HUANG Ping-ping, SUN Chun-quan, MA Xiao-chang, LIU Fu-mei, HOU Heng-yue,XIE Yan-ming?

1. Institute of Clinical Basic Medicine of Traditional Chinese Medicine, Chinese Academy of Sciences, Beijing 100700, China

2. Xi Yuan Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing 100091, China

3. School of Statistics, Renmin University of China, Beijing 100872, China

Keywords:Shengmai Injection Real world Coronary heart disease Angina pectoris Excellent treatment plan

ABSTRACT Objective: To explore the optimal scheme of Shengmai Injection combined with other drugs for clinical doctors. Methods: Based on the large-scale data warehouse established by the institute of Clinical Basic Medicine, Chinese Academy of Traditional Chinese Medicine, the hospital information system of 22 large-scale tertiary hospitals in China was collected and 1751 patients with angina pectoris who were treated with Shengmai Injection were selected.Louvain algorithm and complex network analysis are used to build the model to summarize the rule of Shengmai Injection in the treatment of angina pectoris of coronary heart disease.Results: On the basis of Shengmai Injection, according to the symptom treatment of angina pectoris of coronary heart disease, nitrates or Suxiao Jiuxin Pill was used to dilate coronary artery; for the treatment of risk factors of angina pectoris,a combination of "insulin + acarbose+ bisoprolol + nifedipine + captopril + estazolam "was used to control blood glucose and blood pressure;"Ganmao Qingre Granule + levofloxacin "to treat upper respiratory tract infection and other medication regimens were used as well.For the complications of angina pectoris of coronary heart disease, "furosemide + spironolactone + potassium chloride + magnesium sulfate" was used to reduce edema and “isosorbide nitrate + metoprolol + Shenmai injection +Wenxin Granule " was used to improve symptom of heart failure of qi and yin deficiency type.Conclusion: The therapeutic regimen of Shengmai Injection combined with traditional chinese medicine and western medicine is basically consistent with the current guidelines,but more clinical studies are still needed to explore more effective combination therapy.?Corresponding author: XIE Yan-ming, Principal Investigator, Doctoral Supervisor

1. Introduction

Coronary heart disease (CHD), referred to as CHD for short, is a group of clinical syndromes of myocardial ischemia and hypoxia caused by insufficient coronary blood supply. Angina pectoris (AP)is the most common clinical type [1]. At present, nitrates are mainly used in western medicine for the treatment of angina pectoris. β Receptor blockers, calcium channel blockers and other conventional drugs can alleviate patients' symptoms and improve their coronary blood supply. Clinical research [2] shows that compared with simple western medicine treatment, the combined use of traditional chinese medicine injection can achieve better clinical effect in improving the quality of life and long-term prognosis of patients. Angina pectoris belongs to the category of "chest arthralgia" and "heartache" in traditional chinese medicine, deficiency of heart qi and obstruction of heart pulse are the basic pathogenesis. Clinically, supplementing qi, strengthening heart and promote blood circulation are the main treatment principles. Shengmai Injection is a traditional chinese medicine preparation formed by the ancient prescription "Shengmai Powder" through the modern pharmaceutical technology.Pharmacological research shows that [3] ginsenosides and other drugs in Shengmai Injection have cardiotonic effect, which can improve myocardial tolerance by improving myocardial ischemia, so as to alleviate the symptoms of angina pectoris. However, at this stage,the combination regimen of Shengmai Injection in the treatment of coronary heart disease and angina pectoris is more complicated, and there is a lack of systematic research to summarize and analyze its effectiveness.

In the face of complicated clinical data, we can use computer technology for data analysis. Newman fast algorithm is regarded as a classic representative of community discovery algorithm. However,when dealing with large-scale community networks, relevant researchers found that this algorithm has low efficiency. Vincent D.Blondel [4] perfected this limitation of Newman's fast algorithm in 2008 and proposed a heuristic Louvain algorithm based on modular optimization. This algorithm effectively improves the efficiency and accuracy of community division and has become the basic algorithm of most data network analysis software [5]. Therefore, based on the Louvain algorithm, this study analyzes the combined medication of patients with improved symptoms of coronary heart disease and angina pectoris after the use of Shengmai Injection in the real world.It can help us find the optimal medication scheme of Shengmai Injection in the treatment of angina pectoris of the coronary heart disease ,which provides reference for clinicians.

2. Data and methods

2.1 Data sources

The data comes from the integrated data warehouse of hospital information system (his) established by the Institute of clinical basic medicine of traditional chinese medicine, Chinese Academy of traditional Chinese medicine. The hospital information systems of 22 three-class hospitals in China were collected, including 1751 patients who used Shengmai Injection (Jiangsu Suzhong pharmaceutical Group Co, Ltd.) .The data of basic information, diagnostic information and doctor's order information were extracted.

2.2 Data standardization

Due to the large number of people included in this study and the large amount of information, it is necessary to standardize the data. Refer to the international classification of diseases (ICD-10) to code the disease diagnosis of Western medicine. Refer to the Pharmacopoeia of the people's Republic of China (Part I) for Chinese patent medicine [6] , drugs with different dosage forms but consistent components are combined; after western medicine converts the trade name into chemical name, the drugs are coded according to Anatomical Therapeutic Chemical (ATC), and the data are standardized for the next data analysis.

2.3 Complex network analysis

This study mainly uses the Louvain algorithm to analyze the complex network of the data, and further divide the community.Louvain algorithm is a graph algorithm model based on modularity.Different from the ordinary graph algorithm based on modularity and modularity gain, the algorithm is fast, and the clustering effect is particularly obvious for some graphs with few points and polygons.Initially, each vertex is regarded as a community, and the number of communities is the same as that of vertices; Merge each vertex and its adjacent vertices in turn, and calculate whether their modularity gain is greater than 0. If it is greater than 0, put the node into the community of the adjacent node, and iterate until the algorithm is stable, that is, the community of all vertices does not change.

3. Complex network analysis of the improved population

3.1 Frequency of drug in the improved population

The total number of the improved population is 1751, and the number of drug types is 956. Here are 92 drugs with frequency greater than 100, and the drugs are coded, as shown in table 1.

3.2 Types of drugs used by the improved people

92 drugs , which is shown in tables 2 and 3.

3.3 Complex network of drug combination in the improved population

Different colors are used to represent different community medication schemes. Drugs in the same community are more likely to be used together. The wider the edge and closer to the center, the greater the weight, so as to obtain a complex network of combined medication for improved people. Seeing figure 1 can get more details.

3.4 Extraction of the core subnet of the complex network of drug combination in the improved population

The drug combinations of the same community with the same color are extracted to obtain the core subnet. Orange representswestern medicine and green represents traditional chinese medicine.For example, the group medication represented by the red dot is extracted as core subnet 1, the group medication represented by the yellow dot is extracted as core subnet 2, the group medication represented by the green dot is extracted as core subnet 3, the group medication represented by the blue dot is extracted as core subnet 4,and the group medication represented by the purple dot is extracted as core subnet 5, The group medication represented by pink points is extracted as core subnet 6. Core subnets 1 ～ 4 have the dense distribution. The drugs in subnets 5 and 6 are scattered and have weak correlation. Seeing figure 2 can get more details.

Tab 1 Coding and frequency of core combination drugs

4. Analysis and discussion

4.1 Treatment of angina pectoris

The change of small diameter of coronary artery caused by multiple factors of dilated coronary artery,which is one of the important inducements of angina pectoris. In this real-world study, isosorbide nitrate tablets and isosorbide mononitrate tablets were mainly usedas western medicine for the improvement of angina pectoris. Yichun Xia [7] found that Shengmai Injection combined with isosorbide nitrate tablets can effectively improve the curative effect of traditional chinese medicine symptoms in patients with angina pectoris without obvious damage to liver and kidney function, Therefore, this combination of drugs can be considered as a treatment scheme to alleviate symptoms and improve prognosis. The traditional chinese medicine mainly adopts Suxiao Jiuxin Pill. A study including 42 systematic evaluations shows that [8], the effective rate of Suxiao Jiuxin Pill in improving the symptoms of angina pectoris is higher than that of western medicine, and in the expert application survey of traditional chinese medicine for angina pectoris [9], this drug is also used as a recommended drug. This shows that Suxiao Jiuxin Pill is widely used in the treatment of coronary heart disease and angina pectoris.The pathogenesis of angina pectoris of coronary heart disease is the deficiency of origin and excess in superficiality.On the basis of using Suxiao Jiuxin Pill to promote blood circulation and remove blood stasis and treat the symptoms, Shengmai Injection is added to replenish qi and nourish yin to achieve the purpose of treating the root cause, which may be the main reason for the strong correlation between the two drugs in this real world study.

Tab 2 Types and specific drugs of Western medicine used by the improved people

Tab 3 Types and specific drugs of traditional Chinese medicine used by the improved people

4.2 Treatment of risk factors for coronary heart disease and angina pectoris

Thromboembolism Patelet aggregation is an important process of coronary heart disease plaque rupture, inducing serious complications such as cerebral embolism and pulmonary embolism.Therefore, anti platelet aggregation is the main measure to reduce the frequency of coronary heart disease angina pectoris and improve its prognosis. Relevant evidence-based medicine research also shows that taking anti plate drugs can effectively reduce the incidence of moderate diseases of stroke [10]. This real-world study found that in No.2 core subnet, the improved people often use the"aspirin (code 1) + clopidogrel (code 14)" double antibody scheme to promote blood circulation, which is consistent with the drug recommendation of clinical guidelines [11]. Lihua Dai. [12] found that compared with the simple western medicine group, aspirin combined with Shengmai Injection can effectively improve the left ventricular ejection fraction, increasing the effective blood perfusion of cardiomyocytes, and alleviate the symptoms of angina pectoris to a certain extent. If there is no effective anti plate treatment, or other reasons lead to intimal plaque rupture and bleeding, heparin drugs are the first choice in this treatment stage. It can inhibit the reaction between thrombin and fibrinogen and prevent the formation of fibrin.Clinical studies have shown that [13] Shengmai Injection combined with heparin can effectively reduce the incidence and duration of angina pectoris However, for the improved population, dalteparin is used more frequently than heparin in the real world, which may be related to its ability to delay the process of systemic arteriosclerosis(such as renal atherosclerosis) [14]. However, one of the challenges of antithrombotic therapy is to balance the benefits and reduce the risk of bleeding. Clinicians still need to pay attention to its usage and dosage to avoid the incidence of adverse events.

Hyperlipidemia Ensuring the normal and stable blood fat is the key step to prevent and treat the attack of coronary heart disease and angina pectoris [15]. In the real world, statins are often used to reduce cholesterol synthesis, which has a certain preventive and therapeutic effect on atherosclerosis and coronary heart disease angina pectoris [16]. Shimiao Tang [17] found that compared with statins alone, Shengmai Injection can achieve more ideal results in reducing blood lipid level and improving cardiac function. In realworld studies, atorvastatin is used more frequently than simvastatin in the population with clinically improved coronary heart disease and angina pectoris. However, some experiments [18] show that atorvastatin has greater hepatorenal toxicity. Clinicians should pay attention to timely review liver and renal function when using statins to prevent statin intolerance.

Hypertension and Hyperglycemia Hypertension, which has not been effectively controlled for a long time, will cause progressive damage to cardiomyocytes and ventricular structure.For patients with chronic stable or unstable angina pectoris complicated with hypertension, the guidelines [19] mostly recommend β Receptor blockers were used for initial antihypertensive treatment, and clinical studies proved that Shengmai Injection and β receptor blockers can effectively improve the activity of vascular endothelial cells and improve their cardiac function [20]. In addition, strict glycemic control can bring more benefits to patients with angina pectoris complicated with myocardial infarction, including those with diabetes and those with stress hyperglycemia during myocardial infarction. Kosiborod [21] has shown that there is no correlation between iatrogenic hypoglycemia after insulin treatment and mortality. Therefore, whether or not patients with coronary heart disease and myocardial infarction have diabetes, they can consider increasing the appropriate insulin for clinical treatment. “insulin(code 8)+ acarbose (code 43) + bisoprolol (code 29) + nifedipine (code 9) + captopril (encode 38) + esalpride (encode 17) ” was used in the No.4 core subnet for patients with refractory hypertension and diabetes. This guide [22] points out that ACEI/ARB should be used as a first-line medication for type 2 diabetes with coronary artery disease without any other factors. However, in this study, Kato Pury was not strongly associated in the subnet. Some clinicians should pay more attention to the protective effect of ACEI/ARB drugs on the kidneys and control their blood pressure below 130/80 mmHg.More therapeutic benefits can be provided for such patients.

Upper respiratory tract infection Upper respiratory tract infection increases the level of C-reactive protein, weakens the body's ability to resist atherosclerosis, and increases the mortality of patients with coronary heart disease and angina pectoris [23].Therefore, for patients with coronary heart disease and angina pectoris, the prevention and treatment of upper respiratory tract infection is particularly important. Real world data of the No. 3 subnet shows that Shengmai Injection has a strong correlation with Ganmao Qingre Granule (code 15) and levofloxacin(code 16), which may be related to the age and pathogenesis of patients. Many people, especially as they get older, develop deficiency of vital pneuma and unable to effectively resist external pathogens and susceptible to upper respiratory tract infection, and study [24] shows that the incidence of coronary heart disease angina is positively related to age. Therefore, clinicians can learn from the above medication regimen in order to reduce the incidence rate of cardiovascular events in elderly patients with angina pectoris. With the growth of age, the kidney essence in the body is constantly consumed, yin and yang are rooted in each other, and yang has no attachment. Therefore, the elderly have more yang deficiency constitution and are prone to wind cold; In addition, deficiency of yang affecting yin, and elderly patients with angina pectoris will further develop the symptoms of deficiency of qi, yang and yin. Ganmao Qingre Granule can effectively treat wind cold cold.Shengmai Injection is often suitable for elderly patients with coronary heart disease because of its effects of supplementing qi and yin, strengthening qi of heart and restore the normal rhythm of pulse.Therefore, the combination of two drugs is often used in this real world study, which can achieve better clinical therapeutic effect.

4.3 Treatment of complications about coronary heart disease and angina pectoris

Edema Angina pectoris develops to the final stages of heart failure stage, and volume load has become one of the main factors of patients' discomfort. At this time, diuretics should be used to reduce cardiac volume load [25]. The medication scheme of "Shengmai Injection + furosemide (Code 5) + spironolactone (Code 7) +potassium chloride (Code 6) " is used in No.1 subnet of the real world study. Because the blood potassium level needs to be closely monitored during medication, potassium chloride is often added to correct the electrolyte balance in the real world. This medication scheme can give consideration to the treatment of edema symptoms in patients with angina pectoris, and reduce the side effects such as electrolyte disorder. A meta-analysis shows that [26], on the basis of routine diuretic treatment, Shengmai Injection can significantly improve the symptoms and prognosis of patients with angina pectoris, which may be related to the original pathogenesis of angina pectoris and the disease characteristics after diuresis. Angina pectoris belongs to the category of chest arthralgia in traditional chinese medicine. Qi deficiency and blood stasis are its etiology and pathogenesis. Shengmai Injection can alleviate the symptoms of angina pectoris with its effect of supplementing qi, strengthening heart, generating fluid and restoring pulse. Due to diuretic treatment,the body loses a large amount of water. At this time, the pathogenesis of the patient progresses from qi deficiency to qi and yin deficiency.Ophiopogon japonicus in Shengmai Injection can nourish yin and generate fluid, Schisandra chinensis can restrain yin and replenish qi, and can improve the symptoms of dry mouth, hot flashes, fatigue and so on. In addition, modern pharmacological research shows that [27], Shengmai Injection can improve microcirculation, inhibit platelet aggregation and reduce thrombosis, which has an important impact on the long-term prognosis of patients with angina pectoris.Heart failure If the patients with angina pectoris do not receive effective basic treatment, and the related complications are not effectively controlled, the heart function deteriorates in the later stage, which can develop into heart failure. If the yang qi is consumed and the body fluid is ablated, the scheme of "isosorbide nitrate (Code 3) + metoprolol (Code 4) + Shenmai injection (Code 79) + Wenxin Granule (Code 69)" can be selected according to the No. 2 core subnet. Isosorbide nitrate and metoprolol can reduce the symptoms of angina pectoris and delay the pathological process of ventricular remodeling, This is the target of treatment; Due to the continuous use of diuretics and the consumption of healthy qi, the pathogenesis of the patient in the later stage is deficiency of qi and yin. Shenmai injection is used to replenish vitality, protect yin and preserve liquid, and Wenxin granule is used to replenish qi and yin and remove blood stasis, so as to treat both manifestation and root cause of disease. A study of 168 patients with heart failure showed that [28], metoprolol combined with Wenxin granule was better than western medicine alone in improving left ventricular ejection fraction and controlling heart rate,which shows that the two drugs can reflect the advantages of the scheme of integrated traditional chinese and western medicine.

4.4 Research status and Prospect of drugs for promoting blood circulation and removing blood stasis.

It was observed that the combination of Shengmai Injection and blood-stasis-activating drugs (such as western heparin and dalteparin,Chinese medicine Danhong injection and Dengzhanxixin injection)was more widely used in the improved population. Related studies have shown that the combination of basic treatment with Danhong injection has more significant clinical efficacy in the treatment of angina pectoris in coronary heart disease [29]. Some studies have also found significant advantages in improving angina pectoris in patients from real-world concepts without adverse effects [30]. Several studies have now found that blood-activating herbs improve angina due to myocardial ischemia in coronary artery disease by means of vascular neovascularization mechanisms, genes, and proteins [31-33].

Blood-activating drugs have an irreplaceable role in the treatment of coronary heart disease, but there is a lack of clear evaluation and standardized application. First, the lack of large sample, multicenter,randomized double-blind clinical studies and refined and complete basic experiments to further prove the elaboration of the intrinsic mechanism makes the scientific validity of the efficacy of bloodactivating and stasis-transforming herbal medicines questionable;in addition, although blood-activating and stasis-transforming drugs have significant efficacy in the treatment of angina pectoris in coronary heart disease, there is a lack of evaluation criteria recognized by academic circles, which is the reason why the use of herbal medicines was found to be significantly less frequent than that of western medicines in this real-world survey. Finally, some clinicians only pay attention to modern pharmacological research results such as blood vessel dilatation when using herbal medicines to activate blood circulation and resolve blood stasis, but do not follow the overall concept and fail to treat from the perspective of TCM evidence-based treatment, so the efficacy is poor. We hope that scholars can strengthen relevant research, prepare scientific and accurate efficacy evaluation indexes and conduct objective clinical evidence-based treatment, so as to contribute to the reduction of the incidence of angina pectoris and other complications of coronary heart disease.

4.5 Research status and prospect of the mechanism of Shengmai Injection

In this formula, ginseng is a great tonic for vital energy, maidenhair clears the lung and benefits the stomach, and schisandra chinensis generates fluid and astringes the lung, which together can benefit the vital energy and strengthen the heart, and generate fluid.

Studies have shown [34] that the therapeutic effect of Shengmai Injection on angina pectoris in coronary heart disease is mainly to inhibit NO secretion, regulate vascular tone, increase coronary blood flow to relieve angina pectoris, and at the same time to resist the inflammation caused by myocardial ischemia and reduce the complications. This may be related to the downregulation of cNI and CaM, correction of abnormally open calcium channels, avoidance of "calcium overload" in cardiomyocytes, and enhancement of cardiac pump function [35]. It may also be related to the inhibition of intracellular PKC activation by raw vein injection, which affects the transcriptional activity of the iNOS promoter, thereby inhibiting the increased NO production caused by LPS stimulation of RAW264.7 cells [36]. Some studies [37] found that inflammatory factors play an important role in the progression of coronary heart disease,and the results suggest that Shengmai Injection attenuates or even inhibits the effect of inflammatory factors such as TNF-α and IL-6 expression; on the other hand, it also inhibits the effect of MCP-1 expression, which may be important in inhibiting monocyte and macrophage activation.At present, there are still many research directions to be expanded for clinical studies and basic experiments on Shengmai Injection.We hope that in the future, relevant researchers will pay attention to how the main components of these three chinese herbal medicines function through synergistic effects,such as biochemical significance of action target、compatibility law of main components. In addition, with the widespread use of Shengmai Injection, there are some reports on the adverse reactions of Shengmai Injection, but specific molecular biological mechanism studies are less developed.Pharmacological and toxicological studies [38] found for the first time that 5-HMF and OMBF in Shengmai Injection may cause both type I hypersensitivity and allergy-like reactions, and the generation of dimeric OMBF increases This provides a possibility for quality control of 5-HMF monomer and dimeric OMBF in Shengmai Injection to reduce the incidence of adverse reactions.Many scholars now believe that the occurrence of adverse reactions to Shengmai Injection is related to its soluble medium, and some studies have shown [39] that 5% glucose solution contains fewer insoluble particles compared to 10% glucose solution and 0.9%sodium chloride solution, which can reduce the harm to humans. It is worth noting that most patients with coronary angina are clinically combined with diabetes, and for this population, fructose injection and xylitol injection can be considered, but relevant clinical trials have been conducted less frequently, and their compatibility with Shengmai Injection needs to be further investigated.

5. Conclusions and shortcomings

In this study, the Louvain algorithm was used to analyze the superior treatment regimens of Shengmai Injection for coronary angina in the real world, and to summarize the combined medication regimens of Shengmai Injection for the treatment of angina pectoris in terms of symptoms, risk factors and complications. These medication regimens, on the one hand, reflect the guidance of clinical guidelines [2], on the other hand, highlight the innovation of clinicians' actual medication use: (1) the combination of chinese and western medicine is the best treatment for the prevention and treatment of coronary angina, with western medicine focusing on coronary expansion and antiplatelet anticoagulation and lipid regulating treatment, and chinese traditional medicine focusing on activating blood circulation and resolving blood stasis throughout the treatment of the disease; (2)The treatment must be based on the root of the disease, grasping the pathogenesis at different times of the disease and knowing how to be flexible, not just activating blood circulation and resolving blood stasis. Elderly patients or late stage of disease should pay attention to the application of medicine for supplementing qi and nourishing yin such as Shengmai Injection;(3)The population of Shengmai Injection is mostly elderly patients or patients with deficiency of qi and yin or yin and yang in the late stage of the disease, and these people have a variety of underlying diseases and complications, and they should be used together with antihypertensive and diuretic drugs.

Since this study is a real-world study, there may be missing data,duplication and other unexpected situations, and the development of patients with angina pectoris in coronary artery disease is affected by a variety of factors, therefore, the medication regimen summarized in this study is only for reference, and the specific diagnosis and treatment of related diseases should still grasp pathogenesis. We hope that clinical workers can conduct more randomized, multicenter,double-blind prospective studies on this basis, we will provide more scientific and effective medication regimens for clinical diagnosis and treatment.

Description of author's contribution: Pingping, Huang: paper writing and data analysis; Chunquan, Sun Fumei, Liu: experimental method design; Yanming, Xie, Xiaochang, Ma: paper revision;Hengyue, Hou: statistical management of data.