clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care ... of asthma-specific quality of life in clinical trials because there were no suitable ...
Quality of Life in Asthma Clinical Trials: Comparison of Salmeterol and Salbutamol ELIZABETH F. JUNIPER, PATRICK R. JOHNSTON, CORNELIA M. BORKHOFF, GORDON H. GUYATT, LOUIS-PHILIPPE BOULET, and AUDREY HAUKIOjA Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster University, Hamilton, Ontario; Department of Medicine, laval University, Ste-Foy, Quebec; and Glaxo Canada, Inc., Missisauga, Ontario, Canada
Most clinical trials in asthma have focused on outcomes that are primarily of importance to the clinician. Very few have assessed whether patients feel better and can function better in day-to-day activities. The aim of this study was to compare the effects of salmeterol (50 J.1g twice daily), salbutamol (200 J.1g four times a day), and placebo on asthma-specific quality of life and to relate the findings to conventional clinical asthma outcomes. The study was a 12-wk multicenter, double blind, randomized, placebo-controlled crossover trial with each trial medication taken for 4 wk. The subjects were 140 adults with mild to moderate asthma enrolled from 14 respiratory clinics across Canada. Outcome measures were: (1)the Asthma Qualityof Life Questionnaire and spirometry at the end of each treatment period; and (2) daily asthma symptoms, morning and evening peak expiratory flow rates (PEFRs), and rescue salbutamol use during the last 14 d of each treatment period. Asthma-specific quality of life, both overall and for the individual domains (activity limitation, symptoms, emotional function, and exposure to environmental stimuli) was better with salmeterol than with placebo (p < 0.0001), and better with salmeterol than with salbutamol (p < 0.001). In both comparisons, differences were not only statistically significant, but most were also clinically important. There were moderate correlations between change in quality of life and change in clinical outcomes. In conclusion, salmeterol has a clinically important effect on asthma-specific quality of life when compared with both salbutamol and placebo. The moderate correlations between change in quality of life and change in conventional clinical outcomes suggest that the quality-of-life measures add complementary information. Juniper EF,Johnston PR, Borkhoff CM, Guyatt GH, Boulet L-~ Haukioja A. Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med 1995;151:66-70.
Most clinical trials of the new long-acting ~2-agonist salmeterol have focused on the conventional clinical outcomes of airway caliber, symptoms, and protection against such stimuli as hyperventilation and allergen (1-8). Each outcome is important in evaluating the effect of the medication on the airways, but reveals little about whether patients actually feel better and can function better physically, socially, and emotionally in their day-to-day lives. Clinicians and investigators have assumed that if clinical indices improve, the patient must be feeling better. This may not be the case. Conversely, some patients may experience an improvement in daily functioning that is not captured by the conventional outcomes. Until recently, investigators could not include an assessment of asthma-specific quality of life in clinical trials because there were no suitable instruments. We have used developments in disease-specific instrument methodology to construct the Asthma Quality of Life Questionnaire, which has proved valid in measuring asthma-specific quality of life and responsive to important changes even if they are small (9, 10). In the only study in which quality of life has been measured (Received in original form February 24, 1993 and in revised form June 9, 1994)
Correspondence and requests for reprints should be addressed to Elizabeth Juniper, MCSP, MSc, Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada. Am J Respir Crit Care Med
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in patients using salmeterol, more patients reported a better quality of life with the drug than with placebo (11). This was a significant first step, but it left important questions unanswered. We have used the Asthma Quality of Life Questionnaire to address the following questions: What is the magnitude of the effect of salmeterol in comparison with placebo on asthma-specific quality of life? Is there any difference between salmeterol and salbutamol on asthma-specific quality of life, and if so, is the difference clinically important? What is the relationship between conventional clinical outcomes in asthma and asthma-specific quality of life?
METHODS Subjects We enrolled 140 adult participants (age, 18 to 70 yr) with mild to moderate asthma (FE~ % predicted ~ 600/0) from 14 respiratory clinics across Canada. All gave a history of current asthma symptoms or diurnal variation in peak expiratory flow rates (PEFRs) of greater than 200/0 and showed at least a 150/0 increase in FE~ following a dose of 200 JlQ salbutamol (via a metered dose inhaler [MDI]). Patients requiring a regular stable dose of inhaled steroids or cromoglycate could be enrolled in the study. We excluded subjects who had a history of any other serious or uncontrolled illness, an asthma exacerbation requiring a visit to an emergency room within the previous 3 mo or hospitalization within 1 yr, oral steroids within 1 mo, or a history of acute sudden deterioration in their asthma. We excluded pregnant and lactating women, patients using either J}-receptor antagonists or theophylline, those unable to use a peak flow meter, and those with poor language ability in English or French. All subjects signed
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Juniper, Johnston, Borkhoff, et 01.: Salmeterol: Asthma Quality of Life an informed consent agreement that had been approved by the ethics committees of participating hospitals.
Study Design The study was a 12-wk multicenter, double blind, crossover comparison of salmeterol 50 J,lg twice daily versus salbutamol 200 J,lg four times daily versus placebo, with each medication being taken for 4 wk. Patients who met the entry criteria were randomized to one of six treatment orders (Le., all possible ways of ordering the three treatments). To achieve blinding, patients were issued two trial inhalers (A and B) at the beginning of each treatment period. Inhaler A was used at approximately 7:00 A.M. and 10:00 P.M. and contained salmeterol, salbutamol, or placebo. Inhaler B was used at noon and at 6:00 P.M. and contained either salbutamol or placebo. Rescue medication, consisting of salbutamol at 100 J,lg per puff, was provided throughout the study in a third inhaler. Assessments of outcomes were made in the clinic immediately before randomization and at the end of each of the three treatment periods. During the last 14 d of each treatment period, patients kept diaries of their symptoms, PEFR, trial medication, and rescue salbutamol use.
Outcome Measurements Asthma Quality of Life Questionnaire. The Asthma Quality of Life Questionnaire is a disease-specific, 32-item instrument designed specifically for use in clinical trials (9). The items, identified by asthma patients as being important, are in four domains: symptoms, emotions, exposure to environmental stimuli, and activity limitations. Patients rate the impairments they have experienced during the previous 14 d and respond to each item on a 7-point scale (1 = maximum impairment, 7 = no impairment). This wide range of options allows detection of small but important changes in quality of life. The instrument's responsiveness to within-subject change, its reproducibility (intraclass correlation coefficient = 0.92), and its construct validity have all been demonstrated (10). Five of the eleven items in the activity limitation domain are self-identified by the patient. At the first visit of a clinical trial, each patient is asked to identify five activities that she or he performs regularly, which are important, and in which there is limitation due to asthma. These activities are kept constant throughout the study. This allows impairment of activities that are very important in the individual patient's day-to-day life to be evaluated for each treatment. We have found that a difference in score of ~ 0.5 is clinically important for overall quality of life and for each of the individual domains (12). In the present study, the assessments of Asthma Quality of Life made at the end of each of the three treatment periods were those used for the treatment comparisons. To minimize bias, quality of life was the first outcome assessed at each of these clinic visits. Conventional clinical outcomes. During the last fortnight of each treatment period, each morning and at bedtime, patients measured their PEFR in triplicate with a mini-Wright peak flow meter before taking the trial medication or salbutamol, and recorded the highest PEFR value. On rising in the morning, patients recorded nighttime disturbances and rated the severity of their asthma on morning waking (chest tightness, wheeze, cough, shortness of breath, and phlegm production) on a scale of 0 to 10 (0 = worst, 10 = best). At bedtime, they recorded a daytime score, also on a scale of 0 to 10 (wheeze, cough, shortness of breath, activity restriction, and phlegm production). Every morning and at bedtime, patients recorded all use of rescue salbutamol. Immediately prior to randomization and at the end of each treatment period in the study, spirometry was performed in the clinic.
RESULTS One hundred and forty subjects were randomized to receive salmeterol, salbutamol, or placebo (Table 1). Seventeen withdrew during the study because of exacerbations of asthma (10placebo, three salbutamol, and four salmeterol). Three withdrew because of adverse events (one placebo: headache; one salbutamol: moderate hypertension; and one salmeterol: anxiety). All subjects have been included in the analysis (intention-to-treat). For overall quality of life, salmeterol was more effective than both placebo (mean difference = 0.55,P < 0.001) and salbutamol (mean difference = 0.40, P < 0.0001) (Figure 1 and Table 2). The mean difference between salbutamol and placebo was 0.15(p = 0.05). A mean difference in score of ~ 0.5 for overall quality of life and for each of the individual domains is clinically important (12). Therefore, overall, the difference between salmeterol and placebo met the criterion for clinical importance, the difference between salmeterol and salbutamol approached this criterion, and the difference between salbutamol and placebo was very small. In the symptom and emotional function domains, differences between salmeterol and placebo and between salmeterol and salbutamol were both statistically and clinically important. Ditterences between salbutamol and placebo did not reach statistical significance. Similar patterns were seen for activity limitations and problems associated with exposure to environmental stimuli, but in these two domains the statistically significant differences between salmeterol and salbutamol were not clinically important. The results of the conventional clinical outcomes were very similar to those reported in other clinical trials (Table 3). In summary, salmeterol showed the greatest difference from salbutamol for morning peak flow rates (mean difference = 33.3 Umin, p < 0.0001), morning asthma symptoms (mean difference = 0.46,P < 0.0001)and nights with no sleep disturbance (mean difference = 5.02 percentage points, p = 0.01). At bedtime, peak flow rates with salmeterol were higher than with salbutamol (difference = 16.2 Umin, p < 0.0001). Daytime use of salbutamol rescue medication was greatest when patients were taking placebo (proportion of subjects = 0.90; daily use = 2.6 putts/d), next greatest with salbutamol (proportion of subjects = 0.89; daily use = 1.7 putts/d), and least with salmeterol (proportion of subjects = 0.71; daily use = 1.2 pufts/d). All pairwise ditterences in additional salbutamol use between the three treatments were significant (p < 0.004). We found moderate, statistically significant correlations between the changes observed in the various domains of the Asthma Quality of Life Questionnaire and the changes observed in conventional clinical outcomes (Table 4). The complete repeated ANOVA revealed no evidence of any carryover effects between treatments for either quality of life or clinical outcomes. Time analysis showed that there was a small but gradual overall improvement in quality of life during the 12 wk of the study. Five patients recorded less than 700/0 use of one or more trial medications. Excluding these subjects from the analysis did not alter the overall conclusions.
Statistical Analysis Mean values were calculated for morning and evening PEFRs and for rescue salbutamol use for the last 14 d of each treatment period. All randomized patients were included in the analysis (intention-to-treat). The primary analysis was a three-treatment, three-period analysis of variance (ANOVA)crossover model that included treatment, period, and carryov.er effects. Differences were considered significant at p < 0.05 (two-sided). longitudinal correlations between conventional clinical outcomes and Asthma Quality of Life were examined with a Pearson correlation coefficient, using the changes in outcomes between the first and second treatment periods.
TABLE 1 SUBJECT CHARACTERISTICS Number Mean age (± SO), yr Sex (M/F) FEV 1 % predicted (± SO) Medication requirements Bronchodilators alone Inhaled steroids and bronchodilators
140 37.5 ± 14.5 66/74 76.4 ± 10.9
32 108
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Figure 1. Quality-of-life scores at the end of each treatment period . (1 ment). SM = salmeterol ; SB = salbutamol ; P = placebo.
DISCUSSION The results of this study suggest that in patients with mild to moderate asthma , asthma-specific quality of life, both overall and for indi vidual domains, is better when patients take salmeterol 50 I-Ig twice daily than when they use either salbutamol200 I-Igfour times daily or placebo . The differences between salmeterol and placebo were both statistically significant and clinically important. Although all of the differences between salmete rol and salbutamol were statistically significant, only those differences in the symptoms and emotional funct ion domains reached clinical sign ificance.
II
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= maximum impairment , 7 = no impair-
Differences between salbutamol and placebo were on the borderline of statistical significance and were not clinically important. A very large number of clinical trials and many years of clinical use have established that salbutamol is a very effective bronchodilator. Therefore, the minimal difference between salbutamol and placebo may seem surprising . In this study, salbutamol was also the rescue med ication , and patients were told to use it whenever
TABLE 3 CONVENTIONAL CLINICAL OUTCOMES DIFFERENCES BETWEEN TREATMENTS
TABLE 2
Differences in Scores Between Treatments (mean: 95% CI; n = 140)
QUALITY-OF-LIFE SCORES DIFFERENCES BETWEEN TREATMENTS Differences in Scores Between Treatments (mean: 95% CI; n = 140) Quality of Life Domains Symptoms Emotions Activity limitation Environ ment Overall quality of life
Salmeterol Minus Placebo
Salmeterol Minus Salbutamol
Salbutamol Minus Placebo
0.66 ' 0.48-0.83 0.65' 0.43-0.86 0.43 ' 0.28-0.58 0.45' 0.29-0.61 0.55 ' 0.40-0.70
0.49' 0.32-0.67 0.49' 0.27-0.70 0.30 ' 0.15-0.45 0.28t 0.12-0.44 0.40' 0.25-0.55
0.17 -0.01-0.34 0.16 -0.05-0.38 0.13 - 0.02-0.28 0.17; 0.01-0.33 0.15; 0.00-0.31
Clinical Outcomes Morning PEFR Evening PEFR Morning symptoms
% nights with no sleep disturbance Daytime symptoms FEV, Salbutamol use
• p < 0.0001 .
• p < O.ooOl.
t p < O.OOl. t p < 0.05 .
t p < 0.001 . t p < 0 .05 .
Salmeterol Minus Placebo
Salmeterol Minus Salbulamol
Salbutamol Minus Placebo
30.8 ' 23.9-37.7 21.8' 16.0-27.6 - 0.46' - 0.64- - 0.29 5.05; 1.15-9.00 - 0.48' - 0.65- - 0.31 O.17t 0.07-0.26 -1.25' - 1.58- - 0.91
33.3' 26.4-40.2 16.2 ' 10.5-22.0 - 0.46 ' - 0.63- - 0.29 5.02; 1.14-8.90 - 0.36 ' -0.53--0.18 0.11; 0.01-0.20 - 0.41; - 0.75- - 0.08
- 2.5 - 4.4-9.4 5.6 -0.2-11 .4 0.00 -0.17-0.17 0.03 - 3.87- 3.93 -0.12 -0.29-0.05 0.06 - 0.4- 0.15 - 0.83 ' - 1.16-- 0.49
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Juniper, Johnston, Borkhoff, et al.: Salmeterol: Asthma Quality of Life TABLE 4 LONGITUDINAL CORRELATIONS BETWEEN QUALITY OF LIFE AND CLINICAL OUTCOMES*t Change in Clinical Outcomes Morning PEFR Evening PEFR Morning symptoms Nights with no sleep disturbance Daytime symptoms FEV, Salbutamol use
Change in Quality of Life Overall Quality of Life
Symptoms
Emotions
Activities
Environment
0.58 0.48 0.47
0.60 0.50 0.49
0.56 0.43 0.45
0.43 0.36 0.38
0.42 0.40 0.28
0.28 0.54 0.38 0.43
0.30 0.52 0.36 0.41
0.26; 0.54 0.37 0.46
0.20; 0.45 0.33 0.35
0.17; 0.44 0.28 0.29
• Calculated from changes in outcomes between the first and second treatment periods. Pearson correlation coefficient. All correlations are significant at p < 0.001, except which are significant at p
t
needed. As a result, the average day-time use of rescue salbutamol when patients were taking placebo was more than 250 J,1g/d. Similarly, since patients used significantly more rescue salbutamol when taking salbutamol than salmeterol, the differences between the two drugs would have been greater had we not provided salbutamol on a rescue basis. With a sufficient number of subjects, even the smallest differences in treatment effects can be shown to be statistically significant; consequently, interpretation of the magnitude of differences between treatments is very important. For example, most clinicians will agree that the mean difference of 16.2 Umin (p < 0.0001) in evening peak flow rates between salmeterol and salbutamol is probably not clinically important even though it is statistically significant. For quality-of-life questionnaires and symptom scores, interpretation is usually difficult. However, for the Asthma Quality of Life Questionnaire, the clinically important difference has been determined, and we can therefore comment on the magnitude of differences between treatments. There is no doubt that one of the advantages of salmeterol over salbutamol is its long duration of action. For this reason, this and other studies (2, 3, 6) indicate that the largest differences between the two drugs in terms of conventional clinical outcomes occur at night and on waking in the morning. It seems unlikely, however, that improvements at these times can entirely explain the clinically important improvements seen in quality of life, since the latter is mainly an assessment of the awake and daytime state. It is likely that some improvements in quality of life occur indirectly. For instance, patients who have a good, restful night's sleep are likely to be better able to cope with normal activities and emotions of daily living. To further explore the relationship between clinical outcomes and quality of life, we examined correlations between changes in quality of life and changes in other indices (Table 4). On theoretical groundS, the moderate (rather than very strong) correlations we observed are exactly what one would expect if a qualityof-life questionnaire is doing its job. To illustrate this point, we will consider the relationship between changes in morning PEFR values and changes in overall quality of life (r = 0.58). First, there is strong evidence that perception of airway narrowing varies greatly among patients with asthma (13). Second, asthma patients are very heterogeneous in terms of life styles, expectations, personality, emotional reactions, and other characteristics. Third, peak flows capture only single instances in time during the entire 24 h period of the day. Fourth, treatments may have both direct and indirect effects that are not measured by conventional clinical outcomes (e.g., with salmeterol, the possible beneficial effects of a
* I
< 0.05.
good night's sleep). Fifth, quality-of-life measurements may capture adverse treatment effects. Consider, for example, two patients with identical differences in morning peak flow rate while taking salmeterol and salbutamol. One patient is very perceptive of changes in airway caliber, is in a high-pressure job where she cannot avoid smoky environments, has previously had life-threatening asthma about which she continually worries, and is generally a very anxious person. As a result, she shows major improvements in each domain of the quality-of-life questionnaire when taking salmeterol. The second patient perceives changes in airway caliber poorly and is not working outside of the home, for which reason she can adapt her life to avoid potentially exacerbating environmental stimuli, has never had a severe episode of asthma, and is temperamentally a relaxed and easygoing person. This patient will experience much less improvement in quality of life when taking salmeterol. One finds such patients, and the full spectrum of persons between them, in any group of asthmatic individuals. As a result of these differences in sensitivity to airway caliber, life circumstances, and temperament, one would never expect more than moderate correlations between physiologic measures and measures of quality of life. Indeed, data have consistently shown such moderate relationships between physiologic measures and the scores given by valid quality of life instruments in asthma (10, 14), chronic lung disease (15-17), and a wide variety of other conditions (18-20). In terms of clinical outcomes, quality-of-life measurements contributed importantly to this study. Without such measurements, we would have observed statistically significant differences between each of the three groups of patients, but would have been uncertain about their clinical importance. The quality-ot-life measurements tell us that the differences between salbutamol and placebo are clinically trivial. This finding provides considerable support for a policy of using salbutamol alone on an as-needed basis, without regular administration. On the other hand, the differences between salmeterol and both salbutamol and placebo are appreciably larger, and approximate the smallest difference that is important to individual patients. This suggests that in contrast to regular administration of salbutamol, patients experience a clinically important benefit with regular administration of a long-acting l3-agonist. In this comparison ot a short- and long-acting 132-agonist, we have shown for the first time the physical, emotional, and social benefits to the patient of the longer-acting bronchodilator, and these benefits can now be taken into account when determining the exact role of the long acting 132-agonists within the framework of the guidelines for the treatment of asthma (21). This study em-
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phasizes to clinicians that symptoms, airway caliber, and indices of inflammation are limited in predicting the overall effect of treatment on the day-to-day functioning of patients. We are not suggesting that quality-of-life measures replace physiologic measures. Monitoring indices such as the PEFR remains crucial for a variety of reasons, including the need to respond to deterioration in physiologic function with increased medication. Nevertheless, since one major goal of treatment is to improve patients' sense of well-being and function, measurement of quality of life is necessary for a comprehensive assessment of treatment effectiveness. The implication for further research is that investigators should include quality-of-life measures in all clinical trials in asthma. The implication of this study is that the effects of long-acting l3-agonists on asthma patients' quality of life support the consideration of their use in the management of asthma. Acknowledgment The authors thank Dr. Malcolm Sears for his comments and suggestions during the preparation of the manuscript. Respiratory clinics participating in the study were the Hopital Laval, Quebec City (Drs. ~ Leblanc and L.-~ Boulet), 5MBD Jewish General Hospital, Montreal (Drs. H. Kreisman and N. Wolkove), Hopital du Sacre Coeur, Montreal (Drs. A. Cartier and J.-L. Malo), Sunnybrook Health Science Centre, Toronto (Dr. A. Knight), Mount Sinai Hospital, Toronto (Drs. R. Grossman and A. Day), Toronto Western Hospital (Drs. S. Kesten and K. Chapman), Grey Nuns Hospital, Edmonton (Dr. G.F. MacDonald), University of Alberta Hospitals, Edmonton (Drs. S.F.~ Man and B.J. Spoule), Victoria Hospital, London, Ontario (Drs. J. Mazza and W. Moote), University of Manitoba Respiratory Hospital, Winnipeg (Dr. ~ Warren), Foothills Hospital, Calgary (Drs. R.L. Cowie and S. Field), Trois-Rivieres, Quebec (Drs. M. Lapointe and F. Corbeil), Hotel-Dieu de Montreal (Dr. R. Amyot), Centre Hospitalier de Verdun, Quebec (Dr. F. Plante).
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