LI Rui-han, ZHANG Jian-zhen, HUANG Kai-lin, JIA Hai-nv, YUAN Bing, LIU Jia, WU Huan-lin

Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700,China

Keywords:Wendan Decoction Coronary heart disease Anxiety disorder Depression Meta analysis

ABSTRACT Objective: To systematically evaluate the clinical efficacy of Wendan Decoction series combined with conventional western medicine in the treatment of coronary heart disease complicated with anxiety and depression. Methods: We searched four Chinese databases including CNKI, WanFang, VIP, SinoMed, and five English databases of PubMed, Cochrane Library, Web of Science,EMBASE, Springer Link for clinical randomized controlled trials of using Wendan Decoction series in the treatment of coronary heart disease complicated with anxiety and depression. Time range for searching was from the establishment of these databases to January 2022. Then we screened the retrieved literature according to the inclusion and exclusion criteria,and conducted data extraction and quality evaluation of the selected literature. Meta analysis was conducted using RevMan 5.3 software. Results: A total of 13 RCT studies and 1 007 patients with coronary heart disease complicated with anxiety and depression were included. Meta-analysis showed that Wendan Decoction series combined with conventional western medicine treatment showed better effects in the improvement rate of clinical anxiety [RR=1.21, 95% CI=(1.12,1.31), P＜0.000 01], the improvement rate of depression [RR=1.30, 95% CI=(1.10,1.53), P=0.002], the improvement rate of angina pectoris[RR=1.28, 95% CI=(1.13,1.44), P＜0.000 1], increasing the ECG improvement rate [RR=1.29,95% CI=(1.07, 1.55), P=0.008], increasing the rate of reducing nitroglycerin usage [RR=1.68,95% CI=(1.25,2.25, P=0.000 6], as well as increasing the improvement rate of TCM symptoms[RR=1.15, 95% CI=(1.04, 1.26), P=0.004]. It also showed better effects in reducing clinical anxiety and depression scores (SAS, SDS, HAMA, HAMD), SAQ scores and TCM symptom scores. The differences were statistically significant. Conclusion: Wendan Decoction series combined with conventional western medicine shows advantages in treating coronary heart disease patients complicated with anxiety and depression in reducing the angina pectoris score,anxiety and depression score, as well as improving the clinical TCM symptoms.

1. Introduction

Coronary heart disease refers to the heart disease caused by myocardial ischemia, hypoxia or necrosis due to stenosis, spasm or obstruction of the lumen caused by coronary atherosclerosis [1]. In clinic, most patients with coronary heart disease are double heart disease, and cardiovascular disease and psychological disease often coexist. The survey showed that 71.68% of patients with coronary heart disease had anxiety tendency and 62.83% had depression tendency [2]. At the same time, anxiety and depression could also aggravated the clinical symptoms of patients with coronary heart disease, and the two diseases affected each other. Most studies suggested that adverse emotions were important risk factors for the onset and death of coronary heart disease, and anxiety was an independent risk factor for coronary heart disease [3]. At the same time, adverse emotions such as anxiety and depression could lead to pathological changes in the cardiovascular system through the interaction of neuroendocrine immune mechanism and other ways,thus aggravating the disease [4].

Wendan Decoction originated from The Collection of Prescriptions[5], which was a traditional prescription in ancient China. Then perfected in The Prescriptions for Three Causes and One Disease and Syndrome. The specific drug composition includes pinellia ternata, Bamboo shaving, UB Orangr, Tangerine peel, Licorice Root, Poria cocos, Ginger and Jujube. It was a classic prescription for the treatment of disharmony between gallbladder and stomach and internal disturbance of phlegm and heat. It was widely used in clinic and could be used to treat the syndrome related to the pathogenesis of "gallbladder depression and phlegm disturbance" in cardiovascular and cerebrovascular diseases, mental nervous system diseases and digestive system diseases [5]. Modern pharmacological research showed that Wendan Decoction had the effects of reducing fat, anti-inflammatory, hypoglycemic, antidepressant,anti schizophrenia and protecting cell damage [6]. So, it has unique advantages in the treatment of coronary heart disease complicated with anxiety and depression.

At present, Wendan Decoction has no clinical evaluation on the treatment of coronary heart disease complicated with depression.Therefore, through the method of meta-analysis, this paper summarize the clinical randomized controlled trials of Wendan Decoction compared with conventional western medicine in the treatment of coronary heart disease complicated with anxiety and depression in recent years, so as to comprehensively evaluate its curative effect and provide evidence-based basis for clinical treatment.

2. Methods

2.1 Inclusion criteria for study selection

2.1.1 Type of study

Randomized controlled trial.

2.1.2 PatientsPatients clearly diagnosed with coronary heart disease and meeting the diagnostic criteria for anxiety and depression in Chinese Classification and Diagnostic Criteria for Mental Disorders [7].

2.1.3 Interventions

① the experimental group was treated with Wendan Decoction series, and the control group was treated with conventional western medicine. ② The experimental group was treated with Wendan Decoction series and conventional western medicine, the control group was treated with conventional western medicine. Among them, Wendan Decoction series includes Wendan Decoction,Chaigui Wendan Decoction, Chaiqin Wendan Decoction, Huanglian Wendan Decoction and Shiwei Wendan Decoction. Conventional treatment in Western medicine refer to Guidelines for Rational Drug Use of Coronary Heart Disease (2nd Edition) [1] and Consensus of Chinese Experts on Psychological Prescription of Patients seeking treatment in Cardiovascular Department (2020 Edition) [4], which involve drugs to improve ischemia, improve symptoms and prevent myocardial infarction, improve prognosis, as well as anti-anxiety and depression drugs.

2.1.4 OutcomesTotal clinical response rate, improvement of angina pectoris before and after treatment, improvement of anxiety and depression before and after treatment and other related indicators.

2.2 Exclusion criteria

①Multiple publications; ②Incomplete data or serious errors;③Full text cannot be obtained.

2.3 Search strategy

We systematically searched four Chinese databases: CNKI database, Wanfang Database, Chongqing Weipu Chinese Science and Technology Journal database (VIP), China Biomedical Literature database (SinoMed), and five English databases: PubMed, Cochrane Library, Web of Science, Excerpta Medica Database (EMBASE)and Springer Link. The retrieval period is from the establishment of each database to January 2022. According to different databases to formulate specific retrieval formula, we used the combination of key words and title, subject headings and free-text words to search the literature. Specific search terms included "Wendan Decoction","coronary heart disease", "angina pectoris", "anxiety", "depression","clinical study", "randomized controlled trial", etc.

2.4 Data screening

The bibliographies retrieved were imported into Endnote X9 literature management software for re-checking. First, duplicate literatures were excluded, and then preliminary screening was conducted by reading titles and abstracts to exclude some literatures that did not meet the inclusion criteria. Finally, fine screening was conducted by reading the full text. The process was carried out independently by two researchers.

2.5 Data extraction

Microsoft Excel 2016 was used to establish a data extraction table for data extraction of the final included literature, including:Literature title, author, publication date, number of patients in trial and control groups, baseline level, intervention, drug dose, duration,clinical efficacy, correlation scores, and factors related to bias risk assessment. This process is carried out independently by two researchers, and if there is disagreement, it is determined through discussion or consultation with professionals.

2.6 Quality evaluation

The bias risk assessment tool developed by the Cochrane Collaboration[8] was used to evaluate the quality of the included studies, including: ①Random sequence generation; ②Allocation concealment; ③Blinding of participants and personnel; ④Blinding of outcome assessmen; ⑤Incomplete outcome data; ⑥Selective reporting; ⑦Other bias. Each can be rated as “Low risk of bias”,“High risk of bias”, and “Unclear risk of bias”. This process was completed by two researchers independently and cross-checked, and if there was any disagreement, it was determined through discussion or consultation with professionals.

2.7 Statistical analysis

The Revman 5.3 software in Cochrane collaborative network was used for statistical analysis, in which the continuous variable took the mean difference (MD) as the effect value, and the binary variable took the relative risk (RR) as the effect value to obtain the 95% confidence interval (95% CI) of each effect quantity. Statistical heterogeneity was represented by I2. If I2≤50%, homogeneity among studies was indicated, and the fixed-effect model was used for meta-analysis. If I2＞50%, heterogeneity among studies was indicated, and statistical combination was performed using the random-effect model, or subgroup analysis or sensitivity analysis was performed according to the source of heterogeneity. If there was an outcome index with ≥10 articles, a funnel plot was made to analyze publication bias.

3. Results

3.1 Study screening results

A total of 53 relevant documents were retrieved in the database through a pre-established search strategy, 24 documents were obtained through software rechecking, and the first round of screening was carried out through reading titles and abstracts, and 19 possible documents were read in full, and finally included in meeting the requirements 13 articles[9-21]. The details of the screening process are shown in Figure 1.

Figure 1 Flow diagram of study selection process.

3.2 basic characteristics of the included study

A total of 13 studies were included in the RCT study conducted in China. A total of 1007 patients with coronary heart disease complicated with anxiety and depression were included, including 504 cases in the experimental group and 503 Cases in the control group. The intervention measures were Wendan Decoction plus conventional western medicine vs conventional western medicine,of which 6 studies [9-13,20] were Shiwei Wendan Decoction and 3 studies [14,15,19] were Huanglian Wendan Decoction, Three studies [16-18] were the addition and subtraction of chaigui Wendan Decoction, and one study [21] was the original formula of Wendan Decoction. The intervention time ranged from 10 days to 56 days.The main outcome indicators included the remission rate of anxiety and depression and related indicators, the remission rate of angina pectoris and related indicators. The baseline data (age, gender,course of disease, anxiety and depression score before treatment,etc.) included in the study were comparable. The basic information included in the study is shown in Table 1.

3.3 Methodological quality of the included studies

Of the 13 included studies, 8 studies[11-15, 19-21] used random number tables for random assignment, so they were rated as "Low risk of bias", and 4 studies[9, 10, 17, 18] did not The random allocation method was clearly described, so it was rated as "Unclear risk of bias", and 1 study[16] allocated according to the wishes of patients, so it was rated as "High risk of bias". 13 studies[9-21] did not mention the hiding of random allocation schemes, as well as the blinding of subjects, investigators and outcome evaluators, so they were rated as "Unclear risk of bias". None of the 13 studies[9-21] reported missing data, selective reporting, and other biases, so they were rated as "Low risk of bias". The risks of bias are shown in Figure 2 and Figure 3.

Figure 2 Risk of bias graph

Table 1 Basic characteristics of the included literature

Figure 3 Risk of bias summary

3.4 Meta analysis results

3.4.1 Total clinical response rate

3.4.1.1 Total effective rate of anxiety improvementEight studies[9, 13, 16-21] provided data on the total effective rate of anxiety improvement based on clinical efficacy criteria[22]. A total of 591 patients were enrolled, including 296 in the treatment group and 295 in the control group. The heterogeneity between the studies was low (P=0.09, I2=44%), and the fixed-effects model analysis was adopted. The results showed that the treatment group was better than the control group in improving the improvement rate of clinical anxiety, and the difference was statistically significant [RR= 1.21,95%CI=(1.12,1.31), P＜0.000 01] (Figure 4).

3.4.1.2 Total effective rate of depression improvement

Two studies[9, 18] provided data on the total effective rate of depression improvement based on clinical efficacy criteria[22]. A total of 200 patients were enrolled, including 100 in the treatment group and 100 in the control group. The heterogeneity between the studies was low (P=0.5, I2=0%), and the fixed-effects model analysis was adopted. The results show that the treatment group was better than the control group in improving the improvement rate of clinical depression, and the difference was statistically significant [RR= 1.3,95%CI=(1.1,1.53), P=0.002](Figure 5).

3.4.1.3 Total effective rate of angina pectoris improvement

Three studies[14, 17, 18] provided data on the total effective rate of angina pectoris improvement based on clinical efficacy criteria[22].A total of 250 patients were enrolled, including 125 in the treatment group and 125 in the control group. The heterogeneity between the studies was low (P=0.45, I2=0%), and the fixed-effects model analysis was used. The results showed that the treatment group was better than the control group in improving the symptoms of angina, and the difference was statistically significant [RR=1.28,95%CI=(1.13,1.44), P＜0.000 1](Figure 6).

Figure 4 Total effective rate of anxiety improvement : Forest plot for Meta-analysis

Figure 5 Total effective rate of depression improvement : Forest plot for Meta-analysis

Figure 6 Total effective rate of angina pectoris improvement : Forest plot for Meta-analysis

3.4.1.4 Total effective rate of ECG improvementTwo studies[13, 17] provided data on the total effective rate of ECG improvement based on clinical efficacy criteria[23]. A total of 120 patients were enrolled, including 60 in the treatment group and 60 in the control group. The heterogeneity between the studies was low (P=0.61, I2=0%). The fixed-effects model is used to analyze the results. The results showed that the treatment group was better than the control group in improving the abnormal ECG of patients, and the difference was statistically significant [RR=1.29 ,95%CI=(1.07,1.55), P=0.008](Figure 7).

Figure 7 Total effective rate of ECG improvement : Forest plot for Meta-analysis

3.4.1.5 Nitroglycerin reduction rate

Two studies[13, 17] provided data on the reduction rate of nitroglycerin based on clinical efficacy criteria[23]. A total of 120 patients were enrolled, including 60 in the treatment group and 60 in the control group. The heterogeneity between the studies is low (P=0.23, I2=31%), and the fixed-effects model analysis is used. The results showed that the treatment group was better than the control group in improving the reduction rate of nitroglycerin,and the difference was statistically significant [RR =1.68,95%CI=(1.25,2.25), P=0.000 6](Figure 8).

3.4.1.6 Total effective rate of TCM symptom improvement

Five studies[13, 15-18] provided data on the improvement of TCM symptoms based on clinical efficacy criteria[23]. A total of 290 patients were enrolled, including 145 in the treatment group and 145 in the control group. The heterogeneity between the studies was low (P=0.46, I2=0%), and the fixed-effects model analysis is used. The results showed that the treatment group was better than the control group in improving TCM symptoms, and the difference was statistically significant [RR=1.15, 95%CI=(1.04,1.26), P=0.004](Figure 9).

Figure 8 Nitroglycerin reduction rate : Forest plot for Meta-analysis

Figure 9 Total effective rate of TCM symptom improvement : Forest plot for Meta-analysis

3.4.2 Clinical scoring index

3.4.2.1 SAS score

Six studies[9-11, 13, 15, 16] provided SAS scores and enrolled 446 patients, including 223 in the treatment group and 223 in the control group. The heterogeneity between the studies is relatively high (P＜0.000 01, I2=93%). The random effects model analysis was used. The results showed that the treatment group was better than the control group in reducing the SAS score, and the difference was statistically significant [MD=-7.74 , 95%CI=(-11.28,-4.2), P＜0.000 1] (Figure 10). Sensitivity analysis was carried out through the method of excluding documents one by one, inferring that the heterogeneity may came from the research of Liu Yongjuan et al[10]and Sun Minghong et al[13].

Figure 10 SAS score: Forest plot for Meta-analysis

3.4.2.2 SDS score

Two studies[9, 15] provided SDS scores and included a total of 110 patients, including 55 in the treatment group and 55 in the control group. The heterogeneity between the studies is low (P=0.97,I2=0%), using a fixed-effects model analysis, the results showed that the treatment group was better than the control group in reducing the SDS score, the difference was statistically significant [MD=-8.1 ,95%CI=(-10.13,-6.07), P＜0.000 01] (Figure 11).

3.4.2.3 HAMA score

Nine studies[12-14, 16-21] provided HAMA scores. A total of 663 patients were enrolled, including 337 in the treatment group and 326 in the control group. The heterogeneity between the studies was relatively high (P＜0.000 01, I2=92%). The random effects model analysis was used. The results showed that the treatment group was better than the control group in reducing the HAMA score, and the difference was statistically significant [MD=-3.75 , 95%CI=(-5.21,-2.3), P＜0.000 01] (Figure 5). Sensitivity analysis was carried out by eliminating literature one by one, inferring that the heterogeneity may came from the research of Wang Yingwei et al[20].

3.4.3.4 HAMD score

Figure 11 SDS score: Forest plot for Meta-analysis

Figure 12 HAMA score: Forest plot for Meta-analysis

Four studies[12, 14, 18, 19] provided HAMD scores and included a total of 333 patients, including 167 in the treatment group and 166 in the control group. The heterogeneity between the studies was relatively high (P=000 6, I2=76%), and the random effects model analysis was used. The results showed that the treatment group was better than the control group in reducing the HAMD score, and the difference was statistically significant [MD=-3.75 , 95%CI=(-5.07,-2.43), P＜0.000 01] (Figure 13). Sensitivity analysis was carried out through the method of eliminating documents one by one, inferring that the heterogeneity may came from the research of Liang Wanying et al[19].

Figure 13 HAMD score: Forest plot for Meta-analysis

3.4.3.5 SAQ score

Three studies[13, 14, 20] provided SAQ related indicators, including physical activity limitation score, angina pectoris steady state score,angina pectoris episode score, and treatment satisfaction score,treatment satisfaction score, and disease awareness score. A total of 214 patients were enrolled, including 107 in the treatment group and 107 in the control group. Subgroup analysis was used to analyze the differences between the two groups at each level of SAQ. The results showed that the treatment group was better than the control group in reducing the SAQ score, and the difference was statistically significant. (Figure 14).

3.4.3.6 TCM symptom score

Four studies[13, 16, 17, 20] provided TCM symptom scores. A total of 260 patients were enrolled, including 130 in the treatment group and 130 in the control group. The heterogeneity between the studies was relatively high (P＜0.000 01, I2=89%). The random effects model analysis was used. The results showed that the treatment group was better than the control group in reducing the scores of TCM symptoms, and the difference was statistically significant [MD=-3.44, 95%CI=(-6.28,-0.6), P=0.02] (Figure 15). Sensitivity analysis was carried out by eliminating literature one by one, inferring that the heterogeneity may came from the research of Wang Yingwei et al[20].

3.4.3.7 hsCRP

Two studies[14, 19] provided patient hsCRP levels. A total of 121 patients were enrolled, including 61 in the treatment group and 60 in the control group. The heterogeneity between the studies is relatively high (P=0.000 4, I2=92%). The random effects model analysis was used. The results showed that the treatment group was better than the control group in reducing hsCRP, and the difference was statistically significant [MD=-1.03, 95%CI=(-175,-0.32), P=0.005] (Figure 16).

Figure 14 SAQ score: Forest plot for Meta-analysis

Figure 15 TCM symptom score: Forest plot for Meta-analysis

Figure 16 hsCRP: Forest plot for Meta-analysis

4. Discussion

4.1 Mechanism of Wendan Decoction in the treatment of coronary heart disease complicated with anxiety and depression

The theory center of traditional Chinese medicine was the main blood and God, so coronary heart disease combined with anxiety and depression was a common double heart disease in clinic. Coronary heart disease belonged to the category of "chest arthralgia" in traditional Chinese medicine, anxiety and depression belonged to the category of "depression syndrome". Yang micro Yin string was the main pathogenesis of chest arthralgia and heartache, qi stagnation was the main pathogenesis of depression syndrome, and phlegm turbidity endogenous was the common pathogenic factor of both[24,25]. Phlegm obstructed Qi in the chest and disturbs the heart. As the main representative prescription of regulating qi and resolving phlegm, Wendan Decoction taked Pinellia ternata as the king,drying dampness and resolving phlegm, bamboo Ru as the minister,clearing heat and resolving phlegm, Fructus aurantii reducing Qi and eliminating PI, tangerine peel regulating qi and stomach,regulating qi mechanism, Poria cocos strengthening spleen and dampness, ginger and jujube harmonizing spleen and stomach. The whole prescription played the role of resolving phlegm, regulating qi, clearing gallbladder and stomach. It had a good theoretical basis of traditional Chinese medicine in the treatment of chest arthralgia combined with depression. All the studies included in this metaanalysis were based on Wendan Decoction series, supplemented with Salvia miltiorrhiza, Yujin and other drugs, supplemented with promoting blood circulation and removing blood stasis, promoting qi and resolving depression. Based on resolving phlegm and regulating qi, clearing gallbladder and stomach, strengthen the operation of Qi and blood, so as to smooth the flow of Qi and blood and relieve Bi,Tongyu and depression.

Modern studies had also founded that coronary heart disease and anxiety and depression were related in the pathogenesis, such as inflammation activation, hypothalamic pituitary adrenal axis(HPA) axis disorder and imbalance, autonomic nerve dysfunction,platelet dysfunction, endothelial injury and so on [26,27]. Network pharmacological studies also suggested that Wendan Decoction may mediated adipocyte lipolysis pathway and NF- κ B signaling pathway, PI3K Akt signaling pathway, mTOR macrophage autophagy, renin angiotensin system (RAS), cGMP PKG signaling pathway and calcium signaling pathway regulate lipid metabolism,reduce inflammatory response, regulate vascular endothelial regeneration, regulate neuroendocrine network and improve vasodilation, so as to reduce lipid, anti atherosclerosis, reduce blood pressure Improve vascular endothelial function and delay the process of coronary heart disease [28-30]. Some experimental studies have also founded that Wendan Decoction could anti anxiety and depression by regulating the content of serotonin and the expression of serotonin 1A receptor protein in the emotional processing neural circuit in the prefrontal cortex and hippocampus [31]. Animal experiments showed that Wendan Decoction could up regulate the expression of γ- The expression of amino acid type a receptor regulates postsynaptic chloride homeostasis in hippocampus and prefrontal cortex and balances brain excitation inhibition state [32].Therefore, Wendan Decoction could treat patients with coronary heart disease complicated with anxiety and depression through multiple channels, multiple targets and multiple channels, improve lipid metabolism, protect vascular endothelial function, regulate the expression of important proteins, and then improve clinical symptoms. It has a good theoretical mechanism and pharmacological mechanism basis of Western medicine.

4.2 Effectiveness evaluation

This study conducted a meta-analysis of 13 items of Wendan Decoction Combined with western medicine vs conventional western medicine in the treatment of coronary heart disease complicated with anxiety and depression, It was found that both the total clinical effective rate (improvement rate of anxiety and depression, improvement rate of angina pectoris, improvement rate of clinical indicators and improvement rate of TCM symptoms)and related scoring indicators (anxiety and depression score, angina pectoris score, TCM symptom score and serum inflammation level) suggested that conventional western medicine combined with Wendan Decoction had better advantages. The types of coronary heart disease included in the study include both stable angina pectoris and patients after PCI. It was suggested that the treatment of resolving phlegm and regulating qi represented by Wendan Decoction could improve the symptoms of chest pain and alleviate anxiety in all stages of coronary heart disease.

4.3 limitations and deficiencies of this study

① The 13 included studies were all located in China, with certain regional bias; ② None of the included studies reported random concealment and blind method, which led to the low quality of the included articles; ③ The sample size included in the study is small,and they are all single center studies, which has a certain impact on the reliability of the research results.

To sum up, Wendan Decoction Combined with conventional western medicine has certain advantages in treating the total clinical effective rate of patients with coronary heart disease complicated with anxiety and depression, reducing the score of angina pectoris and anxiety and depression, and improving the clinical symptoms of traditional Chinese medicine. However, due to the low quality of the methodology included in the literature, it is still necessary to carry out large sample, high-quality, multi center and detailed clinical controlled trials for further verification, so as to provide clinical basis for the prevention and treatment of double heart disease with integrated traditional Chinese and Western medicine.

Description of the author's contribution:

Li Ruihan selected the topic of the article, and Wu huanlin conducted quality control and research guidance for the research.Li Ruihan, Zhang Jianzhen and Huang Kailin conducted literature screening and data extraction; Jia hainv and Yuan Bing checked the data; Li Ruihan made the chart, and Liu Jia was responsible for the revision of the chart. Li Ruihan wrote the paper and Wu huanlin revised the paper. There is no conflict of interest in this article.