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formoterol maintenance and reliever therapy? Results of an open label study
Respiratory Medicine (2012) 106, 189e196
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Do asthmatic smokers benefit as much as non-smokers on budesonide/formoterol maintenance and reliever therapy? Results of an open label study Onno C.P. van Schayck a,*, John Haughney b, Michel Aubier c, Olof Selroos d, ¨m e, Juliette Ostinelli f, Roland Buhl g Tommy Ekstro a
Maastricht University/CAPHRI, Postbus 616, 6200 MD, Maastricht, The Netherlands Academic Primary Care, University of Aberdeen, Foresterhill Health Centre, Westburn Road, Aberdeen, Scotland AB25 2AY, UK c Department of Pneumology A, Hoˆpital Bichat, 75018 Paris, France d Semeco AB, Skogsva¨gen 5, SE-266 54 Vejbystrand, Sweden e Medical Department, AstraZeneca Sweden, SE-151 85 So¨derta¨lje, Sweden f Medical Department, AstraZeneca France, 92844 Rueil-Malmaison, France g Pulmonary Department, Mainz University Hospital, Langenbeckstrasse 1, D-55131 Mainz, Germany b
Received 17 May 2011; accepted 30 October 2011 Available online 26 November 2011
KEYWORDS ACQ-5; Asthma; Budesonide/ formoterol maintenance and reliever therapy; Propensity-matched controls; Smokers; Symbicort SMART
Summary Background: Studies with inhaled corticosteroids (ICS) in smoking asthmatics have mostly shown poorer treatment responses than in non-smoking asthmatics. Methods: EuroSMART, an open, randomised, 6-month study, compared budesonide/formoterol (Symbicort Turbuhaler)h maintenance and reliever therapy (Symbicort SMART) at two maintenance doses of budesonide/formoterol (160/4.5 mg), 1 2 and 2 2, in patients with asthma who were symptomatic despite treatment with ICS long-acting b2-agonists. The 8424 randomised patients included 886 smokers (11%; aged <40 years or with a smoking history <10 packyears if older), who were compared with a propensity-matched group of non-smokers. At baseline, smokers had lower post-bronchodilator peak expiratory flow, lower peak flow reversibility and used more reliever medication per day. Severe asthma exacerbations were counted and changes in five-item Asthma Control Questionnaire (ACQ-5) scores from baseline calculated. Results: There were 48 and 47 exacerbations in smokers and non-smokers, respectively. Mean time to first severe exacerbation was not statistically different between the two groups. The mean
* Corresponding author. Tel.: þ31 43 3882152; fax: þ31 43 3619344. E-mail address: [email protected] (O.C.P. van Schayck). h Neither the Symbicort SMART posology nor the dry powder formulation, Turbuhaler, is currently approved in the US. 0954-6111/$ - see front matter Crown Copyright ª 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2011.10.017
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O.C.P. van Schayck et al. change in ACQ-5 score was significantly greater in non-smokers. Considering the two treatment options there was a statistically significant prolonged time to first severe exacerbation with 2 2 versus 1 2 in the smokers, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 2 with similar or greater changes than in smokers treated with 1 2. Conclusion: Asthmatic patients with a limited smoking history benefit from treatment with budesonide/formoterol maintenance and reliever therapy with dosing 2 2 being superior to 1 2. Crown Copyright ª 2011 Published by Elsevier Ltd. All rights reserved.
Introduction Smoking is frequent in asthma patients with a prevalence of around 20%, which is close to that found in the general population.1,2 An emergency department study showed that of adult asthmatics presenting with acute asthma, as many as 35% were cigarette smokers.3 Smoking asthmatics also have an increased asthma-related morbidity and severity.1,2,4,5 Smoking clearly reduces the probability of patients achieving well-controlled asthma.6 Chronic asthma per se may have an effect on lung function decline but this decline is accelerated in smokers,7 and smoking and asthma also have additive, but not multiplicative, effects on lung function decline.8 Most clinical asthma studies have actively excluded smoking patients, with reported efficacy of various interventions extrapolated to this group. The few studies that exist with inhaled corticosteroids (ICS) in smoking asthmatics have shown varying results. Two short-term randomised controlled studies found that the efficacy of inhaled or oral corticosteroid treatment was impaired in smokers with chronic asthma.9,10 A 12-week study found that the response to low-dose beclomethasone dipropionate (BDP; 400 mg/day) was significantly impaired in smoking patients with mild asthma compared with non-smoking patients. However, the difference between smoking and non-smoking patients was reduced with a higher dose of BDP (2000 mg/day), although this was not statistically significant.11 Similarly, a placebocontrolled, double-blind crossover trial with hydrofluoroalkane BDP (160 mg twice daily) or montelukast 10 mg once daily for 8 plus 8 weeks in patients with mild to moderate asthma demonstrated an attenuated response to the treatments in smokers compared with non-smokers.12 Interestingly, montelukast increased the peak expiratory flow (PEF) values in smokers but not in non-smokers.12 A 1-year study investigated the effect of high- or low-dose inhaled budesonide and theophylline separately on blood markers of inflammation and lung function in 85 smoking or non-smoking patients with allergic or non-allergic asthma.13 Lung function (forced expiratory volume in 1 s [FEV1] percent predicted normal [PN] and PC20 histamine) improved and the eosinophil markers eosinophil cationic protein and eosinophil protein X/eosinophil-derived neurotoxin were reduced with budesonide; however, the treatment efficacy was attributed solely to the effect seen in non-smoking patients. The findings in the above and other studies resulted in a generally accepted view that cigarette smoking is associated with resistance to treatment with corticosteroids in asthma.14,15 Possible mechanisms for the steroid insensitivity in smokers have been described and new therapeutic options
to overcome the resistance proposed.16 In contrast, treatment with ICS in patients with moderate to severe asthma was associated with a reduction in the decline in FEV1 over a 23-year period in men who had smoked less than 5 packyears.17 Also, the inhaled Steroid Treatment As Regular Therapy (START) study showed that asthmatic smokers not treated with ICS have a greater decline in FEV1 than asthmatics who do not smoke.18 The benefits of ICS therapy on preventing lung function decline were similar in smokers and non-smokers with mild asthma.18 In a recent double-blind, randomised, placebocontrolled crossover trial 16 non-smoking and 15 smoking mild asthmatics received either fluticasone/salmeterol 250/50 mg twice daily or fluticasone 500 mg twice daily for 2 weeks each with a wash-out period in-between. The change from baseline in methacholine PC20 was measured. Smokers gained benefit from the combination but not fluticasone amounting to a PC20 difference of 1.6 doubling dilutions (95% confidence interval [CI]1.0, 2.2; p < 0.01).19 The aim of the present study was to report predefined analyses of the response in smokers and non-smokers to budesonide/formoterol maintenance and reliever therapy obtained in the pan-European 6-month parallel-group study EuroSMART.20 Ex-smokers were not included in these analyses.
Methods Study design and patients This was an open, randomised, parallel-group, 6-month multicentre study in patients with moderate to severe asthma who were symptomatic despite daily use of an ICS with or without long-acting b2-agonists (LABAs). Patients were 18 years or older and had at least a 6-month documented history of asthma according to the American Thoracic Society definition.21 Patients were required to be uncontrolled, as indicated by a history of short-acting b2agonist (SABA) use for symptom relief during the last month despite ICS with or without LABA maintenance therapy for at least 1 month at a constant daily dose of 500 mg BDP, or other ICS at equivalent doses. To be randomised, patients must have uncontrolled asthma. Those treated with ICS and no LABA must have used at least one terbutaline inhalation for symptom relief on at least 4 of the last 7 days of the run-in period, and those treated with both ICS and LABA must have used as-needed terbutaline for symptom relief on at least 2 of the last 7 days of the run-in period. No change in asthma maintenance
BUD/FORM maintenance and reliever therapy in smokers treatment was allowed during run-in and patients with exacerbations during run-in were excluded. Study entry criteria were broad to reflect the situation in real life. Smokers could be enrolled, but not those older than 40 years with a smoking history of 10 pack-years or more, in order to exclude co-morbidity of chronic obstructive pulmonary disease as far as possible. Moreover, a diagnosis of chronic obstructive pulmonary disease was an exclusion criterion. After the run-in period, eligible patients were randomly allocated to one of the following two treatments: budesonide/formoterol (Symbicort Turbuhaler, AstraZeneca, So ¨derta ¨lje, Sweden) 160/4.5 mg one inhalation twice daily (1 2) or 2 160/4.5 mg two inhalations twice daily (2 2). By definition of the treatment concept, budesonide/formoterol was also used as reliever medication. The study started with a 2-week run-in period, during which patients continued their current asthma maintenance treatment and used terbutaline (Bricanyl Turbuhaler, AstraZeneca, So ¨derta ¨lje, Sweden) as reliever medication. Randomisation was performed via an Interactive Web Response System developed by AstraZeneca R&D, Lund, Sweden. Patients were not stratified based on their smoking history. There were four visits in the study, the first before and the second after the 2-week run-in period (Visit 1 and Visit 2), one after 3 months’ treatment (Visit 3) and the last after 6 months’ treatment (Visit 4). The first patient entered the study in March 2007 and the last patient completed the study in December 2008. Among the 8424 randomised patients in the main study, 8049 patients (including 886 current smokers [11%]) could be included in the analysis.20
Assessments Demographic, lifestyle and clinical data were collected at baseline. During the 2-week run-in period, and during 2week periods prior to visits 3 and 4, patients recorded in a notebook the number of inhalations taken as maintenance medication, the number of reliever inhalations used, asthma symptoms and night-time awakenings due to asthma (yes/no). At randomisation (Visit 2) and at study end (Visit 4) lung function assessments were performed (PEF and, if available due to the real-life setting of the study, spirometry [FEV1]). The five-item Asthma Control Questionnaire (ACQ-5),22,23 excluding FEV1 (as FEV1 was not measured at all clinics) and use of SABA (as budesonide/ formoterol should be used as reliever medication), was selfcompleted at visits 2, 3 and 4. The scale of each ACQ-5 component is from 0 to 6 with 0 as the best. The ACQ-5 total scores were reported in three groups: mean scores <0.75 (well-controlled asthma), 0.75e1.5 (intermediate group) and >1.5 (poorly controlled asthma). These intervals were based on data from a previous large clinical study.24 The primary efficacy variable was time to first severe asthma exacerbation, defined as deterioration in asthma with a need for oral or systemic corticosteroids for at least 3 days and/or leading to hospitalisation, emergency room visit or other patient-initiated unscheduled visits to a healthcare centre. Safety was evaluated by reporting serious adverse events and adverse events leading to discontinuation from the study.
191 The study was performed according to Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by all local ethics committees. All patients gave their written informed consent for participation. The study was performed in 14 European countries.
Statistical analysis Time to first asthma exacerbation was compared using a Cox proportional hazard model, stratified by country in the study and with treatment as factor. The total number of exacerbations was compared between the treatments using a Poisson regression model controlling dispersion, with country and treatment as factors and total time in study as an offset variable. The change in ACQ-5 scores, daytime symptoms, nighttime awakenings and lung function was analysed using an analysis of covariance (ANCOVA) model with treatment and country as factors and baseline value as covariate. The differences between maintenance treatments (1 2 and 2 2) in smokers versus non-smokers were calculated using the same methods. Since the enrolment criteria for smokers created a smoker population younger than the non-smoker population, a propensity-matched non-smoking population was created with 886 neversmokers to eliminate the age effect when comparing smokers with non-smokers.25 In Table 1 the p-values were calculated by a t-test for continuous variables and by a chi-square test for categorical variables without correction for multiplicity.
Results Baseline data Baseline demographic characteristics of the smokers and age-matched non-smokers are shown in Table 1. There were 886 smokers divided into 565 habitual and 321 occasional smokers. The mean ages of the populations to be compared were 38.8 years. The occasional smokers were slightly older than the habitual smokers. There were significantly fewer females among the smokers (56%) compared with the non-smokers (64%; p Z 0.0002). The mean PEF percent PN and the reversibility with b2-agonists were lower in the smokers. The smokers also used more SABA per day and had more days per week with symptoms. Otherwise, no significant differences were seen between the two groups. Of the 886 smokers, 523 were less than 40 years old. A total of 444 smokers had been randomised to treatment with budesonide/formoterol 1 2, and 442 to 2 2. The corresponding figures for the propensity-matched nonsmokers were 454 and 432 (Table 3). The smokers had a mean of 5.9 pack-years (range 1e50 pack-years [occasional smokers 3.9 and habitual smokers 7.1 pack-years]). The use of as-needed medication (SABA) increased by 5% for each pack-year (p < 0.0001) and the number of exacerbations in the past 12 months decreased by 2% for each pack-year (p Z 0.0024). The male smokers smoked more than the female smokers (p < 0.0001).
192 Table 1
O.C.P. van Schayck et al. Patient baseline characteristics.
Females, % Age, years FEV1, % predicted normal post-bronchodilation Reversibility, % PEF, % predicted normal post-bronchodilation ICS dose at entry, mg/dayb LABA use, % patients SABA use, inhalations/day Days with symptoms/week No of nights with awakenings/week ACQ-5 score at baseline No. of exacerbations in past 12 months Pack-years
Habitual Smokers N Z 565
Occasional smokers N Z 321
Smokers N Z 886
Non-smokersa N Z 886
P-value
55.4 37.6 (11.1) 90.9 (19.4)
55.8 40.9 (14.1) 89.8 (18.9)
55.5 38.8 (12.4) 90.5 (19.2)
64.2 38.8 (12.4) 91.8 (18.1)
0.0002 0.9800 0.1817
5.5 (11.4) 87.7 (23.7)
4.5 (13.1) 89.7 (23.9)
5.1 (12.0) 88.4 (23.8)
6.7 (10.2) 91.9 (23.6)
0.0096 0.0026
1018 (573) 73.1 1.83 (1.60) 4.60 (2.14) 1.19 (1.68) 1.94 (1.0) 1.39 (2.32)
992 (600) 77.3 1.68 (1.44) 4.24 (2.27) 1.12 (1.65) 1.86 (1.0) 1.62 (2.58)
1008 (583) 74.6 1.78 (1.55) 4.47 (2.19) 1.17 (1.67) 1.91 (1.0) 1.48 (2.42)
1005 (554) 74.6 1.33 (1.13) 4.26 (2.04) 1.09 (1.53) 1.85 (0.9) 1.61 (2.67)
0.9080 0.9999 <0.0001 0.0369 0.3329 0.1705 0.2693
7.1 (5.3)
3.9 (3.3)
5.9 (4.9)
0
NA
Values shown are mean (standard deviation). ACQ-5 Z five-item Asthma Control Questionnaire; FEV1 Z forced expiratory volume in 1 s; ICS Z inhaled corticosteroids; LABA Z longacting b2-agonist; NA Z not analysed; PEF Z peak expiratory flow; SABA Z short-acting b2-agonist. a Non-smokers are an age-matched subpopulation of all never-smokers. b Expressed as BDP equivalent doses.
Use of study medication The mean doses of maintenance and reliever medication, expressed as budesonide doses in smokers and nonsmokers, are shown in Table 2. The smokers used slightly higher total daily doses due to a more frequent use of asneeded doses, which, in turn, were somewhat higher in the 1 2 group than in the 2 2 group.
Exacerbations During the 6-month study there were a total of 48 severe exacerbations in the smokers and 47 in the 886 age-matched never-smoking controls. The estimated yearly rate of exacerbations in smokers and non-smokers was 12.8 (95% CI 9.82, 16.7) and 11.9 (95% CI 9.1, 15.7), respectively (p Z 0.7207). In smokers, there were 31 exacerbations in the 1 2 group and 17 in the 2 2 group. The corresponding figures
Table 2 Mean daily dose of budesonide (mg) used during the study. Non-smokersa N Z 886
Smokers N Z 886 Maintenance doses As-needed doses Total
12
22
12
22
318 (19)
634 (44)
317 (20)
630 (62)
183 (212)
126 (173)
134 (164)
94 (148)
501 (213)
760 (181)
451 (168)
724 (161)
Values shown are mean (standard deviation). a Non-smokers are an age-matched subpopulation of all neversmokers.
among non-smokers were 20 and 27. The yearly rates of exacerbations were 19.5 (95% CI 13.8, 27.7) and 9.6 (95% CI 5.92, 15.6) per 100 patients in smokers treated with 1 2 and 2 2, respectively (p Z 0.0121). The corresponding yearly rates of exacerbations among non-smokers were 10.3 (95% CI 6.9,15.6) and 13.52 (95% CI 9.5,19.4) per 100 patients, respectively (p Z 0.3226). The times to the first severe asthma exacerbation in smokers and non-smokers are shown in Fig. 1. There was no significant difference between the smokers and nonsmokers (hazard ratio [HR] 0.965; 95% CI 0.646, 1.444; p Z 0.864). Fig. 1 also shows the differences in time to first severe exacerbation in the 1 2 or 2 2 treatment groups. In smokers the difference between 2 2 and 1 2 was statistically significant (HR 0.537; 95% CI 0.297, 0.971; p Z 0.0398). When smokers were subdivided into habitual and occasional smokers the p-values for the differences between 1 2 and 2 2 were 0.55 and 0.57, respectively.
Changes from baseline in patient-reported outcomes With the exception of changes in ACQ-5 scores the patientreported outcomes in smokers are presented as figures for the total smokers group without separation into habitual smokers and occasional smokers as the values did not differ from figures for the total smokers group. Asthma symptoms The changes in number of days with asthma symptoms per week from baseline in smokers and the age-matched nonsmoking population are shown in Table 3. Table 3 also shows the changes separately for patients randomised to the 1 2 and 2 2 treatment groups. When comparing changes in asthma symptoms between smokers
BUD/FORM maintenance and reliever therapy in smokers
193
Figure 1 Times to first severe asthma exacerbation in smokers (black solid line) and propensity-matched non-smokers (black dotted line) irrespective of treatment. The difference between these two groups was not significant (hazard ratio 1.27; 95% CI 0.869, 1.851; p Z 0.218). Also shown is time to first severe exacerbation in smokers and non-smokers treated with budesonide/formoterol maintenance and reliever therapy 1 2 or 2 2 (pale grey lines [smokers] and dark grey lines [non-smokers]) according to treatment: dotted lines 1 2 and solid lines 2 2.
and non-smokers, the difference was not significant (p Z 0.105). The same was true when comparing treatments with 1 2 and 2 2 between smokers and nonsmokers (significance levels for 1 2 and 2 2; p Z 0.144 and p Z 0.405, respectively). In smokers the reduction in asthma symptoms was significantly greater with 2 2 compared with 1 2. Awakenings The changes in number of night-time awakenings per week from baseline are shown in Table 3. The difference in changes between smokers and non-smokers was not statistically significant (p Z 0.133). The numerically smallest reduction was seen in smokers in the 1 2 group; the difference compared with non-smokers using this treatment was significant (p Z 0.022). With 2 2 similar reductions were observed in smokers and non-smokers (p Z 0.887). In smokers the reduction in awakenings was significantly greater with 2 2 compared with 1 2. Use of as-needed medication Before the study, all patients used a SABA as reliever medication. In the study they used the same budesonide/ formoterol inhaler as needed as for maintenance therapy. The reduction in the number of as-needed inhalations is shown in Table 3. The reduction in smokers was significantly greater than that in non-smokers (p Z 0.004). This reduction was mainly due to smokers treated with 2 2 and this reduction was significantly greater than the reduction in the non-smokers using this treatment (p Z 0.002). In smokers, the reduction in the group treated with 2 2 was significantly greater than in the group treated with 1 2. Asthma control questionnaire The reductions in total ACQ-5 scores are shown in Table 3 and Fig. 2. The reductions in total ACQ-5 scores were
significantly greater in the non-smokers (p Z 0.0004). With 1 2, the reductions in ACQ-5 scores were smaller in smokers compared with non-smokers (p Z 0.0005), but with 2 2 treatment, no difference was seen between the groups (p Z 0.109). In smokers, the reduction in ACQ-5 in the group treated with 2 2 (0.72) was significantly greater (p < 0.007) than in the group treated with 1 2 (0.55). When comparing habitual smokers and occasional smokers separately the differences in change in ACQ-5 between 1 2 and 2 2 were also quite similar as for the entire smoking population; changes in habitual smokers 0.54 and 0.71 and in occasional smokers 0.56 and 0.74 with 1 2 and 2 2, respectively. There were no differences in changes in ACQ-5 between smokers with 3, 6 or 10 pack-years. All groups of patients also reached the change in ACQ-5 of 0.5, which is the lower limit for a clinically important change.
Safety In both smokers and age-matched non-smokers, a total of 13 (1.5%) serious adverse events were seen. In the 1 2 treatment group, 1.5% of the smokers reported a serious adverse event compared with 1.4% in the non-smoking population. The corresponding figures in the 2 2 group were 1.4% and 1.6%, respectively. One serious adverse event report among smokers was linked to asthma worsening, while there were three such reports in the agematched non-smokers group. No serious adverse events in smokers were considered related to treatment. No deaths were reported. There were 16 (1.8%) discontinuations due to adverse events in smokers (eight [1.8%] in the 1 2 treatment group and eight [1.9%] in the 2 2 treatment group) and 12 discontinuations due to adverse events (1.4%) in
0.133 0.549
Discussion
Change in ACQ-5 Change in days with asthma symptoms/week Change in as-needed inhalationsb Change in awakenings/week
ACQ-5 Z five-item asthma control questionnaire. a Non-smokers are an age-matched subpopulation of all never-smokers. b Change from SABA doses to budesonide/formoterol doses. c In smokers, the differences between 1 2 and 2 2 for all four variables were statistically significant with greater changes with 2 2 treatment (P-values between < 0.0001 and 0.012).
0.887 0.618 0.632 0.478 0.246
0.022
1.014 0.515 0.599
0.345
0.719 1.98 0.782 1.548 0.548 1.31
0.0005 0.144
non-smokers (eight [1.8%] in the 1 2 treatment group and four [0.9%] in the 2 2 treatment group). The percentage of patients using more than eight inhalations per day of budesonide/formoterol (maintenance plus reliever use), i.e. the highest recommended dose, was 1.6% among smokers and 0.9% among non-smokers.
0.437
0.004 0.626 0.734
0.002
0.805
0.0004 0.105 0.805 1.834 0.827 2.112
0.109 0.405
0.633 1.640
P-value Smokers N Z 442 P-value Non-smokers N Z 454 Smokers N Z 444
c
12 Variable
Table 3
Response to treatment in smokers compared with non-smokers.a
22
c
Non-smokers N Z 432
P-value
Smokers N Z 886
Non-smokers N Z 886
O.C.P. van Schayck et al.
Both treatments
194
We present the results of a pre-planned secondary analysis of the 6-month EuroSMART study, in which the patient population was divided into smokers and non-smokers. As the non-smoking population was much larger than the smokers and had a different age distribution, a propensitybased non-smoking population was used as a control.25 The control subjects were all never-smokers and ex-smokers were not included in the analyses. In order to exclude patients with chronic obstructive pulmonary disease, the smokers had to be less than 40 years old, or if older, their smoking history could not exceed 10 pack-years. Therefore, our results are valid only for this type of younger smokers, or older asthmatics with a limited smoking history. The patients with moderate to severe asthma had symptoms at time of randomisation despite treatment with ICS with or without concomitant use of LABA. In the study, they were treated with budesonide/formoterol 160/4.5 mg 1 2 or 2 2. The primary variable was the time to the first severe asthma exacerbation and we did not find a difference between smokers and non-smokers. We also did not find a statistically significant difference in non-smokers between those treated with 1 2 or 2 2. This is in contrast to the result of the main study, where an 18% greater reduction in the risk of experiencing an exacerbation was seen in patients treated with 2 2.20 In the smokers, however, the difference in response between patients treated with 1 2 and 2 2 was significant (p Z 0.0398), with the 2 2 group having a lower risk of exacerbations. The difference in result between this subgroup analysis and the main study is most likely due to the number of subjects included in the analysis as the power calculation was based on the main study with a sample size of 4000 patients in each group. Our subgroup analysis had much fewer patients. Nevertheless, our result is in line with the trend reported on better efficacy in smokers with a high- dose BDP compared with a standard.11 In ACQ-5 scores, a significantly greater change was seen in the nonsmokers compared with the smokers, and particularly for those treated with the standard 1 2 maintenance dose. Smokers, however, treated with the higher maintenance dose exhibited the same reduction in ACQ-5 scores as the non-smokers. The same was true for the changes in days with symptoms and awakenings per week with 2 2 e no differences were seen between smokers and non-smokers. Our beneficial results with an ICS/LABA combination in smoking asthmatics are also in line with the better results on bronchial hyperresponsiveness reported with fluticasone/salmeterol than with a higher dose of fluticasone alone.19 A limitation of our study is that smokers with a more extensive smoking history were excluded; any conclusions are, therefore, only applicable to smokers below 40 years of age, or older smokers with a smoking history of less than
BUD/FORM maintenance and reliever therapy in smokers
195
Figure 2 Changes in ACQ-5 scores over time in smokers and non-smokers treated with budesonide/formoterol maintenance and reliever therapy.
10 pack-years. A further limitation is that the patients in the main study were not stratified at baseline according to smoking history. This could have been an advantage but would have required an even larger number of patients as stratification in the present study was performed based on baseline ICS dose. This pre-specified subanalysis complements the results of the analyses of the primary outcome parameters of the EuroSMART study. Clearly, for the majority of patients with moderate and moderate to severe asthma, a maintenance dose of 1 2 inhalations of the fixed budesonide/formoterol combination, with more inhalations as needed, is adequate to control the disease.20 This result agrees well with the results of other EuroSMART analyses confirming that the same is true for elderly patients (65 years of age)26 and for patients using high-dose inhaled steroids (1600 mg budesonide or equivalent).27 A maintenance dose of 2 2 inhalations of the fixed budesonide/formoterol combination, with more inhalations as needed, should be considered for patients with low lung function (PEF and/or FEV1 <80% PN).20 The results of the present analyses extend these conclusions to asthma patients who smoke. However, in this group of younger smokers, a higher maintenance dose prolonged significantly the time to a first severe exacerbation and improved parameters defining asthma control more than 1 2. Consequently, a higher budesonide/formoterol maintenance dose is necessary to achieve a level of asthma control that is similar to nonsmokers. We conclude that smokers less than 40 years old, or older with a limited smoking history, benefit from budesonide/formoterol maintenance and reliever therapy in terms of risk of exacerbation. The smokers used somewhat higher doses of budesonide during the study. Considering the two treatment options, there was in the
smokers a statistically significant difference in time to first severe exacerbation between 1 2 and 2 2, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 2 with similar or greater changes than in smokers treated with 1 2.
Conflict of interest C.P. van Schayck has received a fee for consulting from AstraZeneca and has participated as a speaker in scientific meetings or courses organised and financed by GlaxoSmithKline, AstraZeneca, Pfizer and Nycomed. J. Haughney has received reimbursements for attending symposia, fees for speaking and organising educational events, funds for research and fees for consulting from AstraZeneca. He has also received support from a number of pharmaceutical companies (Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, Novartis, Nycomed, sanofi-aventis and Teva). M. Aubier has participated as a speaker in scientific meetings, or courses organised and financed by various pharmaceutical companies (GlaxoSmithKline, AstraZeneca, Novartis, Pfizer and Nycomed). O. Selroos has received consultation fees from AstraZeneca and Galenica, fees for speaking at medical meetings organised by AstraZeneca and fees for medical writing support for publications from AstraZeneca, Orion Pharma and Schering-Plough. T. Ekstro ¨m is a retired employee of AstraZeneca and holds stocks in the company. J. Ostinelli is a full-time employee of, and holds stock in, AstraZeneca.
196 R. Buhl has received reimbursement for attending scientific conferences, and/or fees for speaking and/or consulting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Nycomed and Pfizer. The Pulmonary Department at Mainz University Hospital received financial compensation for services performed during participation in clinical trials organised by various pharmaceutical companies.
Acknowledgement We thank Professor Olof Selroos, MD, PhD, of SEMECO AB, who provided medical writing support funded by AstraZeneca. We thank Dr Manda Gent of MediTech Media, who provided editing assistance funded by AstraZeneca. This study was funded by AstraZeneca.
References 1. Ulrik CS, Lange P. Cigarette smoking and asthma. Monaldi Arch Chest Dis 2001;56:349e53. 2. Siroux V, Pin I, Oryszczyn MP, Le Moual N, Kauffmann F. Relationships of active smoking to asthma and asthma severity in the EGEA study. Eur Respir J 2000;15:470e7. 3. Silvermann RA, Boudreaux ED, Woodruff PG, Clark S, Camargo Jr CA. Cigarette smoking among asthmatic adults presenting to 64 emergency departments. Chest 2003;123:1472e9. 4. Marquette CH, Saulnier F, Leroy O, Wallaert B, Chopin C, Demarcq JM, Durocher A, Tonnel AB. Long-term prognosis of near-fatal asthma. Am Rev Respir Dis 1992;146:76e81. 5. Sippel JM, Pedula K, Vollmer WM, Buist S, Osborne ML. Associations of smoking with hospital-based care and quality of life in patients with obstructive airway disease. Chest 1999;115: 691e6. 6. Pedersen SE, Bateman ED, Bousquet J, Busse WW, Yoxall S, Clark TJ. Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the gaining optimal asthma control study. J Allergy Clin Immunol 2007;120:1036e42. 7. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194e200. 8. James AL, Palmer LJ, Kicic E, et al. Decline in lung function in the Busselton health study. The effect of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171:109e14. 9. Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57:226e30. 10. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308e11.
O.C.P. van Schayck et al. 11. Tomlinson JEM, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus nonsmokers with mild asthma. Thorax 2005;60:282e7. 12. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007;175: 783e90. 13. Pedersen B, Dahl R, Karlstro ¨m R, Peterson CG, Venge P. Eosinophil and neutrophil activity in asthma in a one-year trial with inhaled budesonide. The impact of smoking. Am J Respir Crit Care Med 1996;153:1519e29. 14. Livingston E, Thomson NC, Chalmers GW. Impact of smoking on asthma therapy. Drugs 2005;65:1521e36. 15. Thomson NC, Shepherd M, Spears M, Chaudhuri R. Corticosteroid insensitivity in smokers with asthma: clinical evidence, mechanisms, and management. Ther Respir Med 2006;5:467e81. 16. Ahmad T, Barnes PJ, Adcock IM. Overcoming steroid insensitivity in smoking asthmatics. Curr Opin Invest Drugs 2008;9: 470e7. 17. Dijkstra A, Vonk JM, Jongepier H, et al. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax 2006;61:105e10. 18. O’Byrne PM, Lamm CJ, Busse WW, Tan WC, Pedersen S. The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. Chest 2009;136: 1514e20. 19. Clearie KL, McKinlay L, Williamson PA, Lipworth BJ. Fluticasone/salmeterol combination confers benefits in smoking asthmatics. Chest 2011. doi:10.1378/chest.11e0392. published online June 2, 2011. 20. Aubier M, Buhl R, Ekstro ¨m T, et al. Comparison of two twicedaily doses of budesonide/formoterol maintenance and reliever therapy. Eur Respir J 2010;36:524e30. 21. American Thoracic Society (ATS). Standards for the diagnosis and care of subjects with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225e44. 22. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902e7. 23. Svensson K, Mo ¨rk AC, Juniper EF. ACQ. Is five out of seven items acceptable in large clinical studies? Qual Life Res 2003;12:771. 24. Juniper EF, Bousquet J, Abetz L, Bateman ED, GOAL committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the asthma control questionnaire. Respir Med 2006;100: 616e21. 25. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41e55. 26. Haughney J, Aubier M, Jørgensen L, et al. Comparing asthma treatment in elderly versus younger patients. Respir Med 2011; 105:838e45. 27. Aubier M, Haughney J, Selroos O, et al. Is the patient’s baseline inhaled steroid dose a factor for choosing the budesonide/formoterol maintenance and reliever therapy regimen? Ther Adv Respir Dis 2011;5:289e95.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Do asthmatic smokers benefit as much as non-smokers on budesonide/formoterol maintenance and reliever therapy? Results of an open label study Onno C.P. van Schayck a,*, John Haughney b, Michel Aubier c, Olof Selroos d, ¨m e, Juliette Ostinelli f, Roland Buhl g Tommy Ekstro a
Maastricht University/CAPHRI, Postbus 616, 6200 MD, Maastricht, The Netherlands Academic Primary Care, University of Aberdeen, Foresterhill Health Centre, Westburn Road, Aberdeen, Scotland AB25 2AY, UK c Department of Pneumology A, Hoˆpital Bichat, 75018 Paris, France d Semeco AB, Skogsva¨gen 5, SE-266 54 Vejbystrand, Sweden e Medical Department, AstraZeneca Sweden, SE-151 85 So¨derta¨lje, Sweden f Medical Department, AstraZeneca France, 92844 Rueil-Malmaison, France g Pulmonary Department, Mainz University Hospital, Langenbeckstrasse 1, D-55131 Mainz, Germany b
Received 17 May 2011; accepted 30 October 2011 Available online 26 November 2011
KEYWORDS ACQ-5; Asthma; Budesonide/ formoterol maintenance and reliever therapy; Propensity-matched controls; Smokers; Symbicort SMART
Summary Background: Studies with inhaled corticosteroids (ICS) in smoking asthmatics have mostly shown poorer treatment responses than in non-smoking asthmatics. Methods: EuroSMART, an open, randomised, 6-month study, compared budesonide/formoterol (Symbicort Turbuhaler)h maintenance and reliever therapy (Symbicort SMART) at two maintenance doses of budesonide/formoterol (160/4.5 mg), 1 2 and 2 2, in patients with asthma who were symptomatic despite treatment with ICS long-acting b2-agonists. The 8424 randomised patients included 886 smokers (11%; aged <40 years or with a smoking history <10 packyears if older), who were compared with a propensity-matched group of non-smokers. At baseline, smokers had lower post-bronchodilator peak expiratory flow, lower peak flow reversibility and used more reliever medication per day. Severe asthma exacerbations were counted and changes in five-item Asthma Control Questionnaire (ACQ-5) scores from baseline calculated. Results: There were 48 and 47 exacerbations in smokers and non-smokers, respectively. Mean time to first severe exacerbation was not statistically different between the two groups. The mean
* Corresponding author. Tel.: þ31 43 3882152; fax: þ31 43 3619344. E-mail address: [email protected] (O.C.P. van Schayck). h Neither the Symbicort SMART posology nor the dry powder formulation, Turbuhaler, is currently approved in the US. 0954-6111/$ - see front matter Crown Copyright ª 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2011.10.017
190
O.C.P. van Schayck et al. change in ACQ-5 score was significantly greater in non-smokers. Considering the two treatment options there was a statistically significant prolonged time to first severe exacerbation with 2 2 versus 1 2 in the smokers, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 2 with similar or greater changes than in smokers treated with 1 2. Conclusion: Asthmatic patients with a limited smoking history benefit from treatment with budesonide/formoterol maintenance and reliever therapy with dosing 2 2 being superior to 1 2. Crown Copyright ª 2011 Published by Elsevier Ltd. All rights reserved.
Introduction Smoking is frequent in asthma patients with a prevalence of around 20%, which is close to that found in the general population.1,2 An emergency department study showed that of adult asthmatics presenting with acute asthma, as many as 35% were cigarette smokers.3 Smoking asthmatics also have an increased asthma-related morbidity and severity.1,2,4,5 Smoking clearly reduces the probability of patients achieving well-controlled asthma.6 Chronic asthma per se may have an effect on lung function decline but this decline is accelerated in smokers,7 and smoking and asthma also have additive, but not multiplicative, effects on lung function decline.8 Most clinical asthma studies have actively excluded smoking patients, with reported efficacy of various interventions extrapolated to this group. The few studies that exist with inhaled corticosteroids (ICS) in smoking asthmatics have shown varying results. Two short-term randomised controlled studies found that the efficacy of inhaled or oral corticosteroid treatment was impaired in smokers with chronic asthma.9,10 A 12-week study found that the response to low-dose beclomethasone dipropionate (BDP; 400 mg/day) was significantly impaired in smoking patients with mild asthma compared with non-smoking patients. However, the difference between smoking and non-smoking patients was reduced with a higher dose of BDP (2000 mg/day), although this was not statistically significant.11 Similarly, a placebocontrolled, double-blind crossover trial with hydrofluoroalkane BDP (160 mg twice daily) or montelukast 10 mg once daily for 8 plus 8 weeks in patients with mild to moderate asthma demonstrated an attenuated response to the treatments in smokers compared with non-smokers.12 Interestingly, montelukast increased the peak expiratory flow (PEF) values in smokers but not in non-smokers.12 A 1-year study investigated the effect of high- or low-dose inhaled budesonide and theophylline separately on blood markers of inflammation and lung function in 85 smoking or non-smoking patients with allergic or non-allergic asthma.13 Lung function (forced expiratory volume in 1 s [FEV1] percent predicted normal [PN] and PC20 histamine) improved and the eosinophil markers eosinophil cationic protein and eosinophil protein X/eosinophil-derived neurotoxin were reduced with budesonide; however, the treatment efficacy was attributed solely to the effect seen in non-smoking patients. The findings in the above and other studies resulted in a generally accepted view that cigarette smoking is associated with resistance to treatment with corticosteroids in asthma.14,15 Possible mechanisms for the steroid insensitivity in smokers have been described and new therapeutic options
to overcome the resistance proposed.16 In contrast, treatment with ICS in patients with moderate to severe asthma was associated with a reduction in the decline in FEV1 over a 23-year period in men who had smoked less than 5 packyears.17 Also, the inhaled Steroid Treatment As Regular Therapy (START) study showed that asthmatic smokers not treated with ICS have a greater decline in FEV1 than asthmatics who do not smoke.18 The benefits of ICS therapy on preventing lung function decline were similar in smokers and non-smokers with mild asthma.18 In a recent double-blind, randomised, placebocontrolled crossover trial 16 non-smoking and 15 smoking mild asthmatics received either fluticasone/salmeterol 250/50 mg twice daily or fluticasone 500 mg twice daily for 2 weeks each with a wash-out period in-between. The change from baseline in methacholine PC20 was measured. Smokers gained benefit from the combination but not fluticasone amounting to a PC20 difference of 1.6 doubling dilutions (95% confidence interval [CI]1.0, 2.2; p < 0.01).19 The aim of the present study was to report predefined analyses of the response in smokers and non-smokers to budesonide/formoterol maintenance and reliever therapy obtained in the pan-European 6-month parallel-group study EuroSMART.20 Ex-smokers were not included in these analyses.
Methods Study design and patients This was an open, randomised, parallel-group, 6-month multicentre study in patients with moderate to severe asthma who were symptomatic despite daily use of an ICS with or without long-acting b2-agonists (LABAs). Patients were 18 years or older and had at least a 6-month documented history of asthma according to the American Thoracic Society definition.21 Patients were required to be uncontrolled, as indicated by a history of short-acting b2agonist (SABA) use for symptom relief during the last month despite ICS with or without LABA maintenance therapy for at least 1 month at a constant daily dose of 500 mg BDP, or other ICS at equivalent doses. To be randomised, patients must have uncontrolled asthma. Those treated with ICS and no LABA must have used at least one terbutaline inhalation for symptom relief on at least 4 of the last 7 days of the run-in period, and those treated with both ICS and LABA must have used as-needed terbutaline for symptom relief on at least 2 of the last 7 days of the run-in period. No change in asthma maintenance
BUD/FORM maintenance and reliever therapy in smokers treatment was allowed during run-in and patients with exacerbations during run-in were excluded. Study entry criteria were broad to reflect the situation in real life. Smokers could be enrolled, but not those older than 40 years with a smoking history of 10 pack-years or more, in order to exclude co-morbidity of chronic obstructive pulmonary disease as far as possible. Moreover, a diagnosis of chronic obstructive pulmonary disease was an exclusion criterion. After the run-in period, eligible patients were randomly allocated to one of the following two treatments: budesonide/formoterol (Symbicort Turbuhaler, AstraZeneca, So ¨derta ¨lje, Sweden) 160/4.5 mg one inhalation twice daily (1 2) or 2 160/4.5 mg two inhalations twice daily (2 2). By definition of the treatment concept, budesonide/formoterol was also used as reliever medication. The study started with a 2-week run-in period, during which patients continued their current asthma maintenance treatment and used terbutaline (Bricanyl Turbuhaler, AstraZeneca, So ¨derta ¨lje, Sweden) as reliever medication. Randomisation was performed via an Interactive Web Response System developed by AstraZeneca R&D, Lund, Sweden. Patients were not stratified based on their smoking history. There were four visits in the study, the first before and the second after the 2-week run-in period (Visit 1 and Visit 2), one after 3 months’ treatment (Visit 3) and the last after 6 months’ treatment (Visit 4). The first patient entered the study in March 2007 and the last patient completed the study in December 2008. Among the 8424 randomised patients in the main study, 8049 patients (including 886 current smokers [11%]) could be included in the analysis.20
Assessments Demographic, lifestyle and clinical data were collected at baseline. During the 2-week run-in period, and during 2week periods prior to visits 3 and 4, patients recorded in a notebook the number of inhalations taken as maintenance medication, the number of reliever inhalations used, asthma symptoms and night-time awakenings due to asthma (yes/no). At randomisation (Visit 2) and at study end (Visit 4) lung function assessments were performed (PEF and, if available due to the real-life setting of the study, spirometry [FEV1]). The five-item Asthma Control Questionnaire (ACQ-5),22,23 excluding FEV1 (as FEV1 was not measured at all clinics) and use of SABA (as budesonide/ formoterol should be used as reliever medication), was selfcompleted at visits 2, 3 and 4. The scale of each ACQ-5 component is from 0 to 6 with 0 as the best. The ACQ-5 total scores were reported in three groups: mean scores <0.75 (well-controlled asthma), 0.75e1.5 (intermediate group) and >1.5 (poorly controlled asthma). These intervals were based on data from a previous large clinical study.24 The primary efficacy variable was time to first severe asthma exacerbation, defined as deterioration in asthma with a need for oral or systemic corticosteroids for at least 3 days and/or leading to hospitalisation, emergency room visit or other patient-initiated unscheduled visits to a healthcare centre. Safety was evaluated by reporting serious adverse events and adverse events leading to discontinuation from the study.
191 The study was performed according to Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by all local ethics committees. All patients gave their written informed consent for participation. The study was performed in 14 European countries.
Statistical analysis Time to first asthma exacerbation was compared using a Cox proportional hazard model, stratified by country in the study and with treatment as factor. The total number of exacerbations was compared between the treatments using a Poisson regression model controlling dispersion, with country and treatment as factors and total time in study as an offset variable. The change in ACQ-5 scores, daytime symptoms, nighttime awakenings and lung function was analysed using an analysis of covariance (ANCOVA) model with treatment and country as factors and baseline value as covariate. The differences between maintenance treatments (1 2 and 2 2) in smokers versus non-smokers were calculated using the same methods. Since the enrolment criteria for smokers created a smoker population younger than the non-smoker population, a propensity-matched non-smoking population was created with 886 neversmokers to eliminate the age effect when comparing smokers with non-smokers.25 In Table 1 the p-values were calculated by a t-test for continuous variables and by a chi-square test for categorical variables without correction for multiplicity.
Results Baseline data Baseline demographic characteristics of the smokers and age-matched non-smokers are shown in Table 1. There were 886 smokers divided into 565 habitual and 321 occasional smokers. The mean ages of the populations to be compared were 38.8 years. The occasional smokers were slightly older than the habitual smokers. There were significantly fewer females among the smokers (56%) compared with the non-smokers (64%; p Z 0.0002). The mean PEF percent PN and the reversibility with b2-agonists were lower in the smokers. The smokers also used more SABA per day and had more days per week with symptoms. Otherwise, no significant differences were seen between the two groups. Of the 886 smokers, 523 were less than 40 years old. A total of 444 smokers had been randomised to treatment with budesonide/formoterol 1 2, and 442 to 2 2. The corresponding figures for the propensity-matched nonsmokers were 454 and 432 (Table 3). The smokers had a mean of 5.9 pack-years (range 1e50 pack-years [occasional smokers 3.9 and habitual smokers 7.1 pack-years]). The use of as-needed medication (SABA) increased by 5% for each pack-year (p < 0.0001) and the number of exacerbations in the past 12 months decreased by 2% for each pack-year (p Z 0.0024). The male smokers smoked more than the female smokers (p < 0.0001).
192 Table 1
O.C.P. van Schayck et al. Patient baseline characteristics.
Females, % Age, years FEV1, % predicted normal post-bronchodilation Reversibility, % PEF, % predicted normal post-bronchodilation ICS dose at entry, mg/dayb LABA use, % patients SABA use, inhalations/day Days with symptoms/week No of nights with awakenings/week ACQ-5 score at baseline No. of exacerbations in past 12 months Pack-years
Habitual Smokers N Z 565
Occasional smokers N Z 321
Smokers N Z 886
Non-smokersa N Z 886
P-value
55.4 37.6 (11.1) 90.9 (19.4)
55.8 40.9 (14.1) 89.8 (18.9)
55.5 38.8 (12.4) 90.5 (19.2)
64.2 38.8 (12.4) 91.8 (18.1)
0.0002 0.9800 0.1817
5.5 (11.4) 87.7 (23.7)
4.5 (13.1) 89.7 (23.9)
5.1 (12.0) 88.4 (23.8)
6.7 (10.2) 91.9 (23.6)
0.0096 0.0026
1018 (573) 73.1 1.83 (1.60) 4.60 (2.14) 1.19 (1.68) 1.94 (1.0) 1.39 (2.32)
992 (600) 77.3 1.68 (1.44) 4.24 (2.27) 1.12 (1.65) 1.86 (1.0) 1.62 (2.58)
1008 (583) 74.6 1.78 (1.55) 4.47 (2.19) 1.17 (1.67) 1.91 (1.0) 1.48 (2.42)
1005 (554) 74.6 1.33 (1.13) 4.26 (2.04) 1.09 (1.53) 1.85 (0.9) 1.61 (2.67)
0.9080 0.9999 <0.0001 0.0369 0.3329 0.1705 0.2693
7.1 (5.3)
3.9 (3.3)
5.9 (4.9)
0
NA
Values shown are mean (standard deviation). ACQ-5 Z five-item Asthma Control Questionnaire; FEV1 Z forced expiratory volume in 1 s; ICS Z inhaled corticosteroids; LABA Z longacting b2-agonist; NA Z not analysed; PEF Z peak expiratory flow; SABA Z short-acting b2-agonist. a Non-smokers are an age-matched subpopulation of all never-smokers. b Expressed as BDP equivalent doses.
Use of study medication The mean doses of maintenance and reliever medication, expressed as budesonide doses in smokers and nonsmokers, are shown in Table 2. The smokers used slightly higher total daily doses due to a more frequent use of asneeded doses, which, in turn, were somewhat higher in the 1 2 group than in the 2 2 group.
Exacerbations During the 6-month study there were a total of 48 severe exacerbations in the smokers and 47 in the 886 age-matched never-smoking controls. The estimated yearly rate of exacerbations in smokers and non-smokers was 12.8 (95% CI 9.82, 16.7) and 11.9 (95% CI 9.1, 15.7), respectively (p Z 0.7207). In smokers, there were 31 exacerbations in the 1 2 group and 17 in the 2 2 group. The corresponding figures
Table 2 Mean daily dose of budesonide (mg) used during the study. Non-smokersa N Z 886
Smokers N Z 886 Maintenance doses As-needed doses Total
12
22
12
22
318 (19)
634 (44)
317 (20)
630 (62)
183 (212)
126 (173)
134 (164)
94 (148)
501 (213)
760 (181)
451 (168)
724 (161)
Values shown are mean (standard deviation). a Non-smokers are an age-matched subpopulation of all neversmokers.
among non-smokers were 20 and 27. The yearly rates of exacerbations were 19.5 (95% CI 13.8, 27.7) and 9.6 (95% CI 5.92, 15.6) per 100 patients in smokers treated with 1 2 and 2 2, respectively (p Z 0.0121). The corresponding yearly rates of exacerbations among non-smokers were 10.3 (95% CI 6.9,15.6) and 13.52 (95% CI 9.5,19.4) per 100 patients, respectively (p Z 0.3226). The times to the first severe asthma exacerbation in smokers and non-smokers are shown in Fig. 1. There was no significant difference between the smokers and nonsmokers (hazard ratio [HR] 0.965; 95% CI 0.646, 1.444; p Z 0.864). Fig. 1 also shows the differences in time to first severe exacerbation in the 1 2 or 2 2 treatment groups. In smokers the difference between 2 2 and 1 2 was statistically significant (HR 0.537; 95% CI 0.297, 0.971; p Z 0.0398). When smokers were subdivided into habitual and occasional smokers the p-values for the differences between 1 2 and 2 2 were 0.55 and 0.57, respectively.
Changes from baseline in patient-reported outcomes With the exception of changes in ACQ-5 scores the patientreported outcomes in smokers are presented as figures for the total smokers group without separation into habitual smokers and occasional smokers as the values did not differ from figures for the total smokers group. Asthma symptoms The changes in number of days with asthma symptoms per week from baseline in smokers and the age-matched nonsmoking population are shown in Table 3. Table 3 also shows the changes separately for patients randomised to the 1 2 and 2 2 treatment groups. When comparing changes in asthma symptoms between smokers
BUD/FORM maintenance and reliever therapy in smokers
193
Figure 1 Times to first severe asthma exacerbation in smokers (black solid line) and propensity-matched non-smokers (black dotted line) irrespective of treatment. The difference between these two groups was not significant (hazard ratio 1.27; 95% CI 0.869, 1.851; p Z 0.218). Also shown is time to first severe exacerbation in smokers and non-smokers treated with budesonide/formoterol maintenance and reliever therapy 1 2 or 2 2 (pale grey lines [smokers] and dark grey lines [non-smokers]) according to treatment: dotted lines 1 2 and solid lines 2 2.
and non-smokers, the difference was not significant (p Z 0.105). The same was true when comparing treatments with 1 2 and 2 2 between smokers and nonsmokers (significance levels for 1 2 and 2 2; p Z 0.144 and p Z 0.405, respectively). In smokers the reduction in asthma symptoms was significantly greater with 2 2 compared with 1 2. Awakenings The changes in number of night-time awakenings per week from baseline are shown in Table 3. The difference in changes between smokers and non-smokers was not statistically significant (p Z 0.133). The numerically smallest reduction was seen in smokers in the 1 2 group; the difference compared with non-smokers using this treatment was significant (p Z 0.022). With 2 2 similar reductions were observed in smokers and non-smokers (p Z 0.887). In smokers the reduction in awakenings was significantly greater with 2 2 compared with 1 2. Use of as-needed medication Before the study, all patients used a SABA as reliever medication. In the study they used the same budesonide/ formoterol inhaler as needed as for maintenance therapy. The reduction in the number of as-needed inhalations is shown in Table 3. The reduction in smokers was significantly greater than that in non-smokers (p Z 0.004). This reduction was mainly due to smokers treated with 2 2 and this reduction was significantly greater than the reduction in the non-smokers using this treatment (p Z 0.002). In smokers, the reduction in the group treated with 2 2 was significantly greater than in the group treated with 1 2. Asthma control questionnaire The reductions in total ACQ-5 scores are shown in Table 3 and Fig. 2. The reductions in total ACQ-5 scores were
significantly greater in the non-smokers (p Z 0.0004). With 1 2, the reductions in ACQ-5 scores were smaller in smokers compared with non-smokers (p Z 0.0005), but with 2 2 treatment, no difference was seen between the groups (p Z 0.109). In smokers, the reduction in ACQ-5 in the group treated with 2 2 (0.72) was significantly greater (p < 0.007) than in the group treated with 1 2 (0.55). When comparing habitual smokers and occasional smokers separately the differences in change in ACQ-5 between 1 2 and 2 2 were also quite similar as for the entire smoking population; changes in habitual smokers 0.54 and 0.71 and in occasional smokers 0.56 and 0.74 with 1 2 and 2 2, respectively. There were no differences in changes in ACQ-5 between smokers with 3, 6 or 10 pack-years. All groups of patients also reached the change in ACQ-5 of 0.5, which is the lower limit for a clinically important change.
Safety In both smokers and age-matched non-smokers, a total of 13 (1.5%) serious adverse events were seen. In the 1 2 treatment group, 1.5% of the smokers reported a serious adverse event compared with 1.4% in the non-smoking population. The corresponding figures in the 2 2 group were 1.4% and 1.6%, respectively. One serious adverse event report among smokers was linked to asthma worsening, while there were three such reports in the agematched non-smokers group. No serious adverse events in smokers were considered related to treatment. No deaths were reported. There were 16 (1.8%) discontinuations due to adverse events in smokers (eight [1.8%] in the 1 2 treatment group and eight [1.9%] in the 2 2 treatment group) and 12 discontinuations due to adverse events (1.4%) in
0.133 0.549
Discussion
Change in ACQ-5 Change in days with asthma symptoms/week Change in as-needed inhalationsb Change in awakenings/week
ACQ-5 Z five-item asthma control questionnaire. a Non-smokers are an age-matched subpopulation of all never-smokers. b Change from SABA doses to budesonide/formoterol doses. c In smokers, the differences between 1 2 and 2 2 for all four variables were statistically significant with greater changes with 2 2 treatment (P-values between < 0.0001 and 0.012).
0.887 0.618 0.632 0.478 0.246
0.022
1.014 0.515 0.599
0.345
0.719 1.98 0.782 1.548 0.548 1.31
0.0005 0.144
non-smokers (eight [1.8%] in the 1 2 treatment group and four [0.9%] in the 2 2 treatment group). The percentage of patients using more than eight inhalations per day of budesonide/formoterol (maintenance plus reliever use), i.e. the highest recommended dose, was 1.6% among smokers and 0.9% among non-smokers.
0.437
0.004 0.626 0.734
0.002
0.805
0.0004 0.105 0.805 1.834 0.827 2.112
0.109 0.405
0.633 1.640
P-value Smokers N Z 442 P-value Non-smokers N Z 454 Smokers N Z 444
c
12 Variable
Table 3
Response to treatment in smokers compared with non-smokers.a
22
c
Non-smokers N Z 432
P-value
Smokers N Z 886
Non-smokers N Z 886
O.C.P. van Schayck et al.
Both treatments
194
We present the results of a pre-planned secondary analysis of the 6-month EuroSMART study, in which the patient population was divided into smokers and non-smokers. As the non-smoking population was much larger than the smokers and had a different age distribution, a propensitybased non-smoking population was used as a control.25 The control subjects were all never-smokers and ex-smokers were not included in the analyses. In order to exclude patients with chronic obstructive pulmonary disease, the smokers had to be less than 40 years old, or if older, their smoking history could not exceed 10 pack-years. Therefore, our results are valid only for this type of younger smokers, or older asthmatics with a limited smoking history. The patients with moderate to severe asthma had symptoms at time of randomisation despite treatment with ICS with or without concomitant use of LABA. In the study, they were treated with budesonide/formoterol 160/4.5 mg 1 2 or 2 2. The primary variable was the time to the first severe asthma exacerbation and we did not find a difference between smokers and non-smokers. We also did not find a statistically significant difference in non-smokers between those treated with 1 2 or 2 2. This is in contrast to the result of the main study, where an 18% greater reduction in the risk of experiencing an exacerbation was seen in patients treated with 2 2.20 In the smokers, however, the difference in response between patients treated with 1 2 and 2 2 was significant (p Z 0.0398), with the 2 2 group having a lower risk of exacerbations. The difference in result between this subgroup analysis and the main study is most likely due to the number of subjects included in the analysis as the power calculation was based on the main study with a sample size of 4000 patients in each group. Our subgroup analysis had much fewer patients. Nevertheless, our result is in line with the trend reported on better efficacy in smokers with a high- dose BDP compared with a standard.11 In ACQ-5 scores, a significantly greater change was seen in the nonsmokers compared with the smokers, and particularly for those treated with the standard 1 2 maintenance dose. Smokers, however, treated with the higher maintenance dose exhibited the same reduction in ACQ-5 scores as the non-smokers. The same was true for the changes in days with symptoms and awakenings per week with 2 2 e no differences were seen between smokers and non-smokers. Our beneficial results with an ICS/LABA combination in smoking asthmatics are also in line with the better results on bronchial hyperresponsiveness reported with fluticasone/salmeterol than with a higher dose of fluticasone alone.19 A limitation of our study is that smokers with a more extensive smoking history were excluded; any conclusions are, therefore, only applicable to smokers below 40 years of age, or older smokers with a smoking history of less than
BUD/FORM maintenance and reliever therapy in smokers
195
Figure 2 Changes in ACQ-5 scores over time in smokers and non-smokers treated with budesonide/formoterol maintenance and reliever therapy.
10 pack-years. A further limitation is that the patients in the main study were not stratified at baseline according to smoking history. This could have been an advantage but would have required an even larger number of patients as stratification in the present study was performed based on baseline ICS dose. This pre-specified subanalysis complements the results of the analyses of the primary outcome parameters of the EuroSMART study. Clearly, for the majority of patients with moderate and moderate to severe asthma, a maintenance dose of 1 2 inhalations of the fixed budesonide/formoterol combination, with more inhalations as needed, is adequate to control the disease.20 This result agrees well with the results of other EuroSMART analyses confirming that the same is true for elderly patients (65 years of age)26 and for patients using high-dose inhaled steroids (1600 mg budesonide or equivalent).27 A maintenance dose of 2 2 inhalations of the fixed budesonide/formoterol combination, with more inhalations as needed, should be considered for patients with low lung function (PEF and/or FEV1 <80% PN).20 The results of the present analyses extend these conclusions to asthma patients who smoke. However, in this group of younger smokers, a higher maintenance dose prolonged significantly the time to a first severe exacerbation and improved parameters defining asthma control more than 1 2. Consequently, a higher budesonide/formoterol maintenance dose is necessary to achieve a level of asthma control that is similar to nonsmokers. We conclude that smokers less than 40 years old, or older with a limited smoking history, benefit from budesonide/formoterol maintenance and reliever therapy in terms of risk of exacerbation. The smokers used somewhat higher doses of budesonide during the study. Considering the two treatment options, there was in the
smokers a statistically significant difference in time to first severe exacerbation between 1 2 and 2 2, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 2 with similar or greater changes than in smokers treated with 1 2.
Conflict of interest C.P. van Schayck has received a fee for consulting from AstraZeneca and has participated as a speaker in scientific meetings or courses organised and financed by GlaxoSmithKline, AstraZeneca, Pfizer and Nycomed. J. Haughney has received reimbursements for attending symposia, fees for speaking and organising educational events, funds for research and fees for consulting from AstraZeneca. He has also received support from a number of pharmaceutical companies (Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, Novartis, Nycomed, sanofi-aventis and Teva). M. Aubier has participated as a speaker in scientific meetings, or courses organised and financed by various pharmaceutical companies (GlaxoSmithKline, AstraZeneca, Novartis, Pfizer and Nycomed). O. Selroos has received consultation fees from AstraZeneca and Galenica, fees for speaking at medical meetings organised by AstraZeneca and fees for medical writing support for publications from AstraZeneca, Orion Pharma and Schering-Plough. T. Ekstro ¨m is a retired employee of AstraZeneca and holds stocks in the company. J. Ostinelli is a full-time employee of, and holds stock in, AstraZeneca.
196 R. Buhl has received reimbursement for attending scientific conferences, and/or fees for speaking and/or consulting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Nycomed and Pfizer. The Pulmonary Department at Mainz University Hospital received financial compensation for services performed during participation in clinical trials organised by various pharmaceutical companies.
Acknowledgement We thank Professor Olof Selroos, MD, PhD, of SEMECO AB, who provided medical writing support funded by AstraZeneca. We thank Dr Manda Gent of MediTech Media, who provided editing assistance funded by AstraZeneca. This study was funded by AstraZeneca.
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