Acupuncture Decreased the Risk of Coronary Heart Disease in Patients with Osteoarthritis in Taiwan: A Nationwide Matched Cohort Study

Abstract

Objectives:

Patients with osteoarthritis (OA) are more likely to develop coronary heart disease (CHD) than the general population. Acupuncture is commonly used in OA patients; however, the therapeutic effect of acupuncture on the risk of CHD in patients with OA and the association between OA patients and their risk to develop CHD in Taiwan are unknown. We investigated the risk of CHD according to acupuncture use in OA patients and compared it with the general population.

Design:

Records obtained from Taiwan's National Health Insurance Research Database identified 84,773 patients with OA, which were compared with 727,359 patients without OA diagnosis. Five thousand forty-six of those who met study inclusion criteria had 1:1 frequency matching and were categorized as OA-acupuncture cohort (n = 1682), OA nonacupuncture cohort (n = 1682), and non-OA cohort (n = 1682). Cox proportional hazards regression analysis determined the risk of CHD, which was defined as the study main outcome. Therapeutic effects of acupuncture and medical expenditure were also analyzed.

Results:

OA nonacupuncture cohort had 3.04 higher risk to develop CHD compared with OA-acupuncture cohort (95% confidence interval [CI], 2.54–3.63, p < 0.001) and non-OA cohort had 1.88 higher risk to develop CHD compared with OA-acupuncture cohort (95% CI, 1.52–2.32, p < 0.001). In subgroup analyses, OA patients treated with both acupuncture and oral steroids were at significantly lower risk of CHD compared with those who used neither (adjusted hazard ratio 0.34; 95% CI, 0.22–0.53), and OA patients treated with acupuncture had the lowest medical expenditure in a follow-up time of 6 months, and 3 and 5 years.

Conclusion:

This is the first large-scale investigation in Taiwan that shows the association between OA and CHD and the beneficial effects of acupuncture in OA patients, and their associated risk to develop CHD. Our results may provide valuable information for health policy decision making. Further randomized controlled trials are needed to confirm these observational findings.

Introduction

Osteoarthritis (OA) is the most common form of arthritis among more than 100 different rheumatic diseases¹ and is thought to be a leading cause of disability worldwide.² Because of its high morbidity rate, OA is also a major cause of health care expenditures.² The most predominant symptoms are pain and loss of movement and function, which greatly affect quality of life.³ Women and patients older than 50 are more prone to develop the disease, and the knee, hip, and hand are the most affected joints.⁴ Nonsteroidal anti-inflammatory drugs (NSAIDs) are added to or substituted for pharmacotherapy with paracetamol, which is considered the first line of oral analgesic before seeing a primary care physician^5
–7; however, little evidence exists to support the safety of NSAIDs in patients with cardiovascular risks.⁸ In cases of little analgesic effect or NSAID contraindication, glucocorticoids and weak opioids may be used in the short term.⁹

Previous epidemiological studies have found an association between OA patients and increased risk of developing cardiovascular disease.^10,11 Several causes that may have a role in pathogenesis include shared etiological features and risk factors like hypertension, diabetes, hypercholesterolemia, and obesity.¹¹ Oxidative stress, in which diet may also contribute to this condition, has a role with vascular pathogenesis and the progression of coronary heart disease (CHD).¹² Studies have also shown an association between atherosclerosis and OA,^13,14 and the suspected underlying mechanism is vascular alterations that cause a disruption in the circulation of the synovial membrane and subchondral bone, which leads to cartilage destruction.^10,15

Acupuncture, which is part of Traditional Chinese Medicine (TCM) treatment modalities, is commonly used in Asia,¹⁶ and in recent years, its popularity has increased in Western countries.¹⁷ In Taiwan, TCM use is integrated into a modern health care system, supported and subsidized by the National Health Insurance (NHI) program.¹⁸ In 1996, the World Health Organization published a comprehensive review on controlled clinical trials studying acupuncture¹⁹ and outlined 64 conditions for which acupuncture has proven to be an effective treatment. Among them are several types of pain-related conditions, both acute and chronic.^20,21 In a recent survey conducted in Taiwan, the use of acupuncture for diseases of the musculoskeletal system and connective tissue ranked second among adult patients.¹⁶

Acupuncture has been shown to have anti-inflammatory effects in animal models.²² Moreover, in a randomized clinical trial, electroacupuncture has been observed to have beneficial effect in reducing serum prooxidant antioxidant balance values in obese patients.²³ A recent meta-analysis of randomized controlled trials about the use of acupuncture in OA treatment has demonstrated statistically significant reductions in pain intensity, as well as improvements in functional mobility and health-related quality of life.²⁴ However, no study has yet demonstrated the effects of acupuncture in OA patients and their risk for developing CHD. Moreover, no prior population-based studies exist, which have evaluated an association between OA and the risk of CHD in the Taiwanese population. Thus, we used the National Health Insurance Research Database (NHIRD) to investigate the incidence of CHD after OA diagnosis among three cohorts: OA-acupuncture, OA nonacupuncture, and non-OA.

Materials and Methods

Data resource

The compulsory NHI program was launched in 1995 and now covers nearly the entire Taiwanese population. The Longitudinal Health Insurance Database 2000 (LHID 2000), was used in this cohort study. This dataset, which is part of the NHIRD databases, contains information of 1 million beneficiaries randomly sampled from the NHI program in the year 2000. LHID 2000 comprises records of clinic visit and hospitalization, which includes, demographic features, medical costs, drug prescriptions, and diagnostic codes, all based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).²⁵ This study was approved by the Institutional Review Board of China Medical University (CMUH104-REC2-115(CR-4)).

Sample participant

From 1 million beneficiaries randomly sampled from LHID 2000, we identified three cohorts, which were assigned to a study period between January 1, 2000, and December 31, 2012: OA cohorts that include patients with the principle diagnosis of OA (ICD-9-CM code 715), which were further divided as OA-acupuncture cohort (n = 2263), OA nonacupuncture cohort (n = 82,520), and non-OA cohort (n = 727,359), which includes patients without any principle diagnosis of OA. Patients in the OA cohorts had at least two ambulatory claims or at least one hospitalization claim with a diagnosis of OA. Patients younger than 18 years (n = 87,453), who had a diagnosis date of CHD (ICD-9-CM codes 410–414 and 429.2) before the initial diagnosis date of OA (n = 57,396) and had missing information for age or sex (n = 75,460) were excluded from the analysis.

In the OA-acupuncture cohort, we further restricted the analysis to include patients who underwent at least 10 times of acupuncture treatments, 6 months following their OA diagnosis with the following treatments codes: manual acupuncture (B41, B42, B80–84, B90–94, P27041, P31103, P32103, and P33031), electro acupuncture (B43, B44, B86–89, and P33032), and complex acupuncture (B45). A total of 1723 OA-acupuncture, 60,352 OA nonacupuncture, and 529,748 non-OA patients were included as the study population. The selection procedure between the OA cohorts was performed using 1:1 frequency matching of each cohort by age (per 5 years), sex, initial diagnosis year of OA, and index year, resulting in a total of 1682 patients in each cohort.

The date of first acupuncture use after the principle diagnosis date of OA was defined as the index date for the OA-acupuncture cohort. The immortal time was defined as the period from the initial diagnostic date of OA to the index date. As patients in the OA nonacupuncture cohort could not be assigned an index date for first acupuncture treatment, they were each randomly assigned a “pseudo-diagnostic date” as an index date. The selection procedure between the OA nonacupuncture cohort and non-OA cohort was performed using 1:1 frequency matching, as well for age (per 5 years), sex, and initial diagnosis year of OA; however, because both cohorts did not receive any acupuncture treatment, their index date was defined as the first date of OA diagnosis. As patients in the non-OA cohort could not be assigned an index date for OA diagnosis, the “pseudo-diagnostic date” as an index date was applied in this cohort as well so that all cohorts could enroll in a similar time. All subjects were followed up until December 31, 2012, or until the first incident of any kind of CHD (ICD-9-CM codes 410–414 and 429.2), which was chosen to be the study primary outcome.

Comorbidity and Medications

Baseline comorbidities included hypertension (ICD-9-CM code 401–405), diabetes mellitus (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), chronic obstructive pulmonary disease (COPD, ICD-9-CM codes 490–496), epilepsy (ICD-9-CM codes 345), congestive heart failure (ICD-9-CM codes 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, and 428.0), fibromyalgia (ICD-9-CM codes 729.0 and 729.1), stroke (ICD-9-CM codes 430–438), depression (ICD-9-CM codes 296.2–296.3, 300.4, and 311), anxiety (ICD-9-CM codes 300.0, 300.2, 300.3, 308.3, and 308.91), alcoholism or alcohol-related disorders (ICD-9- CM codes 291, 303, 305.00–305.03, 790.3, and V11.3), tobacco dependence (ICD-9-CM code 305.1), and obesity (ICD-9-CM codes 278 and A183). The use of medications included oral steroids, statins, angiotensin-converting-enzyme (ACE) inhibitors, Plavix, and NSAIDs such as aspirin, ibuprofen, naproxen, and celecoxib.

Statistical analysis

Between-group differences in baseline characteristics were estimated using Chi-squared test to compare categorical variables, whereas the Student's t-test was used to compare continuous variables. Univariate and multivariate Cox proportional hazards regression models were used to assess the risk of OA, and the hazard ratio (HR) and the 95% confidence interval (CI) were estimated. A multivariable model was performed by controlling for potential confounding variables like demographic characteristics such as gender, age, monthly income, urbanization level (highest and lowest levels were defined as level 1 and level 7, respectively), and all included comorbidities and medications. Urbanization levels were defined according to population density (people/km²), education levels, and the physician's number per 100,000 people. The differences between the OA-acupuncture cohort and the two other cohorts in the cumulative incidence of CHD were estimated by Kaplan-Meier curves using a log-rank test. Statistical analyses were performed using SAS software (version 9.4 for Windows 10; SAS Institute, Cary, NC, USA) and the significance level was set at 0.05.

Results

The final analysis included 1682 patients of the OA-acupuncture cohort, 1682 patients of the OA-non acupuncture cohort, and 1682 patients of the non-OA cohort (Fig. 1), 1:1 frequency matched by age (per 5 years), sex, initial diagnosis year of OA, and index year of first OA diagnosis (Table 1). For all 5046 patients in the three cohorts, baseline characteristics, comorbidities, medication use, and follow-up time are detailed in Table 1. There were no significant between-group differences in sex and age distributions, urbanization level, and monthly income. Females, monthly income of more than NTD 20,000 and living in a high level of urbanization, were more predominant in all cohorts. Compared with OA-acupuncture cohort, OA nonacupuncture cohort and non-OA cohort had a higher risk of CHD stratified by gender, age, monthly income, and urbanization. OA-acupuncture cohort demonstrated higher risk of comorbidities, and medication use, including hyperlipidemia, COPD, fibromyalgia, stroke, depression, anxiety, oral steroids, statin, NSAIDs, aspirin, ibuprofen, and naproxen, compared with non-OA cohort. OA nonacupuncture cohort demonstrated higher risk of comorbidities and medications, including hypertension, ACE inhibitors use, and celecoxib use, compared with non-OA cohort. Mean follow-up times were 5.33 (median 3.15) years, 3.73 (median 3) years, and 3.8 (median 2.93) years for OA-acupuncture cohort, OA nonacupuncture cohort, and non-OA cohort, respectively. Mean duration in days between diagnosis of OA and index date of first acupuncture treatment was 50.8, 50.9, and 50.7 for OA-acupuncture cohort, OA nonacupuncture cohort, and non-OA cohort, respectively. Table 2 displays the incidences and crude and adjusted HRs (aHRs) and 95% CIs calculated by univariate and multivariate cox proportional hazard models for all three cohorts. Eight hundred three were diagnosed with CHD, 193 (11.3%) were OA-acupuncture cohort, 405 (24.0%) were OA nonacupuncture cohort. and 205 (12.1%) were non-OA cohort. Cox proportional hazards regression analysis after adjusting for sex, age, comorbidities, and drug use showed that OA nonacupuncture cohort had 3.04 higher risk to develop CHD compared with OA-acupuncture cohort (95% CI, 2.54–3.63, p < 0.001), and non-OA cohort had 1.88 higher risk to develop CHD compared with OA-acupuncture cohort (95% CI, 1.52–2.32, p < 0.001). Table 3 displays the therapeutic effects of acupuncture and oral steroids on the risk of CHD in patients with OA. Patients who used only acupuncture or both acupuncture and oral steroids were at significantly lower risk of CHD compared with patients who used neither (aHR 0.19; 95% CI, 0.08–0.47) (aHR 0.34; 95% CI, 0.22–0.53), as were those who used oral steroids only (aHR 1.03; 95% CI, 0.68–1.56). Table 4 displays the therapeutic effects of acupuncture and NSAIDs on the risk of CHD in patients with OA. Patients who used both acupuncture and NSAIDs had 3 times lower incidence rate compared with patients who used only NSAIDs; however, the results were not significant (aHR 0.30; 95% CI, 0.04–2.34). Table 5 displays the average daily medical expenditure of hospitalization and outpatient care, calculated in New Taiwanese dollars (NT$), of diagnosed OA and non-OA patients categorized by follow-up time of after 6 months, and 3 and 5 years. There was a significant difference in medical expenditure between OA-acupuncture cohort compared with the two other cohorts in a follow-up time of after 6 months, and 3 and 5 years. Table 6 displays the top 10 disease categories in the OA-acupuncture cohort, which were accompanied with OA diagnosis. Disease of the musculoskeletal system and connective tissue and injury and poising were the most common categories. Table 7 displays the top 10 OA diagnostic codes in the OA-acupuncture and OA nonacupuncture cohorts. Figure 2 displays the Kaplan-Meier analysis with the log rank test that indicated a lower cumulative incidence of CHD in OA-acupuncture cohort compared with OA nonacupuncture and non-OA cohort (log-rank test, p < 0.001)

FIG. 1.

Study population flowchart depicting the rationale for the selected study sample of newly diagnosed OA patients and non-OA diagnosed patients in Taiwan's National Health Insurance Research Database. OA, osteoarthritis.

FIG. 2.

Kaplan-Meier curves with differences in cumulative incidence of coronary heart disease between OA patients with acupuncture, OA patients without acupuncture, and non-OA patients using the log-rank test (p < 0.001). OA, osteoarthritis.

Table 3.

Cox Proportional Hazard Regression Analysis Showing the Risk of Coronary Heart Disease Associated with Acupuncture or Oral Steroidal Treatment in Osteoarthritis Patients

Treatment		n	Events	PY	IR	cHR (95% CI)	aHR (95% CI)
Acupuncture	Oral steroids	n	Events	PY	IR	cHR (95% CI)	aHR (95% CI)
No	No	179	26	593	4.38	1 (reference)	1 (reference)
Yes	No	120	6	641	0.94	0.24 (0.10–0.60)^**	0.19 (0.08–0.47)^***
No	Yes	1503	379	5683	6.67	1.61 (1.08–2.39)^*	1.03 (0.68–1.56)
Yes	Yes	1562	187	8317	2.25	0.59 (0.39–0.90)^*	0.34 (0.22–0.53)^***

p < 0.05.

p < 0.01.

***

p < 0.001.

aHR, adjusted hazard ratio for sex, age, monthly income, urbanization, and comorbidities and medication; cHR, crude hazard ratio; CI, confidence interval; IR, incidence rate, per 100 person-years; PY, person-years.

Table 4.

Cox Proportional Hazard Regression Analysis Showing the Risk of Coronary Heart Disease Associated with Acupuncture or Nonsteroidal Anti-Inflammatory Drug Treatment in Osteoarthritis Patients

Treatment		n	Events	PY	IR	cHR (95% CI)	aHR (95% CI)
Acupuncture	NSAIDS	n	Events	PY	IR	cHR (95% CI)	aHR (95% CI)
No	No	6	1	17	5.88	1 (reference)	1 (reference)
Yes	No	6	0	35	0	—	—
No	Yes	1676	404	6259	6.45	1.30 (0.18–9.25)	0.91 (0.12–7.02)
Yes	Yes	1676	193	8923	2.16	0.48 (0.06–3.43)	0.30 (0.04–2.34)

aHR, adjusted hazard ratio for sex, age, monthly income, urbanization, and comorbidities; cHR, crude hazard ratio; CI, confidence interval; IR, incidence rate, per 100 person-years; NSAIDs, nonsteroidal anti-inflammatory drugs; PY, person-years.

Table 5.

Medical Expenditure of Hospitalization and Outpatient Care of Diagnosed Osteoarthritis and Nonosteoarthritis Patients Categorized by Time of Follow-up

	Average daily medical expenditure ^a of hospitalization and outpatient care (NT$, TWD)			p-Value
	6 months	3 years	5 years	p-Value
OA-acupuncture cohort	1209.04	1099.25	1076.88	0.57
OA nonacupuncture cohort	10.791.12	2161.54	1846.23	0.0001^**
Non-OA cohort	3162.41	2289.55	2044.88	0.03^*

Medical expenditure was categorized according to all-cause disease.

p < 0.05.

p < 0.001.

NT$, New Taiwanese dollars; OA, osteoarthritis; TWD, Taiwan New Dollar.

Table 6.

Top 10 Disease Categories in Osteoarthritis-Acupuncture Cohort

Disease categories (ICD-9-CM codes)	No. of person
Disease of the musculoskeletal system and connective tissue (710–739)	1475
Injury and poising (800–999)	1400
Disease of the nervous system and sense organs (320–389)	273
Disease of the circulatory system (390–459)	235
Disease of the digestive system (520–579)	203
Disease of the respiratory system (460–519)	165
Disease of genitourinary system (580–629)	60
Disease of mental disorder (290–319)	39
Disease of the skin and subcutaneous (680–709)	36
Neoplasms (210.0–229.9)	3

ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

Table 7.

The Top 10 Osteoarthritis Diagnostic Codes in Osteoarthritis-Acupuncture and Osteoarthritis Nonacupuncture Cohorts

Disease categories (ICD-9-CM codes)	OA-acupuncture cohort		OA nonacupuncture cohort		p-Value
Disease categories (ICD-9-CM codes)	n	%	n	%	p-Value
Osteoarthrosis, generalized, unspecified site (715.00)	200	11.9	226	13.4	0.17
Osteoarthrosis, localized, primary, unspecified site (715.10)	71	4.22	95	5.65	0.05
Osteoarthrosis, localized, primary, shoulder region (715.11)	41	2.44	56	3.33	0.12
Osteoarthrosis, generalized, hand (715.04)	16	0.95	13	0.77	0.57
Osteoarthrosis, localized, primary, upper arm (715.12)	10	0.59	15	0.89	0.31
Osteoarthrosis, generalized (715.0)	9	0.54	10	0.59	0.81
Osteoarthrosis, localized, primary, lower leg (715.16)	3	0.18	4	0.24	0.7
Osteoarthrosis, localized, not specified whether primary or secondary, lower leg (715.36)	1	0.06	1	0.06	>0.99
Osteoarthrosis, localized, secondary, unspecified site (715.20)	0	0	1	0.06	0.31
Osteoarthrosis, localized, primary, hand (715.14)	0	0	1	0.06	0.31

ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; OA, osteoarthritis.

Table 2.

Incidence Rates and Crude and Adjusted Relative Hazards of Coronary Heart Disease Categorized by Osteoarthritis-Acupuncture, Osteoarthritis Nonacupuncture, and Nonosteoarthritis Cohorts and Stratified by Gender, Age, and Baseline Comorbidity and Medication Use

Variables of CHD		OA-acupuncture cohort			OA nonacupuncture cohort			Non-OA cohort
		0			1			2			1 vs. 0	2 vs. 0	1 vs. 0	2 vs. 0
		Event	PY	IR	Event	PY	IR	Event	PY	IR	cHR (95% CI)	cHR (95% CI)	aHR (95% CI)	aHR (95% CI)
		193	8958	2.2	405	6276	6.5	205	6396	3.2	2.71 (2.28–3.22)^***	1.35 (1.11–1.64)^**	3.04 (2.54–3.63)^***	1.88 (1.52–2.32)^***
Gender
Female		111	5556	2	258	3941	6.5	114	4122	2.8	2.95 (2.36–3.69)^***	1.26 (0.97–1.64)	3.24 (2.57–4.09)^***	1.78 (1.34–2.35)^***
Male		82	3403	2.4	147	2335	6.3	91	2274	4	2.39 (1.82–3.13)^***	1.5 (1.11–2.02)^**	3.04 (2.27–4.07)^***	2.05 (1.48–2.84)^***
Age group (years)
18–39		8	1654	0.48	20	1362	1.5	13	1240	1	2.9 (1.28–6.59)^*	1.99 (0.82–4.81)	5.14 (1.85–14.3)^**	6.42 (2.06–20.0)^**
40–64		108	5576	1.9	278	3916	7.1	125	4268	2.9	3.32 (2.65–4.15)^***	1.41 (1.09–1.82)^**	3.29 (2.60–4.15)^***	1.84 (1.39–2.42)^***
65+		77	1729	4.5	107	998	11	67	888	7.5	2.11 (1.57–2.83)^***	1.41 (1.01–1.96)^*	2.74 (2.01–3.75)^***	1.83 (1.27–2.64)^***
Monthly income (NT$)
<15000		57	2513	2.3	101	1837	5.5	52	1800	2.9	2.23 (1.61–3.08)^***	1.14 (0.78–1.66)	2.91 (2.07–4.10)^***	1.91 (1.26–2.88)^**
15000–19999		62	3100	2	140	1887	7.4	69	2071	3.3	3.31 (2.45–4.46)^***	1.48 (1.05–2.08)^*	3.49 (2.54–4.80)^***	1.96 (1.35–2.85)^***
≥20000		74	3346	2.2	164	2552	6.4	84	2525	3.3	2.63 (2–3.47)^***	1.41 (1.03–1.92)^*	2.95 (2.21–3.93)^***	1.84 (1.32–2.57)^***
Urbanization
High	1	53	3270	1.6	109	1678	6.5	55	1996	2.8	3.69 (2.65–5.13)^***	1.57 (1.08–2.29)^*	3.91 (2.78–5.50)^***	2.28 (1.51–3.46)^***
	2	54	2507	2.2	110	2053	5.4	58	1984	2.9	2.32 (1.68–3.22)^***	1.26 (0.87–1.82)	2.20 (1.56–3.10)^***	1.37 (0.92–2.04)
	3	36	1427	2.5	58	1023	5.7	46	1202	3.8	2.01 (1.32–3.05)^**	1.38 (0.89–2.14)	2.94 (1.87–4.61)^***	2.49 (1.53–4.04)^***
	4	24	1110	2.2	76	845	9	19	844	2.3	3.59 (2.26–5.7)^***	0.94 (0.52–1.73)	6.17 (3.59–10.6)^***	1.93 (0.97–3.83)
	5	3	69	4.3	10	129	7.7	7	92	7.6	1.61 (0.44–5.89)	1.57 (0.41–6.09)	2.48 (0.30–20.2)	1.41 (0.08–24.2)
	6	10	307	3.3	25	295	8.5	11	105	10	2.17 (1.04–4.53)^*	2.12 (0.89–5.05)	3.65 (1.45–9.19)^**	2.44 (0.77–7.76)
Low	7	13	269	4.8	17	252	6.7	9	172	5.2	1.31 (0.63–2.69)	0.91 (0.39–2.12)	1.30 (0.53–3.16)	1.12 (0.41–3.02)
Baseline comorbidity
Hypertension	No	104	6602	1.6	201	4679	4.3	114	5267	2.2	2.53 (1.99–3.2)^***	1.27 (0.98–1.66)	2.86 (2.23–3.66)^***	1.73 (1.30–2.32)^***
Hypertension	Yes	89	2357	3.8	204	1598	13	91	1129	8.1	2.96 (2.31–3.81)^***	1.84 (1.37–2.46)^***	3.20 (2.46–4.16)^***	2.01 (1.48–2.74)^***
Diabetes mellitus	No	142	7700	1.8	314	5562	5.6	156	5782	2.7	2.79 (2.29–3.41)^***	1.35 (1.07–1.69)^*	3.23 (2.63–3.97)^***	2.05 (1.60–2.62)^***
Diabetes mellitus	Yes	51	1259	4.1	91	714	13	49	614	8	2.78 (1.97–3.92)^***	1.63 (1.1–2.41)^*	2.69 (1.86–3.88)^***	1.52 (0.98–2.34)
Hyperlipidemia	No	128	6847	1.9	282	5052	5.6	145	5527	2.6	2.72 (2.21–3.36)^***	1.28 (1.01–1.63)^*	3.18 (2.55–3.95)^***	1.91 (1.48–2.47)^***
Hyperlipidemia	Yes	65	2111	3.1	123	1224	10	60	868	6.9	2.9 (2.14–3.92)^***	1.95 (1.37–2.77)^***	2.88 (2.09–3.96)^***	1.84 (1.26–2.70)^**
COPD	No	117	6619	1.8	289	4845	6	151	5493	2.7	3.05 (2.46–3.78)^***	1.42 (1.11–1.8)^**	3.45 (2.75–4.32)^***	2.07 (1.60–2.69)^***
COPD	Yes	76	2339	3.2	116	1432	8.1	54	902	6	2.28 (1.7–3.04)^***	1.62 (1.14–2.3)^**	2.43 (1.79–3.28)^***	1.59 (1.09–2.32)^*
Epilepsy	No	189	8866	2.1	400	6201	6.5	203	6335	3.2	2.74 (2.3–3.26)^***	1.36 (1.12–1.66)^**	3.08 (2.57–3.69)^***	1.91 (1.54–2.36)^***
Epilepsy	Yes	4	93	4.3	5	75	6.7	2	61	3.3	1.48 (0.4–5.53)	0.86 (0.16–4.74)	—	—
Congestive heart failure	No	188	8824	2.1	389	6195	6.3	198	6342	3.1	2.68 (2.25–3.19)^***	1.33 (1.09–1.63)^**	3.06 (2.56–3.67)^***	1.93 (1.56–2.39)^***
Congestive heart failure	Yes	5	135	3.7	16	81	20	7	54	13	3.88 (1.41–10.62)^**	2.36 (0.75–7.46)	47.4 (4.96–454.0)^***	11.6 (1.84–73.9)^***
Fibromyalgia	No	105	4595	2.3	285	4366	6.5	170	5307	3.2	2.51 (2–3.14)^***	1.24 (0.97–1.58)	3.06 (2.42–3.86)^***	1.88 (1.45–2.43)^***
Fibromyalgia	Yes	88	4364	2	120	1910	6.3	35	1089	3.2	2.9 (2.2–3.83)^***	1.46 (0.99–2.16)	3.11 (2.33–4.14)^***	2.00 (1.34–3.01)^***
Stroke	No	162	8151	2	361	5979	6	175	6166	2.8	2.76 (2.29–3.32)^***	1.31 (1.06–1.62)^*	2.99 (2.47–3.63)^***	1.80 (1.43–2.27)^***
Stroke	Yes	31	807	3.8	44	297	15	30	230	13	3.42 (2.16–5.43)^***	2.69 (1.62–4.47)^***	3.43 (2.02–5.81)^***	2.96 (1.68–5.20)^***
Depression	No	177	8168	2.2	367	5913	6.2	197	6154	3.2	2.59 (2.17–3.1)^***	1.34 (1.09–1.64)^**	2.91 (2.42–3.51)^***	1.85 (1.49–2.30)^***
Depression	Yes	16	791	2	38	363	10	8	242	3.3	4.62 (2.56–8.33)^***	1.52 (0.65–3.56)	5.85 (2.91–11.7)^***	1.84 (0.68–4.95)
Anxiety	No	141	7178	2	328	5320	6.2	181	5907	3.1	2.83 (2.32–3.45)^***	1.41 (1.13–1.76)^**	3.14 (2.65–3.85)^***	1.95 (1.54–2.46)^***
Anxiety	Yes	52	1781	2.9	77	956	8.1	24	489	4.9	2.54 (1.79–3.62)^***	1.53 (0.94–2.48)	2.94 (2.01–4.30)^***	1.70 (0.99–2.90)
Alcoholism or alcohol-related disorders	No	191	8905	2.1	401	6198	6.5	203	6364	3.2	2.73 (2.29–3.24)^***	1.35 (1.11–1.65)^**	3.06 (2.56–3.66)^***	1.89 (1.53–2.33)^***
Alcoholism or alcohol-related disorders	Yes	2	53	3.8	4	78	5.1	2	32	6.3	1.69 (0.31–9.34)	1.67 (0.23–11.86)	—	—
Tobacco dependence	No	191	8896	2.1	400	6224	6.4	204	6356	3.2	2.71 (2.28–3.22)^***	1.36 (1.11–1.65)^**	3.04 (2.54–3.64)^***	1.90 (1.53–2.35)^***
Tobacco dependence	Yes	2	63	3.2	5	52	9.6	1	39	2.5	2.66 (0.51–13.78)	0.84 (0.08–9.36)	—	—
Obesity	No	192	8876	2.2	398	6215	6.4	204	6358	3.2	2.68 (2.25–3.18)^***	1.35 (1.11–1.64)^**	3.02 (2.53–3.62)^***	1.89 (1.53–2.34)^***
Obesity	Yes	1	82	1.2	7	61	11	1	38	2.6	8.61 (1.06–70.23)^*	1.7 (0.11–27.18)	—	—
Medications
Oral steroids	No	6	641	0.94	26	593	4.4	25	1560	1.6	3.94 (1.61–9.63)^**	1.57 (0.64–3.85)	6.54 (2.38–18.0)^***	2.80 (1.06–7.40)^*
Oral steroids	Yes	187	8317	2.25	379	5683	6.7	180	4836	3.7	2.70 (2.26–3.22)^***	1.49 (1.21–1.83)^***	2.96 (2.47–3.55)^***	1.86 (1.50–2.32)^***
Statins	No	91	6521	1.4	195	4837	4	120	5291	2.3	2.60 (2.03–3.34)^***	1.46 (1.11–1.92)^**	3.01 (2.32–3.91)^***	1.95 (1.45–2.60)^***
Statins	Yes	102	2437	4.19	210	1439	15	85	1105	7.7	3.13 (2.46–3.96)^***	1.65 (1.24–2.21)^***	3.09 (2.41–3.95)^***	1.70 (1.24–2.31)^***
ACE inhibitors drugs	No	83	6701	1.24	176	4899	3.6	96	5266	1.8	2.68 (2.06–3.48)^***	1.35 (1.00–1.81)^*	3.33 (2.54–4.37)^***	1.92 (1.40–2.64)^***
ACE inhibitors drugs	Yes	110	2257	4.87	229	1377	17	109	1130	9.7	2.89 (2.30–3.64)^***	1.71 (1.31–2.23)^***	2.81 (2.21–3.58)^***	1.73 (1.30–2.31)^***
Plavix	No	156	8688	1.8	340	6123	5.6	150	6214	2.4	2.79 (2.30–3.37)^***	1.21 (0.97–1.52)	3.15 (2.58–3.83)^***	1.83 (1.44–2.32)^***
Plavix	Yes	37	270	13.7	65	153	42	55	182	30	2.80 (1.86–4.24)^***	2.03 (1.33–3.10)^**	3.13 (1.94–5.05)^***	2.00 (1.22–3.27)^**
NSAIDs	No	0	35	0	1	17	5.9	3	353	0.9	—	—	—	—
NSAIDs	Yes	193	8923	2.16	404	6259	6.5	202	6043	3.3	2.70 (2.27–3.21)^***	1.40 (1.15–1.71)^***	3.03 (2.54–3.63)^***	1.88 (1.52–2.32)^***
Aspirin	No	30	3567	0.84	53	2969	1.8	43	3723	1.2	2.04 (1.30–3.19)^**	1.31 (0.82–2.09)	2.75 (1.72–4.39)^***	2.15 (1.29–3.58)^**
Aspirin	Yes	163	5391	3.02	352	3307	11	162	2673	6.1	3.09 (2.56–3.73)^***	1.76 (1.41–2.19)^***	3.12 (2.57–3.78)^***	1.84 (1.46–2.33)^***
Ibuprofen	No	34	1295	2.63	72	1179	6.1	66	1773	3.7	1.99 (1.32–3.00)^***	1.24 (0.81–1.87)	2.74 (1.73–4.34)^***	2.44 (1.51–3.96)^***
Ibuprofen	Yes	159	7663	2.07	333	5097	6.5	139	4623	3	2.88 (2.38–3.48)^***	1.33 (1.06–1.67)^*	3.20 (2.63–3.89)^***	1.80 (1.41–2.29)^***
Naproxen	No	86	4534	1.9	198	3475	5.7	148	4559	3.3	2.72 (2.11–3.51)^***	1.54 (1.18–2.02)^**	3.20 (2.45–4.19)^***	2.16 (1.62–2.88)^***
Naproxen	Yes	107	4424	2.42	207	2801	7.4	57	1837	3.1	2.57 (2.18–3.48)^***	1.17 (0.85–1.62)	2.96 (2.31–3.77)^***	1.50 (1.07–2.10)^*
Celecoxib	No	4	298	1.34	16	454	3.5	18	907	2	2.24 (0.75–6.73)	1.28 (0.43–3.80)	4.24 (1.15–15.5)^*	2.89 (0.77–10.8)
Celecoxib	Yes	189	8660	2.18	389	5822	6.7	187	5489	3.4	2.77 (2.33–3.30)^***	1.42 (1.16–1.74)^***	3.05 (2.54–3.65)^***	1.86 (1.49–2.30)^***

p < 0.05.

p < 0.01.

***

p < 0.001.

ACE, angiotensin-converting-enzyme; aHR, adjusted hazard ratio for sex, age, monthly income, urbanization, and comorbidities and medication; CHD, coronary heart disease; cHR, crude hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IR, incidence rate per 100 person-years; NSAIDs, nonsteroidal anti-inflammatory drugs; NT$, New Taiwanese dollars; OA, osteoarthritis; PY, person-years.

Table 1.

Baseline Characteristics of Osteoarthritis and Nonosteoarthritis Patients Categorized by With or Without Acupuncture

Variables		OA-acupuncture cohort		OA nonacupuncture cohort		Non-OA cohort		p-Value
		No (n = 1682)		(n = 1682)		(n = 1682)
		n	%	n	%	n	%
Gender								0.99
Female		1031	61.3	1031	61.3	1031	61.3
Male		651	38.7	651	38.7	651	38.7
Age group (years)^a								0.99
18–39		279	16.6	279	16.6	279	16.6
40–64		1062	63.1	1062	63.1	1062	63.1
65+		341	20.3	341	20.3	341	20.3
Mean ± SD (years)		52.7	13.7	52.9	13.7	52.7	13.7	0.97
Monthly income (NT$)								0.06
<15000		482	28.7	485	28.8	497	29.5
15000–19999		576	34.2	522	31	585	34.8
≥20000		624	37.1	675	40.1	600	35.7
Urbanization								<0.001
High	1	590	35.1	440	26.2	510	30.3
	2	501	29.8	530	31.5	526	31.3
	3	269	16	273	16.2	309	18.4
	4	193	11.5	252	15	208	12.4
	5	16	1	35	2.1	25	1.5
	6	57	3.4	88	5.2	47	2.8
Low	7	56	3.3	64	3.8	57	3.4
Baseline comorbidity
Hypertension		487	29	536	31.9	402	23.9	<0.001
Diabetes mellitus		268	15.9	242	14.4	237	14.1	0.27
Hyperlipidemia		439	26.1	384	22.8	278	16.5	<0.001
COPD		477	28.4	413	24.6	284	16.9	<0.001
Epilepsy		23	1.4	24	1.4	19	1.1	0.72
Congestive heart failure		29	1.7	37	2.2	29	1.7	0.5
Fibromyalgia		881	52.4	512	30.4	302	18	<0.001
Stroke		173	10.3	114	6.8	130	7.7	<0.001
Depression		164	9.8	116	6.9	69	4.1	<0.001
Anxiety		368	21.9	265	15.8	135	8	<0.001
Alcoholism or alcohol-related disorders		16	1	19	1.1	10	0.6	0.24
Tobacco dependence		16	1	18	1.1	13	0.8	0.66
Obesity		17	1	17	1	13	0.8	0.71
Medications
Oral steroids		1562	92.8	1503	89.4	1286	76.5	<0.001
Statin		460	27.3	433	25.7	310	18.4	<0.001
ACE inhibitors drugs		425	25.3	473	28.1	367	21.8	0.0001
Plavix		63	3.75	78	4.64	80	4.76	0.29
NSAIDs		1676	99.6	1676	99.6	1580	93.9	<0.001
Aspirin		1003	59.6	971	57.7	763	45.4	<0.001
Ibuprofen		1439	85.5	1333	79.2	1157	68.8	<0.001
Naproxen		823	48.9	753	44.8	462	27.5	<0.001
Celecoxib		1624	96.5	1557	92.6	1406	83.6	<0.001
Follow-up time in years (mean, median)		5.33	3.15	3.73	3	3.8	2.93	<0.001
Duration in days (mean) between diagnosis of OA and index date		50.8		50.9		50.7		0.87

Chi-squared test; a one-way analysis of variance.

ACE, angiotensin-converting-enzyme; COPD, chronic obstructive pulmonary disease; NSAIDs, nonsteroidal anti-inflammatory drugs; NT$, New Taiwanese dollars; OA, osteoarthritis.

Discussion

This study is the first large-scale investigation in Taiwan that shows the association between OA and CHD and the beneficial effects of acupuncture in OA patients and their associated risk of CHD. After controlling for known risk factors for CHD, our results demonstrate that OA patients who used acupuncture had a significantly lower overall risk of CHD compared with OA patients who did not use acupuncture. Our study also reveals that in both cohorts without the use of acupuncture treatment, the OA cohort had a significantly higher overall risk of CHD compared with non-OA cohort. Our data correlated with previous investigations that found an association between OA and the risk to develop CHD,^10,11 and also highlight a possible role of acupuncture treatment in lowering this risk. In subgroup analyses, OA patients who used only acupuncture or both acupuncture and oral steroids were at significantly lower risk of CHD compared with patients who used neither. We also found that OA patients treated with acupuncture had significantly lower medical expenditure in a follow-up time of 6 months, and 3 and 5 years compared with both OA nonacupuncture and non-OA cohorts.

Acupuncture has shown therapeutic effects on chronic pain and significant differences between true and sham acupuncture indicated that acupuncture is more than a placebo.²¹ Acupuncture is a commonly used treatment for painful joints and in a meta-analysis of randomized controlled trials for chronic knee pain, it was reported that acupuncture effect size on pain was similar to that of NSAIDs.²⁶ Moreover, acupuncture as an adjunctive therapy to topical ibuprofen in patients with chronic knee pain due to OA, has shown effectiveness in decreasing pain and improving functionality.²⁷ Based on the findings of this study, we suggest some possible explanations underlying the mechanisms of acupuncture in the reduction of CHD. Several studies have postulated the possible association between OA and atherosclerosis.^10,13 While traditionally OA was considered to be a degenerative joint disorder, nowadays, it is being observed as a disorder that is highly correlated to the metabolic syndrome and chronic inflammation plays an important role in the pathogenesis of OA, as well as with other comorbidities like diabetes mellitus, hypertension, and cardiovascular disease.²⁸ Apart from its analgesic effects, acupuncture has been shown to exert anti-inflammatory effects. In animal models, acupuncture has shown significant reduction of proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, nitric oxide synthase, cycloxygenase-2, and matrix metalloprotease-9.²⁹ Electroacupuncture has shown to exert a neuroprotective function in ischemic stroke through inhibition of TLR4-/NF-κB-mediated inflammation.²² In clinical studies, acupuncture has been observed to have a beneficial therapeutic effect on vascular function by improving lipid profile³⁰ and lowering blood pressure,³¹ known risk factors for CHD. In diabetic patients, acupuncture has shown to improve insulin sensitivity by reducing body weight and inflammation and improving lipid metabolism and adipokines.³² Therefore, acupuncture appears to reduce the incidence of CHD by improving known risk factors for CHD and exerting anti-inflammatory properties. Our study also evaluates the effects of acupuncture, NSAIDs, and oral steroids in a subgroup analysis for the risk of CHD in OA patients. The analgesic effect of NSAIDs in OA of the knee is small and short term.³³ In our study, patients who used both acupuncture and NSAIDs had 3 times lower incidence rate compared with patients who used only NSAIDs (Table 4). Although the result was not significant, given the fact that in patients with cardiovascular risk factors, NSAIDs should be used in caution even for short term and in some cases are contraindicated,³⁴ the use of acupuncture, which is a safe with very minimal adverse effects,³⁵ as a pain relief treatment should be considered for both OA management and CHD prevention. OA is associated with an extremely high economic burden, with direct costs for medical procedures and medication use and indirect costs for time lost for both patients and health care providers.³⁶ Our data suggest that OA-acupuncture cohort was significantly less costly to care for and our finding is similar to other Taiwanese reports that showed that TCM services are associated with lowest medical expenditure.^37,38 Limited physical activity, which is mainly caused by OA of the hip or knee, is considered a known risk factor for CHD.³⁹ At the same time, there is evidence to support the use of exercise to improve the damage of the joints and alleviate pain.⁶ Nevertheless, generalized and unspecified site diagnostic code was found to be the most common and there was no significant change between the OA-acupuncture and OA nonacupuncture cohorts (Table 7). The possibility for acupuncture's prevention effect on CHD might be related to the patient's lifestyle. A previous population-based study found that TCM users, who used acupuncture as well, more regularly engage in physical exercise. However, it was revealed in the same study that TCM users have more comorbidities; their health status is considered to be worse and in need of more comprehensive health care.⁴⁰ In our study, OA-acupuncture cohort also demonstrated a higher risk of comorbidities and medication use; however, this cohort had the lowest incidence of CHD, suggesting the role of acupuncture treatment on CHD prevention.

This study had several limitations, which arise from the nature of retrospective analysis and characteristics of the NHIRD database. First, patient's lifestyle information is not provided by the NHIRD. Therefore, these potential confounding variables such as smoking, alcohol drinking, and dietary habits, patients' body mass index values, exercise, and family medical history may all affect the interpretation of our results. Second, NHIRD does not provide more detailed clinical evaluations, which include, physical, laboratory, and imaging examinations; therefore, the level of OA severity in both cohorts is unknown. In recognition of these limitations and the fact that CHD is a heterogeneous disease, we preformed 1:1 frequency matching to determine the association of OA to CHD with or without acupuncture treatment, resulting in similar baseline characteristics in all cohorts, which also included comorbidities and medications. Moreover, even though information on lifestyle risk factors was lacking, our analysis included diagnostic codes of diseases resulted from these lifestyle habits, such as tobacco dependence, obesity, and alcohol-related disorders. Third, the diagnosis of any type of disease in the NHI database, including OA, CHD, or any other comorbidity, relies entirely on ICD codes. However, NHIRD database is considered to be a reliable and accurate source of information.⁴¹ To ensure correct diagnosis and prevent falsified clinical records, heavy penalties of up to 100-fold of the claimed amount of reimbursement are charged.⁴² Fourth, selection of acupoint and treatment protocols by TCM doctors is not recorded in the database. According to TCM treatment principles, acupoint selection is individualized, may vary during the progress of the disease and based on pattern differentiation. Therefore, we restricted the analysis to include patients who underwent at least 10 times of acupuncture treatments and were followed up for long term. Nevertheless, this large-scale, nationwide matched cohort study offers valuable insights into the protective effect of acupuncture treatment on CHD prevention and the possible role of acupuncture as part of integrative medicine in the reduction of risk for CHD among patients with OA. Future randomized controlled trials, with long-term follow-up, comparing the effects of acupuncture on OA patients and their risk to develop CHD are needed.

Conclusion

Our findings show that patients with OA are at a higher risk to develop CHD and acupuncture has beneficial effects on OA patients and their associated risk of CHD. Our data may provide valuable information for health policy decision making. Therefore, rigorous prospective clinical studies are warranted and further mechanistic studies are needed to confirm these observational findings and to investigate the underlying mechanism.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported, in part, by grants from Taiwan's Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke (MOST 108-2321-B-039-003-), and Tseng-Lien Lin Foundation, Taichung, Taiwan.

References

Yelin

, Weinstein

, King

. The burden of musculoskeletal diseases in the United States. Semin Arthritis Rheum, 2016; 46:259–260.

Johnson

, Hunter

. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol, 2014; 28:5–15.

Bijlsma

, Berenbaum

, Lafeber

. Osteoarthritis: An update with relevance for clinical practice. Lancet, 2011; 377:2115–2126.

Vina

, Kwoh

. Epidemiology of osteoarthritis: Literature update. Curr Opin Rheumatol, 2018; 30:160–167.

Zhang

, Doherty

, Leeb

, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2007; 66:377–388.

Zhang

, Doherty

, Arden

, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2005; 64:669–681.

Jordan

, Arden

, Doherty

, et al. EULAR Recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis, 2003; 62:1145–1155.

Trelle

, Reichenbach

, Wandel

, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Network meta-analysis. BMJ, 2011; 342:c7086.

Zhang

, Nuki

, Moskowitz

, et al. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage, 2010; 18:476–499.

10.

Jonsson

, Helgadottir

, Aspelund

, et al. Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: The AGES Reykjavik study. Ann Rheum Dis, 2009; 68:1696–1700.

11.

Wang

, Bai

, He

, et al. Osteoarthritis and the risk of cardiovascular disease: A meta-analysis of observational studies. Sci Rep, 2016; 6:39672.

12.

Awad

, Aldosari

, Abid

. Genetic alterations in oxidant and anti-oxidant enzymes in the vascular system. Front Cardiovasc Med, 2018; 5:107.

13.

Ekim

, İnal

, Kaya

, et al. Relationship between atherosclerosis and knee osteoarthritis as graded by radiography and ultrasonography in females. J Phys Ther Sci, 2016; 28:2991–2998.

14.

Hoeven

, Kavousi

, Clockaerts

, et al. Association of atherosclerosis with presence and progression of osteoarthritis: The Rotterdam Study. Ann Rheum Dis, 2013; 72:646–651.

15.

Bullough

, DiCarlo

. Subchondral avascular necrosis: A common cause of arthritis. Ann Rheum Dis, 1990; 49:412–420.

16.

Wu M-Y

LY-C

, Lin

C-L

, Huang

M-C

, et al. Trends in use of acupuncture among adults in Taiwan from 2002 to 2011: A nationwide population-based study. PLoS One, 2018; 13:e0195490.

17.

, Li

. Trends in the use of complementary and alternative medicine in the United States: 2002–2007. J Health Care Poor Underserved, 2011; 22:296–310.

18.

Ton

, Liao

, Chiang

, et al. Chinese herbal medicine and acupuncture reduced the risk of stroke after Bell's palsy: A population-based retrospective cohort study. J Altern Complement Med, 2019; 25:946–956.

19.

Lin

, Chen

, Huang

, Chen

. How to design the control group in randomized controlled trials of acupuncture?. Evid Based Complement Alternat Med, 2012; 875284:5.

20.

Sherman

, Cherkin

, Eisenberg

, et al. The practice of acupuncture: Who are the providers and what do they do?. Ann Fam Med, 2005; 3:151–158.

21.

Vickers

, Vertosick

, Lewith

, et al. Acupuncture for chronic pain: Update of an individual patient data meta-analysis. J Pain, 2018; 19:455–474.

22.

Lan

, Tao

, Chen

, et al. Electroacupuncture exerts anti-inflammatory effects in cerebral ischemia-reperfusion injured rats via suppression of the TLR4/NF-kappaB pathway. Int J Mol Med, 2013; 31:75–80.

23.

Mazidi

, Abbasi-Parizad

, Abdi

, et al. The effect of electro-acupuncture on pro-oxidant antioxidant balance values in overweight and obese subjects: A randomized controlled trial study. J Complement Integr Med, 2017; 15. DOI: 10.1515/jcim-2015-0081.

24.

Manyanga

, Froese

, Zarychanski

, et al. Pain management with acupuncture in osteoarthritis: A systematic review and meta-analysis. BMC Complement Altern Med, 2014; 14:312.

25.

Chang

, Huang

, Chou

, et al. Utilization patterns of Chinese medicine and Western medicine under the National Health Insurance Program in Taiwan, a population-based study from 1997 to 2003. BMC Health Serv Res, 2008; 8:1472–6963.

26.

White

, Foster

, Cummings

, Barlas

. Acupuncture treatment for chronic knee pain: A systematic review. Rheumatology (Oxford), 2007; 46:384–390.

27.

Liu

, Qiao

, Tang

, et al. A retrospective study of acupuncture as an adjunctive therapy to topical ibuprofen for chronic knee pain due to osteoarthritis. Medicine (Baltimore), 2019; 98:e15308.

28.

Katz

, Agrawal

, Velasquez

. Getting to the heart of the matter: Osteoarthritis takes its place as part of the metabolic syndrome. Curr Opin Rheumatol, 2010; 22:512–519.

29.

Choi

, Lee

, Moon

, et al. Acupuncture-mediated inhibition of inflammation facilitates significant functional recovery after spinal cord injury. Neurobiol Dis, 2010; 39:272–282.

30.

Cabioglu

, Ergene

. Electroacupuncture therapy for weight loss reduces serum total cholesterol, triglycerides, and LDL cholesterol levels in obese women. Am J Chin Med, 2005; 33:525–533.

31.

Flachskampf

, Gallasch

, Gefeller

, et al. Randomized trial of acupuncture to lower blood pressure. Circulation, 2007; 115:3121–3129.

32.

Firouzjaei

, Li

, Wang

, et al. Comparative evaluation of the therapeutic effect of metformin monotherapy with metformin and acupuncture combined therapy on weight loss and insulin sensitivity in diabetic patients. Nutr Diabetes, 2016; 6:e209.

33.

Bjordal

, Ljunggren

, Klovning

, Slordal

. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: Meta-analysis of randomised placebo controlled trials. BMJ, 2004; 329:1317.

34.

Bijlsma

JWJ

, Berenbaum

, Lafeber

FPJG

. Osteoarthritis: An update with relevance for clinical practice. Lancet, 2011; 377:2115–2126.

35.

MacPherson

, Thomas

, Walters

, Fitter

. A prospective survey of adverse events and treatment reactions following 34,000 consultations with professional acupuncturists. Acupunct Med, 2001; 19:93–102.

36.

Palazzo

, Nguyen

, Lefevre-Colau

, et al. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med, 2016; 59:134–138.

37.

Lai

, Chiang

, Lin

, et al. Chinese herbal medicine reduced the risk of stroke in patients with Parkinson's disease: A population-based retrospective cohort study from Taiwan. PLoS One, 2018; 13:e0203473.

38.

Shih

, Lee

, Chen

, et al. Reduced use of emergency care and hospitalization in patients with traumatic brain injury receiving acupuncture treatment. Evid Based Complement Alternat Med, 2013; 2013:262039.

39.

Pisters

, Veenhof

, van Dijk

, et al. Avoidance of activity and limitations in activities in patients with osteoarthritis of the hip or knee: A 5 year follow-up study on the mediating role of reduced muscle strength. Osteoarthritis Cartilage, 2014; 22:171–177.

40.

Shih

, Lin

, Liao

, Su

. The utilization of traditional Chinese medicine and associated factors in Taiwan in 2002. Chin Med J (Engl), 2009; 122:1544–1548.

41.

Cheng

, Kao

, Lin

, et al. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf, 2011; 20:236–242.

42.

Chen

, Wu

, Yang

, et al. Utilization of Chinese herbal medicine and its association with the risk of fracture in patients with Parkinson's disease in Taiwan. J Ethnopharmacol, 2018; 226:168–175.