Clinical characteristics of Danshen Ligustrazine injection in the treatment of coronary heart disease with hypertension-A real world study

SUN Lin-xi, Gao Yang, XIE Yan-ming, Zhang Li-dan, XU Hong-yan, ZHUANG Yan

1. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences,Beijing 100700, China

2. Institute of Basic Medical Science of Xiyuan Hospital, Beijing 100091, China

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

4. The PLA Navy General Hospital, Beijing 100048, China

Keywords:Real world Danshen Ligustrazine Injection Coronary heart disease Hypertension Combination medication

ABSTRACT Objective: To explore the characteristics and rules of Danshen Ligustrazine Injection in the treatment of coronary heart disease with hypertension. Methods: From the information systems of 12 tertiary tier-one hospitals across the country, we extracted the medical data of the application of Danshen Ligustrazine Injection in the treatment of patients with coronary heart disease and hypertension. After normalization, the model was established by Apriori algorithm, and the association rules were analyzed by Clementine 12.0 software. Results:Most of the 1 928 patients were between 75 and 90 years old (54.26%). There were more males than females, most with type 2 diabetes, cerebral infarction, etc. Each dose was more than 10 mL (52.78%). Aspirin enteric-coated tablets (67.63%), L-carnitine injection (58.77%),and atorvastatin calcium capsules (50.93%) were often used in combination with safflower yellow pigment (22.20%), Shexiang Baoxin Pill (16.55%), Suxiao Jiuxin Pill (15.09%); the most commonly used combination of western medicine was anticoagulant thrombolytic and antiplatelet drugs (85.84%), and the type of Chinese medicine was Huoxuehuayu (72.98%);The most common combination of two western medicines was L-carnitine injection+aspirin enteric-coated tablets, with a support of 41.9%; The most common combination of two Chinese and western medicines is western medicine·anti-anginal medicine + western medicine ·anticoagulant thrombolytic and antiplatelet drugs with a support of 67.6%. Conclusion:Danshen Ligustrazine injection is mainly used in elderly patients with coronary heart disease and hypertension, with many comorbidities. The dosage standard needs to be optimized. The combination of drugs and guidelines should coordinate with each other, which provide clues for clinical diagnosis and treatment and optimization of medication.?Corresponding author: GAO Yang, M.D., E-mail: gaomd2017@163.com;XIE Yanming, Lead Researcher, E-mail: ktzu2018@163.com.

1. Introduction

Danshen ligustrazine injection (hereinafter referred to as Danchuan) is a compound injection composed of Danshen extract and ligustrazine hydrochloride monomer. Its function is to promote blood circulation and remove blood stasis, and is effective in improving heart function and hemodynamics. Modern pharmacological research [1] found that its mechanism of action is to increase coronary blood flow, resist platelet aggregation, protect vascular endothelium and myocardial ischemia and reperfusion,and effectively improve the structure of cardiac microcirculation.Therefore, insufficiency of cerebral blood supply, cerebral thrombosis, cerebral embolism and other occlusive cerebrovascular diseases and ischemic cardiovascular diseases can be used with this drug [2].

Coronary heart disease (CHD) is a disease in which arteriosclerosis,luminal stenosis, and ischemia and hypoxia cause qualitative changes in myocardial generators. It can be clinically manifested as chest angina and shortness of breath. And other symptoms [3]. The clinical treatment of CHD includes surgery and drug treatment, but the value of different measures is different; although the surgical method can better improve the patient's condition, this invasive operation will cause certain trauma and is not suitable for chronic illnesses and serious illnesses. Older and weaker patients often choose conservative treatment with drugs in this case. Hypertension(Hp) is a high-risk cause of CHD. When blood pressure rises, it is easy to cause microvascular disease, leading to decreased coronary reserve and aggravating coronary vascular disease[4, 5]; therefore, the two diseases often coexist and interact with each other. Agitation and interlocking symptoms increase the degree of disease deterioration and increase the difficulty of treatment [6].

The application of the massive medical data in the hospital information system (HIS) can try to dig out clues to the combined medication of people who use Danchuan to treat CHD combined with Hp (hereinafter referred to as CHD-Hp) to provide medical workers and researchers with certain medications Ideas and clinical first-hand data [7]. The author aims to monitor and analyze the HIS data of target patients, and explore representative characteristic laws, in order to give some enlightenment and broaden ideas for the clinical treatment of CHD-Hp. Optimize clinical treatment plans,correctly intervene in lifestyles, and improve the quality of life of patients.

2. Materials and methods

2.1 Data source

Based on the data warehouse (Electronic Medical Record, EMR) of the HIS system of the national top three hospitals constructed by the Chinese Academy of Chinese Medical Sciences Research on Clinical Basic Medicine of Traditional Chinese Medicine [8], the hospital stay period is extracted from October 1, 2006 to December 30, 2015. The patient’s medical information is used to observe and evaluate the current status of drug application.order information, and filter redundant information such as flushing,intradermal needle treatment, etc.

2.3 Data normalization

The HIS system used by various hospitals is not unified, and a unified standard processing and unified standardization of units or formats are required to overcome obstacles in data exchange and statistics. For example, the diagnosis is standardized according to the ICD-10 code; according to the anatomical therapeutics and chemical classification system (Anatomical Therapeutic Chemical,ATC) code classification to merge Western medicines, based on the drug components to re-categorize Chinese patent medicines, and merge the same ingredients with different dosage forms. The unique hospitalization number is used as the associated index between the data tables.

2.4 Analysis content

This study analyzes demographic data such as age and gender of patients from the general data in medical records; also includes information on medical conditions such as diagnosis by western medicine and hospital admission; extracts the start time and end time of Danchuan doctor's order from the doctor's order sheet, whichever is the course of treatment, dosage and usage Analyze the medication use by analyzing the application standardization and combination medication.

2.5 Statistical methods

Use SAS9.3 statistical software to express count data in frequency and composition ratio (%), and display measurement data in the format of mean ± standard deviation; use Apriori algorithm, SPSS Clementine 12.0, and use the form of item sets to mine and show the relationship between drugs and drug types The association rules for the medical data are efficiently screened, optimized, and integrated;for example, the support degree (the probability of the two drugs A and B appearing in the general doctor’s order list at the same time) is the main parameter, and the itemsets in a large amount of data can be discovered by mining the association rules ( That is, the correlation between drugs); supplemented by Excel to display the results [9, 10].

2.2 Inclusion and exclusion standards

①The number of occurrences of Danchuan in the patient's medication record is greater than 3; ②The patient's diagnosis must have both CHD and Hp; ③Age between 18 and 100 years old.After taking the intersection according to the unique hospitalization number, 1928 patients from 12 hospitals were included.

Remove solvent records such as physiological saline in the medical

3. Results

3.1 Basic patient information

The average age of 1928 CHD-Hp patients who used Danchuan was 74.16±10.10 years old. More than half of the patients were between 75 and 90 years old, 975 cases (accounting for 54.26%), and the male to female ratio was 2.09:1. For manual workers, 1804 cases(accounting for 93.57%); 1704 cases of general disease (accounting for 90.69%); each patient suffers from both CHD and Hp, and other diseases, such as type 2 diabetes, 595 cases (accounting for 30.86%),493 cases of cerebral infarction (25.57%), 217 cases of prostate hyperplasia (11.26%), and 162 cases of heart failure (8.40%). See Table 1 for details.

Table 1 Basic information of CHD-Hp patients with Danshen Ligustrazine Injection(n=1 928)

3.2 medication analysis

3.2.1 dosage of usageTake the Danchuan instruction as the reference: intravenous drip,5 to 10 ml each time, 1-2 times a day.The routes used by patients in the study were all intravenous drip.The average volume of a single dose was 12.85 ± 4.46 ml, with 17 patients (accounting for 0.88%)receiving less than 5 ml of each dose, 892 patients (accounting for 46.34%) receiving 5 to 10 ml, and 1016 patients (accounting for 52.78%) receiving more than 10 ml.The usage is in accordance with the instructions, but most of the patient's dosage is not in accordance with the medication instructions.

3.2.2 medication courseThe medication course was a mean of 4.36 ± 2.16 days, with 457(24.27% of patients) on days 1-3, 1257 (66.76% of patients) on days 4-7, 161 (8.55% of patients) on days 8-14, and 7 (0.37% of patients)on days 15-28.

3.3 concomitant medications

3.3.1 combining one drugThe combined traditional and Western medicines were extracted,respectively.The top three most frequently used herbs were aspirin enteric coated tablets (67.63%), levocarnitine injection (58.77%),atorvastatin calcium capsules (50.93%), and the top three most frequently used herbs were safflower yellow (22.20%), musk Baoxin Pill (16.55%), and rapid acting rescuexin pill (15.09%) in that order.See Table 2 for details.The Chinese and Western Medicine (TCM) classes were extracted separately, and it was found that the top three TCM classes most frequently used in combination were anticoagulant thrombolytic and antiplatelet (85.84%), anti anginal (75.78%), lipid-lowering(74.69%), and blood activating and stasis removing agents (72.98%),expectorant (19.87%), and heat clearing and antidote (18.00%) in that order.See Table 3 for details.

Table 2 Western medicine and traditional Chinese medicine (top 10) (for CHD) Hp patients using Danshen Ligustrazine Injection

Table3 Western and Chinese medicine categories (top 10) for CHD-Hp patients using Danshen Ligustrazine Injection

3.3.2 rules for the association of concomitant Western medicines

Medication support was positively correlated with the frequency that the two drugs appeared on the doctor's order form at the same time.The combination combining the two kinds of Western medicine with high support has ① levocarnitine injection + aspirin enteric coated tablets (41.9%) in turn, ② atorvastatin calcium capsules + aspirin enteric coated tablets (40.0%); ③ trimetazidine +levocarnitine injection (37.2%) and so on.The study intercepted the top 5 drug combinations for analysis in order of support, which ispresented in Table 4.

Table 4 Association rules to merge 2 western medicines

Combined three combinations with the highest support of Western medicine are: ① atorvastatin calcium capsules + levocarnitine injection + aspirin enteric coated tablets (29.6%); ② trimetazidine+ levocarnitine injection + aspirin enteric coated tablets (29.5%); ③atorvastatin calcium capsules + trimetazidine + aspirin enteric coatedtablets (27.5%).The remaining combinations are specific in Table 5.

Table 5 Association rules to combine 3 western medicines

Among the combinations of Danchuan combined traditional Chinese medicines, the combination with the highest support was rapid Jiexin pill + muskbouxin pill (6.07%), and the rest of the combinations showed gradually low support, considering that its support was less than 10%, and clinical promotion was not significant, so this article was not analyzed.

3.3.3 association rules for the effects of combined Chinese and Western medicines

3.3.3.1 merging 2 combinations of traditional Chinese and Western medicine effects

The three combinations with the highest support for the effects of combined 2 traditional Chinese and Western medicines are ①Western medicines. Antianginal + western medicines. Anticoagulant thrombolytic and antiplatelet agents (67.6%); ② Western medicines.Lipid-lowering + western medicines. Anticoagulant thrombolytic and antiplatelet agents (67.5%); ③ Western medicines. Vasodilators+ western medicines. Anticoagulant thrombolytic and antiplatelet agents (64.0%).See Table 6 for details.

Table6 Pharmacology association rules to combine two kinds of Chinese and western medicine

4. Discussion

4.1 The population characteristics of CHD-Hp patients using Danchuan are obvious

Most of the study patients are elderly, the number of men is twice that of women, and they often have type 2 diabetes, cerebral infarction, atherosclerosis and other diseases. It is considered that the smoking and drinking rate of women is lower than that of men, and estrogen improves blood coagulation function. Protect the cardiovascular system [11]. Consistent with the characteristics of cardiovascular and cerebrovascular diseases and Hp domestic and foreign epidemiology or data mining studies [12-14], elderly men and those with triple hypertension (Hp, hyperglycemia,hyperlipidemia) are more likely to develop CHD. CHD-Hp patients are often distributed in the Department of Cardiology and Geriatrics,which is related to the high mortality rate of CHD and the good treatment of complex diseases in the Department of Geriatrics. Often accompanied by a variety of comorbid diseases and CHD and Hp are mutually inducing factors, such as type 2 diabetes, atherosclerosis,etc., and often involve each other and aggravate the condition [15];arrhythmia and heart failure are usually seen in the onset and later development of CHD Time.

The above data suggests that the elderly have thickened and hardened arterial walls, slow baroreceptor reflexes, and decreased blood pressure and nerve-humoral regulation ability [16]. Elderly men especially need to have the concept of preventing disease, frequently monitor blood pressure, and strengthen health education; suffering from three highs People with basic diseases such as chronic diseases should prevent the occurrence of CHD-Hp in advance, and prevent changes in existing diseases.

4.2 CHD-Hp patients often have other diseases, and comprehensive treatment strategies should be adopted

According to research information, most CHD-Hp patients who use Danchuan also suffer from type 2 diabetes, cerebral infarction,tumors and other diseases, which complicate the condition and diagnosis and treatment; therefore, looking for efficient treatments that are beneficial to comorbidities is no matter for optimizing clinical treatment. Means, to improve the quality of life of patients,or to enhance patient confidence in treatment and reduce the medical burden of family members are extremely meaningful [17].

In response to this situation, we can refer to integrated medical thinking, integrate theoretical knowledge in various fields and practical experience in various departments, adapt to the social environment and psychology, and emphasize people-oriented, so as to be more suitable for human health and disease diagnosis and treatment [18]. Specifically, the specialist physicians make joint decisions based on the overall situation of the patient, combined with medical information that may affect their treatment options;for example, considering that CHD and Hp are closely related to emotional stress and frequently occur in elderly patients, it is necessary to pay attention to patient psychology Health, enhance treatment confidence and desire to survive [19]. Adopt standardized comprehensive treatment for CHD-Hp patients, pay attention to the individual, and avoid situations such as treating one disease with one disease, superimposing treatment methods, and excessive medical treatment.

4.3 Strengthen the education of Danchuan standard medication

For a single dose of Danchuan, 46.34% met the instructions,only 0.88% for underdose, and more than half of overdose users.Considering that the patient population is mostly elderly, the overdose phenomenon is prone to adverse reactions. It is suggested that the clinical need to strengthen the supervision of medication [20],raise awareness of the standardized use of Danchuan, and expand the intensity of propagating the correct dosage.

4.4 Exploring the law of treatment from the phenomenon of combined medication and optimizing the plan

According to the pathogenesis of CHD-Hp, treatment should be adopted to improve coronary blood flow, prevent thrombosis,reduce myocardial oxygen consumption and reduce blood pressure.The 2016 "Guidelines for the Rational Use of Drugs for Coronary Heart Disease"[21] recommended commonly used treatments to use aspirin and statins to prevent myocardial infarction and improve the prognosis; the 2018 version of the "Guidelines for the Prevention and Treatment of Hypertension in China"[22] believes that β-blockers,Calcium blockers can reduce myocardial oxygen consumption and reduce angina pectoris. It is often used as the first choice for clinical treatment of CHD-Hp. The results of this study also reflect the clinical guidance of the guidelines. At the same time, note that β-blockers are not used for chronicity Arrhythmia.

This retrospective study does not limit the treatment plan of clinicians, so the combination medication should also be analyzed together. For patients suffering from CHD-Hp and instilling Danchuan, western medicine is often combined with the aspirin enteric-coated tablets recommended by various guidelines to dissolve the thrombolytic plate, improve circulation, reduce cardiovascular disease from the perspective of pathogenesis, but also increase the bleeding tendency accordingly. Observe the blood picture [23]; L-carnitine injection can promote lipid metabolism,improve myocardial ischemia and hypoxia [24], atorvastatin calcium capsules reduce lipids and stabilize plaque; trimetazidine balances myocardial oxygen supply and demand; nitric acid Isosorbide tablets dilate blood vessels, improve angina pectoris and lower blood pressure; valsartan and amlodipine tablets (I) are used for long-term blood pressure reduction; furosemide is often used for diuresis and blood pressure reduction and improve heart failure. When combining two western medicines, anticoagulation and anti-embolism are still the mainstay to reduce the incidence of cardiac events and improve the prognosis; it also takes into account complications and comorbidities. For example, atorvastatin calcium capsules +aspirin enteric-coated tablets can alleviate the degree of coronary atherosclerosis For the treatment of atherosclerosis, hyperlipidemia,etc., trimetazidine + L-carnitine injection can increase myocardial energy supply. The combination of the two synergistically exerts a benign effect on myocardial metabolism, and is a commonly used combination for the treatment of heart failure [25] .

While CHD-Hp plays an important role in the study of TCM syndrome types, pathological factors such as blood stasis and qi stagnation [26]. In this study, safflower yellow pigment, Shexiang Baoxin Pills, Suxiao Jiuxin Pills and other drugs for promoting blood circulation and removing blood stasis were the most commonly used Chinese medicines in this study. It can also be effective in treating high blood pressure caused by hepatic wind internal movement,and blood circulation will destroy itself. "The effect is that the blood stasis is scattered, and the ability of the heart to move blood is restored; followed by the Wenxin granules, the compound Difu oral liquid and other medicines for removing blood stasis and replenishing qi; the types of combined Chinese medicines are mostly activating blood and removing blood stasis agents, expectorants, and clearing away heat and detoxification. Tonics, tonics, nourishing qi and nourishing agents, etc., in line with the understanding of traditional Chinese medicine, first improve the symptoms of CHD clinical heartache and asthma by removing blood stasis, removing phlegm and detoxification [27, 28], and then aiming at removing blood stasis and easily hurting vitality and organs in the later stage of illness Deficiency and other characteristics can be used to replenish and soothe the nerves, reduce dizziness, weakness, poor sleep and other symptoms; while elderly patients have weakened digestive function and lose movement of the spleen and stomach in the middle Jiao, so use digestion, spleen and stomach medicines to avoid forced defecation. Increase heart load and risk of chest pain. The effects of each medicine are closely related, reflecting the medicinal mechanism of traditional Chinese medicine multipath.

The association rules of the types of Chinese and Western medicines show that the clinical treatment of CHD-Hp is mainly Western medicine, and anti-angina pectoris drugs are used for symptomatic treatment, anticoagulant thrombolytic drugs, antiplatelet drugs and other Western medicines and traditional Chinese medicines for promoting blood circulation and removing blood stasis are treated from the cause. The overall direction is to focus on anticoagulation and thrombolysis, protecting the heart, and the purpose of treatment is clear, while lowering blood pressure and lipids while taking into account the treatment needs of basic diseases.

The results of this study are objective and universal, and the readers have the following hints: ①The current treatment of CHDHp patients is in line with the recommendations of treatment guidelines; ②Danchuan is often used in CHD-Hp treatment with anticoagulant thrombolysis, anti-angina pectoris, blood circulation and blood stasis. Reflecting contemporary society’s recognition and trust in the combined treatment of Chinese and Western medicine,it can also promote the mutual complementation and continuous development of Chinese and Western treatment concepts; ③CHDHp patients have many comorbidities, and it is advisable to adopt a holistic concept and cross-discipline to find the best plan to improve the overall patient Quality of life, reduce drug abuse, mutual agitation, infection and transmission; ④ Prevent bleeding while anticoagulation, and those with surgical plans should stop using anticoagulants such as aspirin in advance; ⑤ Taking into account the symptoms and symptoms, treat according to symptoms, CHDIt is a routine treatment for patients with chronic disease of qi and blood stasis to remove blood stasis and clear the collaterals. For those with excessive phlegm and shortness of breath, the treatment is to resolve phlegm, and to clear away heat and detoxify if infected with evil toxins. It is also an important treatment for the prevention of changes in existing diseases. [29], explore more individualized treatment methods, make more effective and safe clinical decisions,and improve the quality of life.

3.5 Research deficiencies and prospects

The use of Danchuan CHD-Hp patients with combined medication does not mean that there is a causal link, but only provides clues to the clinic [30]. Real-world research has good extrapolation, but research methods need to be more perfect and standardized [31],such as: ① In the future, we can try to extract the subtypes of CHD and Hp classification to make the research more detailed and explore different types of The characteristics of the population and the differences in treatment are sorted out to deal with more accurate treatment ideas in complex medical environments; ②Try to extract complete TCM syndrome records, as well as records of whether patients take TCM decoctions, and perfect the real-world TCM diagnosis and treatment data The system can better reflect the characteristics of traditional Chinese medicine treatment and observe and compare curative effects, deeply understand the clinical phenomena used by Danchuan, and open up ideas for later scholars who study chest pain and hypertension-type vertigo.

5. summary

The results of this study have enriched the real-world diagnosis and treatment data of traditional Chinese medicine. It was found that CHD-Hp patients who used Danchuan were generally older,multiple diseases were constrained by each other, and the clinical dosage needed to be standardized, warning of the need for increased health awareness and medication supervision in life; combined medication It conforms to the guidelines and recommendations,and has certain rules to follow, rather than simple drug stacking,focusing on anticoagulant thrombolysis, tube expansion, relieving cardiac symptoms and lowering blood pressure, combined with the traditional Chinese medicine method of promoting blood circulation and removing blood stasis and tonic, reflecting the complex disease and easy blood vessels The common diagnosis and treatment ideas and basic programs for CHD-Hp patients whose embolism and syndrome differentiation are mostly blood stasis are to "lighten the burden" of the patients while taking into account the overall quality of life.

Author’s contribution:

Sun Linxi: Article writing;

Gao Yang, Xie Yanming: Extract data and guide modification;

Zhang Lidan: Assist in completing the experiment;

Xu Hongyan, solemn: Analyze the data.