Integrated Chinese and Western Medicine for Coronary Heart Disease Prevention in Polycystic Ovary Syndrome: A 19-Year Nationwide Cohort Study

Figures & data

Table 1 Characteristics of Patients with Polycystic Ovary Syndrome According to Reception of Chinese Herbal Medicine

	Chinese Herbal Medicine				p-value*
	No		Yes
	N = 2913		N = 2913
	n	%	n	%
Age					0.167
20–29	1174	40.30	1162	39.89
30–39	1231	42.26	1289	44.25
≥40	508	17.44	462	15.86
Mean ± SD^†	32.31	7.79	31.99	7.57	0.110
Urbanization					0.976
1 (highest)	1691	58.05	1690	58.02
2	1000	34.33	1005	34.50
3 (lowest)	222	7.62	218	7.48
Income level					0.294
0–19,999	440	15.10	405	13.90
20,000–38,999	1367	46.93	1417	48.64
≥39,000	1106	37.97	1091	37.45
Comorbidity
Diabetes mellitus	189	6.49	166	5.70	0.208
Hypertension	184	6.32	166	5.70	0.321
Hyperlipidemia	276	9.47	253	8.69	0.294
Congestive heart failure	9	0.31	8	0.27	0.808
Stroke	34	1.17	31	1.06	0.708
Chronic kidney disease	19	0.65	18	0.62	0.869
Female infertility	778	26.71	719	24.68	0.077
Mental disorders	683	23.45	644	22.11	0.223
Obesity	177	6.08	145	4.98	0.067
Medications
Metformin	454	15.59	377	12.94	0.004
OCPs	1544	53.00	1572	53.96	0.462
Clomiphene	1563	53.66	1547	53.11	0.674
Spironolactone	175	6.01	146	5.01	0.096
Follow up (years)
Mean ±SD^†	4.24	3.25	4.64	3.47	<0.001

Notes: *Chi-square test; ^†t-test.

Abbreviations: SD, standard deviation; OCP, oral contraceptive pills.

Figure 1 Flowchart illustrating participant selection and cohort formation process in the study.

Table 2 Crude and Adjusted Hazard Ratios for Coronary Heart Disease with Chinese Herbal Medicine and Covariates Among Patients with Polycystic Ovary Syndrome by Multivariable Cox Proportional Hazards Regression Analysis

	Event	PY	IR	Crude HR			Adjusted HR
				CHR	(95% CI)	p-value	AHR	(95% CI)	p-value
CHM
No	217	12,352	17.57	1.00	(reference)	–	1.00	(reference)	–
Yes	15	13,510	1.11	0.06	(0.04, 0.1)***	<0.001	0.06	(0.04, 0.1)***	<0.001
Age
20–29	63	10,184	6.19	1	(reference)	–	1	(reference)	–
30–39	90	11,451	7.86	1.27	(0.92, 1.76)	0.1433	0.94	(0.67, 1.32)	0.7354
≥40	79	4226	18.69	3.09	(2.22, 4.31)***	<0.001	1.8	(1.25, 2.59)**	0.0016
Urbanization
1 (highest)	127	15,049	8.44	1	(reference)	–	1	(reference)	–
2	80	8866	9.02	1.07	(0.81, 1.42)	0.6232	1.08	(0.81, 1.44)	0.5856
3 (lowest)	25	1947	12.84	1.51	(0.98, 2.32)	0.0593	1.61	(1.04, 2.49)*	0.0325
Income level
0–19,999	46	3966	11.60	1.00	(reference)	–	1.00	(reference)	–
20,000–38,999	101	11,931	8.47	0.75	(0.53, 1.07)	0.113	0.89	(0.63, 1.28)	0.5355
≥39,000	85	9965	8.53	0.76	(0.53, 1.08)	0.1251	0.92	(0.64, 1.33)	0.6598
Comorbidity
Diabetes mellitus
No	201	24,230	8.30	1.00	(reference)	–	1.00	(reference)	–
Yes	31	1632	19.00	2.26	(1.55, 3.3)***	<0.001	1.02	(0.63, 1.63)	0.9491
Hypertension
No	182	24,461	7.44	1.00	(reference)	–	1.00	(reference)	–
Yes	50	1401	35.68	4.96	(3.63, 6.79)***	<0.001	2.68	(1.85, 3.89)***	<0.001
Hyperlipidemia
No	173	23,647	7.32	1.00	(reference)	–	1.00	(reference)	–
Yes	59	2215	26.64	3.74	(2.78, 5.03)***	<0.001	1.89	(1.3, 2.75)***	<0.001
Congestive heart failure
No	232
Yes	0
Stroke
No	223	25,632	8.70	1.00	(reference)	–	1.00	(reference)	–
Yes	9	230	39.16	4.79	(2.46, 9.33)***	<0.001	2.04	(1.01, 4.09)*	0.0454
Chronic kidney disease
No	228	25,731	8.86	1.00	(reference)	–	1.00	(reference)	–
Yes	4	131	30.54	3.85	(1.43, 10.38)**	0.0076	1.93	(0.68, 5.46)	0.2132
Female infertility
No	155	19,158	8.09	1.00	(reference)	–	1.00	(reference)	–
Yes	77	6704	11.49	1.41	(1.07, 1.85)*	0.0135	1.49	(1.09, 2.04)*	0.0115
Mental disorders
No	132	20,646	6.39	1.00	(reference)	–	1.00	(reference)	–
Yes	100	5216	19.17	3.15	(2.43, 4.09)***	<0.001	2.47	(1.87, 3.26)***	<0.001
Obesity
No	204	24,504	8.33	1.00	(reference)	–	1.00	(reference)	–
Yes	28	1358	20.62	2.51	(1.69, 3.72)***	<0.001	1.36	(0.86, 2.13)	0.1878
Medications
Metformin
No	198	22,481	8.81	1.00	(reference)	–	1.00	(reference)	–
Yes	34	3381	10.06	1.17	(0.81, 1.69)	0.3952	0.75	(0.49, 1.14)	0.1808
OCPs						–
No	115	12,040	9.55	1.00	(reference)	–	1.00	(reference)	–
Yes	117	13,822	8.47	0.89	(0.69, 1.15)	0.371	0.93	(0.72, 1.21)	0.5773
Clomiphene						–
No	86	11,256	7.64	1.00	(reference)	–	1.00	(reference)	–
Yes	146	14,606	10.00	1.26	(0.97, 1.65)	0.0854	1.27	(0.94, 1.7)	0.1166
Spironolactone						–
No	222	24,444	9.08	1.00	(reference)	–	1.00	(reference)	–
Yes	10	1418	7.05	0.79	(0.42, 1.48)	0.4561	0.78	(0.41, 1.49)	0.4551

Notes: Incidence rate (IR), per 1000 persons/years; Adjusted HR: adjusted for age, insurance amount, urbanization level, all comorbidities, medication in Cox proportional hazards regression. *p<0.05, **p<0.01, ***p<0.001.

Abbreviations: PY, Person-Year; HR, Hazard ratio; CI, confidence interval.

Table 3 Comparison of Incidence Rates and Hazard Ratios for Coronary Heart Disease Between Patients with Polycystic Ovary Syndrome Who Received Chinese Herbal Medicine Treatment and Those Who Did Not

	Chinese Herbal Medicine		Crude HR			Adjusted HR
	No	Yes	CHR	(95% CI)	p-value	AHR	(95% CI)	p-value
	IR	IR
Age
20–29	12.47	0.56	0.04	(0.01, 0.13)***	<0.001	0.04	(0.01, 0.12)***	<0.001
30–39	15.78	0.98	0.06	(0.03, 0.14)***	<0.001	0.06	(0.03, 0.14)***	<0.001
≥40	32.97	2.98	0.09	(0.04, 0.21)***	<0.001	0.07	(0.03, 0.17)***	<0.001
Urbanization
1 (highest)	16.26	1.16	0.07	(0.04, 0.14)***	<0.001	0.07	(0.03, 0.13)***	<0.001
2	18.04	1.06	0.06	(0.02, 0.14)***	<0.001	0.05	(0.02, 0.13)***	<0.001
3 (lowest)	25.67	0.99	0.04	(0, 0.27)**	0.0012	0.02	(0, 0.17)***	<0.001
Income level
0–19,999	22.62	1.45	0.06	(0.02, 0.2)***	<0.001	0.07	(0.02, 0.22)***	<0.001
20,000–38,999	16.68	1.11	0.06	(0.03, 0.14)***	<0.001	0.06	(0.03, 0.14)***	<0.001
≥39,000	16.62	0.97	0.06	(0.02, 0.14)***	<0.001	0.05	(0.02, 0.14)***	<0.001
Comorbidity
No	8.70	0.44	0.05	(0.02, 0.16)***	<0.001	0.05	(0.01, 0.15)***	<0.001
Yes	25.88	1.78	0.07	(0.04, 0.12)***	<0.001	0.06	(0.04, 0.12)***	<0.001
Diabetes mellitus
No	16.27	1.03	0.06	(0.03, 0.11)***	<0.001	0.06	(0.03, 0.1)***	<0.001
Yes	36.33	2.40	0.07	(0.02, 0.28)***	<0.001	0.06	(0.01, 0.26)***	<0.001
Hypertension
No	14.74	0.78	0.05	(0.03, 0.1)***	<0.001	0.05	(0.03, 0.1)***	<0.001
Yes	66.26	6.92	0.1	(0.04, 0.26)***	<0.001	0.08	(0.03, 0.21)***	<0.001
Hyperlipidemia
No	14.53	0.80	0.05	(0.03, 0.1)***	<0.001	0.05	(0.03, 0.1)***	<0.001
Yes	47.58	4.63	0.1	(0.04, 0.24)***	<0.001	0.09	(0.03, 0.22)***	<0.001
Female infertility
No	15.99	1.08	0.07	(0.04, 0.12)***	<0.001	0.06	(0.03, 0.12)***	<0.001
Yes	21.83	1.19	0.05	(0.02, 0.14)***	<0.001	0.05	(0.02, 0.15)***	<0.001
Mental disorders
No	12.64	0.65	0.05	(0.02, 0.11)***	<0.001	0.05	(0.02, 0.1)***	<0.001
Yes	37.35	2.91	0.08	(0.04, 0.16)***	<0.001	0.08	(0.04, 0.16)***	<0.001
Obesity
No	16.39	1.01	0.06	(0.03, 0.11)***	<0.001	0.06	(0.03, 0.1)***	<0.001
Yes	37.39	3.02	0.08	(0.02, 0.32)***	<0.001	0.08	(0.02, 0.35)***	<0.001
Medications
No	12.92	0.91	0.07	(0.02, 0.3)***	<0.001	0.06	(0.01, 0.27)***	<0.001
Yes	18.52	1.15	0.06	(0.03, 0.11)***	<0.001	0.06	(0.03, 0.1)***	<0.001
Metformin
No	17.90	0.76	0.04	(0.02, 0.08)***	<0.001	0.04	(0.02, 0.08)***	<0.001
Yes	15.64	3.77	0.24	(0.1, 0.57)**	0.0014	0.22	(0.09, 0.56)**	0.0016
OCPs
No	18.37	1.29	0.07	(0.03, 0.14)***	<0.001	0.07	(0.03, 0.14)***	<0.001
Yes	16.86	0.96	0.06	(0.03, 0.12)***	<0.001	0.05	(0.02, 0.11)***	<0.001
Clomiphene
No	14.58	1.04	0.07	(0.03, 0.16)***	<0.001	0.07	(0.03, 0.15)***	<0.001
Yes	19.96	1.16	0.06	(0.03, 0.11)***	<0.001	0.06	(0.03, 0.11)***	<0.001

Notes: Incidence rate (IR), per 1000 persons/years. Adjusted HR: adjusted for age, insurance amount, urbanization level, all comorbidities, medication in Cox proportional hazards regression. **p<0.01, ***p<0.001.

Abbreviations: HR, Hazard ratio; CI, confidence interval.

Table 4 Association Between Coronary Heart Disease Incidence and Cumulative Use Days of Chinese Herbal Medicine in Patients with Polycystic Ovary Syndrome

	Event	PY	IR	Crude HR			Adjusted HR
				CHR	(95% CI)	p-value	AHR	(95% CI)	p-value
Non- CHM users	217	12,352	17.57	1.00	(reference)	-	1.00	(reference)	-
CHM users
1–29 days	7	3264	2.14	0.13	(0.06, 0.27)***	<0.001	0.13	(0.06, 0.27)***	<0.001
30–59 days	5	1825	2.74	0.16	(0.06, 0.38)***	<0.001	0.14	(0.06, 0.35)***	<0.001
≥60 days	3	8421	0.36	0.02	(0.01, 0.06)***	<0.001	0.02	(0.01, 0.06)***	<0.001

Notes: Incidence rate (IR), per 1000 persons/years. Adjusted HR: adjusted for age, insurance amount, urbanization level, all comorbidities, medication in Cox proportional hazards regression. ***p<0.001.

Abbreviations: PY, Person-Year; HR, Hazard ratio; CI, confidence interval.

Figure 2 Kaplan–Meier curve demonstrating the cumulative incidence of coronary heart disease in patients with polycystic ovary syndrome in the Chinese herbal medicine (CHM) and non-CHM cohorts.

Table 5 Top 10 Most Frequently Prescribed Single Herbs and Herbal Formulas for Polycystic Ovary Syndrome, and Their Association with Coronary Heart Disease Risk

Chinese Herbal Medicine	Frequency	Number of Person-Days	Average Daily Dose (g)	Average Duration for Prescription (Days)	Crude HR				Adjusted HR
					IR	CHR	(95% CI)	p-value	AHR	(95% CI)	p-value
Single Herbs
Xiang Fu	6396	46,054	1.20	7.20	0.49	0.04	(0.01, 0.13)***	<0.001	0.04	(0.01, 0.13)***	<0.001
Yi Mu Cao	5878	39,405	1.41	6.70	0.33	0.03	(0.01, 0.11)***	<0.001	0.03	(0.01, 0.12)***	<0.001
Da Huang	5072	37,075	0.78	7.31	0.97	0.09	(0.03, 0.23)***	<0.001	0.09	(0.03, 0.24)***	<0.001
Tu Si Zi	4994	36,246	1.39	7.26	0.45	0.04	(0.01, 0.16)***	<0.001	0.04	(0.01, 0.17)***	<0.001
Dan Shen	4457	31,182	1.31	7.00	0.97	0.08	(0.03, 0.2)***	<0.001	0.08	(0.03, 0.21)***	<0.001
Yan Hu Suo	4226	27,830	1.35	6.59	1.12	0.09	(0.04, 0.21)***	<0.001	0.09	(0.04, 0.2)***	<0.001
Huang Qin	3662	24,974	1.45	6.82	0.43	0.04	(0.01, 0.15)***	<0.001	0.04	(0.01, 0.15)***	<0.001
Gan Cao	2859	19,647	1.05	6.87	0.30	0.03	(0, 0.19)***	<0.001	0.03	(0, 0.2)***	<0.001
Du Zhong	2778	19,080	1.25	6.87	0.29	0.03	(0, 0.19)***	<0.001	0.03	(0, 0.19)***	<0.001
Xu Duan	2771	19,291	1.41	6.96	0.28	0.03	(0, 0.18)***	<0.001	0.03	(0, 0.18)***	<0.001
Herbal Formula
Jia Wei Xiao Yao San	8556	60,499	5.37	7.07	0.82	0.06	(0.03, 0.14)***	<0.001	0.06	(0.03, 0.14)***	<0.001
Gui Zhi Fu Ling Wan	5075	34,166	5.82	6.73	0.56	0.05	(0.02, 0.15)***	<0.001	0.05	(0.02, 0.17)***	<0.001
Dang Gui Shao Yao San	5069	33,950	5.25	6.70	0.74	0.06	(0.02, 0.17)***	<0.001	0.06	(0.02, 0.17)***	<0.001
Wen Jing Tang	3938	27,506	4.81	6.98	0.64	0.06	(0.02, 0.18)***	<0.001	0.06	(0.02, 0.19)***	<0.001
Shao Fu Zhu Yu Tang	2618	17,889	5.37	6.83	0.51	0.05	(0.01, 0.18)***	<0.001	0.05	(0.01, 0.2)***	<0.001
Gui Pi Tang	2546	17,499	6.48	6.87	0.27	0.02	(0, 0.18)***	<0.001	0.02	(0, 0.17)***	<0.001
Ma Zi Ren Wan	2392	17,154	3.11	7.17	0
Liu Wei Di Huang Wan	2331	16,894	4.37	7.25	0.58	0.05	(0.01, 0.22)***	<0.001	0.06	(0.01, 0.23)***	<0.001
Xiao Chai Hu Tang	2230	16,095	5.36	7.22	0.57	0.05	(0.01, 0.21)***	<0.001	0.06	(0.01, 0.23)***	<0.001
Ban Xia Xie Xin Tang	2061	14,122	4.01	6.85	0.36	0.03	(0, 0.24)***	<0.001	0.03	(0, 0.25)***	<0.001

Notes: Incidence rate (IR), per 1000 persons/years. Adjusted HR: adjusted for age, insurance amount, urbanization level, all comorbidities, medication in Cox proportional hazards regression. ***p<0.001.

Abbreviations: HR, Hazard ratio; CI, confidence interval.

Table 6 Top 10 Most Frequently Prescribed Dual Combinations of Chinese Herbal Medicines for Polycystic Ovary Syndrome

Rank	CHM Name 1	CHM Name 2	Number of Prescriptions
1	Xiang Fu	Yi Mu Cao	1562
2	Nu Zhen Zi	Han Lian Cao	1259
3	Xiang Fu	Jia Wei Xiao Yao San	1211
4	Yi Mu Cao	Jia Wei Xiao Yao San	1134
5	Yi Mu Cao	Gui Zhi Fu Ling Wan	1048
6	Nu Zhen Zi	Tu Si Zi	974
7	Xiang Fu	Gui Zhi Fu Ling Wan	884
8	Tu Si Zi	Jia Wei Xiao Yao San	855
9	San Leng	E Zhu	854
10	Dan Shen	Jia Wei Xiao Yao San	853

Abbreviation: CHM, Chinese herbal medicine.

Figure 3 Social correlation network depicting relationships between various single herbs and herbal formulas used in Chinese herbal medicine for polycystic ovary syndrome treatment.

Data Sharing Statement

The data in this study are available to other researchers upon request from the corresponding author.