkhoff, Patrick Johnston, A n n e k e Jonker, and Joann Ernst for assistance in preparing the manuscript. Data entry and statistical analyses were performed with the assistance of McDougall Scientific Inc., Toronto, Ontario.

J ALLERGY CLIN IMMUNOL JANUARY 1997

16.

17. REFERENCES

1. L6tvall J, Svedmyr N. Salmeterol. An inhaled 132-agonist with prolonged duration of action. Lung 1993;171:249-64. 2. Brogden RN, Faulds D. Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Allergol et Immunopathol 1992;20:72-84. 3. Boulet LP. Long- versus short-acting 132-agonists. Implications for drug therapy. Drugs 1994;47:207-22. 4. Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled 132 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax 1988;43:674-8. 5. Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients: an evaluation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 1990;142:571-5. 6. Cartier A, Ghezzo H, L'Arch~veque J, Trudeau C, Malo JL. Duration and magnitude of action of 50 and 100 ~g of inhaled salmeterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in subjects with asthma. J Allergy Clin Immunol 1993;92:488-92. 7. Nowak D, Jorres R, Rabe KF, et al. Salmeterol protects against hyperventilation-induced bronchoconstriction over 12 hours. Eur J Clin Pharmacol 1992;43:591-6. 8. Newnham DM, Ingram CG, Earnshaw J, Palmer JBD, Dhillon DP. Salmeterol provides prolonged protection against exercise-induced bronchoconstriction in a majority of subjects with mild, stable asthma. Respir Med 1993;87: 439-44. 9. Anderson SD, Rodwell LT, Du Toit J, Young IH. Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 1991;100:1254-60. 10. 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 Immunol 1992;89:811-5. 11. Simons FER, Soni NR, Watson WTA, Becker AB. Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma. J Allergy Clin lmmunol 1992; 90:840-6. 12. Verberne AAPH, Hop WCJ, Bos AB, Kerribijn KF. Effect of a single dose of inhaled salmeterol on baseline airway caliber and methacholine-induced airway obstruction in asthmatic children. J Allergy Clin Immunol 1993;91:127-34. 13. Campos-Gongora H, Wisniewski AFZ, Tattersfield AE. A single-dose comparison of inhaled albuterol and two formulations of salmeterol on airway reactivity in asthmatic subjects. Am Rev Respir Dis 1991;144:626-9. 14. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990;336:1338-42. 15. Taylor IK, O'Shaughnessy KM, Choudry NB, Adachi M, Palmer JBD, Fuller RW. A comparative study in atopic

18.

19.

20.

21.

22.

23.

24.

25.

26.

27. 28.

29. 30.

31.

32.

subjects with asthma of the effects of salmeterol and salbutamol on allergen-induced bronchoconstriction, increase in airway reactivity, and increase in urinary leukotriene E 4 excretion. J Allergy Clin Immunol 1992;89: 575-83. Pedersen B, Dahl R, Larsen BB, Venge P. The effect of salmeterol on the early- and late-phase reaction to bronchial allergen and postchallenge variation in bronchial reactivity, blood eosinophils, serum eosinophil cationic protein, and serum eosinophil protein X. Allergy 1993;48:377-82. Dahl R, Earnshaw J, Palmer JBD. Salmeterol: a four week study of a long-acting beta-adrenoceptor agonist for the treatment of reversible airways disease. Eur Respir J 1991; 4:1178-84. Palmer J, Hyland ME. Salmeterol in clinical practice: comparator and safety studies, quality of life studies. Eur Respir Rev 1991;1:301-3. Pearlman DS, Chervinsky P, La Force C, Seltzer JM, Southern DL, Kemp JP, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992;327:1420-5. Britton MG, Earnshaw JS, Palmer JBD. A twelve month comparison of salmeterol with salbutamol in asthmatic patients. Eur Respir J 1992;5:1062-7. Lundback B, Rawlinson DW, Palmer JBD. Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients. Thorax 1993;48:148-53. Fitzpatrick MF, Mackay T, Driver H, Douglas NJ. Salmeterol in nocturnal asthma: a double-blind, placebo-controlled trial of a long-acting inhaled 132-agonist. BMJ 1990;301:1365-8. D'Alonzo GE, Nathan RA, Henochowicz S, Morris RJ, Ratner P, Rennard SI. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. JAMA 1994;271:1412-6. Palmer JBD, Stuart AM, Shepherd GL, Viskum K. Inhaled salmeterol in the treatment of patients with moderate to severe reversible obstructive airways disease: a 3-month comparison of the efficacy and safety of twice-daily salmeterol (100 I~g) with salmeterol (50 I~g). Respir Med 1992; 86:409-17. Polgar G, Promadhat V. Pulmonary function testing in children: techniques and standards. Philadelphia: Saunders, 1971. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981;123:659-64. SAS Institute Inc. SAS/STAT® Users Guide. Version 6. 4th ed. Cary, NC: SAS Institute Inc., 1989. van Elteren PH. On the combination of independent two-sample tests of Wilcoxon. Bull Int Stat Inst 1958; 37(part 3):351-61. Wilcoxon F. Individual comparisons by ranking methods. Biometrics 1945;1:80-3. Taylor DR, Sears MR, Herbison GP, Flannery EM, Print CG, Lake DC, et al. Regular inhaled 132-agonist in asthma: effects on exacerbations and lung function. Thorax 1993;48: 134-8. Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting 132-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992;327:1198-1203. U.S. Department of Health and Human Services. Public

J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 1, PART 1

Health Service. International Asthma Management Project. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda: National Institutes of Health, 1992:1-72. 33. Ellul-Micaleff R, Fenech FF. Effect on intravenous prednisolone in asthmatics with diminished adrenergic responsiveness. Lancet 1975;2:1269-71. 34. Hui KKP, Conolly ME, Tashkin DP. Methylprednisolone reverses the 13-agonist-induced decrease in 13-receptor number in human lymphocytes. Clin Pharmacol Ther 1982;32:56. 35. Jenne JW. A critique of dosing strategies for 132-adrenergic agents and theophylline. Lung 1987;159:295-314.

B o u l e t et al.

21

36. Sears MR, Taylor DR, Print CG, Lake DC, Li Q, Flannery EM, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391-6. 37. Spitzer WO, Suissa S, Ernst P, Horvitz RI, Habbick B, Cockcroft D, et al. The use of 13 -agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326:501-6. 38. Chapman KR, Kesten S, Szalai JP. Regular vs. as-needed salbutamol in asthma control. Lancet 1994;343:1379-2. 39. Heino M. Regularly inhaled [32-agonists with steroids are not harmful in stable asthma. J Allergy Clin Immunol 1994;93:80-4.