Microvascular Angina Intervention With Compound Danshen Dripping Pill (MAIDS)

1. Research Background Coronary microvascular disease (MVD) is a clinical syndrome refers to laboratory evidence of exertional angina or myocardial ischemia caused by structural and/or functional abnormalities of precoronary arterioles and arterioles under the influence of multiple pathogenic factors.. The main symptoms of patients with coronary microvascular disease are exertion-related chest pain attacks. It is difficult to distinguish patients with coronary microvascular disease from patients with severe coronary stenosis based on symptoms alone. However, the following clinical characteristics suggest that patients have coronary microvascular disease. It is more likely. First of all, it is more common in women, accounting for about 56%-79% of patients with coronary microvascular disease. However, most female patients with coronary microvascular disease have their first symptoms after menopause, which is no different from traditional female coronary heart disease patients. Secondly, most of the symptoms are induced by exertion, but it is not uncommon to have patients with silent chest pain. There are fewer patients with coronary microvascular disease who simply present with silent chest pain. Impaired coronary dilatation, increased sympathetic stimulation and sensitivity, and exercise-mediated coronary constriction can lead to the development of coronary microvascular dysfunction and reduced coronary flow reserve. Long-term recurrent angina pectoris attacks affect the patient's quality of life. Patients with significantly reduced coronary blood flow reserve or myocardial perfusion reserve, especially female patients, may have a higher incidence of adverse cardiovascular events.

Regarding drug treatment, traditional anti-ischemic treatment methods are currently recommended, including β- blockers, calcium ion antagonists and nitrates. If symptoms persist, other drugs include angiotensin-converting enzyme inhibitors, statins, ivabradine , ranolazine , and estrogen drugs. However, there is no specific clinical drug treatment. Basic and clinical studies of the traditional Chinese medicine Compound Danshen Dripping Pill have found that it can improve vascular endothelial function and relieve angina pectoris, and is widely used in clinical practice. However, its effect on coronary reserve function and angina pectoris in coronary microvascular disease needs further clinical research to confirm. 2. Study drug The main drug studied in this study is Compound Danshen Dripping Pill. Compound Danshen Dripping Pills (Compound Danshen Dripping Pills, produced by Tasly Holding Group Co., Ltd.) is a compound traditional Chinese medicine preparation composed of Salvia miltiorrhiza, Panax notoginseng, and Borneol. In 1994, it was approved as a drug for the treatment of coronary heart disease and angina pectoris. It has good clinical efficacy and has It has the characteristics of fast onset, low toxicity, small adverse reactions and high safety.

The active ingredients of compound Danshen dripping pills are water-soluble phenolic acids such as salvia miltiorrhiza and Panax notoginseng saponins. During the preparation process, borneol and auxiliary materials are added, and a highly dispersed solid dispersion is made through a specific process. The active ingredients of the drug have high purity, are evenly dispersed, and can be quickly absorbed through the mucous membrane. The dripping pills have good solid dispersion effect. The principle is to melt the drug ingredients and matrix into a solid solution, and the active ingredients of the drug are in the molecular state or in extremely fine form. The crystalline state is highly uniformly dispersed in the matrix, with fast drug dissolution and higher bioavailability. It can be taken sublingually and can quickly relieve angina pectoris and chest tightness.

Compound Danshen Dripping Pill has achieved a full-process quality control method from medicinal materials, intermediates to preparations (GAP-GEP-GMP) through the multi-factor fingerprint quality control system of compound oral Chinese medicine preparations, further improving the full-process quality control system of Compound Danshen Dripping Pill , after testing and analyzing nearly 200 batches of Compound Salvia Miltiorrhizae Dropping Pills Extract and Compound Salvia Miltiorrhizae Dropping Pills, the similarity is over 90%, and the quality of the products is stable between batches. It has been confirmed through the toxicology study of Compound Danshen Dripping Pill and the clinical use of hundreds of millions of people: it has no toxicity, few adverse reactions, and is safe and reliable for long-term use.

As a Chinese patent medicine for the treatment of stable angina pectoris, Compound Danshen Dripping Pill are included in Category A of the 2018 National Essential Drugs Catalog and the 2019 National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalogue. Under the name of "Compound Danshen Dripping Pill", it has been written into more than 20 national medical guidelines or consensus, 15 of which involve the cardiovascular field, including "Guidelines for Rational Medication in Coronary Heart Disease (2nd Edition)", "Acute Myocardial Medication "Guidelines for the Diagnosis and Treatment of Infarction by Integrated Traditional Chinese and Western Medicine", "Chinese Expert Recommendations on the Clinical Application of Compound Danshen Dripping Pill", "Expert Consensus on the Diagnosis and Treatment of Atherosclerosis by Integrated Traditional Chinese and Western Medicine", etc.

In terms of international evidence-based research, large-sample, randomized, double-blind, placebo-controlled RCT studies were used, and 1,004 patients were included in phase III clinical studies at 127 centers in 9 countries/regions around the world, indicating that the US FDA-Phase III The main clinical efficacy indicators: significantly increase the patient's exercise flat time and improve exercise tolerance. Compared with the increase time of exercise oxygen tolerance of similar drugs, Compound Danshen Dripping Pill has obvious advantages . Secondary efficacy indicators: effectively reduce the number of angina attacks per week and significantly reduce the weekly nitroglycerin dosage.

In terms of domestic evidence-based research: 1011 studies on Compound Danshen Dripping Pill for the treatment of stable angina, 16 Meta-analyses, with a total enrollment of more than 100,000 people; 137 studies on the treatment of peri-PCI/ thrombolysis period , the total number of participants exceeds 10000 ; there are 36 studies on Compound Danshen Dripping Pill improving coronary microcirculation disorders, filling the gap in Western medicine treatment.

Systematic study of Compound Danshen Dripping Pill combined with Western medicine in the treatment of coronary heart disease angina pectoris: 21 articles were included, with a total number of cases of 2229. Compound Danshen Dripping Pill combined with Western medicine can benefit patients with coronary heart disease angina pectoris, especially in improving clinical symptoms and electrocardiogram . It has outstanding effects on ischemic state and regulating cholesterol levels.

A meta-analysis based on PubMed, EMBASE, CNKI, and Wanfang databases studied the efficacy of aspirin combined with Compound Danshen Dripping Pill in the treatment of coronary heart disease. The analysis included 14 randomized controlled trials with a total of 1,367 patients. The results showed that the combination Compared with aspirin alone, the drug can achieve more significant therapeutic effects in relieving angina pectoris symptoms and lowering blood lipids. Lu Yuhong et al. randomly divided 128 patients with coronary heart disease into groups. The control group took oral aspirin on the basis of conventional treatment, and the observation group took Danshen Dropping Pills on the basis of conventional treatment. After 2 months, the total clinical effective rate of the patients in the observation group was significantly higher than Control group. Compared with before treatment, the maximum platelet aggregation rate and thromboxane B2) levels of the two groups of patients were significantly reduced, and the decrease in the observation group was more obvious than that in the control group . The "Guidelines for the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine in Acute Myocardial Infarction", led by Academicians Chen Keji, Academician Ge Junbo, and Professor Zhang Minzhou, were formulated in conjunction with experts in the fields of traditional Chinese medicine, Western medicine, integrated traditional Chinese and Western medicine, and methodology across the country. The guideline clearly states that Compound Danshen Dripping Pill are recommended for the treatment of acute myocardial infarction. The recommendation level is the highest in the guideline. Compound Danshen Dripping Pill can relieve chest pain, reduce the patient's risk of cardiac death, and improve the patient's cardiac function. and the role of quality of life.

3\. Research purpose A randomized, double-blind, placebo-controlled, multi-center clinical study of Compound Danshen Dripping Pill and blank control was conducted in patients with microvascular angina pectoris .

4\. research design 4.1 Study title and registration The Chinese name of this project is: Microvascular Angina Intervention with Compound Danshen Dripping Pill. English name: Microvascular Angina Intervention with Compound Danshen Dripping Pill. Referred to as MAIDS Study.

4.2 Research design : Randomized, double-blind, placebo parallel-controlled, multi-center clinical study.

4\. 3 dosing regimens (double-blind single simulation)

1. Placebo group: Placebo (the appearance is the same as Compound Danshen Dripping Pill , main ingredient: starch. Production unit: Tianjin Tasly Co., Ltd.), taken orally after meals, 3 times a day, 20 pills each time . 2. Treatment group: Compound Danshen Dripping Pill (Tianjin Tasly Co., Ltd.), taken orally after meals, 3 times a day, 20 pills each time .

Note: The batch number on the drug packaging is unified as " 161299 ". 5. Research objects 5.1 Source of patients: patients with chest pain who had no obvious coronary artery stenosis on coronary angiography or coronary CT examination were admitted to the hospital outpatient clinics and wards .

5.2Selection criteria \_

1. With typical symptoms of exertional angina; 2. Coronary CTA or angiography with normal coronary artery or \<50% stenosis, or \<50% residual coronary stenosis after revascularization; 3. Ischemic downward shift of the ST segment is found in the electrocardiogram at rest or during exercise stress (horizontal or downsloping downward shift behind the J point \>0.1mv, lasting 0.08s ); 4. Transthoracic ultrasound before and after intravenous adenosine injection to check the anterior descending coronary artery blood flow reserve test CFR \<2.5; 5. The patient agreed to participate in this study. 5.3 Exclusion criteria (1) Aged less than 30 years old or older than 75 years old; (2) Have a history of carotid endarterectomy or stent implantation, and have a history of stroke ; (3) Myocarditis, pericardial disease, valvular disease, and cardiomyopathy; (4) Difficult-to-control diabetes (fasting blood glucose \>7.0 mmol/L); ( 5 ) Uncontrollable hypertension (SBP\>150 mmHg and/or DBP\>90 mmHg); ( 6) Familial hypercholesterolemia; ( 7 ) Takayasu arteritis; ( 8 ) Those who are pregnant or lactating, or those who intend to have a child within one year, or those who have not taken effective contraceptive measures during the childbearing age; ( 9 ) Abnormal liver function (serum GPT level exceeds 3.0 times the upper limit of normal value) or abnormal renal function (serum creatinine level exceeds 2 mg/dl); ( 10 ) Other clinically significant respiratory, digestive, blood, infection, immune, endocrine, neuropsychiat

• Number of angina attacks per week. [Time frame: During 6 months of following up.]
• The time of angina pectoris in exercise test. [Time frame: At the end of 6-month follow-up compared to the baseline.]
• The time of ischemic ST segment depression in exercise test. [Time frame: At the end of 6-month follow-up compared to the baseline.]