Efficacy of Chinese Medicine Therapies on Insomnia Associated with Coronary Heart Disease：a Network Meta-analysis

doi:10.12114/j.issn.1007-9572.2019.00.255

Abstract

Abstract:

Efficacy of Chinese Medicine Therapies on Insomnia Associated with Coronary Heart Disease：a Network Meta-analysis

ZHENG Yawei^1,2, WU Lifei², ZHANG Xingxing², GU Dongmei², ZHANG Siqi³, LIU Ming³, FANG Zhuyuan^1,3*1.Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China

2.Nanjing University of Chinese Medicine, Nanjing 210023, China

3.Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China

*Corresponding author: FANG Zhuyuan, Professor, Chief TCM physician; E-mail: jsszyyfzy@163.com

【Abstract】BackgroundCoronary heart disease（CHD） with insomnia can be called a "psycho-cardiological disease", and the persistent existence of insomnia can induce the onset of CHD or aggravate the development of the condition. In recent years, there have been continuous reports on TCM treatment of CHD with insomnia, but the sample size is small and the relevant evidence-based evaluation is insufficient. ObjectiveTo systematically review the efficacy of Chinese medicine therapies and sedative hypnotic drugs on insomnia associated with CHD. MethodsDatabases including CNKI, CBM, Wanfang Data Knowledge Service Platform, VIP, PubMed, Web of Science, EMBase and Cochrane Library were searched from inception to September 2018 for randomized controlled trials （RCT） about insomnia associated with CHD treated with TCM therapies. RCT screening and enrollment, data extraction, and quality assessment were performed by two researchers independently. Meta-analysis was performed with Rev Man 5.3, Stata 15.1 and ADDIS （V.1.16.8）. ResultsA total of 21 studies with 2496 patients were included, involving 11 interventions（including 9 kinds of TCM therapies）. Traditional meta-analysis found that either Chinese patent medicine plus routine treatment or compound Chinese medicine plus routine treatment was associated with better efficacy compared sedative hypnotic drugs plus routine treatment（P<0.05）. Network meta-analysis demonstrated that for treating insomnia associated with CHD, massage plus five-tone therapy and routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, and compound Chinese medicine plus massage, five-tone therapy and routine treatment had better efficacy than sedative hypnotic drugs plus routine treatment（P<0.05）. Moreover, the efficacy of routine treatment was inferior to that of moxibustion with moxa plus routine treatment, baduanjin plus massage and routine treatment, massage plus five-tone therapy and routine treatment, finger-pressure therapy plus routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, compound Chinese medicine plus massage, five-tone therapy and routine treatment（P<0.05）. Of all the interventions, compound Chinese medicine plus massage, five-tone therapy and routine treatment showed best efficacy, while sedative hypnotic drugs plus routine treatment ranked 10th, only superior to routine treatment alone. ConclusionAvailable evidence shows that Chinese medicine therapies have certain effects on insomnia associated with CHD, and the regimen of compound Chinese medicine plus massage, five-tone therapy and routine treatment may be an optimal selection. However, due to limited number and quality of included studies, this conclusion needs to be confirmed by more high-quality multicenter RCT with larger sample sizes.

【Key words】Coronary disease; Sleep initiation and maintenance disorders; TCM therapy; Drug therapy（TCD）; Network Meta-analysis

Coronary heart disease (CHD) complicated with mental and psychological disorders such as insomnia is called ‘double heart disease’. The persistent existence of mental and psychological problems such as insomnia can induce the onset of CHD or aggravate the development of the disease, resulting in poor prognosis ^[1]. Insomnia is a kind of sleep disorder, which makes it difficult to fall asleep or wake up easily after sleeping, and makes it difficult to sleep all night. The initiation and maintenance of sleep are hindered, which seriously affects the quality of life of patients. At present, Western medicine still lacks reliable treatment methods, and sedatives and sleeping pills are the main treatment methods, but their addiction and adverse reactions are difficult to solve ^[2]. Traditional Chinese Medicine believes that this is caused by yangqi not entering yinqi, disharmony between yingqi and weiqi, and imbalance of viscera ^[3]. It is closely related to CHD like ‘xiongbi’ and ‘xintong’. Traditional Chinese Medicine has little adverse reaction and less dependence in treating insomnia. And the patients treated by Traditional Chinese Medicine(TCM) therapies have good compliance and remarkable clinical efficacy ^[4]. In recent years, there have been literature reports on treating CHD complicated with insomnia by TCM therapies, but the sample size was small and the relevant evidence-based evaluation was insufficient. At the same time, due to the wide variety of TCM therapies, different emphasis on efficacy and lack of direct comparative study between different TCM therapies, it is impossible to evaluate the efficacy of various TCM therapies for CHD complicated with insomnia. In this study, the efficacy of different TCM therapies and sedative-hypnotics in treating CHD complicated with insomnia was compared by the method of Network Meta-analysis, and intervention measures were sorted according to the efficacy, in order to provide evidence-based medicine evidence for clinical treatment plan. The report standard of this study refers to the report standard of International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Network Meta-analysis ^[5].

Methods

Inclusion criteria

(1) The study type is randomized clinical trial (RCT) or semi-RCT; (2) The subjects are patients with CHD complicated with insomnia, and the diagnosis of insomnia refers to Chinese Classification and Diagnostic Criteria for Mental Disorders ^[6]; (3) Interventions involve TCM therapy, such as traditional Chinese medicine compound, Chinese patent medicine, Chinese medicine fumigation, acupuncture, massage, five tones, acupoint application, traditional techniques, etc.

Exclusion criteria

(1) Repeated reporting of literature; (2) The outcome index does not contain the total effective rate of insomnia; (3) The key data is missing, and the complete data cannot be obtained after contacting the author.

Search Strategy

Databases including China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (CBM), Wanfang data Information Site, VIP information resource integration service platform, PubMed, Web of Science, EMBase and the Cochrane Library were searched from inception to September 2018. The search terms used were as follows: Coronary heart disease, Insomnia, Traditional Chinese medicine, Acupuncture, Tuina, Qigong, etc.

Study Selection and Data Extraction

Two researchers independently screening articles, extracting data and cross-checking data combining the criteria of literature inclusion and exclusion. Differences were decided through discussion or arbitration by the third researcher. Data extraction includes: first author, publication time, age, sample size, treatment methods, outcome indicators, etc. The outcome index is expressed by the total effective rate of insomnia, and the calculation formula is: total effective rate = (Cured cases + Significant effective cases + Effective cases)/Total cases ×100%. The effect of insomnia was evaluated according to the Guiding Principles of Clinical Research on New Traditional Chinese Medicine: (1) Cured cases: the sleep time returned to normal or the night sleep time was > 6 h, and the sleep was deep and energetic after waking up; (2) Significant effective cases: sleep improved obviously, sleep time increased by more than 3h, and sleep depth increased; (3) Effective cases: the symptoms were relieved, and the sleep time was increased by < 3h; (4) Ineffective cases: Insomnia was not significantly improved or aggravated after treatment ^[7]. Other recognized evaluations of insomnia efficacy are consulted too. The quality evaluation was conducted by two researchers with reference to Cochrane risk assessment tool ^[8].

Data Analysis

Statistical analysis is performed with Rev Man 5.3, Stata 15.1 and ADDIS 1.16.8 software. Counting data are expressed by OR and its 95% confidence interval (CI), while the logOR and its 95%CI is used in the network meta-analysis with sedative hypnotic drugs plus routine treatment as common control. The χ2 test is used to analyze the heterogeneity, and I² is used to evaluate the heterogeneity ^[9]. When I² ≤ 50%, which means the heterogeneous less, the fixed effect model is selected for meta-analysis. Excluding the influence of significant clinical heterogeneity when I²>50%, which means the heterogeneity big. If the heterogeneity is still big, the random effect model is used for meta-analysis ^[10]. When there is a closed loop, the consistency between direct comparison and indirect comparison tested with the consistency test. When the inconsistency factor (IF) of consistency test is close to 0 or the odds ratio of hypothesis test (ROR) is close to 1, it is considered that the direct and indirect evidences are consistent ^[11]. Funnel diagram was used to identify whether there is small sample effect evaluation. Four Markov chains are used to set the initial value. The number of iterations of initial updating is 50000, and the number of iterations of continuous updating is 20000. The first 50000 anneals are used to eliminate the influence of the initial value. When the potential scale reduction factor (PSRF) tends to 1, it is considered that the convergence degree is satisfactory ^[12]. The probability of each intervention being the best one is presented by ranking probability. A P-value of < 0.05 is considered statistically significant.

Results

Search Results

A total of 498 related articles were obtained in the initial examination, and 21 RCT ^[13-33] were included after selected layer by layer in the end. A total of 2496 patients with CHD complicated with insomnia were included. Eleven kinds of intervention measures were involved specifically: 1) moxa plus routine treatment, 2) baduanjin plus massage and routine treatment, 3) massage plus five-tone therapy and routine treatment, 4) finger-pressure therapy plus routine treatment, 5) yangxinshi tablet plus acupuncture and routine treatment, 6) Chinese patent medicine plus routine treatment, 7) compound Chinese medicine plus routine treatment, 8) compound Chinese medicine plus massage, five-tone therapy and routine treatment, 9) fumigation and washing plus routine treatment, 10) routine treatment, 11) sedative hypnotic drugs plus routine treatment. The flow chart of literature screening and result was shown in Figure 1. General data of the included studies was shown in Table 1. The baseline situation of the 21 included studies had been statistically analyzed and comparable. Quality evaluation of the included studies was shown in Table 2.

Table 1The general data of the included studies

Study	Age（year）		Sample（n）		Treatment		Outcome
	c	e	c	e	c	e	Outcome
Zhou Meier 2015	51.7±12.7	51.4±13.0	73	73	J	A	▲
Yu Xuelian 2017	71.0± 5.1	71.0 ± 5.4	60	60	J	B	▲
Li Haiyan 2017	NA	NA	40	40	K	C	▲
Hu Yanning 2011	52.0±13.1	52.8±3.2	40	40	J	D	▲
Zhang Jun 2011	43.3±5.2	42.5±6.5	40	40	K	E	▲
Wang Lin 2016	53.8±6.8	51.2±5.2	60	59	J	F	▲
Ma Yan 2017	73.0±5.0	70.0±6.0	40	40	K	F	▲
Xu Yali 2015	64.2	63.2	100	100	K	F	▲
Zhai Shumin 2016	56.6±15.3	54.2±14.7	26	26	K	F	▲
Xue Zheng 2012	42~80	42~80	50	50	K	F	▲
Zhang Chunrong 2018	54.2±9.6	55.7±8.2	60	60	K	F	▲
Wang Zhuo 2011	53.0±5.0	52.0±6.0	100	100	K	F	▲
Zhang Xiangsu 2011	62.6±6.5	62.6±6.5	30	30	K	F	▲
Zhang Xiangrong 2016	67.3±6.8	70.5±8.1	160	160	K	G	▲
Wang Chuanfang 2018	67.7±10.0	68.4±8.4	53	53	J	G	▲
Wang Jian 2010	54.8±3.8	59.3±6.1	33	35	K	G	▲
Chen Xunshan 2018	73.2±11.2	72.8±12.2	45	45	K	G	▲
Ren Dewang 2011	66.9±10.2	65.2±11.8	39	39	K	G	▲
Yang Jiao 2015	NA	NA	40	80	K	G	▲
Liu Jinglu 2017	NA	NA	40	40	G	H	▲
Xu Yinli 2014	47.9±7.7	48.4±6.5	98	99	K	I	▲

NA, missing value; c, Control group; e, Experimental group; A, moxa plus routine treatment; B, baduanjin plus massage and routine treatment; C, massage plus five-tone therapy and routine treatment; D, finger-pressure therapy plus routine treatment; E, yangxinshi tablet plus acupuncture and routine treatment; F, Chinese patent medicine plus routine treatment; G, compound Chinese medicine plus routine treatment; H, compound Chinese medicine plus massage, five-tone therapy and routine treatment; I, fumigation and washing plus routine treatment; J, routine treatment; K, sedative hypnotic drugs plus routine treatment; ▲, total effective rate of insomnia.

Table 2Quality evaluation of the included studies

Study	Random sequence generation	Allocation concealment	Blind method	Quit or lose visit	Complete outcome data	Selective reporting	Other bias
Zhou Meier 2015	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Yu Xuelian 2017	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Li Haiyan 2017	High risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Hu Yanning 2011	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Zhang Jun 2011	Unclear risk of bias	Unclear risk of bias	High risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Wang Lin 2016	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Ma Yan 2017	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Xu Yali 2015	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Zhai Shumin 2016	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Xue Zheng 2012	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Zhang Chunrong 2018	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Wang Zhuo 2011	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Zhang Xiangsu 2011	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Zhang Xiangrong 2016	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Wang Chuanfang 2018	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Wang Jian 2010	Unclear risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Chen Xunshan 2018	High risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Ren Dewang 2011	High risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Yang Jiao 2015	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Liu Jinglu 2017	High risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias
Xu Yinli 2014	Low risk of bias	Unclear risk of bias	Unclear risk of bias	Low risk of bias	Low risk of bias	Low risk of bias	Unclear risk of bias

Table 3 Network meta-analysis of the overall efficacy of 11 intervetnions for insomnia in patients with coronary heart disease

OR	A	B	C	D	E	F	G	H	I	J	K
A	1.00	-	-	-	-	-	-	-	-	-	-
B	1.69 (0.15，20.14)	1.00	-	-	-	-	-	-	-	-	-
C	0.32 (0.01，7.56)	0.19 (0，5.04)	1.00	-	-	-	-	-	-	-	-
D	1.65 (0.18，19.29)	0.96 (0.09，11.66)	5.10 (0.23，213.00)	1.00	-	-	-	-	-	-	-
E	1.28 (0.07，21.50)	0.78 (0.04，15.58)	3.87 (0.17，150.34)	0.79 (0.04，12.48)	1.00	-	-	-	-	-	-
F	1.55 (0.21，12.94)	0.93 (0.11，8.83)	4.45 (0.44，120.74)	0.98 (0.13，6.59)	1.18 (0.16，12.01)	1.00	-	-	-	-	-
G	2.07 (0.29，15.42)	1.20 (0.16，12.15)	5.92 (0.59，172.50)	1.25 (0.18，9.01)	1.58 (0.21，16.59)	1.32 (0.58，3.28)	1.00	-	-	-	-
H	0.09 (0，1.73)	0.05 (0，1.44)	0.25 (0，21.61)	0.06 (0，1.00)	0.07 (0，1.92)	0.06 (0，0.66)^a	0.05 (0，0.46)^a	1.00	-	-	-
I	3.62 (0.29，36.10)	2.13 (0.17，28.92)	10.73 (0.72，367.56)	2.21 (0.20，20.78)	2.78 (0.27，35.65)	2.28 (0.54，9.95)	1.75 (0.38，7.21)	39.83 (2.51，1 603.66)^a	1.00	-	-
J	9.98 (2.12，57.66)^a	5.87 (1.11，39.05)^a	30.00 (2.33，902.39)^a	6.05 (1.22，30.95)^a	7.58 (0.81，96.78)	6.21 (2.13，22.65)^a	4.76 (1.61，16.01)^a	108.22 (8.50，4 149.32)^a	2.74 (0.52，17.52)	1.00	-
K	7.55 (1.00，60.65)	4.35 (0.50，45.33)	21.44 (2.24，564.61)^a	4.59 (0.60，32.40)	5.69 (0.83，52.64)	4.74 (2.55，9.07)^a	3.62 (1.77，6.96)^a	80.32 (7.38，2 783.96)^a	2.09 (0.56，7.76)	0.76 (0.21，2.26)	1.00

-, repeating data; ^aP<0.05

Table 4Ranking of total effective rate of insomnia in patients with coronary heart disease

Rank	A	B	C	D	E	F	G	H	I	J	K
1	0.03	0.01	0.23	0.01	0.03	0.00	0.00	0.69^a	0.00	0.00	0.00
2	0.15	0.07	0.39^a	0.06	0.11	0.01	0.00	0.21	0.01	0.00	0.00
3	0.23^a	0.13	0.16	0.14^a	0.18^a	0.07	0.02	0.05	0.02	0.00	0.00
4	0.2	0.14^*	0.08	0.14^a	0.15	0.18	0.07	0.02	0.03	0.00	0.00
5	0.12	0.12	0.05	0.13	0.11	0.25^a	0.15	0.01	0.05	0.00	0.00
6	0.09	0.1	0.03	0.13	0.09	0.25^a	0.23	0.00	0.07	0.00	0.00
7	0.07	0.12	0.02	0.13	0.09	0.16	0.27^a	0.00	0.11	0.00	0.01
8	0.06	0.14^a	0.02	0.12	0.11	0.07	0.21	0.00	0.21	0.02	0.04
9	0.03	0.1	0.01	0.09	0.08	0.01	0.05	0.00	0.39^a	0.08	0.16
10	0.01	0.05	0.00	0.04	0.03	0.00	0.00	0.00	0.08	0.26	0.53^a
11	0.00	0.01	0.00	0.01	0.02	0.00	0.00	0.00	0.05	0.64^a	0.26

^a, the most likely ranking of interventions

Traditional Meta-analysis

The results of traditional meta-analysis of total effective rate of insomnia showed that there were significant differences between Chinese patent medicine plus routine treatment and sedative hypnotic drugs plus routine treatment [OR = 4.47,95% CI (2.78,7.20)]. There were significant differences between compound Chinese medicine plus routine treatment and sedative hypnotic drugs plus routine treatment [OR = 4.28,95% CI (2.77,6.62)]. There was only one study in other each pairwise direct comparison items, so meta-analysis was not performed. Excluding each study one by one, the OR values of the combined effects were still within 95%CI of the total combined effects, with no directional change and no significant change in statistical heterogeneity, suggesting that the results of this study were relatively stable.

Network Meta-analysis

Network relationship

The network relationship of included intervention measures was shown in Figure2. Generally speaking, it is a star structure with 11 intervention nodes and no closed loop, centering on sedative hypnotic drugs plus routine treatment. One study ^[31] is a three-arm study with two experimental groups were both compound Chinese medicine plus routine treatment. So, we merged the two experimental groups into one group. As a result, the total number of arms in 21 articles was 42. There was a connection between nodes indicating that there was evidence of direct comparison between the two interventions. There were no connection nodes indicating that there was no direct comparison, which can be indirectly compared through network meta-analysis. There were 11 kinds of intervention measures involved in this study, among which the number of studies comparing Chinese patent medicine plus routine treatment with sedative hypnotic drugs plus routine treatment is the largest. The intervention measure with the largest total sample size was sedative hypnotic drugs plus routine treatment.

Consistency test

In this study, interventions did not form a closed loop, so consistency test was unnecessary.

Evaluation of small sample effect

The funnel chart was used to evaluate the publication bias of 21 included studies. We found one study ^[15] fell outside 95%CI, while the other 20 articles all fell within 95%CI. The included studies were distributed symmetrically on both sides of the vertical line X=0 and the regression line was relatively horizontal, which indicated that there was little possibility of small sample effect in the study (Figure 3).

Convergence diagnosis

Four Markov chains were used. The PSRF tends to 1 and reaches stability after 50000 simulation iterations, 20000 adjustment iterations and 10 refinement iterations, which indicates that the convergence degree of the model is satisfactory.

Network Meta-analysis results

All of 21 studies reported the total effective rate of insomnia. Firstly, the network meta-analysis was carried out with sedative hypnotic drugs plus routine treatment as common control. The results showed that massage plus five-tone therapy and routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, compound Chinese medicine plus massage, five-tone therapy and routine treatment were superior to sedative hypnotic drugs plus routine treatment. The differences were statistically significant (P<0.05, Figure 4). Then Bayesian network meta-analysis was performed. The results shown that moxa plus routine treatment, baduanjin plus massage and routine treatment, massage plus five-tone therapy and routine treatment, finger-pressure therapy plus routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, compound Chinese medicine plus massage, five-tone therapy and routine treatment were superior to routine treatment. At the same time, massage plus five-tone therapy and routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, compound Chinese medicine plus massage, five-tone therapy and routine treatment were superior to sedative hypnotic drugs plus routine treatment. The compound Chinese medicine plus massage, five-tone therapy and routine treatment was superior to Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, fumigation and washing plus routine treatment. The differences were statistically significant (P<0.05, Table 3).

Rank results

The total effective rate of insomnia of intervention was shown in Table 4. According to the results in Table 3, the order from superior to inferior was: compound Chinese medicine plus massage, five-tone therapy and routine treatment; massage plus five-tone therapy and routine treatment; moxa plus routine treatment; yangxinshi tablet plus acupuncture and routine treatment; finger-pressure therapy plus routine treatment; Chinese patent medicine plus routine treatment; baduanjin plus massage and routine treatment; compound Chinese medicine plus routine treatment; fumigation and washing plus routine treatment; sedative hypnotic drugs plus routine treatment; routine treatment.

Discussion

A total of 21 studies were included in our research, involving 2496 patients with CHD complicated with insomnia. A total of 11 kinds of different interventions were included, including 9 kinds of TCM therapy. The results of traditional meta-analysis show that Chinese patent medicine plus routine treatment and compound Chinese medicine plus routine treatment were superior to sedative hypnotic drugs plus routine treatment. The effectiveness of different TCM therapies and sedative hypnotic drugs in treating CHD complicated with insomnia were compared with Bayesian network meta-analysis. The results showed that TCM therapy were superior to routine treatment except yangxinshi tablet plus acupuncture and routine treatment and fumigation and washing plus routine treatment. At the same time, massage plus five-tone therapy and routine treatment, Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, compound Chinese medicine plus massage, five-tone therapy and routine treatment were superior to sedative hypnotic drugs plus routine treatment. The top 3 interventions of ranks were compound Chinese medicine plus massage, five-tone therapy and routine treatment, massage plus five-tone therapy and routine treatment, moxa plus routine treatment. The compound Chinese medicine plus massage, five-tone therapy and routine treatment which was the first order was superior to Chinese patent medicine plus routine treatment, compound Chinese medicine plus routine treatment, fumigation and washing plus routine treatment. The last 2 interventions of ranks were sedative hypnotic drugs plus routine treatment, routine treatment. The specific rank from superior to inferior was as follows: compound Chinese medicine plus massage, five-tone therapy and routine treatment; massage plus five-tone therapy and routine treatment; moxa plus routine treatment; yangxinshi tablet plus acupuncture and routine treatment; finger-pressure therapy plus routine treatment; Chinese patent medicine plus routine treatment; baduanjin plus massage and routine treatment; compound Chinese medicine plus routine treatment; fumigation and washing plus routine treatment; sedative hypnotic drugs plus routine treatment; routine treatment. The interpretation of the rank should be combined with the results of meta-analysis.

Patients with CHD complicated with insomnia exist widely in clinic. It can be proved that insomnia is closely related to CHD from both TCM theory and modern medicine ^[34]. Insomnia complicated or secondary to CHD has become an independent risk factor of cardiovascular disease, which affects the recovery of cardiac function and has a bad prognosis for patients. CHD in modern medicine belongs to ‘xiongbi’, ‘xintong’ and ‘xinji’ in traditional Chinese medicine, while insomnia in modern medicine belongs to ‘bumei’, ‘budemei’ and ‘mubuming’ in traditional Chinese medicine. As early as ‘Huangdi Neijing’, the double-heart theory of ‘heart governing blood vessels’ and ‘heart governing gods’ were expounded. Therefore, CHD complicated with insomnia should be treated with the principle of ‘treating with both hearts’, and with the treatment of tonifying deficiency, purging excess and regulating the mind ^[35]. The ‘holistic concept’ of traditional Chinese medicine has unique advantages and status in the diagnosis and treatment of CHD complicated with insomnia, which has a good therapeutic effect on CHD complicated with insomnia. However, there still was lacking rigorous evidence-based medicine research and standardized experimental research. So, further studies need to be carried out ^[36]. In this study, through the method of network meta-analysis, the curative effects of TCM therapy and sedative hypnotics on CHD complicated with insomnia were preliminarily compared. Results confirmed that the total effective rate of Chinese medicine therapy on CHD complicated with insomnia was higher. This study provided new ideas and evidence for clinical treatment of CHD complicated with insomnia. However, due to the high risk of bias in the original study, the related results are not stable at present. It is impossible to form a standardized clinical guidance for the time being. Therefore, multi-center, large sample and high-quality researches should be organized in the later stage to further clarify the effectiveness and safety of TCM therapy for patients with CHD complicated with insomnia, and to clarify its clinical feasibility, so as to achieve the initial purpose of guiding clinical practice.

The effectiveness of TCM therapy for CHD complicated with insomnia was compared by the method of network meta-analysis. The results of small sample effect evaluation and sensitivity analysis indicate that the results were stable. However, the limitations of this study should not be ignored: (1) All the studies included were Chinese articles, which may lead to the language bias existed; (2) The number of studies involved was small and the sample sizes were insufficient, which may lead to the decrease of statistical efficiency; (3) The low quality of the included studies affected the authenticity and reliability of the results, which may lead to the reduction of inspection efficiency; (4) The long-term effect of TCM therapy on CHD with insomnia could not be evaluated due to the limitation of included studies; (5) There were few safety reports, which cannot form reliable safety evidence. Therefore, in the future, multi-center, large-sample, and high-quality researches can be organized to further clarify the effectiveness and safety of TCM therapies in the treatment of CHD complicated with insomnia and define its clinical feasibility, to achieve the initial purpose of guiding clinical practice.

Conclusion

In conclusion, the effectiveness of the 9 TCM therapies in CHD complicated with insomnia has shown certain advantages. Among the 9 TCM therapies, compound Chinese medicine plus massage, five-tone therapy and routine treatment may be the most effective treatment. In addition, the conclusions of this study still need to be verified by more high-quality, multi-center and large-sample RCTs. Given the limitations of this study, the application of the conclusions of this study should be carefully selected.

Author contributions

ZHENG Yawei carried out research implementation and feasibility analysis, statistical processing, analysis and interpretation of results. ZHENG Yawei, WU Lifei and GU Dongmei collected data. ZHENG Yawei, WU Lifei and ZHANG Xingxing carried out data collation. ZHENG Yawei and WU Lifei wrote the paper. ZHENG Yawei and ZHANG Xingxing revised the paper. ZHANG Siqi and LIU Ming took charge of the quality control and revision of articles. ZHENG Yawei and FANG Zhuyuan took charge of the article and supervised the article.

Conflicts of Interest

The authors declare no conflicts of interest in any aspects.

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Key words: Coronary disease, Sleep initiation and maintenance disorders, TCM therapy, Drug therapy（TCD）, Network meta-analysis, Traditional Chinese medicine therapy

摘要： 背景　冠心病并发失眠可称之为“双心疾病”，而失眠的持续存在又可诱发冠心病的发作或加重病情。近年来，不断有中医药治疗冠心病并发失眠的文献报道，但样本量较小，相关循证评价不足。目的　系统评价中医药疗法及镇静安眠药物治疗冠心病并发失眠的疗效。方法　计算机检索中国知网（CNKI）、中国生物医学文献数据库（CBM）、万方数据知识服务平台、维普网（VIP）、PubMed、Web of Science、EMBase、Cochrane Library数据库，检索时间为建库至2018年9月，搜集干预措施涉及中医药疗法，研究对象为冠心病并发失眠患者的临床随机对照试验（RCT）。由2位研究者独立筛选文献、提取数据和评价纳入研究的质量后，采用 RevMan 5.3、Stata 15.1、ADDIS 1.16.8 软件进行Meta分析。结果　最终纳入21篇文献，共计2 496例样本，涉及11种干预措施，其中中医药疗法9种。传统Meta分析结果显示：中成药+常规、中药复方+常规优于镇静安眠药物+常规（P<0.05）。网状Meta分析结果显示：按摩+五音+常规、中成药+常规、中药复方+常规、中药复方+按摩+五音+常规优于镇静安眠药物+常规（P<0.05）。艾灸+常规、八段锦+按摩+常规、按摩+五音+常规、指针+常规、中成药+常规、中药复方+常规、中药复方+按摩+五音+常规优于常规（P<0.05）。排序第1位的是中药复方+按摩+五音+常规，镇静安眠药物+常规在11项干预措施中排第10位，仅优于常规治疗。结论　现有证据表明，中医药疗法对冠心病并发失眠的疗效均显示出一定优势，并且在常规治疗基础上联合中药复方+按摩+五音治疗冠心病并发失眠患者的疗效成为最优选择的可能最大。但受纳入文献数量和质量限制，本研究结论仍需更多高质量的多中心、大样本RCT予以证实。

关键词: 冠心病, 入睡和睡眠障碍, 中医疗法, 中药疗法, 网状Meta分析, 中医药疗法

ZHENG Yawei,WU Lifei,ZHANG Xingxing, et al. Efficacy of Chinese Medicine Therapies on Insomnia Associated with Coronary Heart Disease：a Network Meta-analysis　[J]. Chinese General Practice, 2020, 23(2): 227-233. DOI: 10.12114/j.issn.1007-9572.2019.00.255.
郑亚威,吴力菲,张星星等. 中医药疗法对冠心病并发失眠疗效的网状Meta分析[J]. 中国全科医学, 2020, 23(2): 227-233. DOI: 10.12114/j.issn.1007-9572.2019.00.255.

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