Coronary MicrovAscular Diseases Intervention With Compound Danshen Dropping Pills

Rationale for the Study：Coronary Microvascular Disease (CMVD) is a clinical syndrome manifested as effort-induced angina pectoris or laboratory evidence of myocardial ischemia, which results from structural and/or functional abnormalities of the coronary pre-arterioles and arterioles under the effects of multiple pathogenic factors. Impaired coronary microcirculatory function is closely associated with long-term clinical outcomes in patients. A reduced coronary flow reserve (CFR) is not only associated with persistent angina, decreased exercise tolerance, and impaired quality of life, but also independently predicts the risk of cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, and major adverse cardiovascular events (MACE).Current domestic and international guidelines recommend risk factor control and anti-ischemic therapy as the foundational treatment for CMVD. However, the pathogenesis of CMVD is complex, involving multiple pathological processes such as endothelial dysfunction, microvascular spasm, microvascular remodeling, and inflammation. There is considerable heterogeneity in the treatment benefits among different patients, and evidence-based therapeutic strategies that can definitively improve coronary microcirculatory function and delay disease progression are still lacking.

Basic and clinical studies have demonstrated that the Chinese medicinal compound Compound Danshen Dripping Pills (CDDP) can improve vascular endothelial function and relieve angina pectoris, and it has been widely applied in clinical practice. In the preliminary study entitled Clinical Study on the Effect of Compound Danshen Dripping Pills on Coronary Flow Reserve in Patients with Coronary Microvascular Angina, CDDP effectively improved coronary flow reserve in patients with CMVD. These findings support the value of conducting larger-scale clinical studies to explore its clinical efficacy for CMVD, symptom improvement, and effects measured by the Seattle Angina Questionnaire.

Objective: To investigate the effect of Compound Danshen Dripping Pills （CDDP）on improving coronary flow reserve（CFR） in patients with coronary microvascular disease (CMVD) and to evaluate their efficacy and safety.

Hypothesis: In patients with CMVD receiving standard anti-ischemic therapy, treatment with CDDP for 12 months will significantly improve CFR, reduce major adverse cardiovascular events（MACE）, and improve quality of life compared with placebo.

This study adopts a stratified-block randomization design. A total of 496 study participants were divided into two subgroups according to disease diagnosis (Subgroup A: Ischemia-related CMVD; Subgroup B: Myocardial infarction-related CMVD, 248 participants in each subgroup). After the classification of participants into disease-specific subgroups, the system automatically activated the block allocation module corresponding to each subgroup. Participants were assigned to pre-defined groups sequentially according to the real-time enrollment order until the full quota of the subgroup was fulfilled.

During the study, a total of 5 visits will be conducted (Baseline/Screening, Month 3, Month 6, Month 9, and Month 12). At each visit, clinical data will be collected, along with an electrocardiogram (ECG), Canadian Cardiovascular Society (CCS) angina grading, and Seattle Angina Questionnaire (SAQ) scoring. Laboratory tests and echocardiography (including CFR assessment) will be performed at Baseline/Screening, Month 6, and Month 12.

Blood Sampling Protocol: Fasting venous blood samples will be collected at the clinical laboratory of Qilu Hospital of Shandong University on the mornings of the Baseline, Month 6, and Month 12 visits. A total of 3 samples will be collected, with 10 mL drawn each time (total volume: 30 mL). All samples will be sent to the clinical laboratory of Qilu Hospital of Shandong University.

Laboratory Assessments: The blood samples will first be used for routine clinical laboratory tests, including complete blood count (CBC), urinalysis, liver function (ALT, AST), renal function (serum creatinine, urea/BUN), coagulation panel (PT, APTT, TT, FIB), lipid profile (TC, TG, LDL-C, HDL-C), and myocardial enzymes (troponin T \[TnT\], creatine kinase \[CK\]). The remaining samples will be utilized for exploratory assessments, such as the detection of inflammatory and endothelial biomarkers, as well as omics screening. Any residual blood samples after the aforementioned tests will be stored uniformly in the cardiovascular laboratory for further exploratory testing in the future.

This study is a large-sample RCT clinical trial targeting CMVD, and is expected to provide evidence-based medical evidence for the treatment of CMVD.

• Compound Danshen Dripping Pills (Drug), also known as CDDP, Fufang Danshen Diwan, Cardiotonic Pill, Dantonic Pill, T89: 20 pills (540 mg) orally three times daily for 12 months. Each pill weighs 27 mg, containing Radix Salviae miltiorrhizae, Radix Notoginseng, and Borneolum Syntheticum. Manufactured and supplied by Tasly Pharmaceutical Group Co., Ltd.
• Placebo (Drug), also known as Matching placebo: Placebo pills identical to Compound Danshen Dripping Pills in appearance, taste, and packaging, 20 pills orally three times daily for 12 months.

Primary outcomes

• Change from baseline in peak coronary flow reserve (CFRmax) of the left anterior descending artery [Baseline, 6 months, and 12 months]: CFRmax is defined as the ratio of hyperemic to basal peak diastolic flow velocity (PDV) in the mid-to-distal left anterior descending artery, measured by transthoracic Doppler echocardiography (TTDE) during regadenoson-induced maximal hyperemia (regadenoson 0.4 mg/5 mL administered as a single intravenous bolus over approximately 10 seconds, followed by a saline flush). Measurements are performed at baseline, 6 months, and 12 months. Change from baseline at each time point is calculated as the value at that time point minus the baseline value. The primary analysis time point is 12 months.

Secondary outcomes

• Change from baseline in mean coronary flow reserve (CFRmean) of the left anterior descending artery [Baseline, 6 months, and 12 months]: CFRmean is defined as the ratio of hyperemic to basal mean diastolic flow velocity (MDV) in the mid-to-distal left anterior descending artery, measured by transthoracic Doppler echocardiography (TTDE) during regadenoson-induced maximal hyperemia (regadenoson 0.4 mg/5 mL administered as a single intravenous bolus over approximately 10 seconds, followed by a saline flush). Measurements are performed at baseline, 6 months, and 12 months. Change from baseline at each time point is calculated as the value at that time point minus the baseline value.
• Change from baseline in Seattle Angina Questionnaire (SAQ) score [Baseline, 3, 6, 9, and 12 months]: The Seattle Angina Questionnaire (SAQ) is a disease-specific health status measure for coronary artery disease. Each of its five domains (Physical Limitation, Anginal Stability, Anginal Frequency, Treatment Satisfaction, and Disease Perception/Quality of Life) is scored from 0 to 100, with higher scores indicating better health status (fewer symptoms/limitations). Change from baseline is calculated as the score at each time point minus the baseline score.
• Change from baseline in CCS angina class [Baseline, 3, 6, 9, and 12 months]: Angina severity is classified by the Canadian Cardiovascular Society (CCS) angina classification, ranging from Class I (angina only during strenuous exertion; least severe) to Class IV (angina at rest; most severe), where a higher class indicates a worse outcome. Improvement is defined as a reduction of ≥1 CCS class grade from baseline at each assessment time point.
• Incidence of major adverse cardiovascular events (MACE) within 12 months [From randomization/enrollment through 12 months]: MACE is a composite endpoint defined as the occurrence of any of the following components during the 12-month follow-up period: (1) cardiovascular death; (2) non-fatal myocardial infarction; (3) hospitalization for angina pectoris; and (4) hospitalization for heart failure.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Male or female participants aged 18 to 80 years (inclusive).
2. Within 6 months prior to randomization, coronary computed tomography angiography(CTA) or angiography demonstrating coronary stenosis ≤50%, or residual stenosis ≤50% after revascularization, or stenosis >50% with FFR >0.8.
3. CFR of the left anterior descending（LAD） artery measured by transthoracic Doppler echocardiography（TTE） <2.5.
4. Clinical diagnosis of CMVD, meeting any one of the following categories:

（1）Ischemia-related CMVD:

* Myocardial Ischemia with Non-Obstructive Coronary Arteries: Presence of symptoms consistent with chronic myocardial ischemia, together with objective evidence of reduced CFR and/or coronary microvascular spasm, in the absence of obstructive epicardial coronary artery disease.

  ②Myocardial Ischemia with obstructive Coronary Arteries: Following successful treatment of epicardial coronary artery stenosis with residual luminal stenosis ≤50%, TTE demonstrates persistent impairment of CFR <2.5 in the LAD.

  （2）Myocardial infarction-related CMVD:
* Myocardial infarction with non-obstructive coronary arteries (MINOCA): Coronary CTA or invasive coronary angiography demonstrates coronary artery stenosis ≤50%.

  * Myocardial infarction with obstructive coronary arteries (MIOCA): Typically associated with coronary microvascular obstruction, including but not limited to ST-segment elevation myocardial infarction (STEMI) complicated by coronary microvascular obstruction.

    5.Voluntary provision of written informed consent by the subject or legal representative.

Exclusion Criteria:

1. Persistent or permanent atrial fibrillation; clinically significant bradyarrhythmias (including severe sinus bradycardia or second-degree type II or higher atrioventricular block); sinus node dysfunction; uncontrolled chronic obstructive pulmonary disease (COPD); or uncontrolled bronchial asthma.
2. Severe valvular heart disease, cardiomyopathy, LVEF <50%, Takayasu arteritis, or aortic dissection.
3. Acute myocardial infarction within 1 month prior to randomization.
4. Unstable angina within 1 week prior to randomization.
5. Hemorrhagic stroke within the previous 6 months.
6. Uncontrolled hypertension, defined as systolic blood pressure (SBP) >150 mmHg and/or diastolic blood pressure (DBP) >90 mmHg despite appropriate medical management.
7. Hepatic dysfunction (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] >2 ×ULN) or renal impairment (estimated glomerular filtration rate \[eGFR\] ≤60 mL/min/1.73m²).
8. Pregnant, planning pregnancy, or breastfeeding.
9. Clinically significant respiratory, gastrointestinal, hematologic, infectious, immunologic, endocrine, neurological, psychiatric, or malignant diseases that, in the investigator's judgment, may pose an unacceptable risk to the participant or interfere with study participation.
10. Current requirement for anticoagulation therapy with warfarin; current use of nicorandil; or concomitant treatment with other traditional Chinese medicine (TCM) preparations.
11. Active bleeding or clinically significant bleeding tendency, including platelet count <50×10⁹/L or documented coagulation disorders.
12. Known or suspected hypersensitivity to intra-arterial contrast media, blood or blood products, or the investigational medicinal product.
13. Participation in another interventional clinical trial within 3 months prior to randomization or concurrent participation in another clinical study.
14. Any other medical condition or circumstance that, in the opinion of the investigator, would make the participant unsuitable for enrollment in this study.

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• Yun Zhang, MD,PhD, Principal investigator, Department of Cardiology,Qilu Hospital of Shandong University