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  • Research article
  • Open Access
  • Open Peer Review

Acupuncture decreased the risk of coronary heart disease in patients with rheumatoid arthritis in Taiwan: a Nationwide propensity score-matched study

Contributed equally
BMC Complementary and Alternative Medicine201818:341

https://doi.org/10.1186/s12906-018-2384-5

  • Received: 8 August 2018
  • Accepted: 26 November 2018
  • Published:
Open Peer Review reports

Abstract

Background

Patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease (CHD). Acupuncture, a commonly used treatment for patients with RA, has not been reported to prevent CHD in patients with RA. We aimed to assess the risk of developing CHD in acupuncture users and non-users of patients with RA.

Methods

We identified 29,741 patients with newly diagnosed RA from January 1997 to December 2010 from the Registry of Catastrophic Illness Patients Database from the Taiwanese National Health Insurance Research Database. Among them, 10,199 patients received acupuncture (acupuncture users), and 19,542 patients did not receive acupuncture (no-acupuncture users). After performing 1:1 propensity score matching by sex, age, baseline comorbidity, conventional treatment, initial diagnostic year, and index year, there were 9932 patients in both the acupuncture and no-acupuncture cohorts. The main outcome was the diagnosis of CHD in patients with RA in the acupuncture and no-acupuncture cohorts.

Results

Acupuncture users had a lower incidence of CHD than non-users (adjusted HR = 0.60, 95% CI = 0.55–0.65). The estimated cumulative incidence of CHD was significantly lower in the acupuncture cohort (log-rank test, p < .001). Subgroup analysis showed that patients receiving manual acupuncture of traditional Chinese medicine style, electroacupuncture, or combination of both all had a lower incidence of CHD than patients never receiving acupuncture treatment. The beneficial effect of acupuncture on preventing CHD was independent of age, sex, diabetes mellitus, hypertension, hyperlipidemia, and statins use.

Conclusions

This is the first large-scale study to reveal that acupuncture might have beneficial effect on reducing the risk of CHD in patients with RA. This study may provide useful information for clinical utilization and future studies.

Keywords

  • Acupuncture
  • Coronary heart disease
  • National Health Insurance Research Database
  • Rheumatoid arthritis
  • Taiwan

Background

Rheumatoid arthritis (RA) is one of the most prevalent chronic and systemic inflammatory disorders, with the characteristics of joint destruction, functional disability, and early death [1]. Autoantibody production, synovial inflammation, cartilage and bone destruction are the main pathological findings in RA patients [2]. Current pharmacotherapies of RA include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs) [3]. DMARDs, including synthetic and biological DMARDs, have been demonstrated to suppress inflammation to reduce structural damage.

The high mortality rate of patients with RA was mainly because of the significantly higher risk of cardiovascular diseases in patients with RA than in the general population [4]. The previous study revealed that patients with RA had an approximately twofold higher risk of coronary heart disease (CHD) [5]. The risk of CHD in patients with RA is highly associated with the traditional risk factors of CHD, which include hypertension, diabetes mellitus (DM), hyperlipidemia, smoking, obesity, and physical inactivity [6]. Chronic inflammation and immune dysregulation play an important role in inducing atherosclerosis and endothelial dysfunction in patients with RA [7]. Among current pharmacotherapy of RA, methotrexate (MTX) might prevent ischemic cardiovascular disorders in patients with RA [8]. Etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, was demonstrated to attenuate endothelial dysfunction in a rat model [9]. These findings suggest that anti-inflammatory therapy may reduce the CHD risk in patients with RA.

A previous cohort study revealed that approximately 27.3% of patients with RA were traditional Chinese medicine (TCM) users in Taiwan, and approximately 23.6% of TCM users with RA received acupuncture [10]. The anti-inflammatory mechanisms of acupuncture have been demonstrated in murine models [11, 12]. Previous clinical trials have demonstrated that acupuncture suppressed inflammation in patients with RA [13, 14]. However, no prior study evaluated whether acupuncture can prevent CHD in patients with RA. To investigate whether acupuncture decreases the incidence of CHD in patients with RA, we conducted this cohort study.

Methods

Data sources

The Taiwanese National Health Insurance Research Database (NHIRD) is a good database for the cohort study because it contains the long-term follow-up data of most of the population in Taiwan. The National Health Insurance (NHI) program was implemented in 1995 in Taiwan by the National Health Insurance Administration. TCM services have been reimbursed through the NHI since 1996 [15]. The reimbursed population reached more than 99.5% in 2015 [16]. NHIRD is a big database that can prevent sampling bias [17].

The data source of this study was the Registry of Catastrophic Illness Patients Database; patients with autoimmune diseases, such as RA [18], systemic lupus erythematosus, multiple sclerosis, Sjögren syndrome, and cancer, are included in this database, which is a subsection of the NHIRD [19]. All of the patients with RA in the database are given catastrophic illness certificates based on the clinical and laboratory diagnoses by rheumatologists. The NHI program waived RA patients’ copayments for receipt of RA-related treatments, including Western medicine and TCM. In this database, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were the most commonly used diagnostic codes. Because the NHIRD contains identified secondary data for research, the present study was waived from informed consent. This study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115).

Study cohort identification and covariates

Patients who were newly diagnosed with RA (ICD-9-CM code 714.0) between January 1, 1997 and December 31, 2010 were identified, as shown in Fig. 1. Patients younger than 18 years old or with incomplete information on the age and sex were excluded. Patients who received acupuncture between the initial diagnosis of RA and happening of CHD or December 31, 2010 were identified as the acupuncture cohort. In the acupuncture cohort, we defined the index date as the first time that the patients started to receive acupuncture. The immortal time of the acupuncture cohort was the period between the initial diagnosis of RA and the index date. Patients who suffered from CHD were identified through ICD-9-CM codes 410, 411, 413, 414.0, 414.8, and 414.9. Patients diagnosed as having CHD before the index date or within one year after their initial diagnosis of RA were excluded. Patients were followed up until December 31, 2011 or withdrawn from the NHIRD.
Fig. 1
Fig. 1

Study population flowchart diagram. Using the inclusion and exclusion criteria, we identified 10,199 patients who underwent acupuncture and 19,542 patients who never underwent acupuncture. After performing 1:1 propensity score matching, there were 9932 patients in the acupuncture and no-acupuncture cohorts

To reduce confounding factors, we used 1:1 propensity-score matching by sex, age (per 5 years), comorbidity, conventional drug use, the initial diagnostic year of RA, and the index year through multiple logistic regression analysis. The comorbidities analyzed in our study included DM (ICD-9-CM: 250), hypertension (ICD-9-CM: 401–405), hyperlipidemia (ICD-9-CM: 272), congestive heart failure (ICD-9-CM: 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, and 428.0), cerebral vascular diseases (ICD-9-CM: 430–438), depression (ICD-9-CM: 296.2–296.3, 300.4, and 311), anxiety (ICD-9-CM: 300.0, 300.2, 300.3, 308.3, and 308.91), alcoholism (ICD-9-CM: 291, 303, 305.00–305.03, 790.3, and V11.3), tobacco dependence (ICD-9-CM: 305.1), and obesity (ICD-9-CM: 278 and A183). Patients with comorbidity were identified if the ICD-9-CM codes of the selected comorbidity appeared two or more times in the outpatient or inpatient claims. The conventional drugs analyzed in our study included MTX, hydroxychloroquine, sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs, and statins. Finally, equal numbers of patients in the acupuncture and no-acupuncture cohorts were analyzed in this study. Patients were divided into 3 groups according to their age: 18–39 years old, 40–59 years old, and older than 60 years old.

Types of acupuncture and disease categories in the acupuncture cohort

We analyzed the acupuncture type that patients received by the treatment codes, which included manual acupuncture of TCM type (B41, B42, B45, B46, B80-B84, B90-B94, P27041, P31103, P32103, and P33031) and electroacupuncture (B43, B44, B86–89, and P33032). Figure 2 illustrated these two types of acupuncture treatments.
Fig. 2
Fig. 2

Diagram of the two types of acupuncture treatment. a Manual acupuncture of traditional Chinese medicine type (b) Electroacupuncture

Statistical analyses

Statistical analysis was performed using SAS 9.4 (SAS Institute, Cary, NC, U.S.A.), and p < 0.05 in two-tailed tests indicate statistical significance. The difference of baseline characteristics between the acupuncture and no-acupuncture cohorts was expressed as standardized mean differences. Standardized mean differences with less than 0.2 s.d. indicated a negligible difference in the mean or proportions between the two cohorts. For each variable, we used Cox proportional hazard regression to analyze the hazard ratios (HRs) and 95% confidence interval (95% CI). The Kaplan-Meier method was used to determine the cumulative incidence of CHD in both cohorts, and the log-rank test was used to compare incidence curves between the acupuncture and no-acupuncture cohorts.

Results

The identified patient numbers in both cohorts were equal after performing the 1:1 propensity score matched method (Fig. 1). There were no significant differences in the sex, age, baseline comorbidity, and conventional drug use between the no-acupuncture and acupuncture cohorts (Table 1). The included patients were female predominant with a mean age at approximately 50 years old in both cohorts. Almost all patients in both cohorts have used NSAIDs, and more than 90% of patients have also used oral steroids. Approximately 15% of patients took statins in both the no-acupuncture and acupuncture cohorts. Manual acupuncture of the TCM type was the most commonly used acupuncture treatment.
Table 1

Characteristics of rheumatoid arthritis patients according to whether they received acupuncture treatment

Variable

Rheumatoid arthritis

Underwent acupuncture

Standardized mean difference

No (n = 9932)

Yes (n = 9932)

n

%

n

%

Sex

 Female

8212

82.68

8225

82.81

0.003

 Male

1720

17.32

1707

17.19

0.003

Age group

 18–39

2267

22.83

2013

20.27

0.003

 40–59

6099

61.41

6659

67.05

0.003

 ≥60

1566

15.77

1260

12.69

0.003

 Mean ± SD (years)

50.39 (13.7)

50.36 (12.53)

0.002

Baseline Comorbidity

 Diabetes mellitus

1211

12.19

1193

12.01

0.006

 Hypertension

2358

23.74

2339

23.55

0.005

 Hyperlipidemia

1488

14.98

1475

14.85

0.004

 Congestive heart failure

94

0.95

107

1.08

0.013

 Stroke

741

7.46

731

7.36

0.004

 Depression

631

6.35

618

6.22

0.005

 Anxiety

1525

15.35

1499

15.09

0.007

 Alcoholism

20

0.20

24

0.24

0.009

 Tobacco dependence

27

0.27

30

0.30

0.006

 Obesity

80

0.81

77

0.78

0.003

Drug use

 Methotrexate

7131

71.80

7130

71.79

0

 Hydroxychloroquine

8372

84.29

8423

84.81

0.014

 Sulfasalazine

7289

73.39

7278

73.28

0.003

 TNF-α inhibitors

1137

11.45

1151

11.59

0.004

 NSAIDs

9908

99.76

9909

99.77

0.002

 Oral steroids

9449

95.14

9438

95.03

0.005

 Statins

1449

14.59

1438

14.48

0.003

Types of acupuncture

 Manual acupuncture of TCM type

  

8614

86.73

 

 Electroacupuncture

  

340

3.42

 

 Combination of manual acupuncture and electroacupuncture

  

978

9.85

 

Immortal time, days (mean, median)

1064.07 (989.63)

1044.96 (1056.50)

 

Acupuncture visits, mean

 

9.81

 

Follow-up time, years (mean, median)

4.02 (3.03)

4.91 (3.44)

 
During the follow-up period, 909 patients in the acupuncture cohort and 1233 patients in the no-acupuncture cohort developed CHD (Table 2). Compared with the no-acupuncture cohort, the incidence of CHD was significantly lower in the acupuncture cohort (adjusted HR = 0.60, 95% CI = 0.55–0.65). RA patients with old age, DM, or hypertension were prone to developing CHD.
Table 2

Cox model with hazard ratios and 95% confidence intervals for coronary heart disease in patients with rheumatoid arthritis who did or did not receive acupuncture treatment

Variable

No. of event

(n = 2142)

Crudea

Adjustedb

HR

(95%CI)

p-value

HR

(95%CI)

p-value

Acupuncture

 No

1233

1.00

reference

 

1.00

reference

 

 Yes

909

0.63

(0.58–0.69)

<.0001

0.60

(0.55–0.65)

<.0001

Sex

 Female

1692

1.00

reference

 

1.00

reference

 

 Male

440

1.32

(1.19–1.47)

<.0001

1.21

(1.09–1.34)

0.0005

Age group

 18–39

126

1.00

reference

 

1.00

reference

 

 40–59

1458

4.22

(3.52–5.07)

<.0001

3.85

(3.20–4.63)

<.0001

 ≥60

548

8.76

(7.22–10.64)

<.0001

5.35

(4.37–6.56)

<.0001

Baseline Comorbidity (ref = non-site comorbidity)

 Diabetes mellitus

443

2.25

(2.03–2.50)

<.0001

1.46

(1.30–1.64)

<.0001

 Hypertension

877

2.65

(2.43–2.89)

<.0001

1.77

(1.61–1.95)

<.0001

 Hyperlipidemia

391

1.64

(1.47–1.83)

<.0001

1.08

(0.95–1.22)

0.2342

 Congestive heart failure

33

1.94

(1.37–2.73)

0.0002

1.00

(0.71–1.42)

0.9783

 Cerebral vascular diseases

267

2.09

(1.84–2.38)

<.0001

1.22

(1.07–1.40)

0.0037

 Depression

127

1.18

(0.99–1.42)

0.0664

0.97

(0.80–1.17)

0.7509

 Anxiety

312

1.20

(1.07–1.36)

0.0028

0.94

(0.83–1.07)

0.3402

 Alcoholism

2

0.54

(0.14–2.17)

0.3886

0.51

(0.13–2.05)

0.3427

 Tobacco dependence

1

0.25

(0.04–1.74)

0.1606

0.22

(0.03–1.57)

0.1316

 Obesity

18

1.38

(0.87–2.20)

0.171

1.15

(0.72–1.83)

0.5623

Drug use

 Methotrexate

1210

0.47

(0.43–0.51)

<.0001

0.64

(0.58–0.70)

<.0001

 Hydroxychloroquine

1680

0.60

(0.55–0.67)

<.0001

0.80

(0.720–.89)

<.0001

 Sulfasalazine

1437

0.66

(0.61–0.73)

<.0001

0.91

(0.82–1.00)

0.0559

 TNF-α inhibitors

105

0.35

(0.29–0.43)

<.0001

0.48

(0.39–0.59)

<.0001

 NSAIDs

2130

1.36

(0.34–5.44)

0.6638

1.73

(0.43–6.93)

0.4412

 Oral steroids

2010

0.66

(0.55–0.79)

<.0001

0.82

(0.68–0.98)

0.033

 Statins

350

1.07

(0.96–1.20)

0.2408

0.69

(0.61–0.78)

<.0001

Crude HRa represents the relative hazard ratio. Adjusted HRb represents the adjusted hazard ratio mutually adjusted for acupuncture use, age, sex, diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, anxiety, alcoholism, tobacco dependence, obesity, Methotrexate, Hydroxychloroquine, Sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs and statins in Cox proportional hazard regression

The beneficial effect of acupuncture on the incidence of CHD was observed in both women and men (Table 3, adjusted HR = 0.62 in women, 95% CI = 0.56–0.68; adjusted HR = 0.58 in men, 95% CI = 0.48–0.70). Acupuncture significantly decreased the incidence of CHD in all age groups. Regardless of whether patients had DM, hypertension, hyperlipidemia, or stroke, acupuncture lowered the risk of CHD. Moreover, the beneficial effect of acupuncture in preventing CHD was independent of conventional drug use, including statins, MTX, hydroxychloroquine, sulfasalazine, oral steroids, and TNF-α inhibitors. Overall, the cumulative incidence of CHD from the index date was significantly lower in the acupuncture cohort (Fig. 3).
Table 3

Incidence rates, hazard ratio and confidence intervals for coronary heart disease in rheumatoid arthritis patients who did or did not receive acupuncture treatment, stratified by sex, age, comorbidity and drug use

Variables

Rheumatoid arthritis

Compared with no-acupuncture cohort

No acupuncture

(n = 9932)

Acupuncture

(n = 9932)

Crude HR

(95%CI)

Adjusted HR

(95%CI)

Event

Person-years

IR

Event

Person-years

IR

Total

1223

39,930.25

30.63

909

48,742.08

18.65

0.63(0.58–0.69)***

0.60(0.55–0.65)***

Sex

 Female

970

33,542.81

28.92

722

40,610.75

17.78

0.64(0.58–0.7)***

0.62(0.56–0.68)***

 Male

253

6387.44

39.61

187

8131.32

23.00

0.60(0.50–0.73)***

0.58(0.48–0.70)***

Age group

 18–39

81

10,544.53

7.68

45

10,665.24

4.22

0.56(0.39–0.81)**

0.53(0.37–0.77)***

 40–59

816

24,725.99

33.00

642

32,628.29

19.68

0.61(0.55–0.68)***

0.59(0.53–0.66)***

 ≥60

326

4659.72

69.96

222

5448.55

40.74

0.61(0.51–0.72)***

0.62(0.52–0.73)***

Baseline Comorbidity

Diabetes mellitus

 No

969

36,055.56

26.88

720

43,658.67

16.49

0.64(0.58–0.70)***

0.60(0.55–0.66)***

 Yes

254

3874.69

65.55

189

5083.41

37.18

0.58(0.48–0.71)***

0.59(0.49–0.72)***

Hypertension

 No

717

32,065.40

22.36

538

38,485.07

13.98

0.64(0.57–0.72)***

0.62(0.56–0.70)***

 Yes

506

7864.85

64.34

371

10,257.00

36.17

0.59(0.51–0.67)***

0.58(0.51–0.67)***

Hyperlipidemia

 No

1000

35,475.99

28.19

741

43,080.05

17.20

0.63(0.58–0.70)***

0.61(0.56–0.67)***

 Yes

223

4454.26

50.06

168

5662.03

29.67

0.59(0.49–0.73)***

0.57(0.47–0.70)***

Congestive heart failure

 No

1202

39,641.02

30.32

897

48,354.94

18.55

0.63(0.58–0.69)***

0.61(0.56–0.66)***

 Yes

21

289.23

72.61

12

387.14

31.00

0.44(0.22–0.90)*

0.50(0.24–1.07)

Cerebral vascular diseases

 No

1069

37,549.80

28.47

796

45,604.09

17.45

0.64(0.58–0.70)***

0.60(0.55–0.66)***

 Yes

154

2380.45

64.69

113

3137.99

36.01

0.58(0.45–0.74)***

0.59(0.46–0.76)***

Depression

 No

1144

38,013.07

30.09

861

46,405.65

18.55

0.64(0.59–0.70)***

0.62(0.56–0.67)***

 Yes

79

1917.19

41.21

48

2336.42

20.54

0.51(0.36–0.73)***

0.51(0.35–0.73)***

Anxiety

 No

1042

35,170.64

29.63

778

43,056.56

18.07

0.63(0.58–0.69)***

0.60(0.55–0.66)***

 Yes

181

4759.61

38.03

131

5685.51

23.04

0.62(0.50–0.78)***

0.62(0.49–0.78)***

Alcoholism

 No

1222

39,865.91

1222

908

48,660.02

908

0.63(0.58–0.69)***

0.61(0.56–0.66)***

 Yes

1

64.34

1

1

82.05

1

0.58(0.03–9.89)

Tobacco dependence

 No

1222

39,862.01

1222

909

48,661.38

909

0.63(0.58–0.69)***

0.61(0.56–0.66)***

 Yes

1

68.24

1

0

80.70

0

Obesity

 No

1214

39,697.39

30.58

900

48,463.26

18.57

0.63(0.58–0.69)***

0.61(0.55–0.66)***

 Yes

9

232.86

38.65

9

278.81

32.28

0.95(0.37–2.42)

0.74(0.26–2.09)

Drug use

Methotrexate

 No

530

10,045.02

52.76

392

13,042.58

30.06

0.60(0.53–0.68)***

0.61(0.54–0.7)***

 Yes

693

29,885.23

23.19

517

35,699.50

14.48

0.64(0.57–0.72)***

0.60(0.53–0.67)***

Hydroxychloroquine

 No

257

5500.43

46.72

195

6736.19

28.95

0.65(0.54–0.78)***

0.62(0.52–0.75)***

 Yes

966

34,429.82

28.06

714

42,005.89

17

0.63(0.57–0.69)***

0.60(0.54–0.66)***

Sulfasalazine

 No

410

9296.59

44.10

285

11,957.00

23.84

0.57(0.49–0.66)***

0.54(0.47–0.63)***

 Yes

813

30,633.66

26.54

624

36,785.07

16.96

0.66(0.59–0.73)***

0.64(0.57–0.71)***

TNF-α inhibitors

 No

1157

34,731.45

33.31

870

42,448.62

20.50

0.64(0.59–0.7)***

0.62(0.56–0.67)***

 Yes

66

5198.80

12.70

39

6293.45

6.20

0.48(0.32–0.72)***

0.42(0.28–0.62)***

NSAIDs

 No

0

42.45

0

2

62.67

31.91

 Yes

1223

39,887.80

30.66

907

48,679.41

18.63

0.63(0.58–0.69)***

0.61(0.56–0.66)***

Oral steroids

 No

68

1442.40

47.14

54

1799.74

30

0.69(0.48–1.00)*

0.74(0.51–1.07)

 Yes

1155

38,487.85

30.01

855

46,942.34

18.21

0.63(0.57–0.69)***

0.60(0.55–0.65)***

Statins

 No

1020

33,516.65

30.43

762

41,308.09

18.45

0.63(0.58–0.69)***

0.61(0.55–0.67)***

 Yes

203

6413.60

31.65

147

7433.99

19.77

0.63(0.51–0.78)***

0.59(0.48–0.73)***

Abbreviations: IR, incidence rates per 1000 person-years; HR, hazard ratio; and CI, confidence interval

Adjusted HR: adjusted for acupuncture use, age, sex, diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, anxiety, alcoholism, tobacco dependence, obesity, Methotrexate, Hydroxychloroquine, Sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs and statins in Cox proportional hazard regression

*: p < 0.05; **: p < 0.01; and ***: p < 0.001

Fig. 3
Fig. 3

Cumulative incidence of coronary heart disease (CHD) between the acupuncture and no-acupuncture cohorts. The cumulative incidence of coronary heart disease in the acupuncture cohort (dashed line) is significantly lower than the no-acupuncture cohort (solid line) (log-rank test, p < .001). The zero point indicated the index date

Subgroup analysis was performed to evaluate whether different types of acupuncture had any correlation and difference on preventing CHD in patients with RA (Table 4). Patients receiving only manual acupuncture, only electroacupuncture, or combination of manual acupuncture and electroacupuncture all had a lower incidence of CHD than patients never receiving acupuncture.
Table 4

Cox model for coronary heart disease in patients with rheumatoid arthritis receiving different types of acupuncture treatment vs. not receiving acupuncture treatment

 

n

CHD

(n = 2132)

Crude HR*(95%CI)

Adjusted HR (95%CI)

No-acupuncture

9932

1223

1 (reference)

1 (reference)

Acupuncture

Manual acupuncture of TCM type

8614

819

0.67(0.62–0.74)***

0.64(0.58–0.69)***

Electroacupuncture

340

19

0.48(0.31–0.76)**

0.46(0.29–0.73)**

Combination of manual acupuncture and electroacupuncture

978

71

0.39(0.30–0.49)***

0.36(0.28–0.46)***

Abbreviations: HR, hazard ratio; CHD, coronary heart disease; CI, confidence interval; and TCM, traditional Chinese medicine

Crude HR* represents relative hazard ratio. Adjusted HR represents adjusted hazard ratio mutually adjusted for age, sex, diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, anxiety, alcoholism, tobacco dependence, obesity, Methotrexate, Hydroxychloroquine, Sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs and statins in Cox proportional hazard regression

**: p < 0.01; and ***: p < 0.001

Among the different types of CHD, patients with acupuncture had a significant lower incidence of chronic ischemic heart disease (Table 5). However, there was no significant difference in the incidence of angina pectoris between the two groups. The effect on acute myocardial infarction was not analyzed (data not shown; only 11 patients had acute myocardial infarction in two groups).
Table 5

Cox model for angina pectoris and chronic ischemic heart disease in patients with rheumatoid arthritis receiving acupuncture treatment vs. not receiving acupuncture treatment

 

N

Angina pectoris

Chronic ischemic heart disease

n

Crude HR*

Adjusted HR

n

Crude HR* (95%CI)

Adjusted HR (95%CI)

Acupuncture

 No

 

8733

24

1 (reference)

1 (reference)

516

1 (reference)

1 (reference)

 Yes

 

9044

21

0.79(0.44–1.43)

0.72(0.4–1.3)

358

0.59(0.52–0.68)***

0.56(0.49 − 0.64)***

Crude HR* represents relative hazard ratio. Adjusted HR represents adjusted hazard ratio mutually adjusted for age, sex, diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, anxiety, alcoholism, tobacco dependence, obesity, Methotrexate, Hydroxychloroquine, Sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs and statins in Cox proportional hazard regression

***: p < 0.001

Table 6 showed the top five disease categories, which represented the reasons for clinical visits, in the acupuncture cohort. Most patients with RA received acupuncture because of musculoskeletal disease.
Table 6

The top five disease categories (as the reasons for clinical visits) in acupuncture user cohort

Disease (ICD-9-CM)

Acupuncture users

(n = 9932)

n

%

Musculoskeletal system and connective tissue (710–739)

6885

69.32

Injury (800–999)

5377

54.14

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

700

7.05

Nervous system (320–389)

463

4.66

Digestive system (520–579)

302

3.04

Maximal of three ICD-9-CM codes could be recorded in one visit

Discussion

To the best of our knowledge, this nationwide population-based study is the first report to reveal that acupuncture decreased the risk of CHD in patients with RA. Our study found that the beneficial effects of acupuncture for developing CHD in patients with RA were independent of sex, age, DM, and hypertension. Moreover, acupuncture decreased the risk of CHD in patients with RA who took statins, which was reported to reduce the risk of cardiovascular diseases [20]. Among different types of CHD, our results demonstrated that patients with acupuncture had a significant lower incidence of chronic ischemic heart disease than patients without receiving acupuncture treatment.

The risk of CHD in patients with RA is highly associated with the conventional risk factors of CHD, such as hypertension, DM, hyperlipidemia, and physical inactivity [6]. Our study also demonstrated that RA patients with comorbidities, including DM, hypertension, or hyperlipidemia, had a higher risk of CHD. Even in RA patients with DM, hypertension, or hyperlipidemia, our study indicated that acupuncture decreased the incidence of CHD. Previous clinical trials indicated that acupuncture improved swelling and range of motion of knee joints, physical activity, and quality of life in patient with RA [14, 21, 22]. Improved physical activity might be one of the possible explanations that acupuncture can prevent CHD in patients with RA. However, we also found that for those RA patients with the comorbidity of congestive heart failure, acupuncture did not reduce the risk of CHD.

The previous study stated that endothelial dysfunction contributed to atherosclerosis and induced cardiovascular disorders [23]. The current conventional drugs for RA treatment, including glucocorticoids [24] and etanercept (a TNF-α inhibitor) [9], have been demonstrated to improve endothelial dysfunction through the anti-inflammatory effect in RA rat models. However, the protective effect of glucocorticoids remains controversial because glucocorticoids also enhance the risk of cardiovascular disorders based on their negative effects on blood pressure, lipid, insulin resistance and obesity [25]. The protective effect of MTX at a low dose against CHD in patients with RA was also demonstrated in a previous meta-analysis study although it did not attenuate hyperlipidemia or insulin resistance [8]. Our study also indicated that patients with RA who took MTX or TNF-α inhibitors had a lower risk of CHD. In addition, regardless of whether patients used TNF-α inhibitors or MTX, acupuncture significantly decreased the risk of CHD in those patients.

Chronic inflammation plays an important role in the pathogenesis of RA and its comorbidities, including DM, hypertension, and CHD [7]. As a result, amelioration of inflammatory activity should be considered in the CHD preventive strategy for patients with RA. The anti-inflammatory mechanisms of acupuncture have been evaluated in murine models of inflammatory disorders [11, 12]. Acupuncture corrected the imbalance between Th17 and Treg cells to attenuate the severity of RA in a rat RA model [26]. IL-17, cytokine secreted by Th17 cells, has been demonstrated to be important in the pathogenesis of RA, and it has been demonstrated to be associated with CHD [27]. Further mechanistic studies are needed to evaluate whether acupuncture can suppress IL-17 in RA to prevent CHD. Previous clinical trials have demonstrated that acupuncture suppressed inflammation in patients with RA [13, 14]. Based on these studies, acupuncture not only had a traditionally recognized analgesic effect, it had an anti-inflammatory effect. Anti-inflammation might be one of the mechanisms by which acupuncture decreased the incidence of CHD in RA patients. In addition, previous studies demonstrated that the combination of acupuncture with current conventional treatment had additive effects on hypertensive patients [28] and diabetic patients [29], which could contribute to how acupuncture decreased the risk of CHD in RA patients with comorbidity or conventional treatment. The mechanistic study is needed in the future. We have established a collagen-induced arthritis murine model and designed a clinical trial to investigate whether acupuncture is effective on the immunological modulation in RA.

The strength of this study was the comprehensive large-scale database, Taiwan’s NHIRD, which provides a large sample size and reduces selection bias while including long-term follow-up data [17]. Although there were a few clinical trials investigating the efficacy of acupuncture for the treatment of patients with RA [13, 14, 21, 22, 3035], none of them addressed the question whether acupuncture treatment reduces the risk of cardiovascular disease among patients with RA.

Some limitations merit attention in our study. First, the detailed information about severity of RA, including pain scores, the severity of inflammation, or the destruction of cartilage and bone were not provided in the database. Because patients with different severities may receive different conventional treatments, we performed a 1:1 propensity score matching to minimize this confounding factor. We found that there were no difference in percentages of patients who used analgesic drugs, including NSAIDs and oral steroids, in the acupuncture and no-acupuncture cohorts. The second limitation is that lifestyle data, such as smoking, alcohol drinking, and body mass index (BMI), were unavailable in the datasets. We were able to acquire information of the illnesses that resulted from these personal habits and lifestyles, including alcoholism, tobacco dependence, and obesity. However, an underestimation of smoking exposure and alcohol drinking in both cohorts still may exist. The third limitation was that the datasets did not provide detailed information of selected acupoints and treatment protocols. Usually, TCM doctors selected acupoints for each patient according to the TCM diagnosis, which may vary during the disease progression. In addition, the duration or visit times of acupuncture in the current study might be underestimated because the NHI program only covers maximal 15 times of acupuncture per month and maximal 2–3 times per week, some patients may use self-pay for additional acupuncture treatment, which could not be identified from the NHIRD database. Future clinical trials should consider comparing the effects of a set of fixed acupoints versus flexible acupoints and different duration/times of acupuncture treatment. Although there are some limitations in the current retrospective cohort study, it’s a “real-world evidence” that can reflect actual use in practice [36] from a comprehensive large-scale database. Evidences gathered from future clinical trials should be able to provide more information regarding the selection of acupoints.

Conclusions

Our study revealed that acupuncture treatment might have beneficial effect on reducing the risk of CHD in patients with RA in Taiwan. This noteworthy finding can provide useful information for further clinical and mechanistic studies.

Notes

Abbreviations

95% CI: 

95% confidence interval

CHD: 

Coronary heart disease

DM: 

Diabetes mellitus

DMARDs: 

Disease-modifying anti-rheumatic drugs

HRs: 

Hazard ratios

ICD-9-CM: 

International Classification of Diseases, Ninth Revision, Clinical Modification

MTX: 

Methotrexate

NHI: 

National Health Insurance

NHIRD: 

National Health Insurance Research Database

NSAIDs: 

Non-steroid anti-inflammatory drugs

RA: 

Rheumatoid arthritis

TCM: 

Traditional Chinese medicine

Declarations

Acknowledgements

This study was based in part on data from the NHIRD, provided by the NHIA, and the Ministry of Health and Welfare and was managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the NHIA, Ministry of Health and Welfare, or National Health Research Institutes. The funding agencies had no role in study design, data collection and analyses, and result interpretation and publication of this study.

Funding

This study was supported in part by China Medical University under the Higher Education Sprout Project, Ministry of Education, Taiwan. It was also supported by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW107-TDU-B-212-123004), the Health and Welfare surcharge of tobacco product, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114-24) and Department of Medical Research, China Medical University Hospital (DMR-107-004), Taiwan.

Availability of data and materials

All data of this study are deposited in a properly managed public repository. We examined and analysed datasets released from the Taiwan NHIRD (http://nhird.nhri.org.tw/en/index.html), maintained and managed by National Health Research Institutes (http://www.nhri.org.tw/), Taiwan. The use of the datasets 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 the 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

MYW conceived the study design, interpreted the data, and drafted the manuscript. MCH conceived the study design, and interpreted the data. HHL conceived the study design interpreted the data. JHC did the statistical analysis. YCL and CYH interpreted the data. MFS conceived the study design, interpreted the data, supervised the study, and finalized the manuscript. HRY conceived the study design, interpreted the data, supervised the study, and finalized the manuscript. MFS and HRY contributed equally. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115) and also the National Health Research Institute, the data holder of the NHI database. The patient consent was exempted for the total anonymity of all research data in this study.

Consent for publication

Not applicable in this section.

Competing interests

The funding agencies had no role in study design, data collection, analyses, result interpretation or publication of this study. This study was based in part on data from the NHIRD, provided by the NHIA, and the Ministry of Health and Welfare and was managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes. All authors declare that they have no conflicts of interest.

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Authors’ Affiliations

(1)
Department of Chinese Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung, 404, Taiwan
(2)
Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung, 404, Taiwan
(3)
Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, 622, Taiwan
(4)
Management Office for Health Data, China Medical University Hospital, Taichung, 404, Taiwan
(5)
School of Medicine, College of Medicine, China Medical University, Taichung, 404, Taiwan
(6)
Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan
(7)
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 404, Taiwan
(8)
Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, 2 Yude Road, North District, Taichung, 404, Taiwan
(9)
Research Center for Chinese Herbal Medicine, China Medical University, Taichung, 404, Taiwan
(10)
Chinese Medicine Research Center, China Medical University, Taichung, 404, Taiwan
(11)
Department of Biotechnology, Asia University, Taichung, 413, Taiwan

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Copyright

© The Author(s). 2018

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