Adjuvant treatment of coronary heart disease angina pectoris with Chinese patent medicine

Abstract Background: Patients with coronary heart disease (CHD) angina pectoris are in critical condition, which can cause sudden death, myocardial infarction, and other adverse events, and bring serious burden to families and society. Timely treatment should be given to improve the condition. Western medicine treatment of angina pectoris failed to meet the demand of angina symptom control. Objective: It is hoped that the research method with higher evidential value will be adopted to compare the short-term, medium-term, and long-term effects of Chinese patent medicine combined with conventional western medicine and conventional western medicine alone in the treatment of CHD angina pectoris, so as to tap the clinical efficacy advantages of traditional Chinese medicine (TCM) and provide reliable data support for its clinical application. Methods: A prospective cohort study was conducted among patients with CHD angina pectoris who were treated with oral Chinese patent medicine and conventional western medicine. The patients were divided into exposed group and nonexposed group according to whether or not the patients with CHD angina pectoris were treated with Chinese patent medicine. The exposed group was treated with TCM combined with conventional western medicine, while the nonexposed group was treated with conventional western medicine alone. Patients need to be hospitalized for 2 weeks as the introduction period and whether to enter the group is determined according to the treatment and medication conditions of the patients. The follow-up time points were 0th, 4th, 12th, 24th, and 48th weeks. The main events and secondary events were used as the evaluation criteria for clinical efficacy of CHD angina pectoris. In the experimental study, we will use strict indicators to detect standard operation procedure for multinomics and bacterial flora detection. Conclusion: This study will provide evidence for the clinical efficacy advantages of Chinese patent medicine and reliable support for its clinical application through test data.


Introduction
Coronary heart disease (CHD) is a heart disease caused by myocardial ischemia and hypoxia due to coronary atherosclero-sis. Angina pectoris is closely related to coronary artery insufficiency and is common in clinical practice. [1][2][3] Patients with CHD angina pectoris are in critical condition, which can cause sudden death, myocardial infarction, and other adverse events, and bring serious burden to families and society. Timely treatment should be given to improve the condition. [2][3][4][5] Clinical attention has long been paid to the treatment of CHD angina pectoris. Western medicine for angina pectoris mainly uses b-receptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, etc. [6] It has good clinical effect, but the demand for angina symptom control is still unsatisfied. [7] As a unique medical resource in China, traditional Chinese medicine (TCM) plays an important role in disease treatment and health services. Chinese patent medicine is made of Chinese herbal medicines as raw materials and processed into various dosage forms of Chinese traditional medicine products, including pills, powders, granules, pastes, capsules, Chinese traditional medicine injections, aerosols, etc. Its advantages are ready availability, adaptability to urgent need, convenient storage, easy carrying, and saving decocting process, etc, and eliminating peculiar smell and adverse stimulation when taking TCM decoction. [8][9][10] According to statistics, the number of Chinese patent medicines in the 2012 edition of the basic medicine catalog has increased to 203, accounting for 39%, of which 23 are Chinese patent medicines for the treatment of cardiovascular diseases. [11] Eight kinds of commonly used cardiovascular Chinese patent medicines and 28 kinds of antiangina Chinese patent medicines are included in New Pharmacology. [12] In recent years, many studies have shown that Chinese patent medicine has achieved certain curative effect in the dialectical treatment of angina pectoris, which has the advantages of good effect and few adverse reactions. [13][14][15][16][17] However, Chinese patent medicine is difficult to match western medicine with large-scale clinical trials in treatment, health education, and publicity. Therefore, a research method with higher evidence value-clinical cohort study is needed to conduct evidence-based research on it.
The results of cohort study belong to class II evidence-based medicine, and its research evidence is second only to randomized controlled trials (RCTs). However, cohort study has its advantages such as long time, large sample, and so on. Cohort study design can follow the characteristics of individualized diagnosis and treatment of TCM and dynamic changes of treatment schemes, and take Chinese patent medicine as a factor to comprehensively evaluate the curative effect of Chinese patent medicine on CHD angina pectoris. [18] In this study, prospective cohort study was used to study the clinical efficacy of Chinese patent medicine in the adjuvant treatment of CHD angina pectoris, so as to enrich the evidence of efficacy evaluation of Chinese medicine. Establish innovative methods and techniques for the evaluation of clinical efficacy of TCM, and then promote its deeper research and application.

Method
A prospective cohort study was conducted among patients with CHD angina pectoris who were treated with oral Chinese patent medicine and conventional western medicine. The patients were divided into exposed group and nonexposed group according to whether or not the patients with CHD angina pectoris were treated with Chinese patent medicine. The exposed group was treated with TCM combined with conventional western medicine, while the nonexposed group was treated with conventional western medicine alone. Patients need to be hospitalized for 2 weeks as the introduction period and whether to enter the group is determined according to the treatment and medication conditions of the patients. The follow-up time points were 0th, 4th, 12th, 24th, and 48th weeks. The main events, secondary events and adverse events were used as the evaluation criteria for clinical efficacy of CHD angina pectoris. In the experimental study, we will use strict indicators to detect standard operation procedure for multigroup and bacteria detection. It is hoped that the research method with higher evidential value will be adopted to compare the short-term, medium-term, and long-term effects of Chinese patent medicine combined with conventional western medicine and conventional western medicine alone in the treatment of CHD angina pectoris, so as to tap the clinical efficacy advantages of TCM and provide reliable data support for its clinical application. The technical route is shown in Figure 1.

Study site
The cooperative network of CHD research medical units formed by the research team includes 5 hospitals, including the First Affiliated Hospital of Tianjin University of TCM, the Second

Sample size calculation
The sample size calculation formula is shown in Figure 2. The expected incidence rates of exposed group and nonexposed group were obtained through literature review, [18,19] P 1 = 0.072, P 0 = 0.059, q = 1 À p, Z a and Z b were the areas under the standard normal distribution, and the table was found to obtain Z a = 2.58, Z b = 1.64. Substituting the above values into the formula can be obtained, and the sample size of each group is about 5677 cases. Control the rate of loss of follow-up within 10%, mainly to ensure a certain professional representation. There were about 6200 cases in each group, and the total sample size of this study was about 12,400.

Adverse reactions
In this study, the adverse reactions of drugs (Chinese patent medicine and conventional western medicine) studied are detailed in the drug instructions.

Regulations on combined use of drugs
Patients with CHD angina pectoris can be treated with the original scheme before admission during the study period, and the admission period is 2 weeks, so that the patient's condition is stable and meets the admission criteria. During the study period, for patients with hypertension, diabetes, hyperlipidemia, and other diseases, the antihypertensive, hypoglycemic, and lipid-lowering treatment schemes before admission can be maintained. The name, dosage, and usage of the drugs are recorded in detail in the study medical records. It is forbidden to adjust the dosage and usage of b-receptor blockers, calcium ion antagonists, and other drugs that affect the curative effect of CHD angina pectoris.

Follow-up time point
Patients need to be hospitalized for 2 weeks as the introduction period and whether to enter the group is determined according to the treatment and medication conditions of the patients. The follow-up time points were 0th, 4th, 12th, 24th, and 48th weeks. The main curative effect, secondary curative effect, and concomitant medication changes of patients were observed.
2.8. Information collection 2.8.1. Demographic data. Including the patient's gender, age, nationality, occupation, height, weight, and body mass index.
2.8.2. TCM syndrome types of CHD angina pectoris. The TCM syndrome type is derived from the diagnosis of the existing cases. If there is no syndrome diagnosis, the 2 trained physicians with more than 5 years of practicing qualifications will judge each other. If there is any dispute, they will be submitted to the superior doctor for final review.  2.8.5. Histology and flora detection. Samples with the same number of cases in exposed group and nonexposed group were respectively selected for testing, in strict accordance with genomics, proteomics, metabolomics, intestinal flora, and tongue coating flora detection methods for analysis. The following points should be paid attention to in the process of index detection: 1. Select patients with good compliance to ensure timely medication and keep a light diet during medication to avoid interference from alcohol and carbonated beverages. 2. Determination of clinical biochemical indexes fasting for 12 hours, and within 24 hours should not be intense sports. Blood should be collected in the decubitus position, and rest in the decubitus position for 1.5 to 2 hours before blood collection.
Morning urine and middle urine should be taken. Feces avoid the pollution of urine and toilet walls, collect fresh feces from the middle and rear part of the excretion, and dig up the feces from the inner side of the middle part as samples. 3. Sample collection is limited to 1 month and the collected samples are transported in a centralized way. Biologic samples should be stored in a refrigerator at À80°C.
Theoretically, all tested samples should be analyzed within 6 months.
2.8.6. Information collection at different time points.
1. 0th week: Collect demographic data, TCM syndromes of CHD angina pectoris, western medicine classification of CHD angina pectoris, SAQ in main curative effect and secondary curative effect, routine admission examination, genomics, proteomics, metabolomics, intestinal flora, and tongue coating flora. 2. 4th week: SAQ, routine admission examination, adverse events, genomics, proteomics, metabolomics, intestinal flora, and tongue coating flora were tested for primary events and secondary events. 3. 12th week: SAQ, routine admission examination, adverse events, genomics, proteomics, metabolomics, intestinal flora, and tongue coating flora were tested in the primary events and secondary events. 4. 24th week: Detect the main curative effect, death in secondary curative effect, readmission due to cardiovascular events and adverse events. 5. 48th week: Check the main curative effect, death in secondary curative effect, readmission due to cardiovascular events and adverse events (Table 1).

Information collection methods
In 0th week, relevant patient information was collected by consulting medical records, medical record systems, or interviews. In the 4th, 12th, 24th, and 48th weeks, interviews, telephone calls, WeChat (which can establish WeChat groups for patients and be managed in a unified way), or outpatient followup system are conducted to record the occurrence time and data of follow-up indicators and establish a statistical database.
2.10. Data management 2.10.1. Original data management and archiving. Cardboard case report form (CRF) is adopted, and all CRFs will come into effect after being reviewed and signed by researchers. All CRFs and CRF modification traces are retained. Each test report of the subject was pasted at the designated position.
2.10.2. Data entry and storage. The data are entered into the computer by 2 persons and 2 persons using EpiData 3.1 database, and the data are entered into the computer by 2 trained professionals, respectively. The database is established by EpiData 3.1 for data entry. According to the research content, a data entry guide will be prepared and data entry personnel will be specially trained before data entry. Data entry personnel enter data according to the entry guide.

Writing of data verification and answers to questions.
The entered data will be checked one by one according to the Data Verification Plan (SAP). SAP needs the signature and approval of the data administrator and statistician. Verification methods include systematic verification and manual medical verification. Systematic verification mainly uses SAS 9.3 software to write verification procedures and generate data clarification form (DCF). All data query contents found through manual medical verification and systematic verification will be input into the project data query database, and the data management unit will make a formal DCF. DCF shall be sent to the clinical research supervisor after being checked and found to be correct. After re-examination by the inspectors, they will be handed over to researchers in various research centers for examination and answer. Only after receiving the DCF with the signature and date of the researcher can it be confirmed that the DCF has been answered and the database can be modified. The original DCF will be stored in the special filing cabinet for the project. Any changes to the database will be recorded, recording when, by whom, and for what reason (Fig. 3).
2.11. Statistical analysis 2.11.1. Statistical analysis of data. Before the statistical analysis of clinical test data, the statistical analysis personnel shall formulate a statistical analysis plan, specify detailed statistical analysis steps, and carefully check, clean up, and confirm the clinical test data. The analysis content includes case elimination and shedding analysis, checking the number of completed cases, elimination and shedding in each center, descriptive statistical analysis, listing the frequency distribution of each variable, comparison of baseline data of clinical characteristics before treatment, analysis of concomitant medication, analysis of curative effect, safety evaluation and analysis of missed visits, etc. All statistical analysis processes are programmed and archived for future reference.
2.11.2. Main statistical analysis methods. Descriptive analysis and inferential analysis of clinical features before and after treatment were as follows:

Discussion
The results of cohort study belong to Class II evidence-based medicine and have advantages such as long-term, large sample, and so on. In the prospective cohort study, we can directly obtain the 1st-hand data on exposure and outcome, so the bias of the data is small. On the basis of the National Basic Research Program of Table 1 China (973 projects), this study has carried out a rigorous and meticulous design of this plan and has the following advantages: 1. Fully collect important clinical-related results and the main indicators, secondary indicators and adverse event reports included in the test.
2. Strict concomitant medication regulations: As patients with CHD are often complicated with hypertension, hyperlipidemia, and other diseases, or undergo PCI surgery, they need to take antihypertensive, antiplatelet agglutination, and other drugs for a long period of time. This study has strict regulations on concomitant medication, reflecting the rigor of the design. 3. Accurate methodology design to reduce the risk of bias: Before statistical analysis of clinical test data, statistical analysts shall formulate statistical analysis plans, specify detailed statistical analysis steps, and carefully check, clean up and confirm clinical test data. 4. Strict quality control in clinical research: Due to different clinical units, to prevent the differences in the process of collecting samples, the research group dispatched uniformly trained supervision and inspection personnel to carry out off-site and on-site supervision and inspection work on clinical units to ensure the strictness of the patients enrolled. The filling of clinical scales is also carried out after training, and professional personnel supervise and verify the data on site. The later research group uniformly conducts 2 rounds of verification on the data to ensure the accuracy of the original data. 5. Unified sample collection and testing: Collected blood and urine samples are collected, transported, processed, and stored in a unified way. Biochemical indexes, liquid chips, and expression spectrum chips are all detected by professional companies to ensure the unity of the detection process.
Due to the complexity of clinical research, although the research scheme has strict regulations on possible problems, it may still affect some research results. The clinical research plan of this kind of research will be further improved in the later period according to the actual research situation. This plan will comprehensively explore the clinical efficacy advantages of Chinese patent medicine in adjuvant treatment of CHD angina pectoris, and provide reliable data support for its clinical application.