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Prescription patterns of traditional Chinese medicine for peptic ulcer disease in Taiwan: A nationwide population-based study
Journal of Ethnopharmacology 176 (2015) 311–320
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Prescription patterns of traditional Chinese medicine for peptic ulcer disease in Taiwan: A nationwide population-based study Chin-Ying Huang a,b,1, Wan-Yu Lai c,d,1, Mao-Feng Sun b,e,f, Che-Chen Lin g, Bor-Chyuan Chen h, Hung-Jen Lin b,i, Ching-Mao Chang j,k, Chung-Hsien Yang b,i, Kuo-Chin Huang b,f, Hung-Rong Yen a,b,e,f,n a Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, 2 Yude Road, North District, Taichung 404, Taiwan b Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan c Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan d School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan e Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan f School of Chinese Medicine, China Medical University, Taichung, Taiwan g Health Data Management Office, China Medical University Hospital, Taichung, Taiwan h Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan i School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan j Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei, Taiwan k Graduate Institute of Clinical Medicine, and Graduate Institute of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
art ic l e i nf o
a b s t r a c t
Article history: Received 11 June 2015 Received in revised form 19 October 2015 Accepted 1 November 2015 Available online 5 November 2015
Ethnopharmacological relevance: Peptic ulcer disease is a common digestive disease. There is a lack of large-scale survey on the use of traditional Chinese medicine (TCM) for the treatment of peptic ulcer disease. This study aimed to investigate the utilization of TCM for the treatment of peptic ulcer disease in Taiwan. Materials and methods: We analyzed a random sample comprised of one million individuals with newly diagnosed peptic ulcer disease between 2001 and 2010 from the National Health Insurance Research Database in Taiwan. Demographic characteristics and TCM usage, including Chinese herbal formulas and the single herbs prescribed for patients with peptic ulcer disease, were analyzed. Results: A total of 96,624 newly diagnosed subjects with peptic ulcer disease were included. 14,983 (15.5%) patients were TCM users. People residing in highly urbanized areas, younger people and female (compared with male) were more likely to use TCM. With regard to the comorbidities, TCM users had a lower prevalence of coronary artery disease, chronic obstructive lung disease, diabetes mellitus and liver cirrhosis and stroke. The average time between onset of peptic ulcer disease and the first visit to a TCM clinic was 4.7 months. Majority of the patients (n ¼ 14,449; 96.4%) received only Chinese herbal remedies. The most frequently prescribed Chinese herbal formula and single herb was Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) and Hai-Piao-Xiao (Os Sepiae), respectivley. The core pattern analysis showed that combination of Ban-Xia-Xie-Xin-Tang, Hai-Piao-Xiao (Os Sepiae), Yan-HuSuo (Rhizoma Corydalis), Bei-Mu (Bulbus Fritillariae Thunbergii) and Chuan-Lian-Zi (Fructus Toosendan) was most frequently used for peptic ulcer disease. Conclusions: Our study identified the core prescription patterns of TCM for patients with peptic ulcer disease in Taiwan. Further basic and clinical studies are necessary to elucidate the efficacy and mechanisms. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ban-Xia-Xie-Xin-Tang Complementary and alternative medicine National health insurance research database Os Sepiae Peptic ulcer disease Traditional Chinese medicine
n Corresponding author at: Research Center for Traditional Chinese Medicine, Department of Medical Research and Department of Chinese Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404, Taiwan. Fax: þ 886-4-2236-5141. E-mail address: [email protected] (H.-R. Yen). 1 These authors contributed equally as co-first authors.
http://dx.doi.org/10.1016/j.jep.2015.11.002 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.
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1. Introduction Peptic ulcer disease is a common digestive disorder, including gastric and duodenal ulcers. In the United States, approximately 15 million people have peptic ulcer disease (Torpy et al., 2012). About 12% of males and 10% of females suffered from peptic ulcer disease over their lifetimes (Wang et al., 2012). The prevalence of peptic ulcer disease in asymptomatic subjects is 9.4% in Taiwan (Wang et al., 2011). Two third of the Taiwanese peptic ulcer disease patients had no remarkable symptoms (Lu et al., 2004). Peptic ulcer disease is an imbalance of aggressive gastric luminal factors and defensive mucosal barrier function. Conventional Western medications for the treatment of peptic ulcer disease include antacids, anti-secretory medications such as H2-receptor antagonists and proton-pump inhibitors. Although triple or quadruple therapy has been developed for the eradication of Helicobacter pylori (Luther et al., 2010), increasing antibiotic resistance and intolerance has made alternative treatments necessary (Malfertheiner et al., 2011). For instance, the primary resistance of amoxicillin, clarithromycin and metronidazole in Taiwan were 2.2%, 7.9%, and 23.7% respectively. The primary levofloxacin resistance even rose from 4.9% in 2000–2007 to 8.3% in 2008–2010 and 13.4% in 2011–2012 in Taiwan (Liou et al., 2015). The use of antibiotics also has an unknown effect on the homeostasis of gut microbiome (Malnick et al., 2014). Other side effects resulting from the conventional medications include constipation and diarrhea (Cohen et al., 2015), impotence (Sabesin, 1993), interference with drug metabolism (Pattichis and Louca, 1995) and parietal cell hypertrophy (Ksiadzyna et al., 2015). These unwanted side effects drive some patients to seek alternative advice. It is necessary to investigate the usage of traditional medicine for the treatment of peptic ulcer disease. Previous study of traditional Chinese medicine (TCM) have found that Si-Jun-Zi-Tang can inhibit the hypersecretion of hydrogen chloride in the stomach in a rate model of stress-induced peptic ulcers (Chen et al., 2013). Chai-Hu-Gui-Zhi-Tang and can prevent the recurrence of peptic ulcers (Chen et al., 2010) and another formula HZJW can heal peptic ulcer and inhibit H. pylori (Xie et al., 2013). Unfortunately, evidence obtained from highquality clinical studies is very limited (Zhou et al., 2007). Many of the studies neglect stringent evidence based diagnostic and therapeutic criteria (Teschke et al., 2015). Due to the lack of knowledge about the prescription profile of TCM, researchers and doctors have found it difficult to select optimal candidates to explore the potential efficacy and mechanisms of Chinese herbal products targeting peptic ulcer disease. TCM, which includes acupuncture and moxibustion, Chinese traumatology and Chinese herbal products, has been integrated as an important part of healthcare in Taiwan. It has been used in various diseases such as gynecologic disease (Yen et al., 2015a), atopic dermatitis (Lin et al., 2014), rhinitis (Yen et al., 2015b, 2015c), asthma (Huang et al., 2013), rheumatoid arthritis (Huang et al., 2015) and endocrinologic disorder (Hsu et al., 2014; Yu et al., 2014). The Taiwanese National Health Insurance program, which was established in 1995, also reimburses the above-mentioned TCM services (Huang et al., 2014; Yen et al., 2013). This mandatory insurance program covers approximately 23 million people, comprising 99.89% of the total population in 2010 (BoNH, 2010). Claims data from the National Health Insurance program were de-identified and sent to the National Health Research Institutes to form the National Health Insurance Research Database (NHIRD). This database provides a nationwide population-based claims database with long-term follow-up. The aim of this study is to analyze this comprehensive database and to determine the TCM utilization patterns of newly diagnosed peptic ulcer disease patients in Taiwan. The results of this study should provide valuable information
for further pharmacological studies and clinical trials.
2. Materials and methods 2.1. Data source This study was designed as a population-based study analyzing a sample of one million subjects randomly selected from the 23 million beneficiaries of the National Health Insurance program in Taiwan. The identification numbers of all individuals were encrypted and transformed to protect the privacy of enrollees. A random number function was used to generate random number and randomly selected the subjects. There is no significant difference in the distribution of age, gender and insured amount between the patients in the randomly selected samples and the original NHIRD. (http://nhird.nhri.org.tw/en/index.html). The datasets contain patient’s gender and date of birth, all records of clinical visits and hospitalization, prescribed drugs and dosages, including Chinese herbal products, and the major diagnoses coded in the International Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9-CM) formats. This study was approved by the Research Ethics Committee of the China Medical University and Hospital (CMU-REC-101-012). 2.2. Study subjects The selection of study subjects from the random sample of one million individuals was represented as Fig. 1. Of the one million randomly selected individuals in the National Heath Insurance Program, we identified 176,300 patients with peptic ulcer disease. Patients who were diagnosed as peptic ulcer disease with ICD-9CM code: 531–534, for more then three times; no matter they are proved by clinical judgment, endoscopy, or H. pylori infection, were included. Prevalent cases (n ¼ 79,676) that had been diagnosed before the end of 2000 were excluded to ensure that all the subjects included were newly diagnosed. Finally, 96,624 study subjects diagnosed as peptic ulcer disease from 2001 to 2008 were included in the study cohort with a follow-up period through 2010. They were further divided into TCM users (n ¼14,983) and non-TCM users (n¼ 81,641). TCM users were defined as those who visited TCM clinics. Non-TCM users were defined as those who never visited TCM clinics after the initial diagnosis of peptic ulcer disease. 2.3. Study variables To determine the key independent variables for utilization of TCM among peptic ulcer disease patients, we selected a series of demographic factors based on previous studies (Huang et al., 2014; Yen et al., 2013). The subjects were categorized into three groups according to age: o 20, 20–39, 45–59, and Z60 years. Urbanization levels in Taiwan are divided into four levels as previous described (Yen et al., 2015c). Level 1 indicates the “most urbanized” communities and level 4 indicates the “least urbanized” communities. We also searched the NHIRD database for clinical comorbidities and treatment records related to peptic ulcer disease as independent variables. The comorbidities were identified by ICD-9-CM codes, including 410–414 (coronary artery disease; CAD), 496 (chronic obstructive lung disease; COPD), 250 (diabetes mellitus; DM), 571 (liver cirrhosis) and stroke (430–438). To investigate the financial outcome of TCM in Taiwan, we measured the medical expenditure of outpatient clinic care and hospitalization between patients with and without TCM treatment within the one year after peptic ulcer was diagnosed and calculated in US dollars. The TCM herbal formulas and single herbs reimbursed by
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Fig. 1. Flow recruitment chart of subjects from the one million samples randomly selected from the National Health Insurance Research Database (NHIRD) from 2001 to 2010 in Taiwan.
the National Health Insurance Program are the so-called “concentrated TCM granules” (finished herbal products) manufactured by good manufacturing practice (GMP)-certified pharmaceutical companies in Taiwan. These Chinese herbal products have good quality control. The TCM indications are based on TCM theory (Bensky et al., 2004; Scheid et al., 2009). 2.4. Statistical analysis Data analysis consisted of descriptive statistics, including the prescription rates of TCM users stratified by patient's demographic characteristics, indications for the prescription of TCM, and the most frequently prescribed Chinese herbal products used when treating peptic ulcer disease. We presented the expenditure of clinic as mean and SD between the peptic ulcer patients with and without TCM and assessed the difference by t-test. The data were analyzed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, U.S.A.). Univariate analysis was utilized to compare the TCM users with the non-TCM users. Pearson's χ2 tests was performed to assess the relationship between the categorical variables and to examine the differences between TCM users and non-TCM users. A p-value o0.05 was considered statistically significant. Analysis of core prescription patterns was described previously (Chang et al., 2015). In brief, an open-sourced freeware NodeXL (http://nodexl. codeplex.com/) was used to identify the core patterns of Chinese herb products for the treatment of patients with peptic ulcer disease, and the most common two herbal combinations were applied in this network analysis. The thicker line width, defined as counts of connections between formulas and herbs, indicated significant prescription patterns in the network. 3. Results There were 96,624 patients who were newly diagnosed with peptic ulcer disease. Among them, 14,983 (15.5%) patients used
TCM outpatient services for the treatment of peptic ulcer disease. The mean age of TCM users was younger than that of non-TCM users (40.3 versus 50.5 years old). Majority (59.7%) of the TCM users were female. Most of the TCM users resided in urbanized areas. With regard to the comorbidities, TCM users had a lower prevalence of coronary artery disease, chronic obstructive lung disease, diabetes mellitus and liver cirrhosis and stroke. The status of H. pylori infection was not available due to the nature of the database. The percentage of patients receiving esophagogastroduodenoscopy within 10 days before or after initial diagnosis were 36.3% and 18.3% for the non-TCM users and TCM users, respectively. The average time between onset of peptic ulcer disease and the first visit to a TCM clinic was 4.7 months (Table 1). Regarding the treatment modalities given to patients with peptic ulcer disease, 14,449 (96.4%) patients received only Chinese herbal remedies, while 277 (1.9%) patients were treated by acupuncture or Chinese traumatology only and 257 (1.7%) patients received combination of both treatments. More than half of the patients (n ¼8327; 55.6%) visited TCM clinics for 1–3 times and 3719 (24.8%) patients visited TCM clinics for more than 6 times (Table 2). To investigate the prescription patterns of the Chinese herbal remedies, we conducted a comprehensive analysis and identified ten most commonly prescribed Chinese herbal formulas and single herbs, respectively. The most frequently prescribed Chinese herbal formula was Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) (Table 3). Regarding the single herbs for the treatment of peptic ulcer disease, Hai-Piao-Xiao (Os Sepiae) was the most frequently prescribed single herb (Table 4). The top 100 herbal formulas and single herbs for peptic ulcer patients were analyzed through open-sourced freeware NodeXL, and the core pattern of the prescriptions was the combination of Ban-Xia-Xie-Xin-Tang, Hai-Piao-Xiao (Os Sepiae), Yan-Hu-Suo (Rhizoma Corydalis), Bei-Mu (Bulbus Fritillariae Thunbergii) and
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Table 1 Demographic characteristics of TCM and non-TCM users among patients with peptic ulcer disease from 2001 to 2010 in Taiwan. Variable
Non-TCM users TCM users N (%) N (%)
p value
No of subjects Age at baseline, mean years (SD)a o20 20–39 40–59 ≧60 Sex Female Male Urbanization 1 (highest) 2 3 4 þ (lowest) Comorbidity CAD COPD DM Stroke Liver cirrhosis Esophagogastroduodenoscopyb No Yes The duration between onset of peptic ulcer disease and the first visit to a TCM clinic, month
81,641 50.5 3247 20,218 32,445 25,731
(15.5) (16.5) (10.4) (40.5) (36.1) (13.0)
o0.0001 o0.0001
40,462 (49.6) 41,179 (50.4)
8941 (59.7) 6042 (40.3)
o0.0001
22,559 23,615 14,352 21,114
(27.6) (28.9) (17.6) (25.9)
4074 4576 2982 3351
(27.2) (30.5) (19.9) (22.4)
14,286 3259 8807 3668 16,484
(17.5) (4.0) (10.8) (4.5) (20.2)
1213 164 626 187 2241
(8.1) (1.1) (4.2) (1.2) (15.0)
(84.5) (17.7) (4.0) (24.8) (39.7) (31.5)
14,983 40.3 1560 6064 5408 1951
o0.0001
51,986 (63.7) 29,655 (36.3) 4.7
o0.0001 o0.0001 o0.0001 o0.0001 o0.0001 o0.0001
12,238 (81.7) 2745 (18.3)
TCM: traditional Chinese medicine; CAD: coronary artery disease; COPD: chronic obstructive lung disease; DM: diabetes mellitus. a
t-test. Esophagogastroduodenoscopy: patients underwent esophagogastroduodenoscopy within 10 days before or after the diagnosis of peptic ulcer was made. b
Table 2 Frequency distribution of TCM clinic visits and treatment modalities among TCM users from 2001 to 2010 in Taiwan. Number of TCM clinic visits
Chinese herbal Acupuncture or remedies only Chinese traumatology N (%) N (%)
Combination of Total of TCM clinic visits both treatments N (%) N (%)
All 1–3 4–6 46
14,449 7838 2916 3695
257 239 4 14
(96.4) (54.2) (20.2) (25.6)
277 250 17 10
(1.9) (90.3) (6.1) (3.6)
(1.7) (93) (1.6) (5.4)
14,983 8327 2937 3719
(100) (55.6) (19.6) (24.8)
TCM: traditional Chinese medicine
Chuan-Lian-Zi (Fructus Toosendan) (Fig. 2). Relative to the peptic ulcer patients without TCM treatment, the TCM users had lower medical expenditure for hospitalization (11687 1703 versus 2275 75880 US dollars, p o0.0001) and for outpatient clinic care (179 7249 versus 237 7484 US dollars, p o0.0001) (Table 5) for the first year after diagnosis of peptic ulcer disease.
4. Discussion This nationwide population-based study investigated the utilization of Chinese herbal products prescribed by licensed TCM doctors for patients who were newly diagnosed with peptic ulcer disease. We found approximately 15.5% of the patients visited TCM clinics. Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) and Hai-Piao-Xiao (Os Sepiae) were the most commonly prescribed herbal formula and single herb, respectively.
This is so far the largest comprehensive analysis of TCM usage among patients with peptic ulcer. The results from this study can be used for further pharmacological investigation or clinical trials. In accordance with previous findings (Shih et al., 2009, 2012; Yen et al., 2013), we found that younger people, women (compared with men), and people living in higher urbanized areas were more likely to visit TCM than non-TCM users. Although sometimes TCM users had self-reported poor health status tended to use TCM services (Shih et al., 2009), we found that TCM users among peptic ulcer patients had a lower prevalence of comorbidities. Those patients with more comorbidity diseases usually receive more complicate kinds of medications, which make them have lower attempts to receive TCM. This baseline difference between TCM users and non-users should be taken into consideration for comparative research on efficacy in the future. In this study, patients visited TCM services on average 4.7 months after initial diagnosis of peptic ulcer. The current Western medical treatment for peptic ulcer disease includes an antibiotics regimen targeting eradication of H. pylori (Luther et al., 2010). Some patients who believe in TCM or cannot tolerate the side effects of this regimen might seek TCM help after the initial diagnosis (Malfertheiner et al., 2011). In consistency with other studies in gastrointestinal disease or internal diseases, herbal remedies are the most common treatment approaches. (Huang et al., 2013; Pasalar and Lankarani, 2015; Yen et al., 2015b). We found that only very few patients received acupuncture therapy. Ban-Xia-Xie-Xin-Tang was the most frequently prescribed formula for peptic ulcer. It was originally documented in an ancient literature “Shang Han Lun”. The chief herb of this formula is Rhizoma Coptidis, which can clean the dampness and heat (Scheid et al., 2009). Its ingredient herbs, Rhizoma Coptidis and Radix Scutellariae are bitter and cold; together they can clear the heat and harmonize the yang. Rhizoma Pinelliae preparatum and Rhizoma Zingiberis are both acrid and warm; together they unblock the “focal distention”(pi in TCM). Radix Ginseng, Frustus Jujubae and Radix Glycyrrhizae preparata benefit the middle burner and prevent the dispersing actions of the bitter and cold herbs from injuring the Qi (Scheid et al., 2009). In an animal study, Ban-XiaXie-Xin-Tang reduced 70.1% of the ulcer areas in mice, while its derivative formula could even inhibited 96.9% ulcers (Xue et al., 2011). Another animal study conducted in Japan also observed that pretreatment with Ban-Xia-Xie-Xin-Tang could markedly inhibit the reduction of gastric mucin content and the development of gastric ulcers (Li et al., 1998). In human study, a meta-analysis including ten randomized controlled trails with a total of 972 patients showed that Ban-Xia-Xie-Xin-Tang had a better effect than Western medicine in treating functional dyspepsia, consisting of epigastric pain, burning, fullness, discomfort, early satiety, nausea, vomiting, and belching (Gan et al., 2014). Intra-gastric administration of Ban-Xia-Xie-Xin-Tang extracts could lead to decreased mRNA expression levels of IL-5 and IL-13 in the colonic tissue (Wang et al., 2014a). In addition, Ban-Xia-Xie-Xin-Tang suppressed TNF-α, IL-1β, IL-17, IL-23 and COX-2 production in a dextran sulfate sodium (DSS)-induced chronic ulcerative colitis model (Chen et al., 2015). The second commonly prescribed herbal formula is Xiang-ShaLiu-Jun-Zi-Tang. It has long been used to treat gastrointestinal discomfort in clinical practice. It ingredient herbs, Rhizoma Atractylodis macrocephalae and Poria, can strengthen the spleen and clean the dampness. Radix Ginseng and Radix Glycyrrhizae preparata benefit the middle burner. Rhizoma Pinelliae preparatum and Pericarpium Citri reticulatae move the Qi and clean the phlegm. Fructus Amomi and Radix Aucklandiae regulate the Qi and relieve pain. (Scheid et al., 2009) In a recent study, it was reported to increase the secretion of plasma motilin, lower serum gastrin levels, and enhance smooth muscle contraction by
Table 3 Ten most common herbal formulas for patients with peptic ulcer diseases from 2001 to 2010 in Taiwan. Herbal formula
(pin-yin name)
(English name)
Ban-Xia-Xie-XinTang
Pinelliae decoction to drain the epigastrium
Xiang-Sha-Liu-JunZi-Tang
Six gentlemen decoction with aucklandia and amomum
Ping-Wei-San
Calm the stomach powder
An-Zhong-San
Calm the middle powder
Jia-Wei-Xiao-YaoSan
Augmented rambling powder
Huo-Xiang-ZhengQi-Tang
Agastache powder to rectify the qi
Number of persondays N ¼2050,356 (%)
Average daily dose (g)
Indications in TCM use
Rhizoma Pinelliae preparatum (ZhiBan-Xia) Rhizoma Zingiberis (Gan-Jiang) Radix Scutellariae (Huang-Qin) Rhizoma Coptidis (Huang-Lian) Radix Ginseng (Ren-Shen) Fructus Jujubae (Da-Zao) Radix Glycyrrhizae preparata (ZhiGan-Cao) Radix Ginseng (Ren-Shen) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Glycyrrhizae preparata (ZhiGan-Cao) Rhizoma Pinelliae preparatum (ZhiBan-Xia) Fructus Amomi (Sha-Ren) Radix Aucklandiae (Mu-Xiang) Rhizoma Zingiberis recens (ShengJiang) Rhizoma Atractylodis (Cang-Zhu) Cortex Magnoliae officinalis (HouPo) Pericarpium Citri reticulatae (ChenPi) Radix Glycyrrhizae preparata (ZhiGan-Cao) Cortex Cinnamomi (Rou-Gui) Rhizoma Corydalis (Yan-Hu-Suo) Concha Ostreae (Mu-Li) Fructus Foeniculi (Xiao-Hui-Xiang) Rhizoma Zingiberis preparata (PaoJiang) Rhizoma Alpiniae officinarum (GaoLiang-Jiang) Radix Glycyrrhizae (Gan-Cao) Radix Angelicae sinensis (Dang-Gui) Radix Paeoniae (Shao-Yao) Poria (Fu-Ling) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Radix Bupleuri (Chai-Hu) Cortex Moutan (Mu-Dan-Pi) Fructus Gardeniae (Zhi-Zi) Radix Glycyrrhizae preparata (ZhiGan-Cao) Herba Pogostemonis (Huo-Xiang) Cortex Magnoliae officinalis (HouPo) Pericarpium Citri reticulatae (ChenPi) Folium Perillae (Zi-Su-Ye)
173,041 (8.4)
6.5
Epigastric focal distention, fullness and tightness with very slight or no pain, dry heaves, vomiting, borborygmus
119,886 (5.8)
5.8
Nausea and vomiting, emaciation, anorexia with a full feeling after very little food, weak abdomen
104,913 (5.1)
5.1
Distention and fullness in epigastrium and abdomen, loss of taste and appetite, heavy sensation in the limbs and body
77,668 (3.8)
6.2
Neurogenic gastric pain, ulcer, over abundance of stomach acid
68,619 (3.3)
5.7
Irritability, short temper, restlessness, fever or tidal fever, dry mouth, lower abdominal pain
46,038 (2.2)
4.8
Fever and chills, headache, abdominal fullness and oppression, pain, nausea and vomiting, borborygmus, diarrhea, loss of taste, aversion to cold
315
Composition
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Herbal formula
316
Table 3 (continued ) Herbal formula
Herbal formula
(pin-yin name)
(English name)
Ginseng, poria and atractylodis macrocephalae powder
Ma-Zi-Ren-Wan
Hemp seed pill
Si-Ni-San
Frigid extremities powder
Radix Angelicae dahuricae (Bai-Zhi) Rhizoma Pinelliae preparatum (ZhiBan-Xia) Pericarpium Arecae (Da-Fu-Pi) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Platycodi (Jie-Geng) Radix Glycyrrhizae preparata (ZhlGan-Cao) Radix Ginseng (Ren-Shen) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Glycyrrhizae preparata (ZhiGan-Cao) Rhizoma Dioscoreae (Shan-Yao) Semen Lablab album (Chao-BianDou) Semen Nelumbinis (Lian-Zi) Semen Coicis (Yi-Yi-Ren) Fructus Amomi (Sha-Ren) Radix Platycodi (Jie-Geng) Semen Cannabis (Hua-Ma-Ren) Semen Armeniacae (Xing-Ren) Radix Paeoniae (Shao-Yao) Fructus Aurantii immaturus (ZhiShi) Cortex Magnoliae officinalis (HouPo) Radix et Rhizoma Rhei (Da-Huang) Radix Bupleuri (Chai-Hu) Fructus Aurantii immaturus (ZhiShi) Radix Paeoniae alba (Bai Shao) Radix Glycyrrhizae preparata (ZhiGan-Cao)
Number of persondays N ¼2050,356 (%)
Average daily dose (g)
Indications in TCM use
43,715 (2.1)
6.3
Loose stools or diarrhea, weak extremities, weight loss, distention and a stifling sensation in abdomen, pale wan, indigestion
43,433 (2.1)
2.4
Constipation with hard, difficult to expel stool, dry skin, hemorrhoids, nocturia, dizziness
40,197 (2.0)
5.2
Cold extremities with heat in the interior, irregular fever, fullness and distention, abdominal pain, severe diarrhea, dysentery
C.-Y. Huang et al. / Journal of Ethnopharmacology 176 (2015) 311–320
Shen-Ling-Bai-ZhuSan
Composition
Table 4 Ten most common single herbs for patients with peptic ulcer disease from 2001 to 2010 in Taiwan. Number of person-days Average daily dose Indications in traditional Chinese medicine N ¼ 2565,558 (%) (g)
Pin-yin name
Latin name
Plant species
Hai-Piao-Xiao
Os Sepiae
Yan-Hu-Suo Bai-Ji
Rhizoma Corydalis Rhizoma Bletillae
Sepiella maindroni de Rochebrune Sepia esculenta Hoyle (not plant) Corydalis yanhusuo W.T. Wang Bletilla striata (Thunb.) Reichb. f.
Bei-Mu Da-Huang
Bulbus Fritillariae Tthunbergii Radix et Rhizoma Rhei
Hou-Po
Cortex Magnoliae Officinalis
Dan-Shen Mu-Xiang
Radix Salviae Miltiorrhizae Radix Aucklandiae
Chuan-Lian-Zi Fructus Toosendan Sha-Ren Fructus Amomi
119,120 (4.6)
1.7
96,337 (3.8) 75,750 (3.0)
1.6 2.3
Fritillaria thunbergii Miq.
66,378 (2.6)
1.9
Stomach acidity with stomach or epigastric pain, distasteful belching or acid regurgitation, bleeding Pain affecting the chest, abdomen or limbs, epigastric pain and dysmenorrhea Bleeding from the lungs and stomach with hematemesis, hemoptysis and epistaxis Neutralize acid, chronic cough, slight sputum
Rheum palmatum L. Rheum tanguticum Maxim. ex. Balf. Rheum officinale Baill. Magnolia officinalis Rehd. et Wils M. officinalis Rehd. et Wils. var. biloba Rehd. et Wils. Salvia miltiorrhiza Bge. Aucklandia lappa Decne
55,338 (2.2)
0.7
Constipation, abdominal distention and pain
52,408 (2.0)
1.4
Abdominal distention and fullness, nausea, and diarrhea
45,621 (1.8) 45,046 (1.8)
1.3 1.2
38,223 (1.5) 37,637 (1.5)
1.1 1.1
Abdominal pain, rib and hypochondriac pain Anorexia, a feeling of food sitting in the stomach, epigastric or abdominal pain or distention, nausea and vomiting Distention and pain and bulging disorders Distention and pain, in the epigastrium and abdomen, anorexia, vomiting and diarrhea
Melia toosendan Sieb. et Zucc. Amomum villosum Lour, Amomum villosum Lour. var. xanthioides T.L. Wu. Et Senjen longiligulare T.L. Wu.
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Single herbs
317
318
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Fig. 2. The top 100 herbal formulas and single herbs for peptic ulcer patients were analyzed through open-sourced freeware NodeXL. The thicker line width, defined as counts of connections between formulas and herbs, indicated significant prescription patterns in the network.
Table 5 Medical expenditure of hospitalization and outpatient care between TCM and nonTCM users for the first year after diagnosis of peptic ulcer disease. Cost
Hospitalization, USD Outpatient Clinic, USD
TCM users
Non-TCM users
N
N
mean (SD)
p-value
mean (SD)
280 1168 (1703) 4896 2275 (5880) 7627 179 (249) 80,643 237 (484)
o 0.0001 o 0.0001
TCM: traditional Chinese medicine; USD: US dollars.
increasing calcium levels (Tian et al., 2014). A multicenter, doubleblind, randomized, placebo-controlled study revealed that XiangSha-Liu-Jun-Zi-Tang reduced dyspepsia, especially effective among H. pylori-infected participants (Suzuki et al., 2014). In addition, it can improve electro-gastrogram, promote gastrointestinal motility and gastric emptying, decrease gastric sensitivity, and regulate gastrointestinal hormone (Feng, 1992). A meta-analysis found that Xiang-Sha-Liu-Jun-Zi-Tang could significantly improve symptoms better than prokinetic drugs for patients suffering from functional dyspepsia (Xiao et al., 2012). Its derivative, Si-Jun-Zi-Tang, has been reported to inhibit stress-induced ulcer by reducing the hypersecretion of hydrogen chloride and lowering the level of 5-HT and dopamine in brain soothe the stress. (Chen et al., 2013) Ping-Wei-San, the third most commonly prescribed formula for peptic ulcer, was used traditionally to alleviate distention and fullness in the epigastrium and abdomen, loss of taste and appetite, loose stools or diarrhea, easily-fatigued, increased desire to sleep, nausea and vomiting, belching, acid reflux (Scheid et al., 2009). It has been reported to relieve dyspeptic symptoms of gastrointestinal disorders (Chao et al., 2014). Jia-Wei-Xiao-Yao-San and Si-Ni-San were widely used to relieve the emotional and psychological symptoms, such as depression or stress (Lin et al., 2015; Tanaka et al., 2013). Huo-Xiang-Zheng-Qi-Tang has been
widely used for treatment of various common gastrointestinal infectious diseases. It was discovered to promote gastroenteric motility, regulate gastrointestinal function and immune response. An earlier study reported that Huo-Xiang-Zheng-Qi-Tang could decrease the level of TNF-α in a murine intestinal infection model (He et al., 2006). Shen-Ling-Bai-Zhu-San has been reported to have an antacid effect (Wu et al., 2010). Ma-Zi-Ren-Wan has been used for functional constipation (Cheng et al., 2011). Bao-He-Ni is also one of the commonly prescribed Chinese herbal formula for postsurgical colon cancer patients (Chao et al., 2014). Regarding the single herbs, Hai-Piao-Xiao (Os Sepiae) was the most commonly prescribed one. Its chief constituent is 80–85% of calcium carbonate (Li et al., 2010), which might acts like an antacid to relieve the discomfort resulted from excessive gastric acid. Combination of Hai-Piao-Xiao and Bei-Mu (Bulbus Fritillariae Thunbergii) prevented ethanol-induced gastric lesions in a rat model (Lin, 1998). Yan-Hu-Suo (Rhizoma Corydalis), the second commonly prescribed single herb, is widely used to treat abdominal pain due to qi stagnation (Scheid et al., 2009). It has been reported to inhibit H. pylori effect (Li et al., 2005), heal ulcer (Tianjiao et al., 2014) and relieve pain (Guo et al., 2014). Bai-Ji (Rhizoma Bletillae) has not only anti-inflammatory but also hemostatic action (Wang et al., 2014b). Chuan-Lian-Zi (Fructus Toosendan) has analgesic effect (Xie et al., 2008). We included the top 100 herbal formulas to identify the network of core prescriptions for patients with peptic ulcers. The core prescription pattern consisted of “Ban-Xia-Xie-Xin-Tang”, “HaiPiao-Xiao”, “Yan-Hu-Suo”, “Bei-Mu” and “Chuan-Lian-Zi”. In TCM theory, the function of raising the clear yang and descending the turbid yin is very important in middle burner. That may explain why Ban-Xia-Xie-Xin-Tang is the core formula. Besides recovering the basic function of the Spleen and the Stomach, quickly relieving the pain is also important. As discussed above, Hai-Piao-Xiao and Bei-Mu neutralize gastric acid and relieve burning sensation. YanHu-Suo and Chuan-Lian-Zi rectify the Qi to relieve pain and also to
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help strengthen the effect of Ban-Xia-Xie-Xin-Tang. Such a core pattern can harmonize the stomach and downbear counterflow, control acidity, move Qi and relieve pain. It may also regulate the function of the stomach and intestine. The core prescription pattern may be used as a candidate for further clinical research.
5. Limitations Some caveats of this study merit comments. First, this study did not include Chinese herbal remedies or decoctions that were purchased directly from TCM herbal pharmacies. Thus, the frequency of utilization might have been underestimated. However, the National Health Insurance covers TCM prescriptions (the concentrated herbal powder) manufactured by GMP-certified pharmaceutical companies in Taiwan. Within the National Health Insurance program, it costs only approximately 10 USD co-payment for visiting TCM clinics. Raw herbs are more expensive and take time to cook. Taiwanese who seek TCM therapy tend to choose the concentrated herbal powder instead of decoction (Huang et al., 2014; Yen et al., 2013). Second, there was no endoscopic data or the status of H. pylori infection available to evaluate the healing of ulcers due to the nature of this database. However, the diagnosis and TCM prescriptions were both made by physicians with qualified license, which means the present study has high credibility. These most common formulas and single herbs can be regarded as the consensus candidates for future studies. However, it has to be noted that evidence-based studies should be done. In addition, indications in TCM use may not apply to Western medicine. Future studies should focus on randomized, placebo-controlled, doubleblind clinical trials (Teschke et al., 2015). Endoscopic findings and the status of H. pylori infection should be documented in the trial.
6. Conclusions Our ethnopharmacological study identified the prescription patterns of Chinese herbal products for patients with peptic ulcer diseases. Several formulas or herbs were already pre-clinically investigated. Studying clinical efficacy has the preference as future objective. As TCM prescriptions are applied according to Chinese criteria for symptomatology, it will not be an easy task to evaluate efficacy on validated outcome scales. Further basic and clinical studies are warranted to elucidate their mechanism and efficacy.
Author contributions HRY, CYH and WYL conceptualized the study. CCL and CMC performed the statistical analysis. CYH, WYL, MFS, BCC, HJL, CHY and HRY contributed to the interpretation of TCM data. CYH, WYL and KCH contributed to the interpretation of pharmacological mechanisms. CYH and WYL contributed equally to draft the manuscript and HRY finalized the manuscript.
Conflict of interest The authors declare that they have no conflicts of interest.
Acknowledgments This study was supported by China Medical University under the Aim for Top University Plan of the Ministry of Education,
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Taiwan. This study was also supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002). This study was based in part on data from the National Health Insurance Research Database, provided by the National Health Insurance Administration, Ministry of Health and Welfare, and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes.
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Prescription patterns of traditional Chinese medicine for peptic ulcer disease in Taiwan: A nationwide population-based study Chin-Ying Huang a,b,1, Wan-Yu Lai c,d,1, Mao-Feng Sun b,e,f, Che-Chen Lin g, Bor-Chyuan Chen h, Hung-Jen Lin b,i, Ching-Mao Chang j,k, Chung-Hsien Yang b,i, Kuo-Chin Huang b,f, Hung-Rong Yen a,b,e,f,n a Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, 2 Yude Road, North District, Taichung 404, Taiwan b Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan c Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan d School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan e Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan f School of Chinese Medicine, China Medical University, Taichung, Taiwan g Health Data Management Office, China Medical University Hospital, Taichung, Taiwan h Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan i School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan j Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei, Taiwan k Graduate Institute of Clinical Medicine, and Graduate Institute of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
art ic l e i nf o
a b s t r a c t
Article history: Received 11 June 2015 Received in revised form 19 October 2015 Accepted 1 November 2015 Available online 5 November 2015
Ethnopharmacological relevance: Peptic ulcer disease is a common digestive disease. There is a lack of large-scale survey on the use of traditional Chinese medicine (TCM) for the treatment of peptic ulcer disease. This study aimed to investigate the utilization of TCM for the treatment of peptic ulcer disease in Taiwan. Materials and methods: We analyzed a random sample comprised of one million individuals with newly diagnosed peptic ulcer disease between 2001 and 2010 from the National Health Insurance Research Database in Taiwan. Demographic characteristics and TCM usage, including Chinese herbal formulas and the single herbs prescribed for patients with peptic ulcer disease, were analyzed. Results: A total of 96,624 newly diagnosed subjects with peptic ulcer disease were included. 14,983 (15.5%) patients were TCM users. People residing in highly urbanized areas, younger people and female (compared with male) were more likely to use TCM. With regard to the comorbidities, TCM users had a lower prevalence of coronary artery disease, chronic obstructive lung disease, diabetes mellitus and liver cirrhosis and stroke. The average time between onset of peptic ulcer disease and the first visit to a TCM clinic was 4.7 months. Majority of the patients (n ¼ 14,449; 96.4%) received only Chinese herbal remedies. The most frequently prescribed Chinese herbal formula and single herb was Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) and Hai-Piao-Xiao (Os Sepiae), respectivley. The core pattern analysis showed that combination of Ban-Xia-Xie-Xin-Tang, Hai-Piao-Xiao (Os Sepiae), Yan-HuSuo (Rhizoma Corydalis), Bei-Mu (Bulbus Fritillariae Thunbergii) and Chuan-Lian-Zi (Fructus Toosendan) was most frequently used for peptic ulcer disease. Conclusions: Our study identified the core prescription patterns of TCM for patients with peptic ulcer disease in Taiwan. Further basic and clinical studies are necessary to elucidate the efficacy and mechanisms. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ban-Xia-Xie-Xin-Tang Complementary and alternative medicine National health insurance research database Os Sepiae Peptic ulcer disease Traditional Chinese medicine
n Corresponding author at: Research Center for Traditional Chinese Medicine, Department of Medical Research and Department of Chinese Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404, Taiwan. Fax: þ 886-4-2236-5141. E-mail address: [email protected] (H.-R. Yen). 1 These authors contributed equally as co-first authors.
http://dx.doi.org/10.1016/j.jep.2015.11.002 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.
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1. Introduction Peptic ulcer disease is a common digestive disorder, including gastric and duodenal ulcers. In the United States, approximately 15 million people have peptic ulcer disease (Torpy et al., 2012). About 12% of males and 10% of females suffered from peptic ulcer disease over their lifetimes (Wang et al., 2012). The prevalence of peptic ulcer disease in asymptomatic subjects is 9.4% in Taiwan (Wang et al., 2011). Two third of the Taiwanese peptic ulcer disease patients had no remarkable symptoms (Lu et al., 2004). Peptic ulcer disease is an imbalance of aggressive gastric luminal factors and defensive mucosal barrier function. Conventional Western medications for the treatment of peptic ulcer disease include antacids, anti-secretory medications such as H2-receptor antagonists and proton-pump inhibitors. Although triple or quadruple therapy has been developed for the eradication of Helicobacter pylori (Luther et al., 2010), increasing antibiotic resistance and intolerance has made alternative treatments necessary (Malfertheiner et al., 2011). For instance, the primary resistance of amoxicillin, clarithromycin and metronidazole in Taiwan were 2.2%, 7.9%, and 23.7% respectively. The primary levofloxacin resistance even rose from 4.9% in 2000–2007 to 8.3% in 2008–2010 and 13.4% in 2011–2012 in Taiwan (Liou et al., 2015). The use of antibiotics also has an unknown effect on the homeostasis of gut microbiome (Malnick et al., 2014). Other side effects resulting from the conventional medications include constipation and diarrhea (Cohen et al., 2015), impotence (Sabesin, 1993), interference with drug metabolism (Pattichis and Louca, 1995) and parietal cell hypertrophy (Ksiadzyna et al., 2015). These unwanted side effects drive some patients to seek alternative advice. It is necessary to investigate the usage of traditional medicine for the treatment of peptic ulcer disease. Previous study of traditional Chinese medicine (TCM) have found that Si-Jun-Zi-Tang can inhibit the hypersecretion of hydrogen chloride in the stomach in a rate model of stress-induced peptic ulcers (Chen et al., 2013). Chai-Hu-Gui-Zhi-Tang and can prevent the recurrence of peptic ulcers (Chen et al., 2010) and another formula HZJW can heal peptic ulcer and inhibit H. pylori (Xie et al., 2013). Unfortunately, evidence obtained from highquality clinical studies is very limited (Zhou et al., 2007). Many of the studies neglect stringent evidence based diagnostic and therapeutic criteria (Teschke et al., 2015). Due to the lack of knowledge about the prescription profile of TCM, researchers and doctors have found it difficult to select optimal candidates to explore the potential efficacy and mechanisms of Chinese herbal products targeting peptic ulcer disease. TCM, which includes acupuncture and moxibustion, Chinese traumatology and Chinese herbal products, has been integrated as an important part of healthcare in Taiwan. It has been used in various diseases such as gynecologic disease (Yen et al., 2015a), atopic dermatitis (Lin et al., 2014), rhinitis (Yen et al., 2015b, 2015c), asthma (Huang et al., 2013), rheumatoid arthritis (Huang et al., 2015) and endocrinologic disorder (Hsu et al., 2014; Yu et al., 2014). The Taiwanese National Health Insurance program, which was established in 1995, also reimburses the above-mentioned TCM services (Huang et al., 2014; Yen et al., 2013). This mandatory insurance program covers approximately 23 million people, comprising 99.89% of the total population in 2010 (BoNH, 2010). Claims data from the National Health Insurance program were de-identified and sent to the National Health Research Institutes to form the National Health Insurance Research Database (NHIRD). This database provides a nationwide population-based claims database with long-term follow-up. The aim of this study is to analyze this comprehensive database and to determine the TCM utilization patterns of newly diagnosed peptic ulcer disease patients in Taiwan. The results of this study should provide valuable information
for further pharmacological studies and clinical trials.
2. Materials and methods 2.1. Data source This study was designed as a population-based study analyzing a sample of one million subjects randomly selected from the 23 million beneficiaries of the National Health Insurance program in Taiwan. The identification numbers of all individuals were encrypted and transformed to protect the privacy of enrollees. A random number function was used to generate random number and randomly selected the subjects. There is no significant difference in the distribution of age, gender and insured amount between the patients in the randomly selected samples and the original NHIRD. (http://nhird.nhri.org.tw/en/index.html). The datasets contain patient’s gender and date of birth, all records of clinical visits and hospitalization, prescribed drugs and dosages, including Chinese herbal products, and the major diagnoses coded in the International Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9-CM) formats. This study was approved by the Research Ethics Committee of the China Medical University and Hospital (CMU-REC-101-012). 2.2. Study subjects The selection of study subjects from the random sample of one million individuals was represented as Fig. 1. Of the one million randomly selected individuals in the National Heath Insurance Program, we identified 176,300 patients with peptic ulcer disease. Patients who were diagnosed as peptic ulcer disease with ICD-9CM code: 531–534, for more then three times; no matter they are proved by clinical judgment, endoscopy, or H. pylori infection, were included. Prevalent cases (n ¼ 79,676) that had been diagnosed before the end of 2000 were excluded to ensure that all the subjects included were newly diagnosed. Finally, 96,624 study subjects diagnosed as peptic ulcer disease from 2001 to 2008 were included in the study cohort with a follow-up period through 2010. They were further divided into TCM users (n ¼14,983) and non-TCM users (n¼ 81,641). TCM users were defined as those who visited TCM clinics. Non-TCM users were defined as those who never visited TCM clinics after the initial diagnosis of peptic ulcer disease. 2.3. Study variables To determine the key independent variables for utilization of TCM among peptic ulcer disease patients, we selected a series of demographic factors based on previous studies (Huang et al., 2014; Yen et al., 2013). The subjects were categorized into three groups according to age: o 20, 20–39, 45–59, and Z60 years. Urbanization levels in Taiwan are divided into four levels as previous described (Yen et al., 2015c). Level 1 indicates the “most urbanized” communities and level 4 indicates the “least urbanized” communities. We also searched the NHIRD database for clinical comorbidities and treatment records related to peptic ulcer disease as independent variables. The comorbidities were identified by ICD-9-CM codes, including 410–414 (coronary artery disease; CAD), 496 (chronic obstructive lung disease; COPD), 250 (diabetes mellitus; DM), 571 (liver cirrhosis) and stroke (430–438). To investigate the financial outcome of TCM in Taiwan, we measured the medical expenditure of outpatient clinic care and hospitalization between patients with and without TCM treatment within the one year after peptic ulcer was diagnosed and calculated in US dollars. The TCM herbal formulas and single herbs reimbursed by
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Fig. 1. Flow recruitment chart of subjects from the one million samples randomly selected from the National Health Insurance Research Database (NHIRD) from 2001 to 2010 in Taiwan.
the National Health Insurance Program are the so-called “concentrated TCM granules” (finished herbal products) manufactured by good manufacturing practice (GMP)-certified pharmaceutical companies in Taiwan. These Chinese herbal products have good quality control. The TCM indications are based on TCM theory (Bensky et al., 2004; Scheid et al., 2009). 2.4. Statistical analysis Data analysis consisted of descriptive statistics, including the prescription rates of TCM users stratified by patient's demographic characteristics, indications for the prescription of TCM, and the most frequently prescribed Chinese herbal products used when treating peptic ulcer disease. We presented the expenditure of clinic as mean and SD between the peptic ulcer patients with and without TCM and assessed the difference by t-test. The data were analyzed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, U.S.A.). Univariate analysis was utilized to compare the TCM users with the non-TCM users. Pearson's χ2 tests was performed to assess the relationship between the categorical variables and to examine the differences between TCM users and non-TCM users. A p-value o0.05 was considered statistically significant. Analysis of core prescription patterns was described previously (Chang et al., 2015). In brief, an open-sourced freeware NodeXL (http://nodexl. codeplex.com/) was used to identify the core patterns of Chinese herb products for the treatment of patients with peptic ulcer disease, and the most common two herbal combinations were applied in this network analysis. The thicker line width, defined as counts of connections between formulas and herbs, indicated significant prescription patterns in the network. 3. Results There were 96,624 patients who were newly diagnosed with peptic ulcer disease. Among them, 14,983 (15.5%) patients used
TCM outpatient services for the treatment of peptic ulcer disease. The mean age of TCM users was younger than that of non-TCM users (40.3 versus 50.5 years old). Majority (59.7%) of the TCM users were female. Most of the TCM users resided in urbanized areas. With regard to the comorbidities, TCM users had a lower prevalence of coronary artery disease, chronic obstructive lung disease, diabetes mellitus and liver cirrhosis and stroke. The status of H. pylori infection was not available due to the nature of the database. The percentage of patients receiving esophagogastroduodenoscopy within 10 days before or after initial diagnosis were 36.3% and 18.3% for the non-TCM users and TCM users, respectively. The average time between onset of peptic ulcer disease and the first visit to a TCM clinic was 4.7 months (Table 1). Regarding the treatment modalities given to patients with peptic ulcer disease, 14,449 (96.4%) patients received only Chinese herbal remedies, while 277 (1.9%) patients were treated by acupuncture or Chinese traumatology only and 257 (1.7%) patients received combination of both treatments. More than half of the patients (n ¼8327; 55.6%) visited TCM clinics for 1–3 times and 3719 (24.8%) patients visited TCM clinics for more than 6 times (Table 2). To investigate the prescription patterns of the Chinese herbal remedies, we conducted a comprehensive analysis and identified ten most commonly prescribed Chinese herbal formulas and single herbs, respectively. The most frequently prescribed Chinese herbal formula was Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) (Table 3). Regarding the single herbs for the treatment of peptic ulcer disease, Hai-Piao-Xiao (Os Sepiae) was the most frequently prescribed single herb (Table 4). The top 100 herbal formulas and single herbs for peptic ulcer patients were analyzed through open-sourced freeware NodeXL, and the core pattern of the prescriptions was the combination of Ban-Xia-Xie-Xin-Tang, Hai-Piao-Xiao (Os Sepiae), Yan-Hu-Suo (Rhizoma Corydalis), Bei-Mu (Bulbus Fritillariae Thunbergii) and
314
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Table 1 Demographic characteristics of TCM and non-TCM users among patients with peptic ulcer disease from 2001 to 2010 in Taiwan. Variable
Non-TCM users TCM users N (%) N (%)
p value
No of subjects Age at baseline, mean years (SD)a o20 20–39 40–59 ≧60 Sex Female Male Urbanization 1 (highest) 2 3 4 þ (lowest) Comorbidity CAD COPD DM Stroke Liver cirrhosis Esophagogastroduodenoscopyb No Yes The duration between onset of peptic ulcer disease and the first visit to a TCM clinic, month
81,641 50.5 3247 20,218 32,445 25,731
(15.5) (16.5) (10.4) (40.5) (36.1) (13.0)
o0.0001 o0.0001
40,462 (49.6) 41,179 (50.4)
8941 (59.7) 6042 (40.3)
o0.0001
22,559 23,615 14,352 21,114
(27.6) (28.9) (17.6) (25.9)
4074 4576 2982 3351
(27.2) (30.5) (19.9) (22.4)
14,286 3259 8807 3668 16,484
(17.5) (4.0) (10.8) (4.5) (20.2)
1213 164 626 187 2241
(8.1) (1.1) (4.2) (1.2) (15.0)
(84.5) (17.7) (4.0) (24.8) (39.7) (31.5)
14,983 40.3 1560 6064 5408 1951
o0.0001
51,986 (63.7) 29,655 (36.3) 4.7
o0.0001 o0.0001 o0.0001 o0.0001 o0.0001 o0.0001
12,238 (81.7) 2745 (18.3)
TCM: traditional Chinese medicine; CAD: coronary artery disease; COPD: chronic obstructive lung disease; DM: diabetes mellitus. a
t-test. Esophagogastroduodenoscopy: patients underwent esophagogastroduodenoscopy within 10 days before or after the diagnosis of peptic ulcer was made. b
Table 2 Frequency distribution of TCM clinic visits and treatment modalities among TCM users from 2001 to 2010 in Taiwan. Number of TCM clinic visits
Chinese herbal Acupuncture or remedies only Chinese traumatology N (%) N (%)
Combination of Total of TCM clinic visits both treatments N (%) N (%)
All 1–3 4–6 46
14,449 7838 2916 3695
257 239 4 14
(96.4) (54.2) (20.2) (25.6)
277 250 17 10
(1.9) (90.3) (6.1) (3.6)
(1.7) (93) (1.6) (5.4)
14,983 8327 2937 3719
(100) (55.6) (19.6) (24.8)
TCM: traditional Chinese medicine
Chuan-Lian-Zi (Fructus Toosendan) (Fig. 2). Relative to the peptic ulcer patients without TCM treatment, the TCM users had lower medical expenditure for hospitalization (11687 1703 versus 2275 75880 US dollars, p o0.0001) and for outpatient clinic care (179 7249 versus 237 7484 US dollars, p o0.0001) (Table 5) for the first year after diagnosis of peptic ulcer disease.
4. Discussion This nationwide population-based study investigated the utilization of Chinese herbal products prescribed by licensed TCM doctors for patients who were newly diagnosed with peptic ulcer disease. We found approximately 15.5% of the patients visited TCM clinics. Ban-Xia-Xie-Xin-Tang (Pinelliae Decoction to Drain the Epigastrium) and Hai-Piao-Xiao (Os Sepiae) were the most commonly prescribed herbal formula and single herb, respectively.
This is so far the largest comprehensive analysis of TCM usage among patients with peptic ulcer. The results from this study can be used for further pharmacological investigation or clinical trials. In accordance with previous findings (Shih et al., 2009, 2012; Yen et al., 2013), we found that younger people, women (compared with men), and people living in higher urbanized areas were more likely to visit TCM than non-TCM users. Although sometimes TCM users had self-reported poor health status tended to use TCM services (Shih et al., 2009), we found that TCM users among peptic ulcer patients had a lower prevalence of comorbidities. Those patients with more comorbidity diseases usually receive more complicate kinds of medications, which make them have lower attempts to receive TCM. This baseline difference between TCM users and non-users should be taken into consideration for comparative research on efficacy in the future. In this study, patients visited TCM services on average 4.7 months after initial diagnosis of peptic ulcer. The current Western medical treatment for peptic ulcer disease includes an antibiotics regimen targeting eradication of H. pylori (Luther et al., 2010). Some patients who believe in TCM or cannot tolerate the side effects of this regimen might seek TCM help after the initial diagnosis (Malfertheiner et al., 2011). In consistency with other studies in gastrointestinal disease or internal diseases, herbal remedies are the most common treatment approaches. (Huang et al., 2013; Pasalar and Lankarani, 2015; Yen et al., 2015b). We found that only very few patients received acupuncture therapy. Ban-Xia-Xie-Xin-Tang was the most frequently prescribed formula for peptic ulcer. It was originally documented in an ancient literature “Shang Han Lun”. The chief herb of this formula is Rhizoma Coptidis, which can clean the dampness and heat (Scheid et al., 2009). Its ingredient herbs, Rhizoma Coptidis and Radix Scutellariae are bitter and cold; together they can clear the heat and harmonize the yang. Rhizoma Pinelliae preparatum and Rhizoma Zingiberis are both acrid and warm; together they unblock the “focal distention”(pi in TCM). Radix Ginseng, Frustus Jujubae and Radix Glycyrrhizae preparata benefit the middle burner and prevent the dispersing actions of the bitter and cold herbs from injuring the Qi (Scheid et al., 2009). In an animal study, Ban-XiaXie-Xin-Tang reduced 70.1% of the ulcer areas in mice, while its derivative formula could even inhibited 96.9% ulcers (Xue et al., 2011). Another animal study conducted in Japan also observed that pretreatment with Ban-Xia-Xie-Xin-Tang could markedly inhibit the reduction of gastric mucin content and the development of gastric ulcers (Li et al., 1998). In human study, a meta-analysis including ten randomized controlled trails with a total of 972 patients showed that Ban-Xia-Xie-Xin-Tang had a better effect than Western medicine in treating functional dyspepsia, consisting of epigastric pain, burning, fullness, discomfort, early satiety, nausea, vomiting, and belching (Gan et al., 2014). Intra-gastric administration of Ban-Xia-Xie-Xin-Tang extracts could lead to decreased mRNA expression levels of IL-5 and IL-13 in the colonic tissue (Wang et al., 2014a). In addition, Ban-Xia-Xie-Xin-Tang suppressed TNF-α, IL-1β, IL-17, IL-23 and COX-2 production in a dextran sulfate sodium (DSS)-induced chronic ulcerative colitis model (Chen et al., 2015). The second commonly prescribed herbal formula is Xiang-ShaLiu-Jun-Zi-Tang. It has long been used to treat gastrointestinal discomfort in clinical practice. It ingredient herbs, Rhizoma Atractylodis macrocephalae and Poria, can strengthen the spleen and clean the dampness. Radix Ginseng and Radix Glycyrrhizae preparata benefit the middle burner. Rhizoma Pinelliae preparatum and Pericarpium Citri reticulatae move the Qi and clean the phlegm. Fructus Amomi and Radix Aucklandiae regulate the Qi and relieve pain. (Scheid et al., 2009) In a recent study, it was reported to increase the secretion of plasma motilin, lower serum gastrin levels, and enhance smooth muscle contraction by
Table 3 Ten most common herbal formulas for patients with peptic ulcer diseases from 2001 to 2010 in Taiwan. Herbal formula
(pin-yin name)
(English name)
Ban-Xia-Xie-XinTang
Pinelliae decoction to drain the epigastrium
Xiang-Sha-Liu-JunZi-Tang
Six gentlemen decoction with aucklandia and amomum
Ping-Wei-San
Calm the stomach powder
An-Zhong-San
Calm the middle powder
Jia-Wei-Xiao-YaoSan
Augmented rambling powder
Huo-Xiang-ZhengQi-Tang
Agastache powder to rectify the qi
Number of persondays N ¼2050,356 (%)
Average daily dose (g)
Indications in TCM use
Rhizoma Pinelliae preparatum (ZhiBan-Xia) Rhizoma Zingiberis (Gan-Jiang) Radix Scutellariae (Huang-Qin) Rhizoma Coptidis (Huang-Lian) Radix Ginseng (Ren-Shen) Fructus Jujubae (Da-Zao) Radix Glycyrrhizae preparata (ZhiGan-Cao) Radix Ginseng (Ren-Shen) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Glycyrrhizae preparata (ZhiGan-Cao) Rhizoma Pinelliae preparatum (ZhiBan-Xia) Fructus Amomi (Sha-Ren) Radix Aucklandiae (Mu-Xiang) Rhizoma Zingiberis recens (ShengJiang) Rhizoma Atractylodis (Cang-Zhu) Cortex Magnoliae officinalis (HouPo) Pericarpium Citri reticulatae (ChenPi) Radix Glycyrrhizae preparata (ZhiGan-Cao) Cortex Cinnamomi (Rou-Gui) Rhizoma Corydalis (Yan-Hu-Suo) Concha Ostreae (Mu-Li) Fructus Foeniculi (Xiao-Hui-Xiang) Rhizoma Zingiberis preparata (PaoJiang) Rhizoma Alpiniae officinarum (GaoLiang-Jiang) Radix Glycyrrhizae (Gan-Cao) Radix Angelicae sinensis (Dang-Gui) Radix Paeoniae (Shao-Yao) Poria (Fu-Ling) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Radix Bupleuri (Chai-Hu) Cortex Moutan (Mu-Dan-Pi) Fructus Gardeniae (Zhi-Zi) Radix Glycyrrhizae preparata (ZhiGan-Cao) Herba Pogostemonis (Huo-Xiang) Cortex Magnoliae officinalis (HouPo) Pericarpium Citri reticulatae (ChenPi) Folium Perillae (Zi-Su-Ye)
173,041 (8.4)
6.5
Epigastric focal distention, fullness and tightness with very slight or no pain, dry heaves, vomiting, borborygmus
119,886 (5.8)
5.8
Nausea and vomiting, emaciation, anorexia with a full feeling after very little food, weak abdomen
104,913 (5.1)
5.1
Distention and fullness in epigastrium and abdomen, loss of taste and appetite, heavy sensation in the limbs and body
77,668 (3.8)
6.2
Neurogenic gastric pain, ulcer, over abundance of stomach acid
68,619 (3.3)
5.7
Irritability, short temper, restlessness, fever or tidal fever, dry mouth, lower abdominal pain
46,038 (2.2)
4.8
Fever and chills, headache, abdominal fullness and oppression, pain, nausea and vomiting, borborygmus, diarrhea, loss of taste, aversion to cold
315
Composition
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Herbal formula
316
Table 3 (continued ) Herbal formula
Herbal formula
(pin-yin name)
(English name)
Ginseng, poria and atractylodis macrocephalae powder
Ma-Zi-Ren-Wan
Hemp seed pill
Si-Ni-San
Frigid extremities powder
Radix Angelicae dahuricae (Bai-Zhi) Rhizoma Pinelliae preparatum (ZhiBan-Xia) Pericarpium Arecae (Da-Fu-Pi) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Platycodi (Jie-Geng) Radix Glycyrrhizae preparata (ZhlGan-Cao) Radix Ginseng (Ren-Shen) Rhizoma Atractylodis macrocephalae (Bai-Zhu) Poria (Fu-Ling) Radix Glycyrrhizae preparata (ZhiGan-Cao) Rhizoma Dioscoreae (Shan-Yao) Semen Lablab album (Chao-BianDou) Semen Nelumbinis (Lian-Zi) Semen Coicis (Yi-Yi-Ren) Fructus Amomi (Sha-Ren) Radix Platycodi (Jie-Geng) Semen Cannabis (Hua-Ma-Ren) Semen Armeniacae (Xing-Ren) Radix Paeoniae (Shao-Yao) Fructus Aurantii immaturus (ZhiShi) Cortex Magnoliae officinalis (HouPo) Radix et Rhizoma Rhei (Da-Huang) Radix Bupleuri (Chai-Hu) Fructus Aurantii immaturus (ZhiShi) Radix Paeoniae alba (Bai Shao) Radix Glycyrrhizae preparata (ZhiGan-Cao)
Number of persondays N ¼2050,356 (%)
Average daily dose (g)
Indications in TCM use
43,715 (2.1)
6.3
Loose stools or diarrhea, weak extremities, weight loss, distention and a stifling sensation in abdomen, pale wan, indigestion
43,433 (2.1)
2.4
Constipation with hard, difficult to expel stool, dry skin, hemorrhoids, nocturia, dizziness
40,197 (2.0)
5.2
Cold extremities with heat in the interior, irregular fever, fullness and distention, abdominal pain, severe diarrhea, dysentery
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Shen-Ling-Bai-ZhuSan
Composition
Table 4 Ten most common single herbs for patients with peptic ulcer disease from 2001 to 2010 in Taiwan. Number of person-days Average daily dose Indications in traditional Chinese medicine N ¼ 2565,558 (%) (g)
Pin-yin name
Latin name
Plant species
Hai-Piao-Xiao
Os Sepiae
Yan-Hu-Suo Bai-Ji
Rhizoma Corydalis Rhizoma Bletillae
Sepiella maindroni de Rochebrune Sepia esculenta Hoyle (not plant) Corydalis yanhusuo W.T. Wang Bletilla striata (Thunb.) Reichb. f.
Bei-Mu Da-Huang
Bulbus Fritillariae Tthunbergii Radix et Rhizoma Rhei
Hou-Po
Cortex Magnoliae Officinalis
Dan-Shen Mu-Xiang
Radix Salviae Miltiorrhizae Radix Aucklandiae
Chuan-Lian-Zi Fructus Toosendan Sha-Ren Fructus Amomi
119,120 (4.6)
1.7
96,337 (3.8) 75,750 (3.0)
1.6 2.3
Fritillaria thunbergii Miq.
66,378 (2.6)
1.9
Stomach acidity with stomach or epigastric pain, distasteful belching or acid regurgitation, bleeding Pain affecting the chest, abdomen or limbs, epigastric pain and dysmenorrhea Bleeding from the lungs and stomach with hematemesis, hemoptysis and epistaxis Neutralize acid, chronic cough, slight sputum
Rheum palmatum L. Rheum tanguticum Maxim. ex. Balf. Rheum officinale Baill. Magnolia officinalis Rehd. et Wils M. officinalis Rehd. et Wils. var. biloba Rehd. et Wils. Salvia miltiorrhiza Bge. Aucklandia lappa Decne
55,338 (2.2)
0.7
Constipation, abdominal distention and pain
52,408 (2.0)
1.4
Abdominal distention and fullness, nausea, and diarrhea
45,621 (1.8) 45,046 (1.8)
1.3 1.2
38,223 (1.5) 37,637 (1.5)
1.1 1.1
Abdominal pain, rib and hypochondriac pain Anorexia, a feeling of food sitting in the stomach, epigastric or abdominal pain or distention, nausea and vomiting Distention and pain and bulging disorders Distention and pain, in the epigastrium and abdomen, anorexia, vomiting and diarrhea
Melia toosendan Sieb. et Zucc. Amomum villosum Lour, Amomum villosum Lour. var. xanthioides T.L. Wu. Et Senjen longiligulare T.L. Wu.
C.-Y. Huang et al. / Journal of Ethnopharmacology 176 (2015) 311–320
Single herbs
317
318
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Fig. 2. The top 100 herbal formulas and single herbs for peptic ulcer patients were analyzed through open-sourced freeware NodeXL. The thicker line width, defined as counts of connections between formulas and herbs, indicated significant prescription patterns in the network.
Table 5 Medical expenditure of hospitalization and outpatient care between TCM and nonTCM users for the first year after diagnosis of peptic ulcer disease. Cost
Hospitalization, USD Outpatient Clinic, USD
TCM users
Non-TCM users
N
N
mean (SD)
p-value
mean (SD)
280 1168 (1703) 4896 2275 (5880) 7627 179 (249) 80,643 237 (484)
o 0.0001 o 0.0001
TCM: traditional Chinese medicine; USD: US dollars.
increasing calcium levels (Tian et al., 2014). A multicenter, doubleblind, randomized, placebo-controlled study revealed that XiangSha-Liu-Jun-Zi-Tang reduced dyspepsia, especially effective among H. pylori-infected participants (Suzuki et al., 2014). In addition, it can improve electro-gastrogram, promote gastrointestinal motility and gastric emptying, decrease gastric sensitivity, and regulate gastrointestinal hormone (Feng, 1992). A meta-analysis found that Xiang-Sha-Liu-Jun-Zi-Tang could significantly improve symptoms better than prokinetic drugs for patients suffering from functional dyspepsia (Xiao et al., 2012). Its derivative, Si-Jun-Zi-Tang, has been reported to inhibit stress-induced ulcer by reducing the hypersecretion of hydrogen chloride and lowering the level of 5-HT and dopamine in brain soothe the stress. (Chen et al., 2013) Ping-Wei-San, the third most commonly prescribed formula for peptic ulcer, was used traditionally to alleviate distention and fullness in the epigastrium and abdomen, loss of taste and appetite, loose stools or diarrhea, easily-fatigued, increased desire to sleep, nausea and vomiting, belching, acid reflux (Scheid et al., 2009). It has been reported to relieve dyspeptic symptoms of gastrointestinal disorders (Chao et al., 2014). Jia-Wei-Xiao-Yao-San and Si-Ni-San were widely used to relieve the emotional and psychological symptoms, such as depression or stress (Lin et al., 2015; Tanaka et al., 2013). Huo-Xiang-Zheng-Qi-Tang has been
widely used for treatment of various common gastrointestinal infectious diseases. It was discovered to promote gastroenteric motility, regulate gastrointestinal function and immune response. An earlier study reported that Huo-Xiang-Zheng-Qi-Tang could decrease the level of TNF-α in a murine intestinal infection model (He et al., 2006). Shen-Ling-Bai-Zhu-San has been reported to have an antacid effect (Wu et al., 2010). Ma-Zi-Ren-Wan has been used for functional constipation (Cheng et al., 2011). Bao-He-Ni is also one of the commonly prescribed Chinese herbal formula for postsurgical colon cancer patients (Chao et al., 2014). Regarding the single herbs, Hai-Piao-Xiao (Os Sepiae) was the most commonly prescribed one. Its chief constituent is 80–85% of calcium carbonate (Li et al., 2010), which might acts like an antacid to relieve the discomfort resulted from excessive gastric acid. Combination of Hai-Piao-Xiao and Bei-Mu (Bulbus Fritillariae Thunbergii) prevented ethanol-induced gastric lesions in a rat model (Lin, 1998). Yan-Hu-Suo (Rhizoma Corydalis), the second commonly prescribed single herb, is widely used to treat abdominal pain due to qi stagnation (Scheid et al., 2009). It has been reported to inhibit H. pylori effect (Li et al., 2005), heal ulcer (Tianjiao et al., 2014) and relieve pain (Guo et al., 2014). Bai-Ji (Rhizoma Bletillae) has not only anti-inflammatory but also hemostatic action (Wang et al., 2014b). Chuan-Lian-Zi (Fructus Toosendan) has analgesic effect (Xie et al., 2008). We included the top 100 herbal formulas to identify the network of core prescriptions for patients with peptic ulcers. The core prescription pattern consisted of “Ban-Xia-Xie-Xin-Tang”, “HaiPiao-Xiao”, “Yan-Hu-Suo”, “Bei-Mu” and “Chuan-Lian-Zi”. In TCM theory, the function of raising the clear yang and descending the turbid yin is very important in middle burner. That may explain why Ban-Xia-Xie-Xin-Tang is the core formula. Besides recovering the basic function of the Spleen and the Stomach, quickly relieving the pain is also important. As discussed above, Hai-Piao-Xiao and Bei-Mu neutralize gastric acid and relieve burning sensation. YanHu-Suo and Chuan-Lian-Zi rectify the Qi to relieve pain and also to
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help strengthen the effect of Ban-Xia-Xie-Xin-Tang. Such a core pattern can harmonize the stomach and downbear counterflow, control acidity, move Qi and relieve pain. It may also regulate the function of the stomach and intestine. The core prescription pattern may be used as a candidate for further clinical research.
5. Limitations Some caveats of this study merit comments. First, this study did not include Chinese herbal remedies or decoctions that were purchased directly from TCM herbal pharmacies. Thus, the frequency of utilization might have been underestimated. However, the National Health Insurance covers TCM prescriptions (the concentrated herbal powder) manufactured by GMP-certified pharmaceutical companies in Taiwan. Within the National Health Insurance program, it costs only approximately 10 USD co-payment for visiting TCM clinics. Raw herbs are more expensive and take time to cook. Taiwanese who seek TCM therapy tend to choose the concentrated herbal powder instead of decoction (Huang et al., 2014; Yen et al., 2013). Second, there was no endoscopic data or the status of H. pylori infection available to evaluate the healing of ulcers due to the nature of this database. However, the diagnosis and TCM prescriptions were both made by physicians with qualified license, which means the present study has high credibility. These most common formulas and single herbs can be regarded as the consensus candidates for future studies. However, it has to be noted that evidence-based studies should be done. In addition, indications in TCM use may not apply to Western medicine. Future studies should focus on randomized, placebo-controlled, doubleblind clinical trials (Teschke et al., 2015). Endoscopic findings and the status of H. pylori infection should be documented in the trial.
6. Conclusions Our ethnopharmacological study identified the prescription patterns of Chinese herbal products for patients with peptic ulcer diseases. Several formulas or herbs were already pre-clinically investigated. Studying clinical efficacy has the preference as future objective. As TCM prescriptions are applied according to Chinese criteria for symptomatology, it will not be an easy task to evaluate efficacy on validated outcome scales. Further basic and clinical studies are warranted to elucidate their mechanism and efficacy.
Author contributions HRY, CYH and WYL conceptualized the study. CCL and CMC performed the statistical analysis. CYH, WYL, MFS, BCC, HJL, CHY and HRY contributed to the interpretation of TCM data. CYH, WYL and KCH contributed to the interpretation of pharmacological mechanisms. CYH and WYL contributed equally to draft the manuscript and HRY finalized the manuscript.
Conflict of interest The authors declare that they have no conflicts of interest.
Acknowledgments This study was supported by China Medical University under the Aim for Top University Plan of the Ministry of Education,
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Taiwan. This study was also supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002). This study was based in part on data from the National Health Insurance Research Database, provided by the National Health Insurance Administration, Ministry of Health and Welfare, and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes.
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