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Utilization and prescription patterns of traditional Chinese medicine for patients with hepatitis C in Taiwan: a population-based study

Contributed equally
BMC Complementary and Alternative MedicineBMC series – open, inclusive and trusted201616:397

https://doi.org/10.1186/s12906-016-1379-3

Received: 15 February 2016

Accepted: 8 October 2016

Published: 21 October 2016

Abstract

Background

To characterize the utilization of Traditional Chinese Medicine (TCM) among patients with hepatitis C (HC).

Methods

This study examined datasets from the National Health Insurance Research Database in Taiwan. One cohort, including one million patients randomly sampled from the beneficiaries of the National Health Insurance Programme from January 1 to December 31 in 2010, was chosen for this analysis. People who had at least three outpatient or inpatient records and had been diagnosed with hepatitis C virus infection from 2000 to 2010 were defined as patients with HC. Patients with HC who had at least one TCM outpatient clinical record from 2000 to 2010 were defined as TCM users (N = 5,691), whereas patients with no TCM outpatient records were defined as non-TCM users (N = 2,876). The demographic data, treatment modalities and disease distributions of TCM users were analysed.

Results

Overall, 66.4 % of the patients with HC had used TCM from 2000 to 2010. Of the TCM users, 54.1 % were female. The utilization rate of TCM increased with age and peaked in the age group of those 40 − 64 years old. Herbal remedies (52.4 %) were the most commonly used agents, followed by combination therapy (46.4 %) and acupuncture alone (1.2 %). Patients who had more extrahepatic diseases and were taking more antiviral agents tended to visit TCM clinics. Jia-Wei-Xiao-Yao-San and Dan-Shen (Salvia miltiorrhiza) were the most commonly used formula and single herb, with 88,124 person-days and 59,252 person-days, respectively.

Conclusions

Our nationwide population-based study revealed a high prevalence and specific usage patterns of TCM in patients with HC in Taiwan.

Keywords

Complementary and alternative medicine Hepatitis C National Health Insurance Research Database Traditional Chinese medicine

Background

The use of complementary and alternative medicine (CAM) is expanding throughout the world [1, 2]. According to the World Health Organization (W.H.O.), CAM includes Ayurveda, traditional Chinese medicine (TCM) and Unani medicine. TCM is widely used in East Asia [3]. Of the twenty-three million people in Taiwan, 29.1 % used TCM to treat disease in 2014, whereas up to three-fourths of South Korean adults utilized TCM to treat a specific disease [4].

Hepatitis C virus (HCV), which affects 180 million people globally, is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma [5]. Conventional anti-viral therapy consisting of pegylated interferon and ribavirin is associated with many intolerable side effects and low response rates in some patients’ genotypes [6]. Therefore, patients often seek for alternative treatments to promote healing and obtain support [7]. However, the communication regarding CAM between patients and physicians is relatively poor [8, 9], and the non-disclosure rate is higher than 70 %. Many physicians feel uncomfortable discussing CAM because of their limited knowledge of the subject. Patients avoid discussing CAM with their doctors because they fear receiving a negative response [10]. To provide holistic care to patients with hepatitis C (HC), physicians should understand the approaches used by patients for symptom relief and health maintenance. In the United States, 80 % of patients with HC used CAM according to a report from 2007 [11]. Compared with patients with fatty liver disease, patients with HC were approximately 3 times more likely to use CAM [12]. Because there has been growing interest in using CAM to treat populations with HC worldwide [13], information about CAM and comprehensive studies on its prevalence, usage patterns, efficacy and safety are important.

TCM, defined by the National Centre for Complementary and Integrative Health (NCCIH, U.S.A.) as an entire medical system of CAM, is a well-established medical system that has been used for more than 2,000 years. TCM is commonly used by the Chinese population, as well as by those in many other countries [14], including Taiwan [15]. In Taiwan, TCM has been reimbursed by the National Health Insurance (NHI) programme since 1996. As of 2014, 99.9 % of Taiwan’s population were enrolled in the NHI. All of the claims data have been collected in the National Health Insurance Research Database (NHIRD). According to the NHI programme guidelines, TCMs are only provided for outpatient care including Chinese herbal prescriptions, acupuncture, and traumatology manipulative therapy. The utilization prevalence of TCM in Taiwan ranges from 19.8 % to 77.9 % for many diseases including colon cancer [16], liver cancer [17], osteoporosis [18], and type II diabetes mellitus [19]. However, the utilization and prescription patterns of TCM in HC are lacking.

To characterize the utilization patterns and trends in TCM usage among patients with HC, we analysed a cohort of one million randomly sampled beneficiaries from the NHIRD in 2010. The results of this study should provide valuable information for physicians and for patients with HC.

Methods

Data source

As previously described in detail [20], all TCM services covered under the NHI are provided only in ambulatory clinics. In Taiwan, TCM physicians (those who have received a series of training in Chinese or both Chinese and Western medicine, all of whom must pass national licensing examinations and complete residency training programmes in hospitals) are requested to make diagnoses based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) coding [16]. This study chose one cohort for the analysis, which included one million patients randomly sampled from the beneficiaries of the NHI programme in 2010. The NHIRD contains information on the medical care facilities, physician specialties, and patients’ gender, dates of birth, dates of visit, masked identification numbers, prescriptions, management and diagnosis codes in the ICD-9-CM. A maximum of three diagnostic codes were listed in the NHIRD, and all the diagnoses were analysed in our study. This study was approved by the Research Ethics Committee of the Taipei City Hospital (TCHIRB-10406112-E).

Study subjects

The study subjects were selected from a random sample of one million individuals in 2010 in the following manner (Fig. 1): People who had at least three outpatient or inpatient records and had been diagnosed with HCV from January 1, 2000, to December 31, 2010, were defined as patients with HC (ICD-9-CM codes 07054, 0707, 07041, 07044, 07051, V0262). Based on this criteria, there were 8,567 patients older than 18 years old with a new HCV infection diagnosed starting from the index date of January 1, 2000. Patients with HC who had at least one TCM clinical record from 2000 to 2010 were defined as TCM users (N = 5,691), whereas those who had no TCM records during the same period were defined as non-TCM users (N = 2,876). All study subjects were followed until December 31, 2011.
Fig. 1

Flow chart of subjects in the one million randomly selected sample from the National Health Insurance Research Database (NHIRD) from 2000 to 2010 in Taiwan

Statistical analysis

The data were analysed using SAS software program, version 9.4 (SAS Institute Inc., Cary, NC, U.S.A.). A univariate analysis was used to compare the TCM users with the non-TCM users. Chi-squared test was performed to assess the relationships between the categorical variables and to examine the differences between TCM users and non-users. Person-years for the follow-up period were calculated for each patient until diagnosis of multisite diseases, censor or December 31, 2011. The person-years and overlapping confidence interval (CI) were calculated to assess incidence density rates. To compare the study cohort to the comparison cohort rate, ratios were examined using a Poisson regression model. Moreover, we estimated the adjusted hazard ratios using Cox proportional hazards model. A P value <0.05 was considered statistically significant.

Results

Demographic characteristics of the TCM users with HC

Of the patients with HC, 66.4 % (N = 5,691) had previously used TCM (Table 1). In the TCM users, 54.1 % were female, and this differed from the percentage in non-TCM users, which was only 39.9 %. In both TCM users and non-users, the highest proportion of patients was in the age group from 40 to 64 years old. Regarding the comorbidities of patients with HC, the incidence of most diseases, including osteoarthritis, sicca syndrome, thyroid disorders, chronic obstructive pulmonary disease, and hepatitis B, were higher in TCM users, except for diabetes mellitus, which had a similar incidence in both groups. In contrast, the incidence of hepatocellular carcinoma, liver cirrhosis, and alcohol-related diseases were higher in non-TCM users.
Table 1

Demographic characteristics of the patients with hepatitis C in Taiwan in 2000-2011

Variable

Non-TCM

TCM

p value

N = 2876 (33.57 %)

N = 5691 (66.43 %)

n

%

n

%

Sex

    

<0.0001

 Female

1148

39.92

3081

54.14

 

 Male

1728

60.08

2610

45.86

 

Age at baseline

    

<0.0001

 18−39

364

12.66

945

16.61

 

 40−64

1451

50.45

3395

59.66

 

  ≥ 65

1061

36.89

1351

23.74

 

 Mean (STD)

58.34

14.85

53.92

13.97

 

Urbanizationa

    

<0.0001

 1 (highest)

574

19.96

1215

21.35

 

 2

731

25.42

1652

29.03

 

 3

447

15.54

939

16.50

 

 4+ (lowest)

1124

39.08

1885

33.12

 

Co-morbidity

 Hepatitis B

570

19.82

1356

23.83

<0.0001

 Liver cirrhosis

989

34.39

1618

28.43

<0.0001

 hepatocellular carcinoma

535

18.60

898

15.78

0.0009

 Alcohol-related disease

294

10.22

477

8.38

0.0049

 Chronic obstructive pulmonary disease

508

17.66

1402

24.64

<0.0001

 Diabetes Mellitus

1046

36.37

2143

37.66

0.2449

 Thyroid disorders

145

5.04

631

11.09

<0.0001

 Rheumatoid arthritis

89

3.09

400

7.03

<0.0001

 Osteoarthritis

953

33.14

2922

51.34

<0.0001

 Depression

174

6.05

650

11.42

<0.0001

 Sicca syndrome

78

2.71

423

7.43

<0.0001

Charlson comorbidity index score

  

<0.0001

 0

1203

41.83

3024

53.14

 

 1

377

13.11

769

13.51

 

 More than 2

1296

45.06

1898

33.35

 

Anti-viral or hepatoprotective agents

 Interferon alfa

392

13.63

974

17.11

<0.0001

 Ribavirin

391

13.60

973

17.10

<0.0001

 Silymarin

1916

66.62

4204

73.87

<0.0001

Times of visits (mean, SD)

15.61

17.18

21.23

23.18

<0.0001

aThe townships within which subjects registered for insurance were grouped into 4 levels of urbanization, based on a score calculated by incorporating variables indicating population density (people/km2), and population ratio of different educational levels, population ratio of elderly, population ratio of people of agriculture workers and the number of physicians per 100,000 people

To examine the frequency of utilization of Western medicine, we analysed the claims data according to the antiviral or hepatoprotective agents used (Table 1). A higher percentage of TCM users than non-TCM users had ever used these agents to control hepatitis C (all p-values < 0.001). TCM users tended to use interferon-alpha, ribavirin, and silymarin to treat HCV (17.1 %, 17.1 %, and 73.9 %, respectively).

With regard to TCM outpatient visits (Table 2), herbal remedies (52.4 %) were the most commonly used therapeutic approach, followed by combined therapy (46.4 %) and acupuncture alone (1.12 %). As for the frequency of visits, the majority of patients visited TCM clinics fewer than three times (74.01 %). Only 16.64 % of the patients visited TCM clinics more than six times.
Table 2

Distribution of Chinese medicine according to type of Chinese Medicine treatment received in patients with hepatitis C, stratified by number of outpatients visits

Number of TCM visits (times/per year)

Only Chinese herbal remedies

Only Acupuncture or traumatology

Combination both treatment

Total of TCM (N = 5691)

N = 2984 (52.43 %)

N = 64 (1.12 %)

N = 2643 (46.44 %)

1-3

2423 (81.20 %)

64 (100 %)

1725 (65.27 %)

4212 (74.01 %)

4-6

212 (7.10 %)

0

320 (12.11 %)

532 (9.35 %)

>6

349 (11.70 %)

0

598 (22.63 %)

947 (16.64 %)

The prevalence of hepatitis B, liver cirrhosis, alcohol-related disease, chronic obstructive pulmonary disease and diabetes mellitus was lower in TCM users than non-TCM users in Taiwanese HC patients

After adjusting for the frequency of outpatient and inpatient visits, Charlson comorbidity index score, and type of service used - only herbal medicine, only acupuncture or a combination - we calculated the disease hazard ratio (HR) of TCM users versus non-TCM users to compare the prevalence of comorbidities between them. We found that TCM users tended to have certain comorbidities less frequently than non-TCM users (Table 3). TCM users had a 0.55 times lower HR of having hepatitis B than non-TCM users (95 % confidence interval 0.46 − 0.66). Patients who received TCM treatment also had a lower ratio for liver cirrhosis (HR 0.42, with 95 % CI 0.37 − 0.48) and alcohol-related disease (HR: 0.31 for the 40−64 age group and 0.41 overall). The prevalence of chronic obstructive pulmonary disease was also lower in the TCM users (HR: 0.59 overall). Diabetes mellitus also showed a lower incidence in TCM users than non-TCM users overall and in each age group (HR: 0.48, 0.40, 0.46 and 0.64 for the sample overall and for the <40, 40–64, and >60 age groups, respectively). However, after adjusting for times of visit, Charlson comorbidity index score, and type of TCM service used, the hazard ratio of comorbidities such as sicca syndrome, rheumatoid arthritis, depression, and thyroid disorders was less than 1, with no significance.
Table 3

Incidence rate ratio for common disease between non-TCM and TCM user in different age groups

Age groups (year-old)

Non-TCM user

TCM user

IRR (95 % CI)

Adjusted HRb

Disease (ICD-9-CM)

N (%)

Person-years

IRa

N (%)

Person-years

IRa

(95 % CI)

Hepatitis B (70.2, 070.3, V02.61)

 All

570(19.82)

13085

43.56

1356(23.83)

39350

34.46

0.79(0.72−0.87)***

0.55(0.46−0.66)***

 18−39

88(24.18)

1901

46.3

239(25.29)

7189

33.24

0.72(0.56−0.92)**

0.41(0.25−0.69)***

 40−64

327(22.54)

6923

47.23

842(24.80)

23900

35.23

0.75(0.66−0.85)***

0.48(0.37−0.6)***

  ≥ 65

155(14.61)

4261

36.37

275(20.36)

8260

33.29

0.92(0.75−1.11)

0.82(0.58−1.17)

Liver cirrhosis (571.2, 571.5, 571.6, 572.2, 572.3, 572.4, 572.8, 573.0)

 All

989(34.39)

13085

75.58

1618(28.43)

39350

41.12

0.54(0.50−0.59)***

0.42(0.37−0.48)***

 18−39

45(12.36)

1901

23.68

108(11.43)

7189

15.02

0.63(0.45−0.90)*

0.43(0.25−0.73)**

 40−64

489(33.70)

6923

70.63

951(28.01)

23900

39.79

0.56(0.51−0.63)***

0.39(0.33−0.46)***

  ≥ 65

455(42.88)

4261

106.77

559(41.38)

8260

67.67

0.63(0.56−0.72)***

0.54(0.44−0.66)***

hepatocellular carcinoma (155)

 All

535(18.60)

13085

40.89

898(15.78)

39350

22.82

0.56(0.50−0.62)***

0.78(0.45−1.36)

 18−39

6(1.65)

1901

3.16

33(3.49)

7189

4.59

1.45(0.61−3.47)

1.25(0.12−12.75)

 40−64

242(16.68)

6923

34.96

514(15.14)

23900

21.51

0.62(0.53−0.72)***

0.98(0.43−2.21)

  ≥ 65

287(27.05)

4261

67.35

351(25.98)

8260

42.49

0.63(0.54−0.74)***

0.72(0.29−1.75)

Alcohol-related disease (291, 303.0, 303.9, 305.0, 571.0, 571.1, 571.3)

 All

294(10.22)

13085

22.47

477(8.38)

39350

12.12

0.54(0.47−0.62)***

0.41(0.32−0.51)***

 18−39

65(17.86)

1901

34.2

124(13.12)

7189

17.25

0.50(0.37−0.68)***

0.37(0.24−0.58)***

 40−64

185(12.75)

6923

26.72

290(8.54)

23900

12.13

0.45(0.38−0.55)***

0.31(0.23−0.42)***

  ≥ 65

44(4.15)

4261

10.33

63(4.66)

8260

7.63

0.74(0.50−1.09)

0.61(0.33−1.16)

Chronic obstructive pulmonary disease (491, 492)

 All

508(17.66)

13085

38.82

1402(24.64)

39350

35.63

0.92(0.83−1.12)

0.59(0.50−0.70)***

 18−39

27(7.42)

1901

14.21

120(12.70)

7189

16.69

1.18(0.77−1.78)

0.94(0.45−1.97)

 40−64

198(13.65)

6923

28.6

786(23.15)

23900

32.89

1.15(0.98−1.34)

0.67(0.52−0.86)**

  ≥ 65

283(26.67)

4261

66.41

496(36.71)

8260

60.05

0.90(0.78−1.05)

0.69(0.53−0.89)**

Diabetes Mellitus (250)

 All

1046(36.37)

13085

79.94

2143(37.66)

39350

54.46

0.68(0.63−0.73)***

0.48(0.42−0.55)***

 18−39

55(15.11)

1901

28.94

151(15.98)

7189

21

0.73(0.53−0.99)*

0.40(0.22−0.71)**

 40−64

572(39.42)

6923

82.62

1358(40.00)

23900

56.82

0.69(0.62−0.76)***

0.46(0.38−0.54)***

  ≥ 65

419(39.49)

4261

98.32

634(46.93)

8260

76.75

0.78(0.69−0.88)***

0.64(0.51−0.8)***

Thyroid disease (240, 241, 242, 244)

 All

145(5.04)

13085

11.08

631(11.09)

39350

16.04

1.44(1.21−1.73)***

0.90(0.67−1.21)

 18−39

21(5.77)

1901

11.05

105(11.11)

7189

14.6

1.32(0.83−2.11)

1.33(0.54−3.28)

 40−64

79(5.44)

6923

11.41

418(12.31)

23900

17.49

1.53(1.21−1.95)***

0.9(0.6−1.36)

  ≥ 65

45(4.24)

4261

10.56

108(7.99)

8260

13.07

1.24(0.87−1.75)

0.92(0.53−1.58)

Rheumatoid arthritis (714)

 All

89(3.09)

13085

6.8

400(7.03)

39350

10.17

1.49(1.19−1.88)***

1.18(0.82−1.69)

 18−39

11(3.02)

1901

5.79

42(4.44)

7189

5.84

1.01(0.52−1.96)

0.88(0.28−2.78)

 40−64

45(3.10)

6923

6.5

266(7.84)

23900

11.13

1.71(1.25−2.35)***

1.38(0.81−2.36)

  ≥ 65

33(3.11)

4261

7.74

92(6.81)

8260

11.14

1.44(0.97−2.14)

1.24(0.69−2.22)

Osteoarthritis (715)

 All

953(33.14)

13085

72.83

2922(51.34)

39350

74.26

1.02(0.95−1.10)

0.75(0.66−0.86)***

 18−39

46(12.64)

1901

24.2

215(22.75)

7189

29.91

1.24(0.90−1.70)

1.2(0.64−2.27)

 40−64

427(29.43)

6923

61.68

1777(52.34)

23900

74.35

1.21(1.08−1.34)***

0.85(0.71−1.03)

  ≥ 65

480(45.24)

4261

112.64

930(68.84)

8260

112.59

1.00(0.90−1.12)

0.82(0.67−1)

Depression (296.2, 296.3, 296.5, 296.6, 305.8, 311, v790, 290.13)

 All

174(6.05)

13085

13.3

650(11.42)

39350

16.52

1.24(1.05−1.47)*

0.78(0.61−1.01)

 18−39

31(8.52)

1901

16.31

128(13.54)

7189

17.8

1.09(0.74−1.62)

0.76(0.42−1.38)

 40−64

86(5.93)

6923

12.42

382(11.25)

23900

15.98

1.29(1.02−1.63)*

0.73(0.52−1.04)

  ≥ 65

57(5.37)

4261

13.38

140(10.36)

8260

16.95

1.27(0.93−1.72)

0.89(0.54−1.48)

Sicca syndrome (370.33, 710.2)

 All

78(2.71)

13085

5.96

423(7.43)

39350

10.75

1.80(1.42−2.30)***

1.27(0.86−1.89)

 18−39

4(1.10)

1901

2.1

42(4.44)

7189

5.84

2.78(1.00−7.74)

-

 40−64

40(2.76)

6923

5.78

266(7.84)

23900

11.13

1.93(1.38−2.69)***

1.14(0.67−1.94)

  ≥ 65

34(3.20)

4261

7.98

115(8.51)

8260

13.92

1.75(1.19−2.56)**

1.71(0.93−3.15)

a IR incidence rate, per 1000 person-years, IRR incidence rate ratio

*:<0.05; **:<0.01; *** p < 0.001

b Hazard Ratio adjusted for times of outpatient and inpatient visit, Charlson comorbidity index score and type of service used - only herbal medicine, only acupuncture and combination of them

Frequency distribution of disease categories in TCM versus non-TCM visits

To delineate the frequency distributions of the disease categories (as the reasons for visits) for the TCM and non-TCM visits, we analysed the ICD-9-CM codes from the claims data (Table 4). There was a significant difference in the disease distributions between the TCM and non-TCM users (P < 0.0001). Among all of the visits, infectious diseases (99.68 %), which included viral hepatitis, were the most common reasons that TCM users visited TCM clinics. Digestive system diseases (99.61 %), which included chronic liver disease, were the second most common reason that TCM users visited TCM clinics. Symptoms/signs and ill-defined conditions (97.96 %) and respiratory system diseases (97.93 %) accounted for the third and fourth disease categories, respectively, followed by diseases of the musculoskeletal system and connective tissue (93.89 %) and injuries (90.77 %). For non-TCM users, infectious diseases (99.51 %) were the most common reason for visiting Western medical clinics, followed by digestive system diseases (97.25 %) and symptoms/signs and ill-defined conditions (89.33 %). When TCM users required medical services, their utilization patterns were similar to those of non-TCM users.
Table 4

The distribution of TCM and non-TCM user by major disease categories /diagnosis in patients with hepatitis C

Disease (ICD-9-CM)

Non-TCM user (N = 2876)

TCM user (N = 5691)

p value

n

%

n

%

Infectious and parasitic disease (001−139)

2862

99.51

5673

99.68

0.2218

Neoplasms (140−239)

1289

44.82

3121

54.84

<0.0001

Malignant(140−208)

824

28.65

1491

26.20

0.0158

Benign (210−229)

597

20.76

2152

37.81

<0.0001

Endocrine, nutritional and metabolic disease and immunity disorder (240−279)

1863

64.78

4133

72.62

<0.0001

Blood and blood-forming organs (280−289)

843

29.31

1876

32.96

0.0006

Mental disorder (290−319)

1206

41.93

3360

59.04

<0.0001

Nervous system (320−389)

2087

72.57

5120

89.97

<0.0001

Circulatory system (390−459)

2123

73.82

4410

77.49

0.0002

Respiratory system (460−519)

2548

88.60

5573

97.93

<0.0001

Digestive system (520−579)

2797

97.25

5669

99.61

<0.0001

Genitourinary system (580−629)

1760

61.20

4485

78.81

<0.0001

Complications of pregnancy, childbirth and the puerperium (630−676)

19

0.66

178

3.13

<0.0001

Skin and subcutaneous tissue (680−709)

1958

68.08

4830

84.87

<0.0001

Musculoskeletal system and connective tissue (710−739)

2091

72.71

5343

93.89

<0.0001

Congenital anomalies (740−759)

126

4.38

511

8.98

<0.0001

Certain conditions originating in the perinatal period (760−779)

13

0.45

43

0.76

0.0997

Symptoms, signs and ill-defined conditions (780−799)

2569

89.33

5575

97.96

<0.0001

Injury and poisoning (800−999)

1997

69.44

5166

90.77

<0.0001

The most commonly used TCM prescriptions

To comprehensively understand the TCM prescriptions, including the formulas and herbs, we analysed the claims data, and the results are shown in Table 5. Of the 10 most common formulas of TCM used by patients with HC, Jia-wei-xiao-yao-san (88,124 person-days) was the most commonly used. Xiao-chai-hu-tang (39,837 person-days) and Long-dan-xie-gan-tang (36,293 person-days) accounted for the second and third most commonly used formulas, respectively. With regard to the single herbs used for TCM by patients with HC, Dan-shen (59,252 person-days) was the most common. Yan-hu-suo (41,875 person-days) and Huang-qin (35,273 person-days) were the second and third most commonly used herbs, respectively.
Table 5

Most common Chinese herbs and formula prescribed for patients with hepatitis C

Prescription name (in Chinese)

Ingredients

Therapeutic action and Indication

Number of person-days

Average daily dose (g)

Average duration for prescription (days)

Single herb

Dan-shen

Salvia miltiorrhiza Bunge

H & E: Activate blood and resolve stasis

anti-fibrosis, antihepatocarcinoma, anti-diabetic, lipid-lowering

59252

2.5

10.1

Yan-hu-suo

Corydalis yanhusuo

H & E: Activate blood, promote flow of qi, and alleviate pain

Also used in peptic ulcer

41875

3

7.1

Huang-qin

Scutellaria baicalensis Georgi

H: Clear heat and drain fire

Anti-inflammation

35273

2.2

8.1

Yin-chen-hao

Artemisia capillaris Thunb

H: Excrete dampness and alleviate jaundice

Anti-fibrosis

33357

2.4

10.1

Da-huang

Rheum officinale Baill

E: Clear heat and drain fire

Anti-tumor

32110

1.1

7.9

Huang-qi

Astragalus membranaceus

H&E: Qi-tonifying/ restore energy

Anti-cancer

30086

2.1

8.8

Bei-mu

Fritillariae thunbergii Bulbus

E: Clear heat and resolve phlegm

Also used in peptic ulcer and asthma

29404

2.7

7.1

Ge-gen

Pueraria thomsonii Benth

E: Release exterior and cure heat

Also used in ischemic heart disease

29143

2

7.4

Ye-jiao-teng

Polygonum multiflorum Thunb.

E: Nourish heart and induce tranquilization

Also used in menopausal syndrome

28559

3.3

8.7

Hai-piao-xiao

Sepiella maindronide Rochebrune

E: Restrain acidity and alleviate pain

27940

2.5

8.4

Formulae

 

Also used in peptic ulcer

   

Jia-wei-xiao-yao-san

Glycyrrhiza uralensis Fisch. Angelica sinensis, Atractylodes macrocephala, Bupleurum chinense, Gardenia jasminoides, Mentha haplocalyx, Paeonia lactiflora, Paeonia suffruticosa, Poria cocos, Zingiber officinale

H & E: Harmonize liver and release spleen;

Also used in thyroid disorders

88124

7.5

9.3

Xiao-chai-hu-tang

Bupleurum chinense, Scutellaria baicalensis Georgi, Pinellia ternata (Thunb.) Makino, Panax ginseng C.A. Mey, Glycyrrhiza uralensis Fisch, Zingiber officinale, Zizyphus jujuba

H: Regulate exterior and interior Qi activity by balancing between yin and yang;

Antihepatocarcinoma

39837

6.7

7.9

Long-dan-xie-gan-tang

Gentiana scabra Bge, Scutellaria baicalensis Georgi, Gardenia jasminoides Ellis, Alisma orientalis, Akebia quinata (Houtt.) Decne., Plantago asiatica L., Angelica sinensis, Rehmannia glutinosa (Gaert.) Libosch., Bupleurum chinense, Glycyrrhiza uralensis Fisch.

H: Purge fire in the liver and gallbladder, clear away damp-heat in the lower burner;

Antiinflammation

36293

11.3

7.9

Shu-jing-huo-xue-tang

Angelica sinensis, Paeonia lactiflora Pall, Glycyrrhiza uralensis Fisch, Rehmannia glutinosa (Gaert.) Libosch, Atractylodes lancea, Achyranthes bidentata Blume, Citrus tangerina pericarpium, Citrus reticulata Blanco, Prunus persica (L.) Batsch, Clematis chinensis Osbeck, Ligusticum striatum DC., Stephania tetrandra S. Moore, Notopterygium incisum, Angelica dahurica (Fisch. ex Hoffm.) Benth, Gentiana scabra Bge, Poria cocos, Zingiber officinale Rosc.,

E: Relax the channels and activate blood;

Also used in osteoarthritis and rheumatoid arthritis

32646

10.3

6.9

Xiang-sha-liu-jun-zi-tang

Aquilaria sinensis, Amomum villosum Lour, Citrus reticulata Blanco, Pinellia ternata (Thunb.), Panax ginseng C.A. Mey, Poria cocos, Atractylodes macrocephala Koidz., Glycyrrhiza uralensis Fisch.

E: Tonify and replenish qi

Also used in functional dyspepsia and post-surgery colon cancer patients

28381

7.1

8.3

Gan-lu-yin

Rehmannia glutinosa, Asparagus cochinchinensis (Lour.) Merr., Liriope spicata (Thunb.) Lour., Dendrobium nobile Lindl., Artemisia capillaris Thunb, Scutellaria baicalensis Georgi, Citrus aurantium L., Eriobotrya japonica (Thunb.) Lindl., Glycyrrhiza uralensis Fisch,

H& E: Clear heat and nourish yin;

Also used in Sicca syndrome

27563

6.1

7.6

Xue-fu-zhu-yu-tang

Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong hort, Paeonia anomala L., Prunus persica (L.), Batsch, Carthamus tinctorius L., Rehmannia glutinosa (Gaert.) Libosch, Citrus aurantium L., Bupleurum chinense DC., Glycyrrhiza uralensis Fisch, Platycodon grandiflorum (Jacq.) A. DC., Achyranthes bidentata Blume,

E: Promote blood circulation to remove blood stasis

Also used in ischemic heart disease and hyperlipidemia.

27493

6.6

8.1

Du-huo-ji-sheng-tang

Angelica pubescens Maxim, Taxillus chinensis (DC.) Danser, Eucommia ulmoides Oliver, Achyranthes bidentata Blume, Asarum heterotropoides F. Schmidt, Gentiana macrophylla Pall, Poria cocos, Cinnamomum cassia Presl, Saposhnikovia divaricata (Turcz.) Schischk, Ligusticum striatum DC., Panax ginseng C.A. Mey., Glycyrrhiza uralensis Fisch, Angelica sinensis, Paeonia lactiflora Pall.

E: Reinforce the liver and kidney and tonify qi and blood;

Also used in fracture, osteoarthritis and rheumatoid arthritis

27388

11.1

8.2

Suan- zao-ren-tang

Ligusticum striatum DC., Ziziphus jujuba Mill. Poria cocos, Glycyrrhiza uralensis Fisch, Anemarrhena asphodeloides Bge

E: Nourish blood to tranquilize the mind;

Also used in insomnia and depression

26417

8

7.5

Ping-wei-san

Citrus reticulata Blanco, Atractylodes lancea (Thunb.), Magnolia officinalis Rehd, Glycyrrhiza uralensis Fisch

E: Activate the flow of Qi and regulate the stomach

Also used in leukemia patients

26083

7.2

7.6

Note: H hepatic action, E extrahepatic action

Discussion

This research is the first large-scale study on the utilization patterns of TCM by patients with HC and was conducted by analysing claims data from TCM and non-TCM clinic visits covered by the NHI in Taiwan. In a previous study [21], Chen et al. investigated the frequency and prescription patterns of Chinese herbal medicine for chronic hepatitis, including viral hepatitis and alcoholic hepatitis, and revealed the same three most common herbal formulas as in our study and a similar age group of patients, approximately in their 40s to 50s, seeking TCM. However, this study focused only on hepatitis C and demonstrated a different gender predominance and more details on comorbidities. According to Sievert’s review [22], the prevalence rate of hepatitis C is as high as 4 %, but the diagnosis rate is only 1.3 %, which is similar to our report. This discrepancy may be due to the fact that only symptomatic patients with HC would visit the hospital and have diagnostic records. Other HCV carriers without medical seeking behaviour would not be recorded in the national health insurance database.

Of the patients with HC, 66.4 % had previously used TCM. The acceptance of TCM among patients with HC is much greater in Taiwan than in other countries [11, 12]. In addition, approximately 16 % of the patients visited TCM clinics more than six times per year (Table 2). This high visiting frequency might be explained by the fact that many of these patients had chronic illnesses that required long-term care and treatment. Moreover, unlike the predisposition towards acupuncture in Europe [23], herbal remedies have been widely used in Taiwanese patients with HC (52.4 %). People in Taiwan believe that TCM can adjust the constitution of the human body, allowing small doses of herbal remedies to remain safe and suitable for long-term use [24]. Furthermore, the insurance coverage for TCM treatments might play a significant role in the high TCM usage in Taiwan [25]. As for receiving the current standard treatment, the rate of treatment in both arms was low (14 % and 17 %) in our study. This result is consistent with a previous nationwide survey in Taiwan (13.7 %) [26]. Although the anticipated treatment success rate is as high as 80 % in Taiwan, only 8.1 % of the population with HC achieved successful treatment. The major treatment barriers included fear of adverse effects, major disorders, ineligibility for insurance reimbursement, and lack of awareness of therapy.

Comparing the hazard ratio of comorbidities between TCM users and non-TCM users, the TCM users tended to have a lower risk (0.4 − 0.6 times) of hepatic diseases, suggesting a negative association of hepatitis B, liver cirrhosis, and alcoholic liver disease with TCM usage. One possible explanation for this finding is that the use of TCM might have a protective effect on liver diseases. Another explanation is that patients with impaired liver function would avoid herbal medications to prevent disease progression. The causal relationship warrants further research in the future. However, thyroid diseases, rheumatoid arthritis, osteoarthritis, and sicca syndrome were extrahepatic syndromes that had higher incidence rates in TCM users in Taiwan (Table 4). After adjusting for time of visit, Charlson comorbidity index score, and type of TCM service used, the hazard ratio of these comorbidities became less than 1 and was non-significant. This means the TCM-seeking behaviour is associated with extrahepatic diseases rather than hepatitis C. This finding might be attributed to the side effects of interferon-based antiviral therapy and the lack of satisfaction with the current conventional therapies [27].

To date, the NHIRD has collected diagnosis data via ICD-9-CM codes, which do not classify TCM syndromes or diagnosis. However, TCM prescriptions including formula or herbs are recorded in the NHIRD. By analysing the prescription patterns, we could obtain the possible TCM syndromes and indications for subjects with HC (Table 5). In our database, the most commonly used formulas and single herbs for HC were categorized into hepatic or extrahepatic based on their therapeutic action and clinical indications. Jia-Wei-Xiao-Yao-San, the most commonly used formula, has demonstrated pleiotropic effects in patients with HC, including anti-hepatic fibrosis [28], anti-hepatic cancer [29], anti-depressant [30, 31], and anti-hyperthyroidism effects [32]. However, it is unclear whether it has antiviral effects on HCV, and future investigations on this subject are warranted. Dan-Shen (Salvia miltiorrhiza), the most commonly used single herb, also has multiple hepatoprotective and extrahepatic effects, such as anti-hepatic fibrosis [33], anti-hepatic cancer [34, 35], anti-diabetic [36], and lipid-lowering [37] effects, but no apparent antiviral effects. Other commonly used prescriptions had similar multi-target effects, which implied that TCM physicians used these prescriptions to prevent disease progression or to relieve relevant extra-hepatic syndromes rather than to eradicate HCV.

The present study had some limitations. First, this study did not include therapies that were not covered by the NHI, such as newly antiviral agents or folk medicines [38], which were purchased directly from TCM herbal pharmacies. Consequently, the TCM utilization rates might have been underestimated. However, because only licensed TCM physicians can be reimbursed by the NHI system, the quality of the diagnoses and treatments in the NHIRD were ensured. Second, safety data in this retrospective study are lacking, and thus we cannot evaluate the safety of TCM. Third, our study only examined ambulatory visits to TCM or non-TCM clinics. Our results for visits to Western medical clinics, including inpatient services and emergency department visits, basically concurred with a previous study of outpatient visits [39]. TCM inpatient services, which mostly included hospital-based healthcare for senile populations, were not that popular and therefore only represented a small proportion of the TCM services received by HC patients.

Conclusion

In summary, we conducted a nationwide, population-based study on the use of TCM in patients with HC based on one randomly selected cohort in 2010 from the NHIRD healthcare claims data in Taiwan. It is that more than 60 % of the TCM users were female and that the utilization of TCM increased with age and peaked in the age group of those 40 − 64 years old. Patients who had more extrahepatic diseases and were taking more antiviral agents tended to visit TCM clinics. Jia-Wei-Xiao-Yao-San and Dan-Shen (Salvia miltiorrhiza) were the most commonly used formula and single herb, with 88,124 person-days and 59,252 person-days, respectively. The high prevalence and distinct usage patterns of TCM in the Taiwanese HC population warrant more substantial, high-quality and/or well-designed clinical trials of TCM use.

Abbreviations

CAM: 

Complementary and alternative medicine

HC: 

Hepatitis C

HCV: 

Hepatitis C virus

HR: 

Hazard ratio

ICD-9-CM: 

International Classification of Disease, 9th Revision, Clinical Modification

NCCIH: 

National Centre for Complementary and Integrative Health

NHI: 

National Health Insurance

NHIRD: 

National Health Insurance Research Database

TCM: 

Traditional Chinese Medicine

WHO: 

World Health Organization

Declarations

Acknowledgements

This study is based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Department of Health and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of National Health Insurance Administration, Department of Health or National Health Research Institutes.

Funding

This study is supported by Taipei City Government under the research plan in 2015; China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan. This study is also supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039 -005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.

Availability of data and materials

All data are deposited in a properly managed public repository. In this study, we examined and analyzed datasets released from the NHIRD (http://nhird.nhri.org.tw/en/index.html), which are maintained and managed by National Health Research Institutes (http: www.nhri.org.tw/), Taiwan. The use of NHIRD is limited to research purposes only. Applicants must follow the Computer-Processed Personal Data Protection Law (http://www.winklerpartners.com/?p=987) and related regulations of National Health Insurance Administration and National Health Research Institutes, and an agreement must be signed by the applicant and his/her supervisor upon application submission. All applications are reviewed for approval of data release.

Authors’ contributions

CYL, HRY and CHH conceptualized the study. CYL and JHC performed the statistical analysis. CYL, JYC, HRY, CHH, and JHC contributed to the interpretation of TCM data. CYL, JYC, and HRY drafted the manuscript. CYL, HRY, and CHH finalized the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interest.

Consent for publication

Not applicable.

Ethics approval and consent to participate

All of the datasets from the NHIRD were encrypted and de-identified to protect enrollee privacy. It was not possible to identify individual patients by any means. The Research Ethics Committees of Taipei City Hospital (TCHIRB-10406112-E), and China Medical University and Hospital (CMUH104-REC2-115) approved this study.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University
(2)
Department of Chinese Medicine, Branch of Linsen and Chinese Medicine, Taipei City Hospital
(3)
School of Traditional Chinese Medicine, College of Medicine, Chang Gung University
(4)
Research Centre for Chinese Medicine & Acupuncture, China Medical University
(5)
Health Data Management Office, China Medical University Hospital
(6)
Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University
(7)
Department of Chinese Medicine, China Medical University Hospital
(8)
School of Chinese Medicine, College of Chinese Medicine, China Medical University

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Copyright

© The Author(s). 2016