{"paper_id":"06128d67-c8ec-4a31-9cf3-3c854ff15bcc","body_text":"Efficacy and Safety of Shexiang Tongxin Dropping Pill in Angina Patients with Coronary Slow Flow Phenomenon: A Multi-center, Randomized, Double-blind, Placebo-controlled Phase IV Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Efficacy and Safety of Shexiang Tongxin Dropping Pill in Angina Patients with Coronary Slow Flow Phenomenon: A Multi-center, Randomized, Double-blind, Placebo-controlled Phase IV Trial Na Li, Zhiqing He, Yasha Chen, Liansheng Wang, Ye Gu, Shenghuang Wang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6600627/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Previous preclinical studies suggested that Shexiang Tongxin Dropping Pill (STDP) would be effective for coronary slow flow phenomenon (CSFP), but its clinical efficacy and safety remain uncertain. A multicenter, randomized, controlled phase IV trial was implemented to enroll 200 participants diagnosed with angina and CSFP between July 2016 and August 2020 to examine the drug’s effectiveness and safety. The analysis revealed that corrected TIMI frame count (CTFC) values in left anterior descending(LAD) and left circumflex(LCX) arteries in STDP group could be decreased, respectively (both p <0.01), whereas no significant changes were seen with placebo; between group differences were significant for both LAD (p = 0.008) and LCX (p = 0.044). Furthermore, STDP was well tolerated. Taken together, the results demonstrated STDP could significantly improve coronary blood flow and maintain an excellent safety profile, making it a favorable option in clinic for angina patients with CSFP. Trial registration The trial was registered in Chinese Clinical Trial Registry (ID: ChiCTR-IPR-16008950) Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases Health sciences/Diseases/Cardiovascular diseases/Vascular diseases/Coronary artery disease and stable angina/Ischaemia Shexiang Tongxin Dropping Pills coronary slow flow phenomenon corrected TIMI frame count angina Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Highlights Current clinical evidence supporting effective management strategies for coronary slow flow phenomenon (CSFP) remains limited. This multi-center, randomized, placebo-controlled trial evaluated the efficacy, safety and tolerability of Shexiang Tongxin Dropping Pill (STDP) in angina patients with CSFP. A significant improvement in coronary blood flow was observed in the left anterior descending (LAD) and left circumflex (LCX) arteries following four weeks of treatment. Oral administration of STDP demonstrated well tolerability and safety. Background The coronary slow flow phenomenon (CSFP) was first reported by Tambe et al. 1 in 1972, who observed delayed vascular opacification during coronary angiography. CSFP is characterized by the presence of delayed distal perfusion visualized on coronary angiography, even in the absence of significant coronary lesions (stenosis <40%) 2 . The clinical burden of CSFP is considerable; its incidence among patients undergoing conventional coronary angiography ranges from 1% to 7%, and among thos e with clinically suspected angina, it varies between 5.5% and 34.0% 3,4 . A substantial body of research has established a significant association between slow coronary blood flow and poor clinical outcomes 5-7 . CSFP can precipitate severe adverse cardiovascular events, including myocardial infarction and sudden death. The management of CSFP is particularly challenging due to the absence of standardized treatment guidelines and the limited efficacy of current medications. Presently, therapeutic strategies are primarily aimed at enhancing microcirculatory function through a multimodal approach. In recent years, the integration of modern medical technology and traditional Chinese medicine has brought remarkable advance in the management of CSFP. Shexiang Tongxin Dropping Pill (STDP), a traditional Chinese medicine approved by the Chinese FDA in 2008, is composed of Salvia miltiorrhiza Bunge, Moschus, Bovis Calculus Artifactus, Bufonis Venenum, Borneolum Syntheticum, total ginsenoside of ginseng stems and leaves, and Fel Ursi. Based on the retention time and MS spectra, forty-one constituents were identified in STDP, including bile acids, salvianolic acids, triterpene saponins, bufadienolides, and tanshinones 8 . STDP has been widely used in China for the treatment of stable coronary heart disease. Recent investigations have demonstrated that STDP offers beneficial effects such as endothelial and vascular protection, plaque stabilization, and lipid metabolism modulation, in addition to reducing the expression of serum inflammatory and oxidative stress factors 9-11 . Based on these mechanistic insights, a pilot trial involving 22 CSFP patients was conducted, revealing rapid improvements in coronary blood flow as early as five minutes following the sublingual administration of STDP 12 . Therefore, we performed a randomized, double-blind, placebo-controlled clinical trial to rigorously evaluate the long-term efficacy and safety of STDP for angina patients with CSFP in real-world clinical settings. Methods Study design and Participants A randomized, double-blind, multicenter, placebo-controlled trial was conducted across ten centers in China between July 2016 and August 2020. A detailed overview of the study design is presented in the flowchart (Figure 1). The trial was performed at the following sites: 1) Shanghai Changzheng Hospital, Shanghai; 2) Shanghai Xinhua Hospital, Shanghai; 3) Yueyang Hospital of Integrated of Traditional Chinese and Western Medicine, Shanghai; 4) Ningbo First Hospital, Ningbo; 5) Fujian Provincial Hospital, Fuzhou; 6) The First Affiliated Hospital of Sun Yat-sen University, Guangzhou; 7) The Third Xiangya Hospital of Central South University, Changsha; 8) Renmin Hospital of Wuhan University, Wuhan; 9) Puai Hospital of Wuhan City, Wuhan; 10) Northern Jiangsu People's Hospital, Yangzhou(Figure 2). Patients aged 18 to 75 years who presented with angina or angina-like symptoms were screened for eligibility via coronary angiography. CSFP was diagnosed when at least one major coronary artery exhibited delayed perfusion on angiography, with the findings confirmed by both investigator and coordinator. Key exclusion criteria included poorly controlled hypertension, severe cardiac dysfunction or arrhythmia, severe infections, moderate to severe anemia, and severe primary diseases of the hepatic, renal, or hematopoietic systems. Additionally, pregnant or lactating women, patients with a history of recent surgery, those with bleeding tendencies within past four weeks were excluded (Supplemental Table 1). Reporting in this article followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The protocol was approved by the central Institutional Review Board of Shanghai Changzheng Hospital affiliated to the Naval Medical University (approval number: STDP-2016-V2.0), as well as by the local institutional review boards of each site if required. Written informed consent was obtained from all participants before enrollment. The coordinating investigator ensured effective oversight by regularly convening meetings— via teleconference or face-to-face — to review the status of the trial with all investigators. Data supporting the findings of this study are available from the corresponding author (L.C.) upon reasonable request. This diagram illustrates the screening, randomization, allocation, follow-up, and analysis processes of the randomized, double-blind, placebo-controlled, multicenter trial. A total of 200 participants were enrolled and randomly assigned to either the STDP group or the placebo group. The final analysis included 199 participants who completed the study. This map indicates the locations of the ten clinical centers across China where the trial was conducted. Each star represents a participating site involved in patient recruitment and data collection for the multicenter study. CSF Definition and Analysis At least four views of the left coronary artery and two views of the right coronary artery (RCA) were performed during coronary angiography. Coronary blood flow was quantitatively assessed using the thrombolysis in myocardial infarction frame count (TFC) technique on cineangiographic sequences recorded at 30 frames per second. The first frame count was defined as the frame in which concentrated dye completely occupied the proximal coronary artery lumen--making contact with both vessel borders--and exhibited forward motion. The last frame was designated when the leading edge of the contrast column initially reached the distal end. The distal end was defined as follows: for the left anterior descending artery (LAD), it was the distal bifurcation; for the left circumflex artery (LCX), it was the distal bifurcation of the segment with the longest total distance; and for the right coronary artery (RCA), it was the first branch of the posterolateral artery. CSFP was diagnosed when TFC > 27 in at least one coronary artery. The LAD frame counts were corrected by dividing by 1.7 to obtain the corrected TFC (CTFC) 13 . All angiograms were analyzed in the Angiographic Core Laboratory at Shanghai Changzheng Hospital. Two reviewers, along with a senior reviewer were blinded to clinical outcomes, simultaneously determined the frame counts. If the discrepancy between reviewers was ≤5 frames, the senior reviewer’s determination was accepted. In cases where the variation > 5 frames among any of the three readings, a consensus reading was performed by all three reviewers. If consensus could not be reached, the final frame count was determined by the director of the core laboratory. Randomisation The random allocation sequence indicating assignment to treatment or placebo group was generated in SAS [Strategic Applications Software], version 9.1.3) by statisticians from department of Statistics, Second Military Medical University. The sequence was sealed in envelopes and stored in the major study unit and statistic unit. These envelopes kept closed until the study end. Intervention Angiography was performed immediately upon arrival at the cardiac catheterization laboratory and repeated five minutes following the administration of four pills of STDP or placebo. Subsequently, patients in the STDP group received a regimen consisting of two pills (35 mg per pill; Inner Mongolia Conba Pharmaceutical Group, Co., Ltd., Inner Mongolia, China) administered three times daily over a period of four weeks. The placebo, identical in appearance and smell, was administered following the same schedule. Study Outcomes The primary outcome was the change in CTFC values in the LAD, LCX, and RCA before and after sublingual drug administration. Secondary endpoints included angina-specific health status, as measured by Seattle Angina Questionnaire (SAQ), as well as alterations in electrocardiogram (ECG) parameters. Adverse events (AEs) were documented in Case Report Forms throughout the trial, and their potential association with the study medication was carefully evaluated by the investigators. Major adverse cardiovascular events (MACE) were defined as a composite outcome consisting of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Additionally, vital signs such as heart rate and respiratory rate were recorded. Statistical Analysis The sample size calculation was based on mean CTFC values from a prior pilot study. Assuming SD of 9 for the change in CTFC values attributable to the intervention, it was estimated that 44 participants each group would be required to achieve 80% statistical power to detect a significant difference using a two-tailed test with an alpha level of 0.05. To accommodate an anticipated dropout rate of approximately 20%, the total sample size was increased to 108 participants. Statistical analyses were conducted according to the intent-to-treat (ITT) principle and were performed on the full analysis set (FAS). The FAS comprised all randomized participants who had completed baseline assessments and at least one post-baseline efficacy evaluation. An analysis of covariance (ANCOVA) was conducted for post-treatment CTFC while adjusting for pre-treatment CTFC. Means and standard deviations were used to summarize continuous data with a normal distribution, while medians and interquartile ranges were used for data with an un-normal distribution. Group comparisons for continuous variables were conducted by two-sample t-tests or Wilcoxon's Rank Sum tests for data depending on whether the data followed a normal distribution. Differences between pre- and post-treatment values within groups were assessed using paired t-tests or Wilcoxon's signed rank tests depending on whether the data followed a normal distribution. Categorical data comparisons were conducted using Chi-square tests, with Fisher's exact test applied when expected frequencies in any cell count below five. The angiographic features of CSFP were also compared between groups using the jvenn visualization tool 14 . All data analyses were performed using SAS software (version 9.4, SAS Institute, Inc., Cary, NC), and a p-value of less than 0.05 was considered statistically significant. Results Patient Characteristics A total of 199 patients were randomly assigned to either the STDP group (n = 100) or the placebo group (n = 99), with one patient withdrew consent (Figure 1). The mean age was 60.30 years in STDP group and 61.37 years in placebo group, with no significant difference between the two group (p = 0.435). The duration of chronic angina pectoris history was comparable between the two groups (11.00[95%CI:1.00,36.00] vs. 12.00[95%CI:1.00,36.50], p = 0.519). A significantly higher proportion of patients in the placebo group had diabetes compared to the STDP group (22.47% vs. 8.99%, p = 0.014). Other demographic and baseline characteristics, including etiological factors of CSF such as smoking, hypertension, and hyperlipidemia, as well as angiographic features, were balanced between the groups (p > 0.05) (Table1, Figure3). Furthermore, no statistically significant differences were observed in baseline oral medication usage between the groups. The proportions of patients using calcium channel blockers, beta-blockers, statins, ACE inhibitors, ARBs, antiplatelet agents, and long-acting nitroglycerin were comparable between two groups (p > 0.05) (Table 2). Table 1 Baseline Characteristics of participants in STDP and Placebo group Baseline Characteristics STDP group Placebo group p Age (years) 60.30 (10.42) 61.37(8.87) 0.435 Male 64 (64.00) 71 (71.72) 0.285 BMI (kg/m2) 24.94(3.08) 25.03(3.27) 0.845 Smoking 34 (36.17) 39 (42.39) 1.000 Hypertension 46 (51.11) 44 (49.44) 0.823 Diabetes 8 (8.99) 20 (22.47) 0.014 Hyperlipidemia 25 (25.25) 23 (23.23) 0.740 SBP (mmHg) 124.00 (110.00,135.00) 129.00 (116.00,138.00) 0.396 DBP (mmHg) 80.00 (74.00,87.00) 80.00 (71.00,89.00) 0.909 Heart rate (beat per minute) 72.00 (65.00,80.00) 70.00 (66.00,76.00) 0.305 Course of angina pectoris(months) 11.00 (1.00,36.00) 12.00 (1.00,36.50) 0.519 Data were presented as n (%), mean (SD) and median (95%CI). STDP, Shexiang Tongxin dropping Pill; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure Table 2 Baseline oral medication usage of participants in STDP and Placebo group Medications STDP group Placebo group p Calcium channel blocker 23 (23.00) 29 (29.29) 0.312 Beta-blocker 37 (37.00) 43 (43.43) 0.354 Statin 73 (73.00) 76 (76.76） 0.540 ACEI 14 (14.00) 10 (10.10) 0.398 ARB 18 (18.00) 18 (18.18) 0.973 Antiplatelet (aspirin and/or P2Y12 inhibitor) 74 (74.00) 78 (78.79) 0.426 Long-acting nitroglycerin 38 (38.00) 42 (42.42) 0.524 ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker Primary Outcomes Overall, a statistically significant difference in the average CTFC was observed between the two groups(p = 0.003). In the LAD branch, patients in the STDP group demonstrated a marked reduction in CTFC values, declining from 47.06 (95% CI: 39.08–58.24) at baseline to 42.94 (95% CI: 34.12–55.29) after 4 weeks of treatment. The mean change was -4.12 (95% CI: -10.59-0.59), which was statistically significant (p < 0.001). In contrast, the placebo group exhibited no significant change in LAD CTFC (p = 0.540). The between-group difference in LAD CTFC improvement was also statistically significant (p = 0.008). For the LCX branch, the STDP group showed a significant decrease in CTFC from 54.00 (95% CI: 40.71–66.00) at baseline to 48.00 (95% CI: 40.71–61.00) post-treatment, yielding a mean change of -4.00 (95% CI: -14.00-4.00; p = 0.001). The placebo group, however, did not exhibit a meaningful change (p = 0.343). A statistically significant difference was observed between the two groups in terms of LCX CTFC reduction (p = 0.044). In the case of the RCA branch, although a downward trend was observed in the STDP group (from 53.50 [95% CI: 39.00–72.86] to 53.00 [95% CI: 38.71–66.43]), the change of -1.00 (95% CI: -13.29-7.00) did not reach statistical significance (p = 0.082). Similarly, the placebo group exhibited a slight, non-significant increase in CTFC (p = 0.563), and the difference in change between groups was not statistically significant (p = 0.073) (Figure4, Figure 5). The CTFC values can be found in Table S2. Secondary Outcomes Significant within-group improvements were observed in both the STDP and placebo groups from baseline to 4-week after treatment across SAQ, including physical limitation, angina stability, angina frequency, treatment satisfaction, and illness perception (p < 0.001). However, the magnitude of improvement did not differ significantly between the two groups (p>0.05) (Figure 6). Regarding ECG parameters, no significant changes in ST segment depression were observed in either group (p= 0.351), with no significant difference between the groups (p= 0.702). In contrast, T-wave inversion significantly decreased in the placebo group at 4-week after treatment (p = 0.025), whereas the STDP group showed a non-significant increase (p = 0.105); notably, the between-group difference for T-wave inversion was statistically significant (p = 0.035). The SAQ scores and ECG parameters are presented in Table S3. Safety and Tolerability No MACE events occurred in all patients. The proportion of patients reporting at least one AE was similar between the STDP and placebo groups (22 [22.00%] vs. 25 [25.25%], respectively; p = 0.589). The most common adverse events were hyperlipidemia, circulatory and urinary-related symptoms and gastrointestinal symptoms (Table 3 ); none of these were considered treatment-related. Additionally, a total of 9 serious AEs occurred during the study period, with 7 in the placebo group and 2 in the STDP group. Among these, 2 serious AEs in the placebo group (drug allergy and multiple lacunar cerebral infarctions) were not definitively attributed to the study treatments, while the other 7 events (micronodular cirrhosis, bilateral cataracts, allergic dermatitis, sick sinus syndrome, pre-excitation syndrome, acute lower extremity arterial thrombosis, and benign nasopharyngeal tumors) were considered unrelated to treatment. Also, the post-administration vital signs did not differ significantly between the two groups (Table 4 ). Table 3 Summary of common AEs observed in the STDP and placebo groups Common AEs STDP group Placebo group Total Hyperlipidemia 8 3 11 Circulatory & Urinary-related Symptoms 3 9 6 Gastrointestinal Symptoms 3 5 8 Liver Function Abnormalities 2 4 6 Skin & Immune-related Symptoms 2 3 5 Neurological (fatigue and dizziness) 3 2 5 Table 4 Vital sign measurements following sublingual administration of STDP or placebo STDP group Placebo group p Heart rate 71.00(62.00,78.00) 69.00(61.00,78.00) 0.461 Respiratory Rate 18.00(16.00,20.00) 18.00(17.00,20.00) 0.942 SBP 119.00(104.00,130.00) 120.00(107.50,132.00) 0.590 DBP 80.00(73.00,92.00) 81.00(72.00,91.00) 0.962 Oxygen saturation 99.00(97.00,100.00) 99.00(98.00,100.00) 0.194 Discussion This study demonstrated that STDP could significantly improve coronary blood flow in patients with CSFP, particularly in LAD and LCX arteries, as evidenced by a significant reduction in CTFC compared with placebo. Also, no treatment-related AEs were identified, and the incidence of serious AEs was lower in the STDP group than in the placebo group. These findings suggest that STDP may offer potential benefits in improving coronary microvascular perfusion in angina patients with CSFP without compromising safety. Our study showed a significant reduction in CTFC of both LAD and LCX arteries within the STDP group, compared with the placebo group. Although CTFC of RCA branch did not exhibit a statistically significant improvement, a positive trend was nonetheless observed in the treatment group compared to the control group. Moreover, both groups showed enhancements across the SAQ. These findings align with previous studies. The pilot study 12 showed that 22 patients with slow coronary artery blood flow experienced a decrease in thrombolytic therapy frame counts for myocardial infarction after taking STDP, as evidenced by coronary angiography performed five minutes post-administration (p < 0.05). Also, Zhuang et al. 15 reported that the combination of STDP and metoprolol effectively alleviated angina symptoms, reduced myocardial ischemia, and delayed disease progression in 90 patients with coronary heart disease and angina pectoris. Additionally, another study discovered that the microcirculatory resistance index was lower in the observation group treated with STDP compared to the control group, and both SAQ and Canadian Cardiovascular Society (CCS) scores were superior (p< 0.05) 16 . Collectively, these results reinforce the efficacy of STDP in CSFP treatment, thereby providing robust support for clinical interventions. The pathogenesis of CSFP remains incompletely understood, while multiple studies have suggested potential associations with coronary microvascular dysfunction (CMD), endothelium-dependent vasodilatory abnormalities, abnormal blood cell morphology and function, and inflammatory responses 17 . It has been established that STDP treatment significantly decreases the pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), and oxidative stress markers such as malondialdehyde (MDA) 10,11,18 . Moreover, STDP enhances angiogenesis by upregulating of the PI3K/Akt/mTORC1 signaling pathway, which increases the release of vascular endothelial growth factor (VEGF-A) and facilitates endothelial cell proliferation and migration 19 . In CMD models, STDP improves endothelial function by inhibiting the Dectin-1/Syk/IRF5 and S1PR2/RhoA/ROCK signaling pathways, ultimately enhancing endothelial barrier function and reducing microvascular leakage 20,21 . Furthermore, studies in cerebral microvasculature have demonstrated that STDP both suppresses the TXNIP/NLRP3 inflammasome—restoring oxidative balance and blood–brain barrier integrity—and enhances endothelial cystathionine-γ-lyase (CSE) expression expression with H₂S production, contributing to the inactivation of P66shc, thereby restoring mitochondrial respiration and alleviating cerebral microvascular dysfunction 22,23 . Collectively, these mechanisms are closely linked to the observed improvements in CTFC and relief of angina symptoms in this study, thereby providing robust theoretical support for the further exploration and optimization of clinical treatment strategies. Our study has strong strengths. Firstly, it is a randomized, double-blind clinical trial, which can reduce the selection biases. Secondly, not only the immediate coronary flow changes assessed by angiography were compared, but also the angina symptoms and ECGs parameters were evaluated after administration of the drug for 2 months, which could give some added information of the safety and efficacy of the STDP. However, there are limitations to consider. Firstly, the current study was conducted in Chinese population, it is uncertain whether the effects of STDP would be expanded to other ethnic populations. Secondly, given the nature and clinical prognosis of CSFP and limited effective drugs, comparison with placebo might not be an ideal design for efficacy evaluation. Thirdly, the treatment period was limited to 4 weeks. Although the 4-week duration of the trial was in reference to several previous studies, the long-term efficacy and safety remain to be further investigated in the future. And the last one might be the sample size of our study, which would lead to no detection of the potential differences of MACEs by STDP in such patient subpopulation. References Tambe, A. A., Demany, M. A., Zimmerman, H. A. & Mascarenhas, E. Angina pectoris and slow flow velocity of dye in coronary arteries--a new angiographic finding. Am Heart J 84 , 66-71. Chalikias, G. & Tziakas, D. Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management. Angiology 72 , 808-818. Gomaa, A., Radwan, H. I. & Gad, M. M. Predictors of coronary slow flow in stable coronary artery disease. Journal of Indian College of Cardiology 7 , 109-115. Hawkins, B. M., Stavrakis, S., Rousan, T. A., Abu-Fadel, M. & Schechter, E. Coronary slow flow--prevalence and clinical correlations. Circ J 76 , 936-942. Mareai, R. M. et al. Prognostic implication of coronary slow flow assessed by cTFC in patients with myocardial infarction with Non-obstructive coronary arteries. Eur J Intern Med 108 , 74-80. Montone, R. A. et al. Coronary slow flow is associated with a worse clinical outcome in patients with Takotsubo syndrome. Heart 106 , 923-930. Wang, X. & Nie, S. P. The coronary slow flow phenomenon: characteristics, mechanisms and implications. Cardiovasc Diagn Ther 1 , 37-43. Chen, D. et al. Qualitative and Quantitative Analysis of the Major Constituents in Shexiang Tongxin Dropping Pill by HPLC-Q-TOF-MS/MS and UPLC-QqQ-MS/MS. Molecules 20 , 18597-18619. Lin, Y. J., Jiao, K. L., Liu, B., Fang, L. & Meng, S. Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial. J Integr Med 20 , 126-134. Liu, H. et al. Shexiang Tongxin dropping pill protects against sodium laurate-induced coronary microcirculatory dysfunction in rats. J Tradit Chin Med 41 , 89-97. Xiong, M. et al. Shexiang Tongxin dropping pill attenuates atherosclerotic lesions in ApoE deficient mouse model. J Ethnopharmacol 159 , 84-92. Wang, S. H. et al. Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow. Chin J Integr Med 25 , 360-365. Jespersen, L., Abildstrøm, S. Z., Peña, A., Hansen, P. R. & Prescott, E. Predictive value of the corrected TIMI frame count in patients with suspected angina pectoris but no obstructive coronary artery disease at angiography. Clin Res Cardiol 103 , 381-387. Bardou, P., Mariette, J., Escudié, F., Djemiel, C. & Klopp, C. jvenn: an interactive Venn diagram viewer. BMC Bioinformatics 15 , 293. X.H., Z., Y.H, F., J, L. & Y, X. Efficacy Observation of Shexiang Tongxin Dropping Pills Combined with Metoprolol in the Treatment of Coronary Heart Disease Angina. Modern Drugs and Clinics 33 , 1052-1055. W.L., T. et al. Improvement of Coronary Slow Flow by Shexiang Tongxin Dropping Pills. Advances in Clinical Medicine 10 . Karauzum, K. et al. The Systemic Immune-Inflammation Index May Predict the Coronary Slow Flow Better Than High-Sensitivity C-Reactive Protein in Patients Undergoing Elective Coronary Angiography. Cardiol Res Pract 2022 , 7344639. Bai, Y. et al. Efficacy of Shexiang Tongxin Dropping Pills in a Swine Model of Coronary Slow Flow. Front Physiol 13 , 913399. Lu, X. et al. Shexiang Tongxin Dropping Pills Promote Macrophage Polarization-Induced Angiogenesis Against Coronary Microvascular Dysfunction via PI3K/Akt/mTORC1 Pathway. Front Pharmacol 13 , 840521. Sun, Y. et al. Shexiang Tongxin dropping pills ameliorate myocardial ischemia-reperfusion injury progression via the S1PR2/RhoA/ROCK pathway. Journal of Traditional Chinese Medical Sciences 12 , 31-43. Cui, L. et al. Shexiang Tongxin Dropping Pill alleviates M1 macrophage polarization-induced inflammation and endothelial dysfunction to reduce coronary microvascular dysfunction via the Dectin-1/Syk/IRF5 pathway. J Ethnopharmacol 316 , 116742. Zhu, L. et al. Shexiang Tongxin Dropping Pills attenuate ischemic microvascular dysfunction via suppressing P66Shc-mediated mitochondrial respiration deficits. J Ethnopharmacol 346 , 119664. Zhu, L. et al. Shexiang Tongxin dropping pills protect against ischemic stroke-induced cerebral microvascular dysfunction via suppressing TXNIP/NLRP3 signaling pathway. J Ethnopharmacol 322 , 117567. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6600627\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":454994059,\"identity\":\"db3aea68-687e-40c8-840b-9ae1b5bfd4b8\",\"order_by\":0,\"name\":\"Na Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Naval Medical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Na\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":454994060,\"identity\":\"4e91c74f-e029-4f04-a27a-9abd37fcae06\",\"order_by\":1,\"name\":\"Zhiqing 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Gu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Puai Hospital of Wuhan City\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ye\",\"middleName\":\"\",\"lastName\":\"Gu\",\"suffix\":\"\"},{\"id\":454994064,\"identity\":\"061e7adb-2620-4b4e-b950-110b436f09e2\",\"order_by\":5,\"name\":\"Shenghuang Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ningbo First Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shenghuang\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":454994065,\"identity\":\"c72c2c4a-c151-4890-9d5f-c3093e049267\",\"order_by\":6,\"name\":\"Yachen Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shanghai Xinhua Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yachen\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":454994066,\"identity\":\"acf16183-a726-4769-bfeb-1e7d7c63058d\",\"order_by\":7,\"name\":\"Min Fan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shanghai University of Traditional Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Min\",\"middleName\":\"\",\"lastName\":\"Fan\",\"suffix\":\"\"},{\"id\":454994067,\"identity\":\"df7542ad-2508-4d85-b23a-b4e56cd79eff\",\"order_by\":8,\"name\":\"Bo Yang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Renmin Hospital of Wuhan University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Bo\",\"middleName\":\"\",\"lastName\":\"Yang\",\"suffix\":\"\"},{\"id\":454994068,\"identity\":\"24b47268-333b-49ad-9749-54c61bae880a\",\"order_by\":9,\"name\":\"Jianjiang Xu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Jiaxing Second Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jianjiang\",\"middleName\":\"\",\"lastName\":\"Xu\",\"suffix\":\"\"},{\"id\":454994069,\"identity\":\"c56b1cea-ef72-423c-9243-3424aa9d11ca\",\"order_by\":10,\"name\":\"Yansong Guo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fujian Province Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yansong\",\"middleName\":\"\",\"lastName\":\"Guo\",\"suffix\":\"\"},{\"id\":454994070,\"identity\":\"e5d0b150-3217-47a9-9725-118eb9b5c359\",\"order_by\":11,\"name\":\"Yu Cao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Xiangya Third Hospital of Central South University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yu\",\"middleName\":\"\",\"lastName\":\"Cao\",\"suffix\":\"\"},{\"id\":454994071,\"identity\":\"aed2130b-9f68-4399-ae27-74efc4e061eb\",\"order_by\":12,\"name\":\"Wei Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Guangzhou University of Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Wei\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":454994072,\"identity\":\"3377dfa9-68d4-4379-a478-8be984b796eb\",\"order_by\":13,\"name\":\"Chun Liang\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACCSB+YAAk2BkbgKQNDz97AxFaEkBamMFa0mQkew4QowXEYAZzD9sY3HDAr4N/do/Zg4QCuzx5Z+bGzwW/zvMw3GBg/PAxB48ld86YGyQYJBcbHmZslp7Zd5uHcXYDs+TMbbi1GEjkmEkkGDAnbmxmbJDm7bnNwyxzgI2Zl7CWepCW5t+8Ped42CQSiNJyOHE+M2ObNM+PAzw8hLRI3EgrA2o5nrgBqMWatyGZR4LnYDNev/DPSN4m8eFPdeL89vbHt3n+2NnbH28++OEjHi0IFx4AEoxtICY4TokA8mB1f4hTPApGwSgYBSMLAACDPk3zPauVKAAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Naval Medical University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Chun\",\"middleName\":\"\",\"lastName\":\"Liang\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-05-06 08:23:25\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6600627/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6600627/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":82794609,\"identity\":\"38996910-f1d0-488f-8cc0-5cc33b6c398c\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:30:34\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":161231,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eFlowchart of the study design and participant enrollment.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis diagram illustrates the screening, randomization, allocation, follow-up, and analysis processes of the randomized, double-blind, placebo-controlled, multicenter trial. A total of 200 participants were enrolled and randomly assigned to either the STDP group or the placebo group. The final analysis included 199 participants who completed the study.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/8fb6c7a973045b65ccf78b01.png\"},{\"id\":82799214,\"identity\":\"667f3427-9280-497a-82ab-4574559ddd2e\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:54:35\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":482694,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eGeographic distribution of study sites.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis map indicates the locations of the ten clinical centers across China where the trial was conducted. Each star represents a participating site involved in patient recruitment and data collection for the multicenter study.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/f189854776435bb0bc063012.png\"},{\"id\":82794623,\"identity\":\"6fc3a1f3-a8b5-4f55-a963-91574b150ab3\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:30:35\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":143327,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eVenn‐based jvenn visualization of CTFC improvements in coronary branches for the Placebo (A) and STDP (B) group\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/3ffec321cc5cbe0dc9084458.png\"},{\"id\":82794612,\"identity\":\"00005b31-0793-422d-94d1-39c446cefae3\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:30:35\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":535451,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eChanges in CTFC in the LAD, LCX, and RCA branches after 4 weeks of treatment.\\u003c/strong\\u003eError plots show the median CTFC values at baseline and at 4-week follow-up for both the STDP and placebo groups. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/9af248d91c71327b865d37d9.png\"},{\"id\":82797752,\"identity\":\"0eaf6fd7-cf8a-4ed1-a9a6-b505cb655c94\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:46:35\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":91196,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eRadar chart illustrating the differences in CTFC improvement across LAD, LCX, and RCA branches between the STDP and placebo groups.\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/8fe7dbe95a592fe385b04698.png\"},{\"id\":82796111,\"identity\":\"d7cdf450-d355-47b7-97ba-cb07a1ab1681\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:38:35\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":611459,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSAQ scores across five domains before and after 4 weeks of treatment.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eError plots display the scores for physical limitation, angina stability, angina frequency, treatment satisfaction, and illness perception in both the STDP and placebo groups. ***p \\u0026lt; 0.001\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/cc771fbba5acca9e61d37632.png\"},{\"id\":82799733,\"identity\":\"24813f17-33c6-4495-9fc7-0cde4eebb92f\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 11:02:35\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2861744,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/4b0a232f-a162-4495-862b-8d2fbea74124.pdf\"},{\"id\":82797750,\"identity\":\"18c3f368-f9cb-4387-9f74-d2670c6ac100\",\"added_by\":\"auto\",\"created_at\":\"2025-05-15 10:46:35\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":20687,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SUPPLEMENTALMATERIAL.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6600627/v1/564741b4526d4070cda68178.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Efficacy and Safety of Shexiang Tongxin Dropping Pill in Angina Patients with Coronary Slow Flow Phenomenon: A Multi-center, Randomized, Double-blind, Placebo-controlled Phase IV Trial\",\"fulltext\":[{\"header\":\"Highlights\",\"content\":\"\\u003cul start=\\\"50\\\"\\u003e\\n \\u003cli\\u003eCurrent clinical evidence supporting effective management strategies for coronary slow flow phenomenon (CSFP) remains limited. This multi-center, randomized, placebo-controlled trial evaluated the efficacy, safety and tolerability of Shexiang Tongxin Dropping Pill (STDP) in angina patients with CSFP.\\u003c/li\\u003e\\n \\u003cli\\u003eA significant improvement in coronary blood flow was observed in the left anterior descending (LAD) and left circumflex (LCX) arteries following four weeks of treatment.\\u003c/li\\u003e\\n \\u003cli\\u003eOral administration of STDP demonstrated well tolerability and safety.\\u003c/li\\u003e\\n\\u003c/ul\\u003e\"},{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eThe coronary slow flow phenomenon (CSFP) was first reported by Tambe et al. \\u003csup\\u003e1\\u003c/sup\\u003ein 1972, who observed delayed vascular opacification during coronary angiography. CSFP is characterized by the presence of delayed distal perfusion visualized on coronary angiography, even in the absence of significant coronary lesions (stenosis \\u0026lt;40%)\\u003csup\\u003e2\\u003c/sup\\u003e. The clinical burden of CSFP is considerable; its incidence among patients undergoing conventional coronary angiography ranges from 1% to 7%, and among thos\\u003cu\\u003ee\\u003c/u\\u003e with clinically suspected angina, it varies between 5.5% and 34.0%\\u003csup\\u003e3,4\\u003c/sup\\u003e.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eA substantial body of research has established a significant association between slow coronary blood flow and poor clinical outcomes\\u003csup\\u003e5-7\\u003c/sup\\u003e. CSFP can precipitate severe adverse cardiovascular events, including myocardial infarction and sudden death. The management of CSFP is particularly challenging due to the absence of standardized treatment guidelines and the limited efficacy of current medications. Presently, therapeutic strategies are primarily aimed at enhancing microcirculatory function through a multimodal approach.\\u003c/p\\u003e\\n\\u003cp\\u003eIn recent years, the integration of modern medical technology and traditional Chinese medicine has brought remarkable advance in the management of CSFP. Shexiang Tongxin Dropping Pill (STDP), a traditional Chinese medicine approved by the Chinese FDA in 2008, is composed of Salvia miltiorrhiza Bunge, Moschus, Bovis Calculus Artifactus, Bufonis Venenum, Borneolum Syntheticum, total ginsenoside of ginseng stems and leaves, and Fel Ursi. Based on the retention time and MS spectra, forty-one constituents were identified in STDP, including bile acids, salvianolic acids, triterpene saponins, bufadienolides, and tanshinones\\u003csup\\u003e8\\u003c/sup\\u003e. STDP has been widely used in China for the treatment of stable coronary heart disease. Recent investigations have demonstrated that STDP offers beneficial effects such as endothelial and vascular protection, plaque stabilization, and lipid metabolism modulation, in addition to reducing the expression of serum inflammatory and oxidative stress factors\\u003csup\\u003e9-11\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eBased on these mechanistic insights, a pilot trial involving 22 CSFP patients was conducted, revealing rapid improvements in coronary blood flow as early as five minutes following the sublingual administration of STDP\\u003csup\\u003e12\\u003c/sup\\u003e. Therefore, we performed a randomized, double-blind, placebo-controlled clinical trial to rigorously evaluate the long-term efficacy and safety of STDP for angina patients with CSFP in real-world clinical settings.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eStudy design and Participants\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA randomized, double-blind, multicenter, placebo-controlled trial was conducted across ten centers in China between July 2016 and August 2020. A detailed overview of the study design is presented in the flowchart (Figure 1). The trial was performed at the following sites: 1) Shanghai Changzheng Hospital, Shanghai; 2) Shanghai Xinhua Hospital, Shanghai; 3) Yueyang Hospital of Integrated of Traditional Chinese and Western Medicine, Shanghai; 4) Ningbo First Hospital, Ningbo; 5) Fujian Provincial Hospital, Fuzhou; 6) The First Affiliated Hospital of Sun Yat-sen University, Guangzhou; 7) The Third Xiangya Hospital of Central South University, Changsha; 8) Renmin Hospital of Wuhan University, Wuhan; 9) Puai Hospital of Wuhan City, Wuhan; 10) Northern Jiangsu People\\u0026apos;s Hospital, Yangzhou(Figure 2).\\u003c/p\\u003e\\n\\u003cp\\u003ePatients aged 18 to 75 years who presented with angina or angina-like symptoms were screened for eligibility via coronary angiography. CSFP was diagnosed when at least one major coronary artery exhibited delayed perfusion on angiography, with the findings confirmed by both investigator and coordinator. Key exclusion criteria included poorly controlled hypertension, severe cardiac dysfunction or arrhythmia, severe infections, moderate to severe anemia, and severe primary diseases of the hepatic, renal, or hematopoietic systems. Additionally, pregnant or lactating women, patients with a history of recent surgery, those with bleeding tendencies within past four weeks were excluded (Supplemental Table 1).\\u003c/p\\u003e\\n\\u003cp\\u003eReporting in this article followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The protocol was approved by the central Institutional Review Board of Shanghai Changzheng Hospital affiliated to the Naval Medical University (approval number: STDP-2016-V2.0), as well as by the local institutional review boards of each site if required. Written informed consent was obtained from all participants before enrollment. The coordinating investigator ensured effective oversight by regularly convening meetings\\u0026mdash; via teleconference or face-to-face \\u0026mdash; to review the status of the trial with all investigators. Data supporting the findings of this study are available from the corresponding author (L.C.) upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003eThis diagram illustrates the screening, randomization, allocation, follow-up, and analysis processes of the randomized, double-blind, placebo-controlled, multicenter trial. A total of 200 participants were enrolled and randomly assigned to either the STDP group or the placebo group. The final analysis included 199 participants who completed the study.\\u003c/p\\u003e\\n\\u003cp\\u003eThis map indicates the locations of the ten clinical centers across China where the trial was conducted. Each star represents a participating site involved in patient recruitment and data collection for the multicenter study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eCSF Definition and Analysis\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAt least four views of the left coronary artery and two views of the right coronary artery (RCA) were performed during coronary angiography. Coronary blood flow was quantitatively assessed using the thrombolysis in myocardial infarction frame count (TFC) technique on cineangiographic sequences recorded at 30 frames per second. The first frame count was defined as the frame in which concentrated dye completely occupied the proximal coronary artery lumen--making contact with both vessel borders--and exhibited forward motion. The last frame was designated when the leading edge of the contrast column initially reached the distal end. The distal end was defined as follows: for the left anterior descending artery (LAD), it was the distal bifurcation; for the left circumflex artery (LCX), it was the distal bifurcation of the segment with the longest total distance; and for the right coronary artery (RCA), it was the first branch of the posterolateral artery. CSFP was diagnosed when TFC \\u0026gt; 27 in at least one coronary artery. The LAD frame counts were corrected by dividing by 1.7 to obtain the corrected TFC (CTFC)\\u003csup\\u003e13\\u003c/sup\\u003e .\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAll angiograms were analyzed in the Angiographic Core Laboratory at Shanghai Changzheng Hospital. Two reviewers, along with a senior reviewer were blinded to clinical outcomes, simultaneously determined the frame counts. If the discrepancy between reviewers was \\u0026le;5 frames, the senior reviewer\\u0026rsquo;s determination was accepted. In cases where the variation \\u0026gt; 5 frames among any of the three readings, a consensus reading was performed by all three reviewers. If consensus could not be reached, the final frame count was determined by the director of the core laboratory.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eRandomisation\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe random allocation sequence indicating assignment to treatment or placebo group was generated in SAS [Strategic Applications Software], version 9.1.3) by statisticians from department of Statistics, Second Military Medical University. The sequence was sealed in envelopes and stored in the major study unit and statistic unit. These envelopes kept closed until the study end.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eIntervention\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAngiography was performed immediately upon arrival at the cardiac catheterization laboratory and repeated five minutes following the administration of four pills of STDP or placebo. Subsequently, patients in the STDP group received a regimen consisting of two pills (35 mg per pill; Inner Mongolia Conba Pharmaceutical Group, Co., Ltd., Inner Mongolia, China) administered three times daily over a period of four weeks. The placebo, identical in appearance and smell, was administered following the same schedule.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eStudy Outcomes\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe primary outcome was the change in CTFC values in the LAD, LCX, and RCA before and after sublingual drug administration. Secondary endpoints included angina-specific health status, as measured by Seattle Angina Questionnaire (SAQ), as well as alterations in electrocardiogram (ECG) parameters.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAdverse events (AEs) were documented in Case Report Forms throughout the trial, and their potential association with the study medication was carefully evaluated by the investigators. Major adverse cardiovascular events (MACE) were defined as a composite outcome consisting of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Additionally, vital signs such as heart rate and respiratory rate were recorded.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eStatistical Analysis\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe sample size calculation was based on mean CTFC values from a prior pilot study. Assuming SD of 9 for the change in CTFC values attributable to the intervention, it was estimated that 44 participants each group would be required to achieve 80% statistical power to detect a significant difference using a two-tailed test with an alpha level of 0.05. To accommodate an anticipated dropout rate of approximately 20%, the total sample size was increased to 108 participants.\\u003c/p\\u003e\\n\\u003cp\\u003eStatistical analyses were conducted according to the intent-to-treat (ITT) principle and were performed on the full analysis set (FAS). The FAS comprised\\u0026nbsp;all randomized participants who had completed baseline assessments and at least one post-baseline efficacy evaluation.\\u0026nbsp;An analysis of covariance (ANCOVA) was conducted for post-treatment CTFC while adjusting for pre-treatment CTFC. Means and standard deviations were used to summarize continuous data with a normal distribution, while medians and interquartile ranges were used for data with an un-normal distribution.\\u0026nbsp;Group comparisons for continuous variables were conducted by two-sample t-tests or Wilcoxon\\u0026apos;s Rank Sum tests for data depending on whether the data followed a normal distribution.\\u0026nbsp;Differences between pre- and post-treatment values within groups were assessed using paired t-tests or Wilcoxon\\u0026apos;s signed rank tests depending on whether the data followed a normal distribution.\\u0026nbsp;Categorical data comparisons were conducted using Chi-square tests, with Fisher\\u0026apos;s exact test applied when expected frequencies in any cell count below five. The angiographic features of CSFP were also compared between groups using the jvenn visualization tool\\u003csup\\u003e14\\u003c/sup\\u003e. All data analyses were performed using SAS software (version 9.4, SAS Institute, Inc., Cary, NC), and a p-value of less than 0.05 was considered statistically significant.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePatient Characteristics\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 199 patients were randomly assigned to either the STDP group (n = 100) or the placebo group (n = 99), with one patient withdrew consent (Figure 1). The mean age was 60.30 years in STDP group and 61.37 years in placebo group, with no significant difference between the two group (p = 0.435). The duration of chronic angina pectoris history was comparable between the two groups (11.00[95%CI:1.00,36.00] vs. 12.00[95%CI:1.00,36.50], p = 0.519). A significantly higher proportion of patients in the placebo group had diabetes compared to the STDP group (22.47% vs. 8.99%, p = 0.014). Other demographic and baseline characteristics, including etiological factors of CSF such as smoking, hypertension, and hyperlipidemia, as well as angiographic features, were balanced between the groups (p \\u0026gt; 0.05) (Table1, Figure3).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eFurthermore, no statistically significant differences were observed in baseline oral medication usage between the groups. The proportions of patients using calcium channel blockers, beta-blockers, statins, ACE inhibitors, ARBs, antiplatelet agents, and long-acting nitroglycerin were comparable between two groups (p \\u0026gt; 0.05) (Table 2).\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1 Baseline Characteristics of participants in STDP and\\u0026nbsp;Placebo group\\u003c/p\\u003e\\n\\u003cdiv\\u003e\\n \\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"96%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eBaseline Characteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003eSTDP group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003ePlacebo group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003ep\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eAge (years)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e60.30 (10.42)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e61.37(8.87)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.435\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eMale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e64 (64.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e71 (71.72)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.285\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eBMI (kg/m2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e24.94(3.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e25.03(3.27)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.845\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eSmoking\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e34 (36.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e39 (42.39)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e1.000\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eHypertension\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e46 (51.11)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e44 (49.44)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.823\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eDiabetes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e8 (8.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e20 (22.47)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.014\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eHyperlipidemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e25 (25.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e23 (23.23)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.740\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eSBP (mmHg)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e124.00 (110.00,135.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e129.00\\u003c/p\\u003e\\n \\u003cp\\u003e(116.00,138.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.396\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eDBP (mmHg)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e80.00\\u003c/p\\u003e\\n \\u003cp\\u003e(74.00,87.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e80.00\\u003c/p\\u003e\\n \\u003cp\\u003e(71.00,89.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.909\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eHeart rate (beat per minute)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e72.00\\u003c/p\\u003e\\n \\u003cp\\u003e(65.00,80.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e70.00\\u003c/p\\u003e\\n \\u003cp\\u003e(66.00,76.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.305\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eCourse of angina pectoris(months)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 29px;\\\"\\u003e\\n \\u003cp\\u003e11.00\\u003c/p\\u003e\\n \\u003cp\\u003e(1.00,36.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34px;\\\"\\u003e\\n \\u003cp\\u003e12.00\\u003c/p\\u003e\\n \\u003cp\\u003e(1.00,36.50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 10px;\\\"\\u003e\\n \\u003cp\\u003e0.519\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd height=\\\"34\\\" style=\\\"width: 0px;\\\"\\u003e\\u003cbr\\u003e\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003eData were presented as n (%), mean (SD) and median (95%CI). STDP, Shexiang Tongxin dropping Pill; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2 Baseline oral medication usage of participants in STDP and Placebo group\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eMedications\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eSTDP group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003ePlacebo group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003ep\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eCalcium channel blocker\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e23 (23.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e29 (29.29)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.312\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eBeta-blocker\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e37 (37.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e43 (43.43)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.354\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eStatin\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e73 (73.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e76 (76.76）\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.540\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eACEI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e14 (14.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e10 (10.10)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.398\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eARB\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e18 (18.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e18 (18.18)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.973\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eAntiplatelet (aspirin and/or P2Y12 inhibitor)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e74 (74.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e78 (78.79)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.426\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003eLong-acting nitroglycerin\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e38 (38.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e42 (42.42)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd\\u003e\\n \\u003cp\\u003e0.524\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePrimary Outcomes\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOverall, a statistically significant difference in the average CTFC was observed between the two groups(p = 0.003). In the LAD branch, patients in the STDP group demonstrated a marked reduction in CTFC values, declining from 47.06 (95% CI: 39.08\\u0026ndash;58.24) at baseline to 42.94 (95% CI: 34.12\\u0026ndash;55.29) after 4 weeks of treatment. The mean change was -4.12 (95% CI: -10.59-0.59), which was statistically significant (p \\u0026lt; 0.001). In contrast, the placebo group exhibited no significant change in LAD CTFC (p = 0.540). The between-group difference in LAD CTFC improvement was also statistically significant (p = 0.008). For the\\u0026nbsp;LCX branch, the STDP group showed a significant decrease in CTFC from 54.00 (95% CI: 40.71\\u0026ndash;66.00) at baseline to 48.00 (95% CI: 40.71\\u0026ndash;61.00) post-treatment, yielding a mean change of -4.00 (95% CI: -14.00-4.00; p = 0.001). The placebo group, however, did not exhibit a meaningful change (p = 0.343). A statistically significant difference was observed between the two groups in terms of LCX CTFC reduction (p = 0.044). In the case of the\\u0026nbsp;RCA branch, although a downward trend was observed in the STDP group (from 53.50 [95% CI: 39.00\\u0026ndash;72.86] to 53.00 [95% CI: 38.71\\u0026ndash;66.43]), the change of -1.00 (95% CI: -13.29-7.00) did not reach statistical significance (p = 0.082). Similarly, the placebo group exhibited a slight, non-significant increase in CTFC (p = 0.563), and the difference in change between groups was not statistically significant (p = 0.073) (Figure4, Figure 5). The CTFC values can be found in Table S2.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eSecondary Outcomes\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eSignificant within-group improvements were observed in both the STDP and placebo groups from baseline to 4-week after treatment across SAQ, including physical limitation, angina stability, angina frequency, treatment satisfaction, and illness perception (p \\u0026lt; 0.001). However, the magnitude of improvement did not differ significantly between the two groups (p\\u0026gt;0.05) (Figure 6).\\u003c/p\\u003e\\n\\u003cp\\u003eRegarding ECG parameters, no significant changes in ST segment depression were observed in either group (p= 0.351), with no significant difference between the groups (p= 0.702). In contrast, T-wave inversion significantly decreased in the placebo group at 4-week after treatment (p\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003e= 0.025), whereas the STDP group showed a non-significant increase (p = 0.105); notably, the between-group difference for T-wave inversion was statistically significant (p = 0.035). The SAQ scores and ECG parameters are presented in Table S3.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eSafety and Tolerability\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNo MACE events occurred in all patients. The proportion of patients reporting at least one AE\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003ewas similar between the STDP and placebo groups (22 [22.00%] vs. 25 [25.25%], respectively;\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003ep = 0.589). The most common adverse events were hyperlipidemia, circulatory and urinary-related symptoms and gastrointestinal symptoms (Table \\u003cins cite=\\\"mailto:GY\\\" datetime=\\\"2025-05-06T09:00\\\"\\u003e3\\u003c/ins\\u003e); none of these were considered treatment-related. Additionally, a total of 9 serious AEs occurred during the study period, with 7 in the placebo group and 2 in the STDP group. Among these, 2 serious AEs in the placebo group (drug allergy and multiple lacunar cerebral infarctions) were not definitively attributed to the study treatments, while the other 7 events (micronodular cirrhosis, bilateral cataracts, allergic dermatitis, sick sinus syndrome, pre-excitation syndrome, acute lower extremity arterial thrombosis, and benign nasopharyngeal tumors) were considered unrelated to treatment. Also, the post-administration vital signs did not differ significantly between the two groups (Table \\u003cins cite=\\\"mailto:GY\\\" datetime=\\\"2025-05-06T09:01\\\"\\u003e4\\u003c/ins\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eTable 3 Summary of common AEs observed in the STDP and placebo groups\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"100%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eCommon AEs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003eSTDP group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003ePlacebo group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003eTotal\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eHyperlipidemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e11\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eCirculatory \\u0026amp; Urinary-related Symptoms\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eGastrointestinal Symptoms\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eLiver Function Abnormalities\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eSkin \\u0026amp; Immune-related Symptoms\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003eNeurological (fatigue and dizziness)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 11px;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cbr\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTable 4 Vital sign measurements following sublingual administration of STDP or placebo\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"100%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003eSTDP group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003ePlacebo group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003ep\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eHeart rate\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e71.00(62.00,78.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e69.00(61.00,78.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003e0.461\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eRespiratory Rate\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e18.00(16.00,20.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e18.00(17.00,20.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003e0.942\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eSBP\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e119.00(104.00,130.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e120.00(107.50,132.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003e0.590\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eDBP\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e80.00(73.00,92.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e81.00(72.00,91.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003e0.962\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 26px;\\\"\\u003e\\n \\u003cp\\u003eOxygen saturation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e99.00(97.00,100.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 31px;\\\"\\u003e\\n \\u003cp\\u003e99.00(98.00,100.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 9px;\\\"\\u003e\\n \\u003cp\\u003e0.194\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThis study demonstrated that STDP could significantly improve coronary blood flow in patients with CSFP, particularly in LAD and LCX arteries, as evidenced by a significant reduction in CTFC compared with placebo. Also, no treatment-related AEs were identified, and the incidence of serious AEs was lower in the STDP group than in the placebo group. These findings suggest that STDP may offer potential benefits in improving coronary microvascular perfusion in angina\\u0026nbsp;patients with CSFP without compromising safety.\\u003c/p\\u003e\\n\\u003cp\\u003eOur study showed a significant reduction in CTFC of both LAD and LCX arteries within the STDP group, compared with the placebo group. Although CTFC of RCA branch did not exhibit a statistically significant improvement, a positive trend was nonetheless observed in the treatment group compared to the control group. Moreover, both groups showed enhancements across the SAQ. These findings align with previous studies. The pilot study\\u003csup\\u003e12\\u003c/sup\\u003eshowed that 22 patients with slow coronary artery blood flow experienced a decrease in thrombolytic therapy frame counts for myocardial infarction after taking STDP, as evidenced by coronary angiography performed five minutes post-administration (p \\u0026lt; 0.05). Also, Zhuang et al. \\u003csup\\u003e15\\u003c/sup\\u003ereported that the combination of STDP and metoprolol effectively alleviated angina symptoms, reduced myocardial ischemia, and delayed disease progression in 90 patients with coronary heart disease and angina pectoris. Additionally, another study discovered that the microcirculatory resistance index was lower in the observation group treated with STDP compared to the control group, and both SAQ and Canadian Cardiovascular Society (CCS) scores were superior (p\\u0026lt; 0.05)\\u003csup\\u003e16\\u003c/sup\\u003e. Collectively, these results reinforce the efficacy of STDP in CSFP treatment, thereby providing robust support for clinical interventions.\\u003c/p\\u003e\\n\\u003cp\\u003eThe pathogenesis of CSFP remains incompletely understood, while multiple studies have suggested potential associations with coronary microvascular dysfunction (CMD), endothelium-dependent vasodilatory abnormalities, abnormal blood cell morphology and function, and inflammatory responses\\u003csup\\u003e17\\u003c/sup\\u003e. It has been established that STDP treatment significantly decreases the pro-inflammatory cytokines (IL-6, TNF-\\u0026alpha;, and IL-1\\u0026beta;), and oxidative stress markers such as malondialdehyde (MDA)\\u003csup\\u003e10,11,18\\u003c/sup\\u003e . Moreover, STDP enhances angiogenesis by upregulating of the PI3K/Akt/mTORC1 signaling pathway, which increases the release of vascular endothelial growth factor (VEGF-A) and facilitates endothelial cell proliferation and migration\\u003csup\\u003e19\\u003c/sup\\u003e. In CMD models, STDP improves endothelial function by inhibiting the Dectin-1/Syk/IRF5 and S1PR2/RhoA/ROCK signaling pathways, ultimately enhancing endothelial barrier function and reducing microvascular leakage\\u003csup\\u003e20,21\\u003c/sup\\u003e. Furthermore, studies in cerebral microvasculature have demonstrated that STDP both suppresses the TXNIP/NLRP3 inflammasome\\u0026mdash;restoring oxidative balance and blood\\u0026ndash;brain barrier integrity\\u0026mdash;and enhances endothelial cystathionine-\\u0026gamma;-lyase (CSE) expression expression with H₂S production,\\u0026nbsp;contributing to the inactivation of P66shc, thereby restoring mitochondrial respiration and alleviating cerebral microvascular dysfunction\\u003csup\\u003e22,23\\u003c/sup\\u003e. Collectively, these mechanisms are closely linked to the observed improvements in CTFC and relief of angina symptoms in this study, thereby providing robust theoretical support for the further exploration and optimization of clinical treatment strategies.\\u003c/p\\u003e\\n\\u003cp\\u003eOur study has strong strengths. Firstly, it is a randomized, double-blind clinical trial, which can reduce the selection biases. Secondly, not only the immediate coronary flow changes assessed by angiography were compared, but also the angina symptoms and ECGs parameters were evaluated after administration of the drug for 2 months, which could give some added information of the safety and efficacy of the STDP.\\u003c/p\\u003e\\n\\u003cp\\u003eHowever, there are limitations to consider. Firstly, the current study was conducted in Chinese population, it is uncertain whether the effects of STDP would be expanded to other ethnic populations. Secondly, given the nature and clinical prognosis of CSFP and limited effective drugs, comparison with placebo might not be an ideal design for efficacy evaluation. Thirdly, the treatment period was limited to 4 weeks. Although the 4-week duration of the trial was in reference to several previous studies, the long-term efficacy and safety remain to be further investigated in the future. And the last one might be the sample size of our study, which would lead to no detection of the potential differences of MACEs by STDP in such patient subpopulation.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eTambe, A. A., Demany, M. A., Zimmerman, H. A. \\u0026amp; Mascarenhas, E. Angina pectoris and slow flow velocity of dye in coronary arteries--a new angiographic finding. \\u003cem\\u003eAm Heart J\\u003c/em\\u003e \\u003cstrong\\u003e84\\u003c/strong\\u003e, 66-71.\\u003c/li\\u003e\\n\\u003cli\\u003eChalikias, G. \\u0026amp; Tziakas, D. Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management. \\u003cem\\u003eAngiology\\u003c/em\\u003e \\u003cstrong\\u003e72\\u003c/strong\\u003e, 808-818.\\u003c/li\\u003e\\n\\u003cli\\u003eGomaa, A., Radwan, H. I. \\u0026amp; Gad, M. M. Predictors of coronary slow flow in stable coronary artery disease. \\u003cem\\u003eJournal of Indian College of Cardiology\\u003c/em\\u003e \\u003cstrong\\u003e7\\u003c/strong\\u003e, 109-115.\\u003c/li\\u003e\\n\\u003cli\\u003eHawkins, B. M., Stavrakis, S., Rousan, T. A., Abu-Fadel, M. \\u0026amp; Schechter, E. Coronary slow flow--prevalence and clinical correlations. \\u003cem\\u003eCirc J\\u003c/em\\u003e \\u003cstrong\\u003e76\\u003c/strong\\u003e, 936-942.\\u003c/li\\u003e\\n\\u003cli\\u003eMareai, R. M.\\u003cem\\u003e et al.\\u003c/em\\u003e Prognostic implication of coronary slow flow assessed by cTFC in patients with myocardial infarction with Non-obstructive coronary arteries. \\u003cem\\u003eEur J Intern Med\\u003c/em\\u003e \\u003cstrong\\u003e108\\u003c/strong\\u003e, 74-80.\\u003c/li\\u003e\\n\\u003cli\\u003eMontone, R. A.\\u003cem\\u003e et al.\\u003c/em\\u003e Coronary slow flow is associated with a worse clinical outcome in patients with Takotsubo syndrome. \\u003cem\\u003eHeart\\u003c/em\\u003e \\u003cstrong\\u003e106\\u003c/strong\\u003e, 923-930.\\u003c/li\\u003e\\n\\u003cli\\u003eWang, X. \\u0026amp; Nie, S. P. The coronary slow flow phenomenon: characteristics, mechanisms and implications. \\u003cem\\u003eCardiovasc Diagn Ther\\u003c/em\\u003e \\u003cstrong\\u003e1\\u003c/strong\\u003e, 37-43.\\u003c/li\\u003e\\n\\u003cli\\u003eChen, D.\\u003cem\\u003e et al.\\u003c/em\\u003e Qualitative and Quantitative Analysis of the Major Constituents in Shexiang Tongxin Dropping Pill by HPLC-Q-TOF-MS/MS and UPLC-QqQ-MS/MS. \\u003cem\\u003eMolecules\\u003c/em\\u003e \\u003cstrong\\u003e20\\u003c/strong\\u003e, 18597-18619.\\u003c/li\\u003e\\n\\u003cli\\u003eLin, Y. J., Jiao, K. L., Liu, B., Fang, L. \\u0026amp; Meng, S. Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial. \\u003cem\\u003eJ Integr Med\\u003c/em\\u003e \\u003cstrong\\u003e20\\u003c/strong\\u003e, 126-134.\\u003c/li\\u003e\\n\\u003cli\\u003eLiu, H.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin dropping pill protects against sodium laurate-induced coronary microcirculatory dysfunction in rats. \\u003cem\\u003eJ Tradit Chin Med\\u003c/em\\u003e \\u003cstrong\\u003e41\\u003c/strong\\u003e, 89-97.\\u003c/li\\u003e\\n\\u003cli\\u003eXiong, M.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin dropping pill attenuates atherosclerotic lesions in ApoE deficient mouse model. \\u003cem\\u003eJ Ethnopharmacol\\u003c/em\\u003e \\u003cstrong\\u003e159\\u003c/strong\\u003e, 84-92.\\u003c/li\\u003e\\n\\u003cli\\u003eWang, S. H.\\u003cem\\u003e et al.\\u003c/em\\u003e Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow. \\u003cem\\u003eChin J Integr Med\\u003c/em\\u003e \\u003cstrong\\u003e25\\u003c/strong\\u003e, 360-365.\\u003c/li\\u003e\\n\\u003cli\\u003eJespersen, L., Abildstr\\u0026oslash;m, S. Z., Pe\\u0026ntilde;a, A., Hansen, P. R. \\u0026amp; Prescott, E. Predictive value of the corrected TIMI frame count in patients with suspected angina pectoris but no obstructive coronary artery disease at angiography. \\u003cem\\u003eClin Res Cardiol\\u003c/em\\u003e \\u003cstrong\\u003e103\\u003c/strong\\u003e, 381-387.\\u003c/li\\u003e\\n\\u003cli\\u003eBardou, P., Mariette, J., Escudi\\u0026eacute;, F., Djemiel, C. \\u0026amp; Klopp, C. jvenn: an interactive Venn diagram viewer. \\u003cem\\u003eBMC Bioinformatics\\u003c/em\\u003e \\u003cstrong\\u003e15\\u003c/strong\\u003e, 293.\\u003c/li\\u003e\\n\\u003cli\\u003eX.H., Z., Y.H, F., J, L. \\u0026amp; Y, X. Efficacy Observation of Shexiang Tongxin Dropping Pills Combined with Metoprolol in the Treatment of Coronary Heart Disease Angina. \\u003cem\\u003eModern Drugs and Clinics\\u003c/em\\u003e \\u003cstrong\\u003e33\\u003c/strong\\u003e, 1052-1055.\\u003c/li\\u003e\\n\\u003cli\\u003eW.L., T.\\u003cem\\u003e et al.\\u003c/em\\u003e Improvement of Coronary Slow Flow by Shexiang Tongxin Dropping Pills. \\u003cem\\u003eAdvances in Clinical Medicine\\u003c/em\\u003e \\u003cstrong\\u003e10\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eKarauzum, K.\\u003cem\\u003e et al.\\u003c/em\\u003e The Systemic Immune-Inflammation Index May Predict the Coronary Slow Flow Better Than High-Sensitivity C-Reactive Protein in Patients Undergoing Elective Coronary Angiography. \\u003cem\\u003eCardiol Res Pract\\u003c/em\\u003e \\u003cstrong\\u003e2022\\u003c/strong\\u003e, 7344639.\\u003c/li\\u003e\\n\\u003cli\\u003eBai, Y.\\u003cem\\u003e et al.\\u003c/em\\u003e Efficacy of Shexiang Tongxin Dropping Pills in a Swine Model of Coronary Slow Flow. \\u003cem\\u003eFront Physiol\\u003c/em\\u003e \\u003cstrong\\u003e13\\u003c/strong\\u003e, 913399.\\u003c/li\\u003e\\n\\u003cli\\u003eLu, X.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin Dropping Pills Promote Macrophage Polarization-Induced Angiogenesis Against Coronary Microvascular Dysfunction via PI3K/Akt/mTORC1 Pathway. \\u003cem\\u003eFront Pharmacol\\u003c/em\\u003e \\u003cstrong\\u003e13\\u003c/strong\\u003e, 840521.\\u003c/li\\u003e\\n\\u003cli\\u003eSun, Y.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin dropping pills ameliorate myocardial ischemia-reperfusion injury progression via the S1PR2/RhoA/ROCK pathway. \\u003cem\\u003eJournal of Traditional Chinese Medical Sciences\\u003c/em\\u003e \\u003cstrong\\u003e12\\u003c/strong\\u003e, 31-43.\\u003c/li\\u003e\\n\\u003cli\\u003eCui, L.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin Dropping Pill alleviates M1 macrophage polarization-induced inflammation and endothelial dysfunction to reduce coronary microvascular dysfunction via the Dectin-1/Syk/IRF5 pathway. \\u003cem\\u003eJ Ethnopharmacol\\u003c/em\\u003e \\u003cstrong\\u003e316\\u003c/strong\\u003e, 116742.\\u003c/li\\u003e\\n\\u003cli\\u003eZhu, L.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin Dropping Pills attenuate ischemic microvascular dysfunction via suppressing P66Shc-mediated mitochondrial respiration deficits. \\u003cem\\u003eJ Ethnopharmacol\\u003c/em\\u003e \\u003cstrong\\u003e346\\u003c/strong\\u003e, 119664.\\u003c/li\\u003e\\n\\u003cli\\u003eZhu, L.\\u003cem\\u003e et al.\\u003c/em\\u003e Shexiang Tongxin dropping pills protect against ischemic stroke-induced cerebral microvascular dysfunction via suppressing TXNIP/NLRP3 signaling pathway. \\u003cem\\u003eJ Ethnopharmacol\\u003c/em\\u003e \\u003cstrong\\u003e322\\u003c/strong\\u003e, 117567.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"npj-cardiovascular-health\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"\",\"sideBox\":\"Learn more about [npj Cardiovascular Health](https://www.nature.com/npjcardiohealth)\",\"snPcode\":\"44325\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/44325/3\",\"title\":\"npj Cardiovascular Health\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Shexiang Tongxin Dropping Pills, coronary slow flow phenomenon, corrected TIMI frame count, angina\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6600627/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6600627/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003ePrevious preclinical studies suggested that Shexiang Tongxin Dropping Pill (STDP) would be effective for coronary slow flow phenomenon (CSFP), but its clinical efficacy and safety remain uncertain. A multicenter, randomized, controlled phase IV trial was implemented to enroll 200 participants diagnosed with angina and CSFP between July 2016 and August 2020 to examine the drug’s effectiveness and safety. The analysis revealed that corrected TIMI frame count (CTFC) values in left anterior descending(LAD) and left circumflex(LCX) arteries in STDP group could be decreased, respectively (both p \\u0026lt;0.01), whereas no significant changes were seen with placebo; between group differences were significant for both LAD (p = 0.008) and LCX (p = 0.044). Furthermore, STDP was well tolerated. 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