- Email: [email protected]
formoterol maintenance and reliever therapy in real-world settings
Accepted Manuscript A multicenter, cross-sectional, observational study of budesonide/formoterol maintenance and reliever therapy in real-world settings Jiangtao Lin, Jing Li, Wencheng Yu, Yuejian Liu, Chuntao Liiu, Ping Chen, Huijie He, Bei He, Shuang Liu, Xiangdong Zhou PII:
S0954-6111(17)30106-3
DOI:
10.1016/j.rmed.2017.04.004
Reference:
YRMED 5148
To appear in:
Respiratory Medicine
Received Date: 26 January 2017 Revised Date:
31 March 2017
Accepted Date: 5 April 2017
Please cite this article as: Lin J, Li J, Yu W, Liu Y, Liiu C, Chen P, He H, He B, Liu S, Zhou X, A multicenter, cross-sectional, observational study of budesonide/formoterol maintenance and reliever therapy in real-world settings, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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A multicenter, cross-sectional, observational study of budesonide/formoterol
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maintenance and reliever therapy in real-world settings
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Jiangtao LINa, Jing LIb, Wencheng YUc, Yuejian LIUd, Chuntao LIIUe, Ping CHENf,
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Huijie HEg, Bei HEh, Shuang LIUi, Xiangdong ZHOUj
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5 a
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Department of Respiratory Diseases, China-Japan Friendship Hospital, Peking University, Beijing 100029, China. [email protected]
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b
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Immunology, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of
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Guangzhou Medical University, Guangzhou 510120, China. [email protected]
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c
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College, Qingdao 266071, China. [email protected]
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d
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State Key Laboratory of Respiratory Disease, Department of Allergy and Clinical
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Department of Respiratory Medicine, Affiliated Hospital of Qingdao Medical
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Department of Respiratory Medicine, Sichuan Provincial People’s Hospital, Chengdu 610072, China. [email protected]
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e
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f
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University, Changsha 410011, China. [email protected]
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g
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Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. [email protected]
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Department of Respiratory Medicine, The Second Xiangya Hospital of Central South
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h
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100191, China. [email protected]
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i
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Medical University, Beijing 100029, China. [email protected]
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j
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Third
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Department of Respiratory and Critical Care, The First Affiliated Hospital of Baotou Medical College, Baotou 014040, China. [email protected] Department of Respiratory Medicine, Peking University Third Hospital, Beijing
Department of Respiratory and Critical Care, Beijing Anzhen Hospital, Capital
Department of Respiratory Medicine, Southwest Hospital, 1st Affiliated Hospital of Military
Medical
University,
Chongqing
400038,
China. 1
ACCEPTED MANUSCRIPT [email protected]
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Corresponding author:
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Prof. Jiangtao Lin, Department of Respiratory Diseases, China-Japan Friendship
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Hospital, Peking University, No.2 Yinghua East Street, Chaoyang District, Beijing
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100029, China
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Tel: 86-10-84206187; E-mail: [email protected]
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Abstract
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Background:
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budesonide/formoterol in Chinese patients with asthma, based on the Global Initiative
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for Asthma (GINA) definition and Asthma Control Test (ACT) score.
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Methods: This multicenter, cross-sectional study (NCT01785901) evaluated asthma
6
control
7
budesonide/formoterol treatment. Adults with a diagnosis of asthma ≥6 months and
8
receiving budesonide/formoterol treatment ≥3 months before screening were
9
consecutively enrolled. Data including medical and medication history were collected
in
the
Chinese
level
of
patients
asthma
control
receiving
achieved
with
physician-prescribed
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levels
assess
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using face-to-face questionnaires and physical examinations during a single visit.
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Results: A total of 1483 asthma out-patients from 27 medical centers were enrolled;
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217 (14.6%) were treated with budesonide/formoterol using a fixed-dose strategy and
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1266 (85.4%) with the SMART (Symbicort® Maintenance And Reliever Therapy)
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strategy. According to GINA criteria, asthma was controlled in 58.6% (95% CI:
15
56.1%–61.1%) of patients and was either controlled or partly controlled in 94.1%
16
(95% CI: 92.8%–95.3%) of patients. According to ACT score, asthma was completely
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controlled in 22.4% (95% CI: 20.3%–24.6%) of patients and was either completely or
18
well controlled in 83.3% (95% CI: 81.4%–85.2%) of patients. Multivariate logistic
19
regression analysis revealed that a >5-year history of asthma and an age of >50 years
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were factors associated with lower levels of asthma control.
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Conclusions: This study demonstrated high levels of asthma control (GINA:
22
controlled and partly controlled and ACT: completely and well controlled) in Chinese
23
patients with asthma treated with budesonide/formoterol. Greater age and a longer
24
disease history were associated with lower levels of asthma control.
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ACCEPTED MANUSCRIPT Trial registration: ClinicalTrials.gov NCT01785901. Registered February 5, 2013.
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Abbreviations: ACT: Asthma Control Test; COPD: chronic obstructive pulmonary
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disease; GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; LABA:
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long-acting inhaled β2-agonist; SMART: Symbicort® Maintenance And Reliever
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Therapy
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Keywords:
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SMART, ICS/LABA, Symbicort Maintenance and Reliever Therapy, GINA, Asthma Control Test
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ACCEPTED MANUSCRIPT Introduction
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Asthma is a chronic inflammatory airway disorder associated with a reduction in
3
quality of life and work productivity, affecting more than 300 million people
4
worldwide [1]. The disease is characterized by episodic symptoms and fluctuating
5
levels of inflammation, which may culminate in an exacerbation [1]. The Global
6
Initiative for Asthma (GINA) recommends the use of medications to control the
7
underlying inflammation and symptoms, and to prevent exacerbations as part of an
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asthma management plan [1]. In current clinical practice, inhaled corticosteroids (ICS)
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are the most effective anti-inflammatory medication for treating asthma and are used
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in combination with long-acting inhaled β2-agonists (LABA) for patients not
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controlled on ICS alone [1]. The use of an ICS combined with LABA has several
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advantages, including improvements in symptoms and lung function, and reductions
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in asthma-related hospitalizations and exacerbations [1].
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Currently, several ICS/LABA combination agents are available in China,
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including
salmeterol/fluticasone,
budesonide/formoterol,
and
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beclomethasone/formoterol. Of these combination agents, budesonide/formoterol is
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authorized for use in asthma as maintenance therapy (fixed dose) or as both
18
maintenance and reliever therapy (SMART), providing greater flexibility in dosing. In
19
at risk patients, SMART significantly reduces exacerbations while providing similar
20
levels of symptom control at a relatively low dose of ICS in comparison to fixed-dose
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ICS/LABA regimens [1]. Multiple randomized, double-blind studies have shown that
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budesonide/formoterol treatment using a fixed dose or SMART strategy can achieve
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similar asthma control compared with other ICS/LABA combinations [2–4]. A
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real-world study of the budesonide/formoterol SMART strategy demonstrated that
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86.5% of patients achieved asthma control, defined as an Asthma Control Test (ACT)
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score ≥20 [5]. However, there have been few studies of GINA-defined asthma control
3
levels in patients receiving budesonide/formoterol in real-world settings. In China, there are now 30 million people with asthma [6], which places an
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enormous burden on healthcare resources. Furthermore, a recent report showed that
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57% of adults and 26% of children have poorly controlled asthma [7]. Understanding
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the level of asthma control achieved with ICS/LABA is important to inform
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treatment decisions. To date, few real-world data have been published on the level of
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asthma control achieved with budesonide/formoterol in China.
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Therefore, this study aimed to determine the levels of, and factors associated
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with, asthma control achieved with budesonide/formoterol, in real-world settings at
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tertiary hospitals in mainland China. Patients and Methods
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Study Design
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This was a multicenter, cross-sectional, observational study of asthma control in
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patients treated with budesonide/formoterol in mainland China (NCT01785901). The
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study was conducted between May 9, 2013, and October 14, 2014, at 27 tertiary
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hospitals. Patients were eligible if they were ≥18 years with a diagnosis of asthma ≥6
19
months,
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AstraZeneca, UK) treatment for ≥3 months before enrollment (at a stable maintenance
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dose ≥4 weeks prior to enrollment). Patients were excluded if they met any of the
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following criteria: (a) participation in any other clinical studies in the 3 months prior
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to enrollment; (b) ≥10 pack years of smoking history; (c) chronic obstructive
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pulmonary disease (COPD) or suspected COPD; (d) the use of any other asthma
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and
receiving
budesonide/formoterol
(Symbicort®
Turbuhaler®;
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months; (e) acute asthma exacerbation during the previous 4 weeks. Written informed
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consent was obtained from all patients. All study procedures, including informed
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consent forms, were approved by the ethics committee at each institution in
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accordance with laws and regulations.
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Data collection and outcome measures
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The primary outcome measure was the level of asthma control according to the
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GINA (2011) definition (controlled, partly controlled, and uncontrolled as
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summarized in Table S1, Additional File 1) [8]. Secondary outcome measures
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included the level of asthma control defined by ACT score (completely controlled
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asthma: overall ACT score of 25; well-controlled asthma: 20–24; and uncontrolled
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asthma: ≤19) and the frequency of reliever use in the week prior to enrollment.
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Patients were interviewed by investigators and completed a face-to-face
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questionnaire and physical examination during a single visit. All patients were
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required to complete an ACT form to determine their level of asthma control during
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the previous 4 weeks.
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Statistical analysis
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Statistical analysis was performed using SAS 9.2 (SAS Institute Inc., Cary, NC,
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USA). Associations between categorical variables and asthma control were analyzed
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using the Chi square test or Fisher’s exact test. Multivariate logistic regression was
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used to investigate the factors affecting asthma control. Significance was defined by a
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p-value <0.05.
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Results
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Patient characteristics
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A total of 1502 patients from 27 medical centers in mainland China were enrolled and
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1483 patients (98.7%) were included in the full analysis set (FAS; Table 1).
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Table 1 Patient characteristics
Education level
Smoking status
Time since diagnosis (years)
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BMI (kg/m2)*
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Gender
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<30 30–50 >50 Male Female Mean (standard deviation) Median Min, max Illiterate Primary school Secondary school University and above Never At enrollment Before enrolment <2 2–5 >5
Age (years)
Asthma Patients (N=1483) n (%) 251 (16.9%) 781 (52.7%) 451 (30.4%) 529 (35.7%) 954 (64.3%) 23.7 (3.5) 23.5 14.2, 38.0 24 (1.6%) 210 (14.2%) 706 (47.6%) 543 (36.6%) 1308 (88.2%) 38 (2.6%) 137 (9.2%) 729 (49.2%) 276 (18.6%) 478 (32.2%)
BMI, body mass index * Data unavailable for 1 patient
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The average duration of illness was 6.2±9.0 years. The mean treatment duration with
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budesonide/formoterol was 15.7±18.2 months, and of the three available dosages (80
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µg/4.5 µg, 160 µg/4.5 µg, and 320 µg/9 µg), 160 µg/4.5 µg was most commonly
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prescribed (97.0% of patients). All patients administered budesonide/formoterol via a
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dry-powder-inhaler and the most common regimen was one inhalation, twice daily
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(71.4% of patients). At enrollment, 217 patients (14.6%) were using fixed-dose
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budesonide/formoterol and 1266 patients (85.4%) were using the SMART strategy.
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GINA-defined asthma control level
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According to the GINA definition, asthma was controlled in 868 (58.6%) patients,
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partly controlled in 526 (35.5%) patients, and uncontrolled in 87 (5.9%) patients
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(Table 2).
4 Table 2 Clinical control of asthma according to GINA definition Asthma Patients (N=1483*)
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n (%)
Clinical control of asthma
868 (58.6%)
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Controlled
526 (35.5%)
Uncontrolled
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Partly controlled
87 (5.9%)
Proportion of patients with controlled asthma (95% CI)
58.6% (56.1%–61.1%)
Proportion of patients with controlled and partly controlled asthma (95% CI)
94.1% (92.8%–95.3%)
CI, confidence interval * Data unavailable for 2 patients
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Sub-analysis demonstrated that the factors associated with asthma control status
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included age (p<0.0001), gender (p=0.0029), asthma history (p<0.0001), and
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education level (p<0.0001; Table 3).
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Table 3 Sub-analysis of variables influencing asthma control according to GINA definition Patients Controlled
Partly Controlled
Uncontrolled
(N=868)
(N=526)
(N=89)
N (%)
P Values
0.0029
Gender 285 (54.0%)
201 (38.1%)
42 (8.0%)
Female*
583 (61.2%)
325 (34.1%)
45 (4.7%)
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Male*
<0.0001
172 (68.8%)
70 (28.0%)
30–50 years*
470 (60.3%)
259 (33.2%)
>50 years
226 (50.1%)
197 (43.7%)
8 (3.2%)
51 (6.5%)
28 (6.2%)
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<30 years*
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Age
Asthma history <2 years*
503 (69.1%)
206 (28.3%)
19 (2.6%)
2–5 years
154 (55.8%)
104 (37.7%)
18 (6.5%)
>5 years*
211 (44.2%)
216 (45.3%)
50 (10.5%)
Primary school and below Secondary school† University and above
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Education level
123 (52.6%)
92 (39.3%)
19 (8.1%)
375 (53.3%)
283 (40.2%)
46 (6.5%)
370 (68.1%)
151 (27.8%)
22 (4.1%)
<0.0001
<0.0001
*
Data unavailable for 1 patient
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†
Data unavailable for 2 patients
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There was a significantly greater proportion of patients with controlled asthma among
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those with a disease course of <2 years (69.1%) compared with those with a disease
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course of 2–5 years and >5 years (55.8% and 44.2%, p<0.0001). The proportion of
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patients with partly controlled and uncontrolled asthma followed a similar pattern:
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28.3% and 2.6% in those with a disease course of <2 years; 37.7% and 6.5% in those
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with a disease course of 2–5 years; and 45.3% and 10.5% in those with a disease
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course of >5 years, respectively. A higher level of education was associated with a
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higher level of asthma control (Table 3). Multivariate logistic regression analysis indicated that an asthma history of >5
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years (versus <2 years; odds ratio [OR]: 1.49 [95% CI: 1.18–1.88] p = 0.0008) and
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age of >50 years (versus <30 years; OR: 1.42 [95% CI: 1.02–1.96] p = 0.0379) were
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the factors affecting asthma control (Table 4). Gender and education level were no
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longer associated with the level of asthma control.
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Table 4 Multivariate logistic regression analysis for GINA-defined asthma control with variables in the full analysis set Odds Ratio and 95% CI Standard Coefficient Error
Wald Statistics
P Value
OR value
Lower limit
Upper limit
Variables 0.0055
0.1518
0.0013
0.9710
1.006
0.747
1.354
Age (years) >50 vs <30
0.3472
0.1672
4.3090
0.0379
1.415
1.020
1.964
Gender (male vs female)
0.0680
0.1096
0.3851
0.5349
1.070
0.863
1.327
Asthma history (years) 2–5 vs <2
0.2009
0.1425
1.9875
0.1586
Asthma history (years) >5 vs <2
0.3984
0.1192
11.1696
0.0008
Education level (university and above vs primary school and below)
-0.2472
0.1634
2.2895
Education level (secondary school vs primary school and below)
0.0652
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Age (years) 30–50 vs <30
0.925
1.616
1.490
1.179
1.882
0.1303
0.781
0.567
1.076
0.6675
1.067
0.793
1.437
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0.1518
0.1845
CI, confidence interval; OR, odds ratio
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The significance level for variable inclusion and exclusion in the stepwise algorithm was 0.15
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ACT score and asthma control level ACT scores indicated that asthma was completely controlled in 332 (22.4%)
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patients, well controlled in 904 (61.0%) patients, and uncontrolled in 247 (16.7%)
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patients (Table 5).
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Table 5 Clinical control of asthma according to ACT definition Asthma Patients (N=1483) Clinical control of asthma 332 (22.4%)
Well controlled
904 (61.0%)
Uncontrolled
247 (16.7%)
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Completely controlled
22.4% (20.3%, 24.6%)
Proportion of patients with completely and well controlled asthma (95% CI)
83.3% (81.4%, 85.2%)
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Proportion of patients with completely controlled asthma (95% CI)
Sub-analysis demonstrated that the factors associated with ACT-defined asthma
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control status included gender (p=0.002), asthma history (p<0.0001), and educational
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level (p<0.0137) (Table 6). No associations survived multivariate analysis
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(Supplementary Table 2, Additional File 2).
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Table 6 Sub-analysis of variables influencing asthma control according to ACT definition Patients Completely controlled N (%)
Well controlled
Uncontrolled
(N=904)
(N=247)
(N=332) 0.0022
Male
101 (19.1%)
322 (60.9%)
106 (20.0%)
Female
231 (24.2%)
582 (61.0%)
141 (14.8%)
0.3980
Age 62 (24.7%)
153 (61.0%)
36 (14.3%)
30–50 years
167 (21.4%)
480 (61.5%)
134 (17.2%)
>50 years
103 (22.8%)
271 (60.1%)
77 (17.1%)
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<30 years
Asthma history
214 (29.4%)
438 (60.1%)
77 (10.6%)
2–5 years
46 (16.7%)
169 (61.2%)
61 (22.1%)
>5 years
72 (15.1%)
297 (62.1%)
109 (22.8%)
Primary school and below Secondary school
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<2 years
Education level
<0.0001
0.0137
45 (19.2%)
148 (63.2%)
41 (17.5%)
148 (21.0%)
426 (60.3%)
132 (18.7%)
139 (25.6%)
330 (60.8%)
74 (13.6%)
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University and above
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Gender
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P Values
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Reliever use in the week prior to enrollment
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Most patients (87.1%) did not use a reliever medication in the week prior to
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enrollment. Among patients who used a reliever, 4.4% did so once, 3.9% did so twice,
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2.0% used a reliever 3 times, and 2.7% used a reliever ≥4 times.
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Discussion The goal of asthma treatment is to achieve and maintain good symptom control
3
and to minimize the future risk of exacerbations [1]. The results of this study show
4
that the proportion of patients with GINA-defined, controlled and partially controlled
5
asthma was 58.6% and 35.5%, respectively. In contrast, results from a
6
questionnaire-based survey in China showed that 28.7% and 45.0% of patients
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achieved GINA-defined control and partial control, respectively [9].
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cross-sectional, real-world study that assessed asthma control in patients using either
9
budesonide/formoterol or fluticasone/salmeterol as maintenance therapy reported
10
similar findings; the proportion of patients with controlled and partially controlled
11
asthma according to a questionnaire based on the GINA guidelines was 36.2% and
12
44.8%, respectively [10]. The discrepancies between these studies may be explained
13
in part by the fact that, despite being the most commonly used regimen, less than half
14
(45.6%) of the patients in the Chinese survey were using ICS/LABA [9]. Besides, the
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Hungarian study used a different assessment tool, which could also affect the number
16
of patients who were considered controlled or partially controlled [10].
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The ACT is a patient-based approach to measure asthma control using questions
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on activity restrictions, shortness of breath, night-time symptoms, and frequency of
20
rescue medication use [11]. In the present study, the proportion of patients with
21
complete asthma control (ACT score = 25), well controlled asthma (ACT score = 20–
22
24), and overall control (ACT score ≥20) was 22.4%, 61.0%, and 83.3%, respectively.
23
The level of overall asthma control observed in this study is similar to that
24
in a non-interventional study of budesonide/formoterol SMART strategy conducted in
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Thailand [5], in which 86.5% of patients were judged to have controlled asthma (ACT
2
score of ≥20) after treatment for ≥3 months. In another prospective observational
3
study,
4
an ACT score≥20 [12]. Similar results was also achieved in a real-life, cross-sectional
5
study in Italy, in which an ACT score ≥20 was achieved by 79.9% patients treated
6
with
7
budesonide/formoterol or fluticasone/salmeterol) alone [13]. Furthermore, most
8
patients in the present study (87.1%) did not use a reliever medication in the week
9
leading up to their interview. These results demonstrate that budesonide/formoterol
10
treatment has a favorable therapeutic effect on asthma control and continuous
11
standardized therapy is a viable treatment option in real-world settings.
fixed
combination
(beclomethasone/formoterol,
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85.1% of patients using budesonide/formoterol fixed-dose combination had
This study identified a number of factors associated with the level of asthma
13
control. According to the GINA definition, asthma was controlled and partly
14
controlled in 54.0% and 38.1% of male patients, respectively. In contrast, asthma was
15
controlled and partially controlled in 61.2% and 34.1% of female patients,
16
respectively. This translates to a significantly greater level of overall control in female
17
patients (95.3%) in comparison to male patients (92.1%, p=0.0029). The duration of
18
disease was also a factor for asthma control; in patients with a <2-year course of
19
disease, the proportion achieving either controlled or partly controlled asthma was
20
97.4%, which was significantly higher than that in patients with a longer course of
21
disease (93.5% for 2–5 years and 89.5% for >5 years).
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The present study demonstrated that age is another factor that may influence
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asthma control. The proportion of patients with GINA-defined, controlled asthma
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aged <30 years or >50 years was 68.8% and 50.1%, respectively, and the proportion 16
ACCEPTED MANUSCRIPT of those with either controlled or partly controlled asthma was 96.8% and 93.8%,
2
respectively. Complexity of treatment regimens together with poor treatment
3
compliance and inhaler technique may contribute to poor asthma control in older
4
patients [1]. Furthermore, older patients often present with comorbidities such as
5
chronic bronchitis and COPD [1]. In contrast, asthma control in middle-aged patients
6
may be more related to economic status and duration of smoking [14]. Therefore,
7
different approaches may be required to improve asthma control in different age
8
groups.
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It should be noted that education level is a risk factor for hospitalization in older
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asthma patients, suggesting an impact of education level on asthma control and
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prognosis [15]. The multivariate regression analysis presented here did not suggest
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that education level was a factor affecting asthma control.
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According to the Chinese guidelines, spirometry is optional for the evaluation of
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asthma control level [16]. Therefore, in this non-interventional study, spirometry data
15
were collected at the investigators’ discretion and were not available to validate
16
asthma control levels in all patients. Limitations of this study include the reliance on
17
the patient’s own recall of the use of reliever medication during the previous week and
18
the use of patient completed questionnaires rather than investigator-led assessments.
19
However, the ACT has been validated as a useful tool for asthma screening, which is
20
not only suitable for patients’ self-management but also long-term monitoring of
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asthma control [17,18].
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Conclusions
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In conclusion, this study demonstrates that a high proportion of Chinese asthma
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patients can achieve GINA-defined asthma control with budesonide/formoterol in a 17
ACCEPTED MANUSCRIPT 1
real-world setting. Greater attention should be paid to male patients, older patients,
2
patients with a longer disease course, and those with a low level of education in the
3
clinical treatment of asthma.
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Appendices 1. Supplementary Table 1. Levels of asthma control according to the Global Initiative
6
for Asthma (GINA) 2011.
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2. Supplementary Table 2. Multivariate logistic regression analysis for ACT-defined
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asthma control with variables in the full analysis set.
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Declarations
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Ethics approval and consent to participate
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The Ethics Committee of the China-Japan Friendship Hospital, the leading site,
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approved the study protocol and informed consent form (ICF) prior to study initiation
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(approval number 2013-19). All patients participating in this study voluntarily signed
14
the ICF and received a copy of the ICF before study initiation.
15
Consent for publication
16
Not applicable
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Availability of data and materials
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All data generated and/or analyzed during this study are included in this published
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article [and its supplementary information files]
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Competing Interests
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Chuntao Liu reports financial relationships, in the form of personal fees, with
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AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. Yuejian Liu reports
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financial relationships, in the form of personal fees, with AstraZeneca, Boehringer
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Ingelheim, GlaxoSmithKline and Pfizer. All other authors have no conflict of interest 18
ACCEPTED MANUSCRIPT to declare.
2
Funding
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This work was sponsored by AstraZeneca. The sponsor funded and was involved in
4
study design, collection, analysis and interpretation of data, medical writing and the
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final decision to submit the manuscript.
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Authors’ contributions
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Study design: All authors. Data analysis: All authors. Writing manuscript: All authors.
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Approval of the final version: All authors.
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Acknowledgments
The authors would like to thank Hanson Deng of Shanghai Ingsci Information
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Technology Co., LTD, and Dr Tom Priddle of Nucleus Global for providing the
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necessary writing assistance and editorial support during development of the
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manuscript funded by AstraZeneca.
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References
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1. GINA. 2016 GINA Report, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma - GINA. http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-pr evention/. Accessed 1 December 2016.
23 24 25
2. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martínez-Jimenez NE, Buhl, R. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61:725-36.
26 27
3. Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations
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ACCEPTED MANUSCRIPT in adults with persistent asthma. Respir Med. 2006;100:1152-62.
2 3 4
4. Bousquet J, Boulet L-P, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007;101:2437-46.
5 6
5. Boonsawat W, Thinkhamrop B. Role of budesonide/formoterol maintenance and reliever therapy: a pragmatic study. Asian Pac J Allergy Immunol. 2014;32:160-5.
7 8 9
6. Lin J, Shen H, Zhou X, Yin C, Chen P, Liu G, Su N. Review and outlook of asthma management within the past 60 years in China. Zhonghua Jie He He Hu Xi Za Zhi. 2013;36:907-10.
10 11 12 13
7. Zhong N, Lin J, Shen K. Asthma Control In China: Current Status And Influencing Factors. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingA bstracts.A4595. Accessed 1 December 2016.
14 15 16 17
8. GINA. 2011 GINA Report: Global Strategy for Asthma Management and Prevention. http://www.qu.edu.qa/pharmacy/professional_development/documents/GINA_Report _2011-1.pdf. Accessed 01 December 2016.
18 19 20
9. Su N, Lin J, Chen P, Li J, Wu C, Yin K, Liu C, Chen Y, Zhou X, Yuan Y, Huang X. Evaluation of asthma control: a questionnaire-based survey in China. Chin Med J (Engl). 2014;127:2030-6.
21
25
10. Müller V, Gálffy G, Eszes N, Losonczy G, Bizzi A, Nicolini G, Chrystyn H, Tamási L. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extra fine formulation. BMC Pulm Med. 2011:11:40.
26 27 28
11. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray PJ, Pendergraft TB. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113:59-65.
29
12. Füsun Yıldız, On behalf of the ASIT Study Group. Factors influencing asthma control: results of a real-life prospective observational asthma inhaler treatment (ASIT) study. J Asthma Allergy. 2013:6:93–101.
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30 31
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13. Allegra L, Cremonesi G, Girbino G, Ingrassia E, Marsico S, Nicolini G, Terzano C, On behalf of the PRISMA (PRospectIve Study on asthMA control) Study Group.
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Real-life prospective study on asthma control in Italy: Cross-sectional phase results.
32
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ACCEPTED MANUSCRIPT Respir Med. 2012:106:205-214.
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14. Burgess JA, Matheson MC, Gurrin LC, Byrnes GB, Adams KS, Wharton CL, Giles GG, Jenkins MA, Hopper JL, Abramson MJ, Walters EH, Dharmage SC. Factors influencing asthma remission: a longitudinal study from childhood to middle age. Thorax. 2011;66:508-13.
6 7 8
15. Diette GB, Krishnan JA, Dominici F, Haponik E, Skinner EA, Steinwachs D, WU, AW. Asthma in older patients: factors associated with hospitalization. Arch Intern Med. 2002;162:1123-32.
9 10
16. Asthma Workgroup, Chinese Thoracic Society, Chinese Medial Association. Chinese guideline for the prevention and management of bronchial asthma (2016).
11
Chin J Tuberc Respir Dis. 2016:39:675-697.
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17. Zhou X, Ding F-M, Lin J-T, Yin K-S, Chen P, He Q-Y, Shen HH, Wan HY, Liu CT, Li J, Wang CZ. Validity of Asthma Control Test in Chinese patients. Chin Med J (Engl). 2007;120:1037-41.
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18. Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, Kosinski M, Pendergraft TB, Jhingran P. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol. 2006;117:549-56.
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Asthma control level with budesonide/formoterol in real-world in China was assessed 1483 asthma out-patients from 27 medical centers were enrolled in this study Asthma was controlled in 58.6% patients and partly controlled in 35.5% patients Long asthma duration and old age were associated with lower control levels
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ACCEPTED MANUSCRIPT Conflict of Interest Statment Chuntao Liu reports financial relationships, in the form of personal fees, with AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. Yuejian Liu reports financial relationships, in the form of personal fees, with AstraZeneca, Boehringer Ingelheim,
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GlaxoSmithKline and Pfizer. All other authors have no conflict of interest to declare.
S0954-6111(17)30106-3
DOI:
10.1016/j.rmed.2017.04.004
Reference:
YRMED 5148
To appear in:
Respiratory Medicine
Received Date: 26 January 2017 Revised Date:
31 March 2017
Accepted Date: 5 April 2017
Please cite this article as: Lin J, Li J, Yu W, Liu Y, Liiu C, Chen P, He H, He B, Liu S, Zhou X, A multicenter, cross-sectional, observational study of budesonide/formoterol maintenance and reliever therapy in real-world settings, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
A multicenter, cross-sectional, observational study of budesonide/formoterol
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maintenance and reliever therapy in real-world settings
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Jiangtao LINa, Jing LIb, Wencheng YUc, Yuejian LIUd, Chuntao LIIUe, Ping CHENf,
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Huijie HEg, Bei HEh, Shuang LIUi, Xiangdong ZHOUj
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5 a
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Department of Respiratory Diseases, China-Japan Friendship Hospital, Peking University, Beijing 100029, China. [email protected]
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b
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Immunology, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of
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Guangzhou Medical University, Guangzhou 510120, China. [email protected]
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c
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College, Qingdao 266071, China. [email protected]
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d
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State Key Laboratory of Respiratory Disease, Department of Allergy and Clinical
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Department of Respiratory Medicine, Affiliated Hospital of Qingdao Medical
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Department of Respiratory Medicine, Sichuan Provincial People’s Hospital, Chengdu 610072, China. [email protected]
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e
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f
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University, Changsha 410011, China. [email protected]
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g
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Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. [email protected]
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Department of Respiratory Medicine, The Second Xiangya Hospital of Central South
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h
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100191, China. [email protected]
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i
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Medical University, Beijing 100029, China. [email protected]
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j
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Third
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Department of Respiratory and Critical Care, The First Affiliated Hospital of Baotou Medical College, Baotou 014040, China. [email protected] Department of Respiratory Medicine, Peking University Third Hospital, Beijing
Department of Respiratory and Critical Care, Beijing Anzhen Hospital, Capital
Department of Respiratory Medicine, Southwest Hospital, 1st Affiliated Hospital of Military
Medical
University,
Chongqing
400038,
China. 1
ACCEPTED MANUSCRIPT [email protected]
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Corresponding author:
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Prof. Jiangtao Lin, Department of Respiratory Diseases, China-Japan Friendship
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Hospital, Peking University, No.2 Yinghua East Street, Chaoyang District, Beijing
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100029, China
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Tel: 86-10-84206187; E-mail: [email protected]
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ACCEPTED MANUSCRIPT 1
Abstract
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Background:
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budesonide/formoterol in Chinese patients with asthma, based on the Global Initiative
4
for Asthma (GINA) definition and Asthma Control Test (ACT) score.
5
Methods: This multicenter, cross-sectional study (NCT01785901) evaluated asthma
6
control
7
budesonide/formoterol treatment. Adults with a diagnosis of asthma ≥6 months and
8
receiving budesonide/formoterol treatment ≥3 months before screening were
9
consecutively enrolled. Data including medical and medication history were collected
in
the
Chinese
level
of
patients
asthma
control
receiving
achieved
with
physician-prescribed
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levels
assess
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To
using face-to-face questionnaires and physical examinations during a single visit.
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Results: A total of 1483 asthma out-patients from 27 medical centers were enrolled;
12
217 (14.6%) were treated with budesonide/formoterol using a fixed-dose strategy and
13
1266 (85.4%) with the SMART (Symbicort® Maintenance And Reliever Therapy)
14
strategy. According to GINA criteria, asthma was controlled in 58.6% (95% CI:
15
56.1%–61.1%) of patients and was either controlled or partly controlled in 94.1%
16
(95% CI: 92.8%–95.3%) of patients. According to ACT score, asthma was completely
17
controlled in 22.4% (95% CI: 20.3%–24.6%) of patients and was either completely or
18
well controlled in 83.3% (95% CI: 81.4%–85.2%) of patients. Multivariate logistic
19
regression analysis revealed that a >5-year history of asthma and an age of >50 years
20
were factors associated with lower levels of asthma control.
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Conclusions: This study demonstrated high levels of asthma control (GINA:
22
controlled and partly controlled and ACT: completely and well controlled) in Chinese
23
patients with asthma treated with budesonide/formoterol. Greater age and a longer
24
disease history were associated with lower levels of asthma control.
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ACCEPTED MANUSCRIPT Trial registration: ClinicalTrials.gov NCT01785901. Registered February 5, 2013.
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Abbreviations: ACT: Asthma Control Test; COPD: chronic obstructive pulmonary
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disease; GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; LABA:
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long-acting inhaled β2-agonist; SMART: Symbicort® Maintenance And Reliever
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Therapy
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Keywords:
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SMART, ICS/LABA, Symbicort Maintenance and Reliever Therapy, GINA, Asthma Control Test
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ACCEPTED MANUSCRIPT Introduction
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Asthma is a chronic inflammatory airway disorder associated with a reduction in
3
quality of life and work productivity, affecting more than 300 million people
4
worldwide [1]. The disease is characterized by episodic symptoms and fluctuating
5
levels of inflammation, which may culminate in an exacerbation [1]. The Global
6
Initiative for Asthma (GINA) recommends the use of medications to control the
7
underlying inflammation and symptoms, and to prevent exacerbations as part of an
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asthma management plan [1]. In current clinical practice, inhaled corticosteroids (ICS)
9
are the most effective anti-inflammatory medication for treating asthma and are used
10
in combination with long-acting inhaled β2-agonists (LABA) for patients not
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controlled on ICS alone [1]. The use of an ICS combined with LABA has several
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advantages, including improvements in symptoms and lung function, and reductions
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in asthma-related hospitalizations and exacerbations [1].
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Currently, several ICS/LABA combination agents are available in China,
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including
salmeterol/fluticasone,
budesonide/formoterol,
and
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beclomethasone/formoterol. Of these combination agents, budesonide/formoterol is
17
authorized for use in asthma as maintenance therapy (fixed dose) or as both
18
maintenance and reliever therapy (SMART), providing greater flexibility in dosing. In
19
at risk patients, SMART significantly reduces exacerbations while providing similar
20
levels of symptom control at a relatively low dose of ICS in comparison to fixed-dose
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ICS/LABA regimens [1]. Multiple randomized, double-blind studies have shown that
22
budesonide/formoterol treatment using a fixed dose or SMART strategy can achieve
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similar asthma control compared with other ICS/LABA combinations [2–4]. A
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real-world study of the budesonide/formoterol SMART strategy demonstrated that
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86.5% of patients achieved asthma control, defined as an Asthma Control Test (ACT)
2
score ≥20 [5]. However, there have been few studies of GINA-defined asthma control
3
levels in patients receiving budesonide/formoterol in real-world settings. In China, there are now 30 million people with asthma [6], which places an
5
enormous burden on healthcare resources. Furthermore, a recent report showed that
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57% of adults and 26% of children have poorly controlled asthma [7]. Understanding
7
the level of asthma control achieved with ICS/LABA is important to inform
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treatment decisions. To date, few real-world data have been published on the level of
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asthma control achieved with budesonide/formoterol in China.
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Therefore, this study aimed to determine the levels of, and factors associated
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with, asthma control achieved with budesonide/formoterol, in real-world settings at
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tertiary hospitals in mainland China. Patients and Methods
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Study Design
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This was a multicenter, cross-sectional, observational study of asthma control in
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patients treated with budesonide/formoterol in mainland China (NCT01785901). The
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study was conducted between May 9, 2013, and October 14, 2014, at 27 tertiary
18
hospitals. Patients were eligible if they were ≥18 years with a diagnosis of asthma ≥6
19
months,
20
AstraZeneca, UK) treatment for ≥3 months before enrollment (at a stable maintenance
21
dose ≥4 weeks prior to enrollment). Patients were excluded if they met any of the
22
following criteria: (a) participation in any other clinical studies in the 3 months prior
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to enrollment; (b) ≥10 pack years of smoking history; (c) chronic obstructive
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pulmonary disease (COPD) or suspected COPD; (d) the use of any other asthma
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and
receiving
budesonide/formoterol
(Symbicort®
Turbuhaler®;
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ACCEPTED MANUSCRIPT maintenance medication in addition to budesonide/formoterol during the previous 3
2
months; (e) acute asthma exacerbation during the previous 4 weeks. Written informed
3
consent was obtained from all patients. All study procedures, including informed
4
consent forms, were approved by the ethics committee at each institution in
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accordance with laws and regulations.
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Data collection and outcome measures
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The primary outcome measure was the level of asthma control according to the
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GINA (2011) definition (controlled, partly controlled, and uncontrolled as
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summarized in Table S1, Additional File 1) [8]. Secondary outcome measures
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included the level of asthma control defined by ACT score (completely controlled
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asthma: overall ACT score of 25; well-controlled asthma: 20–24; and uncontrolled
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asthma: ≤19) and the frequency of reliever use in the week prior to enrollment.
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Patients were interviewed by investigators and completed a face-to-face
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questionnaire and physical examination during a single visit. All patients were
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required to complete an ACT form to determine their level of asthma control during
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the previous 4 weeks.
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Statistical analysis
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Statistical analysis was performed using SAS 9.2 (SAS Institute Inc., Cary, NC,
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USA). Associations between categorical variables and asthma control were analyzed
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using the Chi square test or Fisher’s exact test. Multivariate logistic regression was
21
used to investigate the factors affecting asthma control. Significance was defined by a
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p-value <0.05.
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Results
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Patient characteristics
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A total of 1502 patients from 27 medical centers in mainland China were enrolled and
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1483 patients (98.7%) were included in the full analysis set (FAS; Table 1).
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Table 1 Patient characteristics
Education level
Smoking status
Time since diagnosis (years)
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BMI (kg/m2)*
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Gender
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<30 30–50 >50 Male Female Mean (standard deviation) Median Min, max Illiterate Primary school Secondary school University and above Never At enrollment Before enrolment <2 2–5 >5
Age (years)
Asthma Patients (N=1483) n (%) 251 (16.9%) 781 (52.7%) 451 (30.4%) 529 (35.7%) 954 (64.3%) 23.7 (3.5) 23.5 14.2, 38.0 24 (1.6%) 210 (14.2%) 706 (47.6%) 543 (36.6%) 1308 (88.2%) 38 (2.6%) 137 (9.2%) 729 (49.2%) 276 (18.6%) 478 (32.2%)
BMI, body mass index * Data unavailable for 1 patient
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The average duration of illness was 6.2±9.0 years. The mean treatment duration with
7
budesonide/formoterol was 15.7±18.2 months, and of the three available dosages (80
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µg/4.5 µg, 160 µg/4.5 µg, and 320 µg/9 µg), 160 µg/4.5 µg was most commonly
9
prescribed (97.0% of patients). All patients administered budesonide/formoterol via a
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dry-powder-inhaler and the most common regimen was one inhalation, twice daily
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(71.4% of patients). At enrollment, 217 patients (14.6%) were using fixed-dose
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budesonide/formoterol and 1266 patients (85.4%) were using the SMART strategy.
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GINA-defined asthma control level
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According to the GINA definition, asthma was controlled in 868 (58.6%) patients,
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partly controlled in 526 (35.5%) patients, and uncontrolled in 87 (5.9%) patients
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(Table 2).
4 Table 2 Clinical control of asthma according to GINA definition Asthma Patients (N=1483*)
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n (%)
Clinical control of asthma
868 (58.6%)
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Controlled
526 (35.5%)
Uncontrolled
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Partly controlled
87 (5.9%)
Proportion of patients with controlled asthma (95% CI)
58.6% (56.1%–61.1%)
Proportion of patients with controlled and partly controlled asthma (95% CI)
94.1% (92.8%–95.3%)
CI, confidence interval * Data unavailable for 2 patients
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Sub-analysis demonstrated that the factors associated with asthma control status
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included age (p<0.0001), gender (p=0.0029), asthma history (p<0.0001), and
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Table 3 Sub-analysis of variables influencing asthma control according to GINA definition Patients Controlled
Partly Controlled
Uncontrolled
(N=868)
(N=526)
(N=89)
N (%)
P Values
0.0029
Gender 285 (54.0%)
201 (38.1%)
42 (8.0%)
Female*
583 (61.2%)
325 (34.1%)
45 (4.7%)
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Male*
<0.0001
172 (68.8%)
70 (28.0%)
30–50 years*
470 (60.3%)
259 (33.2%)
>50 years
226 (50.1%)
197 (43.7%)
8 (3.2%)
51 (6.5%)
28 (6.2%)
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<30 years*
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Age
Asthma history <2 years*
503 (69.1%)
206 (28.3%)
19 (2.6%)
2–5 years
154 (55.8%)
104 (37.7%)
18 (6.5%)
>5 years*
211 (44.2%)
216 (45.3%)
50 (10.5%)
Primary school and below Secondary school† University and above
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Education level
123 (52.6%)
92 (39.3%)
19 (8.1%)
375 (53.3%)
283 (40.2%)
46 (6.5%)
370 (68.1%)
151 (27.8%)
22 (4.1%)
<0.0001
<0.0001
*
Data unavailable for 1 patient
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†
Data unavailable for 2 patients
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There was a significantly greater proportion of patients with controlled asthma among
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those with a disease course of <2 years (69.1%) compared with those with a disease
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course of 2–5 years and >5 years (55.8% and 44.2%, p<0.0001). The proportion of
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patients with partly controlled and uncontrolled asthma followed a similar pattern:
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28.3% and 2.6% in those with a disease course of <2 years; 37.7% and 6.5% in those
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with a disease course of 2–5 years; and 45.3% and 10.5% in those with a disease
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course of >5 years, respectively. A higher level of education was associated with a
3
higher level of asthma control (Table 3). Multivariate logistic regression analysis indicated that an asthma history of >5
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years (versus <2 years; odds ratio [OR]: 1.49 [95% CI: 1.18–1.88] p = 0.0008) and
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age of >50 years (versus <30 years; OR: 1.42 [95% CI: 1.02–1.96] p = 0.0379) were
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the factors affecting asthma control (Table 4). Gender and education level were no
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longer associated with the level of asthma control.
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Table 4 Multivariate logistic regression analysis for GINA-defined asthma control with variables in the full analysis set Odds Ratio and 95% CI Standard Coefficient Error
Wald Statistics
P Value
OR value
Lower limit
Upper limit
Variables 0.0055
0.1518
0.0013
0.9710
1.006
0.747
1.354
Age (years) >50 vs <30
0.3472
0.1672
4.3090
0.0379
1.415
1.020
1.964
Gender (male vs female)
0.0680
0.1096
0.3851
0.5349
1.070
0.863
1.327
Asthma history (years) 2–5 vs <2
0.2009
0.1425
1.9875
0.1586
Asthma history (years) >5 vs <2
0.3984
0.1192
11.1696
0.0008
Education level (university and above vs primary school and below)
-0.2472
0.1634
2.2895
Education level (secondary school vs primary school and below)
0.0652
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Age (years) 30–50 vs <30
0.925
1.616
1.490
1.179
1.882
0.1303
0.781
0.567
1.076
0.6675
1.067
0.793
1.437
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0.1518
0.1845
CI, confidence interval; OR, odds ratio
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The significance level for variable inclusion and exclusion in the stepwise algorithm was 0.15
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ACT score and asthma control level ACT scores indicated that asthma was completely controlled in 332 (22.4%)
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patients, well controlled in 904 (61.0%) patients, and uncontrolled in 247 (16.7%)
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patients (Table 5).
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Table 5 Clinical control of asthma according to ACT definition Asthma Patients (N=1483) Clinical control of asthma 332 (22.4%)
Well controlled
904 (61.0%)
Uncontrolled
247 (16.7%)
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Completely controlled
22.4% (20.3%, 24.6%)
Proportion of patients with completely and well controlled asthma (95% CI)
83.3% (81.4%, 85.2%)
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Proportion of patients with completely controlled asthma (95% CI)
Sub-analysis demonstrated that the factors associated with ACT-defined asthma
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control status included gender (p=0.002), asthma history (p<0.0001), and educational
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level (p<0.0137) (Table 6). No associations survived multivariate analysis
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(Supplementary Table 2, Additional File 2).
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Table 6 Sub-analysis of variables influencing asthma control according to ACT definition Patients Completely controlled N (%)
Well controlled
Uncontrolled
(N=904)
(N=247)
(N=332) 0.0022
Male
101 (19.1%)
322 (60.9%)
106 (20.0%)
Female
231 (24.2%)
582 (61.0%)
141 (14.8%)
0.3980
Age 62 (24.7%)
153 (61.0%)
36 (14.3%)
30–50 years
167 (21.4%)
480 (61.5%)
134 (17.2%)
>50 years
103 (22.8%)
271 (60.1%)
77 (17.1%)
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<30 years
Asthma history
214 (29.4%)
438 (60.1%)
77 (10.6%)
2–5 years
46 (16.7%)
169 (61.2%)
61 (22.1%)
>5 years
72 (15.1%)
297 (62.1%)
109 (22.8%)
Primary school and below Secondary school
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<2 years
Education level
<0.0001
0.0137
45 (19.2%)
148 (63.2%)
41 (17.5%)
148 (21.0%)
426 (60.3%)
132 (18.7%)
139 (25.6%)
330 (60.8%)
74 (13.6%)
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University and above
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Gender
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P Values
4
Reliever use in the week prior to enrollment
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Most patients (87.1%) did not use a reliever medication in the week prior to
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enrollment. Among patients who used a reliever, 4.4% did so once, 3.9% did so twice,
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2.0% used a reliever 3 times, and 2.7% used a reliever ≥4 times.
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ACCEPTED MANUSCRIPT 1
Discussion The goal of asthma treatment is to achieve and maintain good symptom control
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and to minimize the future risk of exacerbations [1]. The results of this study show
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that the proportion of patients with GINA-defined, controlled and partially controlled
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asthma was 58.6% and 35.5%, respectively. In contrast, results from a
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questionnaire-based survey in China showed that 28.7% and 45.0% of patients
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achieved GINA-defined control and partial control, respectively [9].
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cross-sectional, real-world study that assessed asthma control in patients using either
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budesonide/formoterol or fluticasone/salmeterol as maintenance therapy reported
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similar findings; the proportion of patients with controlled and partially controlled
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asthma according to a questionnaire based on the GINA guidelines was 36.2% and
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44.8%, respectively [10]. The discrepancies between these studies may be explained
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in part by the fact that, despite being the most commonly used regimen, less than half
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(45.6%) of the patients in the Chinese survey were using ICS/LABA [9]. Besides, the
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Hungarian study used a different assessment tool, which could also affect the number
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of patients who were considered controlled or partially controlled [10].
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A Hungarian
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2
The ACT is a patient-based approach to measure asthma control using questions
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on activity restrictions, shortness of breath, night-time symptoms, and frequency of
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rescue medication use [11]. In the present study, the proportion of patients with
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complete asthma control (ACT score = 25), well controlled asthma (ACT score = 20–
22
24), and overall control (ACT score ≥20) was 22.4%, 61.0%, and 83.3%, respectively.
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The level of overall asthma control observed in this study is similar to that
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in a non-interventional study of budesonide/formoterol SMART strategy conducted in
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observed
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ACCEPTED MANUSCRIPT 1
Thailand [5], in which 86.5% of patients were judged to have controlled asthma (ACT
2
score of ≥20) after treatment for ≥3 months. In another prospective observational
3
study,
4
an ACT score≥20 [12]. Similar results was also achieved in a real-life, cross-sectional
5
study in Italy, in which an ACT score ≥20 was achieved by 79.9% patients treated
6
with
7
budesonide/formoterol or fluticasone/salmeterol) alone [13]. Furthermore, most
8
patients in the present study (87.1%) did not use a reliever medication in the week
9
leading up to their interview. These results demonstrate that budesonide/formoterol
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treatment has a favorable therapeutic effect on asthma control and continuous
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standardized therapy is a viable treatment option in real-world settings.
fixed
combination
(beclomethasone/formoterol,
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ICS/LABA
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85.1% of patients using budesonide/formoterol fixed-dose combination had
This study identified a number of factors associated with the level of asthma
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control. According to the GINA definition, asthma was controlled and partly
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controlled in 54.0% and 38.1% of male patients, respectively. In contrast, asthma was
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controlled and partially controlled in 61.2% and 34.1% of female patients,
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respectively. This translates to a significantly greater level of overall control in female
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patients (95.3%) in comparison to male patients (92.1%, p=0.0029). The duration of
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disease was also a factor for asthma control; in patients with a <2-year course of
19
disease, the proportion achieving either controlled or partly controlled asthma was
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97.4%, which was significantly higher than that in patients with a longer course of
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disease (93.5% for 2–5 years and 89.5% for >5 years).
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22
The present study demonstrated that age is another factor that may influence
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asthma control. The proportion of patients with GINA-defined, controlled asthma
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aged <30 years or >50 years was 68.8% and 50.1%, respectively, and the proportion 16
ACCEPTED MANUSCRIPT of those with either controlled or partly controlled asthma was 96.8% and 93.8%,
2
respectively. Complexity of treatment regimens together with poor treatment
3
compliance and inhaler technique may contribute to poor asthma control in older
4
patients [1]. Furthermore, older patients often present with comorbidities such as
5
chronic bronchitis and COPD [1]. In contrast, asthma control in middle-aged patients
6
may be more related to economic status and duration of smoking [14]. Therefore,
7
different approaches may be required to improve asthma control in different age
8
groups.
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1
It should be noted that education level is a risk factor for hospitalization in older
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asthma patients, suggesting an impact of education level on asthma control and
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prognosis [15]. The multivariate regression analysis presented here did not suggest
12
that education level was a factor affecting asthma control.
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According to the Chinese guidelines, spirometry is optional for the evaluation of
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asthma control level [16]. Therefore, in this non-interventional study, spirometry data
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were collected at the investigators’ discretion and were not available to validate
16
asthma control levels in all patients. Limitations of this study include the reliance on
17
the patient’s own recall of the use of reliever medication during the previous week and
18
the use of patient completed questionnaires rather than investigator-led assessments.
19
However, the ACT has been validated as a useful tool for asthma screening, which is
20
not only suitable for patients’ self-management but also long-term monitoring of
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asthma control [17,18].
22
Conclusions
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In conclusion, this study demonstrates that a high proportion of Chinese asthma
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patients can achieve GINA-defined asthma control with budesonide/formoterol in a 17
ACCEPTED MANUSCRIPT 1
real-world setting. Greater attention should be paid to male patients, older patients,
2
patients with a longer disease course, and those with a low level of education in the
3
clinical treatment of asthma.
4
Appendices 1. Supplementary Table 1. Levels of asthma control according to the Global Initiative
6
for Asthma (GINA) 2011.
7
2. Supplementary Table 2. Multivariate logistic regression analysis for ACT-defined
8
asthma control with variables in the full analysis set.
9
Declarations
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Ethics approval and consent to participate
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The Ethics Committee of the China-Japan Friendship Hospital, the leading site,
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approved the study protocol and informed consent form (ICF) prior to study initiation
13
(approval number 2013-19). All patients participating in this study voluntarily signed
14
the ICF and received a copy of the ICF before study initiation.
15
Consent for publication
16
Not applicable
17
Availability of data and materials
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All data generated and/or analyzed during this study are included in this published
19
article [and its supplementary information files]
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Competing Interests
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Chuntao Liu reports financial relationships, in the form of personal fees, with
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AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. Yuejian Liu reports
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financial relationships, in the form of personal fees, with AstraZeneca, Boehringer
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Ingelheim, GlaxoSmithKline and Pfizer. All other authors have no conflict of interest 18
ACCEPTED MANUSCRIPT to declare.
2
Funding
3
This work was sponsored by AstraZeneca. The sponsor funded and was involved in
4
study design, collection, analysis and interpretation of data, medical writing and the
5
final decision to submit the manuscript.
6
Authors’ contributions
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Study design: All authors. Data analysis: All authors. Writing manuscript: All authors.
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Approval of the final version: All authors.
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Acknowledgments
The authors would like to thank Hanson Deng of Shanghai Ingsci Information
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Technology Co., LTD, and Dr Tom Priddle of Nucleus Global for providing the
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necessary writing assistance and editorial support during development of the
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manuscript funded by AstraZeneca.
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References
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1. GINA. 2016 GINA Report, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma - GINA. http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-pr evention/. Accessed 1 December 2016.
23 24 25
2. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martínez-Jimenez NE, Buhl, R. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61:725-36.
26 27
3. Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations
AC C
18
19
ACCEPTED MANUSCRIPT in adults with persistent asthma. Respir Med. 2006;100:1152-62.
2 3 4
4. Bousquet J, Boulet L-P, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007;101:2437-46.
5 6
5. Boonsawat W, Thinkhamrop B. Role of budesonide/formoterol maintenance and reliever therapy: a pragmatic study. Asian Pac J Allergy Immunol. 2014;32:160-5.
7 8 9
6. Lin J, Shen H, Zhou X, Yin C, Chen P, Liu G, Su N. Review and outlook of asthma management within the past 60 years in China. Zhonghua Jie He He Hu Xi Za Zhi. 2013;36:907-10.
10 11 12 13
7. Zhong N, Lin J, Shen K. Asthma Control In China: Current Status And Influencing Factors. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingA bstracts.A4595. Accessed 1 December 2016.
14 15 16 17
8. GINA. 2011 GINA Report: Global Strategy for Asthma Management and Prevention. http://www.qu.edu.qa/pharmacy/professional_development/documents/GINA_Report _2011-1.pdf. Accessed 01 December 2016.
18 19 20
9. Su N, Lin J, Chen P, Li J, Wu C, Yin K, Liu C, Chen Y, Zhou X, Yuan Y, Huang X. Evaluation of asthma control: a questionnaire-based survey in China. Chin Med J (Engl). 2014;127:2030-6.
21
25
10. Müller V, Gálffy G, Eszes N, Losonczy G, Bizzi A, Nicolini G, Chrystyn H, Tamási L. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extra fine formulation. BMC Pulm Med. 2011:11:40.
26 27 28
11. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray PJ, Pendergraft TB. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113:59-65.
29
12. Füsun Yıldız, On behalf of the ASIT Study Group. Factors influencing asthma control: results of a real-life prospective observational asthma inhaler treatment (ASIT) study. J Asthma Allergy. 2013:6:93–101.
24
30 31
SC
M AN U
TE D
EP
23
AC C
22
RI PT
1
33
13. Allegra L, Cremonesi G, Girbino G, Ingrassia E, Marsico S, Nicolini G, Terzano C, On behalf of the PRISMA (PRospectIve Study on asthMA control) Study Group.
34
Real-life prospective study on asthma control in Italy: Cross-sectional phase results.
32
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ACCEPTED MANUSCRIPT Respir Med. 2012:106:205-214.
2 3 4 5
14. Burgess JA, Matheson MC, Gurrin LC, Byrnes GB, Adams KS, Wharton CL, Giles GG, Jenkins MA, Hopper JL, Abramson MJ, Walters EH, Dharmage SC. Factors influencing asthma remission: a longitudinal study from childhood to middle age. Thorax. 2011;66:508-13.
6 7 8
15. Diette GB, Krishnan JA, Dominici F, Haponik E, Skinner EA, Steinwachs D, WU, AW. Asthma in older patients: factors associated with hospitalization. Arch Intern Med. 2002;162:1123-32.
9 10
16. Asthma Workgroup, Chinese Thoracic Society, Chinese Medial Association. Chinese guideline for the prevention and management of bronchial asthma (2016).
11
Chin J Tuberc Respir Dis. 2016:39:675-697.
12 13 14
17. Zhou X, Ding F-M, Lin J-T, Yin K-S, Chen P, He Q-Y, Shen HH, Wan HY, Liu CT, Li J, Wang CZ. Validity of Asthma Control Test in Chinese patients. Chin Med J (Engl). 2007;120:1037-41.
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18. Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, Kosinski M, Pendergraft TB, Jhingran P. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol. 2006;117:549-56.
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Asthma control level with budesonide/formoterol in real-world in China was assessed 1483 asthma out-patients from 27 medical centers were enrolled in this study Asthma was controlled in 58.6% patients and partly controlled in 35.5% patients Long asthma duration and old age were associated with lower control levels
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ACCEPTED MANUSCRIPT Conflict of Interest Statment Chuntao Liu reports financial relationships, in the form of personal fees, with AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. Yuejian Liu reports financial relationships, in the form of personal fees, with AstraZeneca, Boehringer Ingelheim,
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GlaxoSmithKline and Pfizer. All other authors have no conflict of interest to declare.