Real-World Prescribing Pattern of Asthma Management in China: A Retrospective, Descriptive Analysis

is a chronic inammatory disorder of the airway that requires long-term medication management. Objective To describe the real-world prescribing patterns for asthma management in the Chinese population. Methods A retrospective analysis of 8,732 patients from January 2011 to September 2019 in 10 hospitals was conducted. Prescribing patterns of short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), inhaled corticosteroids (ICS), intravenous corticosteroids, antihistamines, leukotriene receptor antagonists (LTRA), theophylline, antibiotics, and Chinese patent medicines were included in the analysis. Chi-square and logistic regression were calculated. P value of <0.05 was considered as statistical signicance.


Abstract Background
Asthma is a chronic in ammatory disorder of the airway that requires long-term medication management.

Objective
To describe the real-world prescribing patterns for asthma management in the Chinese population.

Methods
A retrospective analysis of 8,732 patients from January 2011 to September 2019 in 10 hospitals was conducted. Prescribing patterns of short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), inhaled corticosteroids (ICS), intravenous corticosteroids, antihistamines, leukotriene receptor antagonists (LTRA), theophylline, antibiotics, and Chinese patent medicines were included in the analysis. Chi-square and logistic regression were calculated. P value of <0.05 was considered as statistical signi cance.

Conclusions
This study provides valuable insight into clinical practices of asthma management in China. Poor adherence to clinical reports was identi ed. Efforts are required to improve the quality of asthma care.

Background
Asthma is a chronic in ammatory disease of the airway presented with episodes of wheezing, shortness of breath, chest tightness [1][2][3].
Over 300 million people suffer from asthma worldwide, causing about 461,000 deaths per year [4,5]. A recent epidemiology study pointed out that about 45.7 million people in China have asthma, 28.8% of which were physician diagnosed[6]. Asthma poses a signi cant burden on the lives of patients and healthcare systems. An analysis of the UK national databases revealed that asthma resulted in 93,000 hospitalizations and 1,800 intensive-care unit visits [7]. The average asthma cost, varied from country to country, is $USD 1,900 to $USD3,100. The cost is much higher in patients with severe, uncontrolled asthmas, or asthma exacerbations [8,9].
Asthma exacerbations are commonly triggered by viral/bacterial infections, allergen exposure, and tobacco smoke [10]. It is presented as episodes of progressive increase in signs and symptoms, often leading to emergency department (ED) visits and hospital admissions. Therefore, proper asthma management and optimizing asthma medications are essential to alleviate the disease burden and economic burden on asthma patients. Inhale corticosteroids (ICS) remain the cornerstone of asthma treatment due to their e cacy in lowering risks of airway in ammations, exacerbations, and decline in lung function [11,12]. The 2021 Global Initiative for Asthma (GINA) Report recommends ICS-formoterol as the preferred therapy in adult patients with mild asthma while using short-acting beta-agonist (SABA) alone is considered as an alternative [13]. Maintenance long-acting beta-agonists (LABA) are considered as part of the preferred therapy to whose asthma cannot be controlled with as-needed ICS/LABA [13,14].
Several studies regarding the real-world pharmacological management of asthma mainly focused on the effectiveness of different types of inhalers, the risk of exacerbations in asthma of different severities, the choices of medications when initiating asthma treatment, and patient adherence to asthma medications [15][16][17][18]. Few research described the different prescribing patterns for asthma between traditional Chinese medication TCM and western medicine, well and poorly controlled asthma, as well as changes in the number of medications prescribed over the past decade. Whether these factors are associated with the risk of acute asthma exacerbations is still unclear.
This study used longitudinal data of an asthma cohort from 10 hospitals in Jinan, China. The primary objective was to describe the realworld prescribing patterns for asthma management.

Study Design
This was a retrospective, descriptive analysis of patients over the age of 18 with at least one diagnosis of asthma from January 2011 to September 2019 in 10 hospitals. Patients were excluded if they had missing data for age or had surgical interventions during the same o ce visit. Data were extracted through a review of medical encounters documented in the Jinan Health Medical Big Data Platform, administered by Shandong Health Medical Big Data Co., Ltd.

Clinical data and de nitions
Medications considered as parts of asthma regimens were short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), inhaled corticosteroids (ICS), intravenous corticosteroids, antihistamines, leukotriene receptor antagonists (LTRA), theophylline, antibiotics, and Chinese patent medicines. Treatments using TCM were de ned as any visit with prescription of Chinese medicine or proprietary Chinese medicine preparations to traditional Chinese medicine hospitals, department of TCM in tertiary hospitals, and/or department of TCM and integrative medicine in medical institutions. All other o ce visits were considered as western medicine treatments.

Primary Endpoint
The primary endpoint of the study is the proportion of different classes of asthma prescriptions. differences between western and Chinese medicine, stable asthma and acute asthma exacerbations, and yearly changes of asthma prescriptions were analyzed.

Statistical analysis
The counts and proportion of prescriptions in different aspects were calculated. The statistical analysis was conducted with R software,

Medication use during the study period
During the study period, 14,264 patients with asthma were identi ed, of which 8,789 patients had prescription-lling records. A total of 8,732 patients had prescriptions for stable asthma; 499 patients had prescriptions for acute asthma exacerbations. Classes of medications prescribed are presented in Table 1. A total of 1,192 ICS prescriptions were documented in 698 (7.99%) patients with stable asthma and 160 prescriptions in 105 patients had asthma exacerbations. ICS/LABA was prescribed for 2,940 (33.67%) patients with stable asthma and 141 (31.4%) patients with asthma exacerbations, respectively. LTRA was prescribed in 2,006 (22.97%) patients with stable asthma and 86 (19.15%) patients with asthma exacerbations. Chinese herbal medicines or Chinese patent medicines were used in over 40% of patients with stable asthma and over 30% of patients with asthma exacerbations. Systemic antibiotics (57.91%), systemic corticosteroids (46.1%), and theophylline (51.45%) were three of the top medications prescribed during acute asthma exacerbations. Patients receiving TCM and western medicine for asthma management Of the identi ed asthma patients, 8,877 patients received TCM, of which 6 (0.07%) had physician o ce visits that did not specify the department they visited; 3,237 patients were managed by western medicine (Table 2). Prescription lling records were found in 3,212 patients, out of which 3,160 took medications for stable asthma. A total of 282 patients took medications for acute asthma exacerbations.

Discussion
There is a sharp increase in asthma prevalence since the 1960s, especially in developed countries [4]. It was proposed that decreased exposure to house dust, mites, fungi, and other unhygienic environments in the developed country contributes to the increasing number of asthma patients [19]. As expected, our study highlights the increase in total prescription counts per year and the number of patients with asthma exacerbations. However, the rise in physician-identi ed patients and the implementation of electronic medical records can also contribute to the increase in our ndings.
In this retrospective, real-world analysis, we demonstrated the prevalence of different medications used for asthma management in China. ICS is part of the rst-line therapy in asthma, regardless of disease severity. It is delivered directly into the lungs, thus, limiting the systemic adverse effects of corticosteroids [20]. The underuse of ICS may be due to poor adherence, intolerable side effects, contraindications, and concerns for increased risk of pneumonia, especially in patients with mild or moderate asthma. Over half of the cohort uses ICS for stable asthma. ICS-containing medications were prescribed to 44.66% of patients with stable asthma, similar to ICS uses in the U.K. and the U.S, both over 40% [21,22], and much higher than those in Japan and Korea, which were around 10% [23]. This proportion is also higher than 10.2% reported by Huang, et al in patients with physician-diagnosed asthma[6]. The con icting results of ICS use may be due to the changes in the guidelines, the perceptions of long-term steroid use, and the transformation of hand-written medical records to electronic data.
According to the GINA report, ICS/LABA is recommended in almost all adult asthma patients. Regular use of ICS and LABA allows a lower dose of ICS, improves symptom management, and reduces the risk of exacerbations [24]. In addition, the combination is more effective than ICS+LTRA [25]. In our study, ICS/LABA was the most frequently prescribed medication (33.67%) to patients with stable asthma, much lower than 90.2% of patients in the INITIAL study [26]. There was a signi cantly decreased risk of exacerbations (P < 0.05) in patients using ICS+LTRA. Our nding is consistent with earlier studies regarding the bene ts of ICS/LABA [24,[27][28][29].
LTRA improves asthma control and reduces the frequency of asthma exacerbations, but is less effective than ICS [30]. Therefore, LTRA is listed by the guidelines as an alternative add-on in patients with moderate or severe asthma. LTRA is the second most prescribed medication in our cohort (22.97%). However, LTRA did not show signi cant bene t in preventing exacerbations in this study.
In our cohort, over 60% of patients received TCM management. Though the exact mechanisms of TCM are still unclear, it has shown some effects in anti-in ammation, airway relaxation, and reducing airway hypersensitivity [31]. TCM, used as adjuvant therapy, can reduce asthma symptoms, enhance patients' lung function, and improve the quality of life, but the treatment effects were limited and may not reduce the risk of exacerbations [31,32]. Our study showed a continuous decrease in TCM use over the years while increasing use of western medicine, which may be explained by the implementation of the guidelines or the limited e cacy of TCM in patients with moderate to severe asthma.
The GINA report recommends using SABA, oxygen, intravenous corticosteroids, and ICS for managing exacerbations. Other studies showed that 87% to 92.24% of patients with asthma exacerbation received ICS or ICS/LABA or ICS/LABA [33,34]. In the current study, systemic antibiotics (57.91%), systemic corticosteroids (46.1%), and theophylline (51.45%) were frequently prescribed to patients with asthma exacerbations. The rate (51.45%) of theophylline use during acute exacerbations of asthma, which is comparable to theophylline application in the UK [35]. Theophylline reduces days of hospitalizations but is not as effective as SABA in improving lung functions in acute settings [36]. In addition, theophylline requires frequent blood concentration monitoring to avoid toxicity. It is no longer recommended due to its poor e cacy and safety pro le.

Strengths and Limitations
To our knowledge, this is the largest retrospective observational cohort study evaluating real-world prescribing patterns of asthma medications in China. It is also the rst one that includes both western medicine and TCM for asthma management, and changes in asthma medication use over time. The study has several limitations. First, the data extraction was based on the medical encounters recorded in the data platform. O ce visits and prescriptions that were in paper-based records were not included which might account for the lower proportion of patients receiving each medication. Changes in medications in patients did not experience exacerbations, and medication adherence was also not analyzed in the study. Due to the nature of retrospective observational design, the strength and frequency of medication were decided by physicians. In addition, it is unclear why each medication was prescribed. Lastly, the speci c TCM prescribed was not included in the study, thus the effect of TCM in addition to western medicine on asthma management cannot be determined.

Conclusions
Our study suggests that more asthma patients in China were managed with TCM than western medicine. In those managed with western medicine, there are gaps between practical medication management and guideline recommendations, partly due to the study design and physicians' perspectives of asthma management. The study provided valuable insight into clinical practices of asthma management in China. Whether TCM reduced the rate of asthma exacerbation requires further investigation. National and regional efforts are necessary to improve the medication selections for patients with asthma.