Study design and settings
Prospective observational studies, randomized, double-blind, parallel design, single-center studies. The study will collect patients in the following four districts: 1. Guangdong Provincial Hospital of Traditional Chinese Medicine Dade Road General Hospital; 2. Guangdong Provincial Hospital of Traditional Chinese Medicine Ersha Branch; 3. Guangdong Provincial Hospital of Traditional Chinese Medicine University City Branch; 4. Guangzhou Traditional Chinese Medicine University Shunde Hospital; 160 patients will be recruited to meet the eligibility criteria. Subsequently, the participants were divided into four groups in a ratio of 1:1:1:1 (three groups of treatment groups: treatment group A: will receive conventional drugs plus Astragalus injection treatment; treatment group B: will receive conventional drugs plus Salvia Miltiorrhiza injection Treatment; treatment group C: will receive conventional drugs plus Salvia Miltiorrhiza injection plus Astragalus injection treatment), the control group will receive conventional drugs plus 0.9% NaCl injection. The study design is illustrated in Figure.1.
Objectives
This study intends to explore the effects of Astragalus injection, Salvia Miltiorrhiza injection and their synergistic treatment on stable coronary heart disease from the anti-inflammatory advantage, and provide the basis and basis for its clinical application.
Research standard
All patients enrolled in the study should meet the following diagnostic criteria and inclusion criteria and sign an informed consent form.
Diagnostic criteria
Coronary heart disease diagnosis: (1) coronary angiography or coronary CTA confirmed at least one major branch lumen diameter stenosis more than 50%, clinical with or without angina, heart failure, arrhythmia, sudden death recovery. (2) There was a clear evidence of ST-segment elevation or non-ST-segment elevation myocardial infarction. (3) Defining the history of percutaneous coronary intervention (PCI) or / and coronary artery bypass grafting (CABG).
Clinical diagnostic criteria for chronic stable angina[15]: Chronic stable angina is a patient whose degree, frequency, nature, and predisposing factors of angina pectoris have not changed significantly within one month. (1) Pain area: The typical part is the posterior sternum or left front chest, which can be radiated to the neck, pharynx, jaw, upper abdomen, shoulder and back, left arm and left finger. (2) The nature of pain: often showing a sense of tightness, squeezing, pressure, burning, chest, chest tightness or suffocation, heavy feeling, subjective feelings vary widely, and some manifest as fatigue, shortness of breath. (3)Duration: A paroxysmal episode lasting for a few minutes, generally no more than 10 minutes. (4) Predisposing factors and mitigation methods: seizures are related to labor or emotional excitement, can be relieved after stopping to rest, sublingual nitroglycerin can quickly relieve symptoms within 2–5 minutes.
Inclusion criteria
The inclusion criteria are as follows:
- Meet the Stable coronary atherosclerotic heart disease (SCAD) diagnostic criteria;
- The medical history is more than three months, and the frequency of angina pectoris is ≥3 times in the past one week, and the severity of angina pectoris is grade I~II/I~III;
- Age 18–75 years old;
- SCAD patients were treated with any combination of cardiac-related drugs for more than three months prior to enrollment, including atorvastatin, ASA, ACEIs, ARBs, and beta-blockers;
- Sign the informed consent form.
Exclusion criteria
The exclusion criteria are as follows:
- Patients with acute coronary syndrome (ACS) who are asymptomatic or have stable symptoms after stabilization;
- Patients requiring revascularization, including myocardial infarction, left ventricular dysfunction, multivessel disease, and/or large-scale myocardial ischemia (ischemic area over 10%), left main disease, etc.;
- Chronic refractory angina pectoris;
- Combined with chronic kidney disease and severe heart, lung, liver and other important organ dysfunction; Serious primary diseases such as hematopoietic system and endocrine system, malignant tumor, gastrointestinal bleeding, gastric ulcer and bleeding tendency are not expected complete the tester;
- Severe and uncontrolled hypertension (SBP ≥ 180 mmHg or DBP ≥ 110 mmHg);
- Severe arrhythmia (ventricular dichotomy, ventricular tachycardia, ventricular fibrillation, third degree atrioventricular block, arrest, severe sinus bradycardia, sick sinus syndrome, reentrant supraventricular tachycardia, etc. Arrhythmia causing hemodynamic changes)
- Participate in other clinical trials or take other proprietary Chinese medicines within one month;
- Pregnancy or preparation for pregnancy, lactating women;
- There are mental, psychological, and other problems that cannot be matched with the completion of the research.
Shedding criteria
Patients who were enrolled but have not completed clinical observations, including patients withdrawing themselves, losing their follow-up, poor compliance, or being withdrawn by a physician. If there is valid data for shedding disease, the result of the last major efficacy index is converted to the final result for statistical analysis.
Suspension criteria
1. Serious adverse reactions occurred in the test;
2. The trial found that the clinical trial program has major errors, or the program is good, but serious deviations occur in the implementation, it is difficult to evaluate the efficacy of the drug.
Sample size
This study used parallel design, randomized controlled trials, with hs-CRP as the main effect index, conventional western medicine treatment can reduce hs-CRP 32%, according to clinical conditions, it can be estimated that Chinese medicine can reduce hs-CRP 52%, set α = 0.025, β = 0.2, the superiority limit value δ = 20%, and the sample size of each group was calculated as 30 cases; Considering the loss of follow-up, 40 patients with stable coronary heart disease and 160 patients with four combinations were selected.
Randomization
Random numbers are generated using SAS 9.2 software according to the principle of randomization. In order to implement random hiding, the random sequence is kept by a special person. The “remote” random hiding method is used to determine that the basic information of the qualified subject will be transmitted by telephone to the person who keeps the random number, and then the treatment allocation plan of each patient is obtained. Random grouping according to a pre-defined random plan.
Blinding
Due to the special color problem of traditional Chinese medicine injection, this study is difficult to achieve double blindness. However, in order to avoid the bias in the process, the following specific measures are proposed: (1) The researchers are strictly based on the principle of randomization; (2) The doctors who participated in the evaluation of the outcome are non-researchers, so that the evaluation of the efficacy of the test is blind; (3) blood Detection and data analysis and statisticians are non-clinical researchers.
Intervention
Trial treatment methods
According to the principle of randomization, the screening group was divided into the following four groups, three groups of treatment components: Group A: received conventional drug treatment plus Astragalus injection treatment (size 20ml / support, packaging 10 / container); Group B: Will accept Conventional medicine plus Salvia Miltiorrhiza injection treatment (specification 20ml / support, packaging 10 / container); Group C: receiving conventional medicine plus Salvia Miltiorrhiza injection plus Astragalus injection treatment; Both Salvia Miltiorrhiza and Astragalus injection prepared prepared with 250ml 5% glucose injection. The control group received 250ml conventional drug plus 5% glucose injection. For diabetic patients, 250ml 5% glucose injection was changed into 250ml 0.9% sodium chloride injection. All patients received intravenous drip once a day for 60 minutes and the treatment period is seven Days.
The conventional drugs used in the stable coronary heart disease test are as follows:
Refer to 2013 ESC Guidelines for the diagnosis and treatment of stable coronary atherosclerotic heart disease (SCAD)[16]. The standard is given aspirin, clopidogrel, low molecular weight heparin, statins, nitrates, beta-blockers, ACEI and other drugs.
Pharmaceutical and combination methods
The methods of allocation and combination used in this test are as follows:
1. Prepare Salvia Miltiorrhiza injection and Astragalus injection with 250ml 5% glucose injection. If the patient is diabetic, change 250ml 5% glucose injection into 250ml 0.9% sodium chloride injection.
2. It is forbidden to use other injections simultaneously during intravenous infusion.
Matters needing attention
1.Patients received the study drug within 24 hours of enrollment 2. Conventional treatment of stable coronary heart disease (such as anti-poly drug, lipid-lowering drug, antihypertensive drug) should be carried out at the same time. Injection of Astragalus and Salvia Miltiorrhiza injection should not be used as a substitute.
Content and data capture points
The contents and key points of the data capture in the experiment are as follows:
1. Screening period (1 day): 24 hours before recruitment
2. Treatment period (1–7 days): daily recording
3. After treatment (28 days after treatment): follow-up on day 28
Outcome measures
Primary outcome measures
Cell count, serum hs-CRP level, MCP–1, IL–6, TNF-α, IL–1β, IL–8, IL–18, OX-LDL, IL–10,improvement of angina[17] and TCM symptom change scale[18], see Table 1 and Table 2.
Secondary outcome measures
Blood lipid levels, BNP levels, cTn, CK-MB, H-FABP; electrocardiogram.
Safety outcome
Includes vital signs, blood routine, urine routine, fecal routine, liver function, renal function and coagulation. Monitor these indicators closely during this process.
Observation record of adverse events
Any adverse events that occur during the course of the trial, including laboratory abnormalities, must be carefully interrogated and tracked. All adverse events must be judged for their nature, severity, and drug relevance and are strictly recorded in the case report form.
Research process record points
Record the subject content and data at each time point according to the patient’s hospitalization period (Figure. 2).
- Screening period (0 days): 24 hours before recruitment.
- Dry expectations (1–7 days): data were tracked and recorded every day.
- Time after intervention (within 28 days after treatment): follow-up on day 28.
Statistical analysis
Statistical analysis was performed using SPSS19.0 statistical software. The measurement data is described by means of mean and standard deviation, and the number and percentage of count data are described. Baseline analysis was performed on the demographic characteristics of the four selected cases, and the balance and comparability of the four groups were examined. Then compare the effectiveness indicators and safety indicators of the four groups. The quantitative data of the experimental group and the control group were compared by the t-test of the two-sample comparison of the group design; the comparison of the two classification indicators such as gender was performed by the 2 test or the exact probability method. The validity and ineffectiveness of each group were compared using the rank sum test of the two-sample comparison of the group design. All statistical tests were performed on both sides. A p-value of less than or equal to 0.05 was considered statistically significant.
Data management
In this clinical study, the person in charge of the research needs to fill out the CRF form in time. The patient should fill in the relevant information carefully, avoid missing, save it, and then check it regularly by clinical researchers. The revisions provided by the clinical researcher should be implemented and corrected by the researcher in a timely manner. The researchers at each clinical research center confirm and sign the complete CRF form, which cannot be modified after the trial, and the data management will save the submitted data. The entire research process must be conducted in a confidential manner, prohibiting the disclosure of any information to other parties, and the main researcher will eventually have access to all data.
Quality control
Construction of research institutions
In the process of clinical research, multi-department construction and composition are required, and each department must be firmly cooperating to ensure the completion of research quality. The main departments of this research include the following components: (1)The competent department, composed of clinicians, pharmaceutical researchers and quality supervision experts, mainly responsible for the problems in clinical research, providing solutions in a timely manner; (2)Composed of members of the ethics committee: responsible for the ethical implementation process; (3) Data statistics and management: mainly by statistical experts, responsible for the implementation and confidentiality of the entire data; (4) Safety management: the researchers of each center are responsible for timely observation of the patient’s vital signs and laboratory indicators, and timely adjustments and feedback.
Supervision and inspection
Effective supervision and inspection must be carried out throughout the clinical trial study. Each research center needs to conduct an examination once a week, including the patient’s CRF form completeness, whether there is a complete informed consent, whether the patient’s inclusion criteria are accurate, laboratory indicators and related scale collection and preservation. During the test, the patient had any adverse reactions and whether there was a record of withdrawal. Researchers at each clinical research center need to ensure the authenticity and integrity of all data.
Ethical issues
Ethics statement
In clinical trials, the main researcher is required to follow the Helsinki Declaration and ethical principles. The investigator must fully respect the subject’s choices, and must not force the subject to perform the trial. The subject has the right to participate voluntarily, voluntarily provide and sign a written informed consent form, and may withdraw at any time. In the process, each subject will be randomly assigned a random number to ensure random and blind implementation during the trial. In addition, researchers must protect the privacy, confidentiality, and confidentiality of the subject.
Ethical approval
This subject was approved by the Ethics Committee of the Guangdong Provincial Hospital of Traditional Chinese Medicine on February 1, 2019.The clinical research plan and the relevant documents of the informed consent form were approved by the Ethics Committee of the Guangdong Provincial Hospital of Traditional Chinese Medicine.[Approval registration number BF2018–182–01] (Table 3).
Informed consent form
The informed consent form is completely read and signed by the patient or his representative. The written must be complete. After signing, the main researcher will collect and save it. The researcher will save the informed consent form for review and test.