Efficacy and safety of Chinese herbal medicine Guanxinshutong capsule for the treatment of chronic heart failure with ejection fraction decrease (<50%) caused by coronary heart disease: study protocol for a randomized controlled trial

Efficacy and safety of Chinese herbal medicine Guanxinshutong capsule for the treatment of chronic heart failure with ejection fraction decrease (<50%) caused by coronary heart disease: study protocol for a randomized controlled 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 Study protocol Efficacy and safety of Chinese herbal medicine Guanxinshutong capsule for the treatment of chronic heart failure with ejection fraction decrease (<50%) caused by coronary heart disease: study protocol for a randomized controlled trial Yu Wang, Jiaping Xu, Jie-hong Yang, Ling Zhang, Yuan-jiang Pan, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.22735/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chronic Heart failure (CHF) is a global epidemic and common cardiovascular disease with high mortality and poor prognosis, which bring heavy burdens to society and family. Traditional Chinese medicine (TCM) has been extensively used in China as an adjunct treatment for CHF. Guanxinshutong capsule (GXST), approved by the China Food and Drug Administration (CFDA) in 2002 (No. Z20020055), is commonly used Chinese herbal medicine (CHM) for the treatment of coronary heart disease (CHD) currently. Both experimental research and small-sample clinical trials have shown that GXST could attenuate CHF. However, the effects of GXST on CHF as an adjunct therapy are lack of high-quality clinical evidence. This study is a large-scale, multi-center, double-blinded clinical trial to explore the efficacy and safety of GXST in CHF with ejection fraction decrease (<50%) caused by CHD. Methods This study is a multi-center, randomized, double-blind, placebo-controlled clinical trial. After 1week baseline period, a total of 480 participants will be randomly assigned to the intervention group and placebo group in ratio 2:1. Based on routine medications, the intervention group will be treated with GXST while the control group will be treated with placebo (both 0.3g/capsule, op, 3 capsules/time, thrice daily) for 12 weeks, and then be followed-up for another 40 weeks. The primary outcome is the effect of 6 min walk test (6MWT). The secondary outcomes include NT-proBNP, classification of the New York Heart Association (NYHA) heart function, Minnesota heart failure quality of life scale (MLHFQ), echocardiographic parameters, blood stasis syndrome symptom scale and clinical endpoint events. Metabolomics and proteomics will also be assessed. Adverse events (AEs) will be monitored throughout the trial. All the data will be recorded in electronic case report forms (eCRF) system database and analyzed in accordance with a predefined statistical analysis plan. Ethical approval of this trial has been granted by the Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (ID: 2019-Y-003-02). Written informed consent of patients will be required. The results will be disseminated to the public through peer-reviewed journals and academic conferences. Discussion This study integrates the advantages of TCM and western medicine in the treatment of CHF, the result of this study will offer the efficacy and safety evidence of GXST on CHF with ejection fraction decrease (<50%). Cardiac & Cardiovascular Systems Internal Medicine Guanxinshutong capsule Chronic heart failure Coronary heart disease Chinese medicine Randomized controlled trial Figures Figure 1 Background Chronic Heart failure (CHF) is a complex clinical syndrome characterized by decreased cardiac output, insufficient organ perfusion and venous congestion due to cardiac dysfunction [ 1 , 2 ]. And it is a global epidemic, affecting about 26 million people worldwide, with more than 1 million hospitalized people in the United States and Europe each year [ 3 ]. In China, it is estimated that 4.5 million aged from 35 to 74 suffered from CHF, and with the growing aging of population and changes of lifestyle, the incidence of common cardiovascular diseases such as hypertension, coronary heart disease (CHD), and CHF continues to rise [ 4 , 5 ]. CHF has resulted in a growing economic and public health burden on individuals, their families and society and calls for new therapies, as well as prevention. Currently, angiotensin converting enzyme inhibitors (ACEI), β-blockers and aldosterone receptor antagonists are called "Golden Triangle", which are listed as the standard and basic treatment for CHF. According to 2018 China HF diagnosis and treatment guidelines, "Golden Triangle" should be used for CHF as soon as possible without waiting for the poor curative effect of the combined use of ACEI and β-blockers or the left ventricular ejection fraction (LVEF) must be less than 35% [ 6 ]. However, the improvement of the curative effect results in more side effects, such as electrolyte disorder, the increase of serum creatinine, and even renal function impairment. Furthermore, due to the contraindications, side effects, and unsatisfied relief of symptoms, the compliance of patients receiving conventional drug treatment needs to be improved. Therefore, it is crucial to develop supplementary therapeutic approaches for the treatment of CHF. TCM has been widely and successfully used in treating cardiovascular diseases in China for more than 2000 years and has great advantages in less harmful side effects, high safety, and ideal effects. As early as the Han Dynasty, CHF was classified as “palpitation” or “heartache” according to its symptoms. Based on thousands of years clinical practice, TCM has accumulated many experiences in the treatment of CHF, currently, CHM combined with western routine therapy have shown promising benefits in controlling symptoms, reducing mortality, improving cardiac function and promoting life quality in patients with CHF [ 7 ]. Within the framework of TCM theory, all the related symptoms, signs, tongue appearances and pulse feelings at a certain stage of disease are summarized as a syndrome (‘ Zheng ’ in TCM) [ 8 ]. Syndrome is not only the core of TCM theory but also the base of definite diagnosis and effective therapies [ 9 ]. In TCM, patients with CHF can be divided into varied syndromes, and according to previous data the syndrome of ‘blood stasis’ is the most common and important subtype[ 10 ]. Guanxinshutong capsule (GXST), which is commonly used to treat CHD in China, was developed by Shaanxi Buchang Pharmaceutical Co., Ltd, and approved by China Food and Drug Administration (CFDA) for the treatment of CHD in 2002 (approval number Z20020055). GXST consists of five herbal medicines (Table 1 ), and was reported to promote blood circulation, remove blood stasis and relieve pain [ 11 ]. Experimental studies showed that GXST inhibited the ventricular remodeling process through increasing mitochondrial productivity [ 11 , 12 ], repressing the expression of matrix metalloprotein 9, angiotensin receptors 1 and extracellular regulated protein kinases 2 [ 13 , 14 ], and transforming growth factor-β/Smad signaling pathway [ 15 ] and finally to treat patients with CHF. A clinical trial with 61 patients reported that compared to conventional treatment, combination with GXST could significantly increase LVEF and cardiac output and reduce end-systolic and diastolic volume in acute myocardial infarction patients with CHF [ 16 ]. Meanwhile, in our previous clinical study, GXST exerted obvious effect on CHF (unpublished data) which implied it might be the potentially promising CHM for the treatment of CHF. However, current data of GXST as complementary therapy in CHF are insufficient, and the present clinical trials are limited in the methodology and sample size. Therefore, in this study, we conduct a large-scale, multi-center, double-blinded clinical trial to investigate the efficacy and safety of GXST in CHF caused with ejection fraction decrease (< 50%) by CHD. Table 1 Components of GXST (intervention drug) Main composition Chinese Pinyin Latin scientific name Plant part Choerospondiatis Fructus Guang Zao Choerospondiatis Fructus Fruit Salvia miltiorrhiza Dan Shen Salvia miltiorrhiza Bunge Rhizome Clove Ding Xiang Caryophylli Flos Flower Borneol Bing Pian Borneolum Syntheticum Resin Tabasheer Tian Zhu Huang Concretio Silcea Bambusae Resin Methods In this trial, we aim to assess the efficacy and safety of GXST for CHF with ejection fraction decrease (< 50%) caused by CHD. Design and settings This study is a prospective, randomized, double-blind, placebo-controlled, multicenter, superior trial. Researchers must explain to participants the trial properties, purpose, potential benefits and risks, alternative treatment options, and the rights of participants under the Helsinki declaration, Participants fully understand and voluntarily sign the informed consent. After the participants have enrolled and signed the informed consent, participants will be randomized in a 2:1 ratio to the intervention group and the placebo group. The trial will be conducted by 11 medical centers throughout China (Table 2 ), and a total of 480 participants will be recruited. This trial consists of 1-week baseline period, 12-week intervention period and 40-week follow-up period. A flow diagram of the study procedures is illustrated in Fig. 1 . Table 2. Research setting Code Participating hospitals 01 Second Affiliated Hospital of Zhejiang Chinese Medical University 02 Zhoukou Central Hospital 03 Pingdingshan First People's Hospital 04 Hangzhou First People's Hospital 05 Fenyang Hospital of Shanxi Province 06 The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine 07 Lishui Traditional Chinese Medicine Hospital 08 First People's Hospital of Huzhou 09 PizhouTraditional Chinese Medicine Hospital 10 Zhumadian Central Hospital 11 First Affiliated Hospital of Xinxiang Medical University Study population Inclusion criteria The inclusion criteria are as follows: (1) meet the diagnosis of CHD [ 17 ] and CHF[ 6 , 18 ]; (2) meet the diagnostic criteria of blood stasis syndrome in TCM [ 19 ]; (3) aged 40 to 80, both male and female; (4) NYHA class II ~ III; (5) LVEF < 50% (by two-dimensional echocardiographic Simpson method); (6) course of disease ≥ 3 months, stable condition in recent 1 month or receiving routine treatment with stable doses more than 1 month; (7) plasma NT-proBNP ≥ 125 ng/L; (8) volunteer, understand and sign informed consent. Exclusion criteria The exclusion criteria for recruitment of participants into the study are: (1) acute coronary syndrome occurred in the past 1 month; (2) plan to take cardiac surgery during the trial; (3) with severe diseases like cardiogenic shock, acute myocarditis, uncontrollable malignant arrhythmia, hypertrophic obstructive cardiomyopathy, pulmonary embolism or severe valvular disease requiring surgery; (4) uncontrolled hypertension with systolic blood pressure ≥ 180 mmHg, diastolic blood pressure > 110 mmHg, or hypotension < 90/50 mmHg; (5) with severe liver or kidney dysfunction or active liver disease, or AST, ALT ≥ 3 times the upper limit of normal; (6) psychiatric patients, or patients with severe depression, or a history of alcohol or drug abuse; (7) pregnant women, or breast-feeding women, or those who are trying to get pregnant during the trial; (8) with allergic constitution, or be allergic to test drug; (9) with previous or present tumor history, or with precancerous lesions confirmed by pathological examination; (10) participate in other clinical studies 3 months before this trial. Randomization, allocation concealment mechanism and blinding Participants are randomized to the intervention group or the placebo group in a 2:1 ratio using the Central Randomization System to achieve computerized randomization in blocks of 6, stratified by center. The random sequence will be placed in an envelope and subsequently sealed. According to the randomization number, the statistician will send the envelope directly to the Shaanxi Buchang Pharmaceutical Co., Ltd for the labeling of the invention and placebo drugs. All researchers, subjects, physicians, drug administrators and dispensing nurses will be blinded until the study is completed. The blinding codes can't be broken until all the clinical data are entered into eCRF database and locked, except subjects experience an SAE or need to be rescued in an emergency situation. Once unblinded, the cases will withdraw from the study, and researchers should report the reasons to the inspector within 24 h and the precise cause, date, treatment situation, and results should be recorded in eCRF. Interventions Eligible patients will be randomly allocated to the intervention group and the placebo group, both of which are given conventional therapies. Intervention group GXST, 0.3 g/capsule, op, 3capsules/time, thrice daily; Placebo group capsule stimulants, 0.3 g/capsule, op, 3capsules/time, thrice daily. The GXST and capsule stimulants are both provided by Shaanxi Buchang Pharmaceutical Co. Ltd. The capsule stimulant's primary content is starch and dextrin, adding food colorants and flavoring agents, and achieves a smell, color, taste, and texture comparable to GXST. After the treatment, the packaging will be returned to the researches. Outcomes Primary and secondary outcomes The primary outcome is the difference in 6 MWT [ 20 ]. The secondary outcomes are as follows: (1) changes in NT-proBNP; (2) improvement in heart function assessed by NYHA classifications [ 21 ]; (3) improvement of MLHFQ [ 22 ]; (4) improvement in echocardiographic parameters of left ventricular end-diastolic diameter and LVEF; (5) incidence rate of clinical endpoint events (rehospitalization for CHF acute aggravation, cardiogenic death, and all-cause death); (6) improvement of blood stasis syndrome symptom scale score. According to the degree of the symptoms from normal, mild, moderate to severe, the scores of 0, 2, 4 and 6 will be given respectively of the primary symptoms and signs, and 0, 1, 2 and 3 of the secondary symptoms and signs. The higher the score, the severer the symptoms. The patient with syndrome scores decreasing by more than 70% are considered as effective cases, which will be counted as a percentage of all cases. The details of items to be measured and the time window of data collection are shown in Table 3 . Table 3. Study schedule Study phase Time Baseline period Intervention period Follow-up period Visit 1 Visit 2 Visit 3 Visit 4 every 4 weeks until 52 weeks -7～0 days 4 weeks 8 weeks 12weeks Baseline data collection Informed consent × Inclusion/exclusion criteria × Demographic data × Get the central random number × Previous history、medical history and allergies × Concomitant disease and treatment × Safety evaluation Vital signs × × × × Physical examination × × × × Blood routine × × Urine routine × × Blood biochemistry × × Myocardial Zymogram and troponin × × ECG × × Chest X-ray or CT × × Urine pregnancy test × × Efficiency evaluation 6MWT × × NT-proBNP × × NYHA class × × × × MLHFQ × × × × Echocardiographic parameters × × Blood stasis syndrome symptom scale × × × × Clinical endpoint events × × × × Other work Dispense drug × × × Recovery and record of study drug × × × Metabolomics and proteomics × × Record AE × × × × Concomitant medications × × × Evaluate the adherence × × × × Abbreviations: CT-computed tomography, 6MWT-6 min walk test, NYHA class classification of the New York Heart Association heart function, MLHFQ Minnesota Heart Failure Quality of Life Scale, AE adverse event. Safety outcomes Safety outcomes include vital signs (temperature, heart rate, breathing, and blood pressure), image examinations (X-ray or CT), laboratory examinations (blood and urine test, blood biochemistry test, myocardial zymogram, and troponin test, and urine pregnancy test) and AEs. AEs will be recorded throughout the trial. Metabolomics and proteomics 50 subjects are randomly selected and blood samples are taken for metabolomics and proteomics examination to explore the therapeutic biomarkers and pharmacodynamic material basis of GXST in treating CHF. Metabolomics: gas chromatography-mass spectrometer (GC-MS) and liquid chromatograph-mass spectrometer (LC-MS) techniques are used to detect the chemical and biological fingerprints, describe the possible metabolic pathways, and identify biomarkers of GXST for the treatment of CHF. Proteomics: two-dimensional difference gel electrophoresis (2D-DIGE) method is used to establish the protein patterns; Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) is applied to identify differentially expressed proteins; bioinformatics is used to analyze the biological functions of differentially expressed proteins; String analysis and ingenuity pathway analysis (IPA) are applied to establish the protein network and explore the pharmacodynamic material basis of GXST for the treatment of CHF. Data Management The data management will be performed by the department of Medical Statistics, First Hospital of Peking University with electronic data management system (EDC). According to the requirements of Good Clinical Practice (GCP) and research plan, two researchers entry electronic case report form (eCRF) accurately, timely, completely and normatively. Clinical research associate adopt system automatic and manual logic verification to check the consistency of eCRF data and source data, and issues questions online at any time in case of any problem. After all subjects have completed the trial, all medical records have been entered into EDC, and the primary researcher, sponsor, statistical analyst and data management personnel review and confirm the data, then the data will be locked and submitted to the statistician for statistical analysis by the administrator. After the data is locked, data can be corrected in the statistical analysis program after confirmation, and if there is exact evidence to prove that it is necessary to unlock, the researcher and the sponsor need to sign relevant documents. After the trial, the data management report will be written according to the actual implementation of the project. In this study, due to CHM is added to the basic treatment of western medicine, which can guarantee the rights and therapeutic effects of patients, no data monitoring committee is established. Personal information about potential and enrolled participants will be protect confidentiality before, during, and after the trial, and researchers should keep the data for five years after the termination of the clinical trial. Sample size The formula for calculating the sample size is as follows, which is based on the superior clinical trial sample size estimation [ 23 ]. The sample size is driven by the expected improvement in 6MWT. Referring to previous clinical researches [ 24 – 27 ], we assumed that the improvement in 6MWT is 30 meters, and the combined standard deviation (SD) is 100 meters in this study. Given a type I error rate of α = 0.025, a power of 80% (type II error rate of β = 0.2), considering of 20% possible dropout rate, a total of 470 patients need to be allocated. For the convenience of randomization, the final sample size was 320 cases in the intervention group and 160 cases in the placebo group, total of 480 cases. In this formula k is the ratio between two sample cases, δ is the expected improvement in 6MWT, σ is the combined SD. Statistical analysis The statistical analysis plan (SAP) will be specified before data analysis. The statistical analysis will be performed by the department of Medical Statistics, First Hospital of Peking University using SAS software version 9.4 (or higher version). The full analysis set (FAS) includes patients who received allocated treatment and provided assessable outcome data. The safety analysis set (SAS) includes patients who received allocated treatment at least once. The per protocol set (PPS) includes patients who received allocated treatment and for whom planned outcome data as per the protocol are available. According to the intention-to-treat (ITT) principle, the FAS is used for the primary endpoint, and the FAS and PPS are used for the important secondary and other secondary endpoints. For quantitative data, we will calculate the mean, SD, median, minimum, maximum, interquartile range, and for classified data, we will describe various cases and percentages. Inter-group comparisons will be analyzed by appropriate methods according to the type of data, independent t-test (homogeneity of variance, normal distribution) or Mann-Whitney-Wilcoxon test (nonnormal distribution) will be used for comparison of quantitative data, chi-square test or Fisher's exact test (if chi-square test is not applicable) will be used for classified data, and Wilcoxon rank-sum test or Cochran-Mantel-Haenszel test will be used for ranking data. Paired t-test will be applied to assess the difference of outcome before and after treatment in the same group. Significance will be assumed at a p level of less than 5%. The superiority of the GXST group to the placebo group in terms of 6MWT will be examined with a superiority of 30 metres. The last observation carried forward (LOCF) method is used for missing values. Adverse events Any AEs that occur during the observation period must be recorded. AEs within one week after the end of the trial are recorded by the patient's initiative reporting method. The development of AEs will also be observed until all the AEs disappear. The classification and coding of AEs are formulated with reference to Common Terminology Criteria for AEs 4.03. Quality control of the intervention In order to further ensure the quality of this trial, a multi-center trial Coordination Committee and the general director are set up to implement and solve related problems. The Coordination Committee includes the leaders of each center and the head of sponsor, and all passes pre-clinical training. All staff including the operators, researchers, physicians, data collectors, and analyzers can fully understand the purpose and content of the trial. This trial is inspected by the CFDA, sponsor and clinical research organization throughout the trial. Ethics and dissemination This study has approved by the Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (No. 2019-Y-003-02), and all participate centers will receive approval from their local ethics committee. All data will be recorded in eCRF and imported into public clinical trial management platform ( www.medresman.org ) and posted on Chinese Clinical Trial Registry within 6 months after completion of the trial. Study results will be published in academic conferences and peer-reviewed journals. Discussion CHF is a global public health problem. According to the 2018 China Cardiovascular report [ 5 ], hypertension and CHD are the main causes of HF. An analysis of the predisposing factors of 426 elderly patients with HF suggests that CHD is the leading cause of HF, accounting for 43.2% [ 28 ]. GXST was approved by CFDA for the treatment of CHD in 2002. Experimental studies and small-sample clinical trials have confirmed that GXST could reduce the symptoms of the patients with CHF [ 11 – 16 ]. Therefore, we choose CHF with ejection fraction decrease (< 50%) caused by CHD as the inclusion criteria. Currently, there are three methods for the assessment of functional capacity and exercise tolerance in patients with HF. First, the self-assessed or physician-reported categorization of patients’ physical status which is mainly dependent on the patients’ perceives. Second, peak oxygen consumption, which is a maximal symptom-limited exercise test (cardiopulmonary exercise test; CPET), will explain the reason of dyspnea and fatigue based on the assessment of all systems involved in physical activity. However, because of the demand for special equipment and trained personnel, it is unavailable in some hospital settings. Third, submaximal exercise tests including 6MWT, which is well-tolerated by patients. 6MWT is a simple and inexpensive test that requires no special equipment and advanced training for physicians and assesses the submaximal level of functional capacity of patients while walking on a flat barrier-free corridor in a period of 6 min [ 20 ]. NT-proBNP, as an important biomarker of cardiac function, is recommended for the diagnosis, screening, differential diagnosis, severity and prognosis evaluation of HF [ 29 – 33 ]. In this study, we choose 6MWT as the primary outcome and NT-proBNP as the secondary outcome. In order to reduce the possible differences caused by the detection of each center, metabolomics, proteomics, and NT-proBNP adopt centralized detection methods. The samples are tested in the Central Laboratory of Zhejiang Chinese Medical University. TCM has developed for thousands of years and is one of the positive signs of globalization in the world. An increasing proofs demonstrates that integrative medicine, combined with TCM and western medicine, emerges as an optimal approach for achieving better effectiveness in patients with CHF [ 34 – 36 ]. According to the TCM theory and syndrome differentiation, blood stasis syndrome is the core pathogenesis of CHF [ 37 – 38 ], and GXST play an important role in promoting blood circulation and removing blood stasis and is optimal for treating CHF. As the principal active components, salvia miltiorrhiza and choerospondiatis fructus were showed to perform the function of microcirculation improvement, vascular endothelial cells protection, anti-arrhythmia, and antioxidation [ 39 – 41 ]. Caryophylliflos was effective in anticoagulation, antiplatelet aggregation and antithrombotic [ 42 ]. However, whether GXST as the supplementary therapy is better than western medicine alone in patients with CHF still requires confirmation by large sample, multicentre and randomized controlled clinical trials. This study is a multicentre, double-blinded, placebo-controlled clinical trial with the hope of verifying the effectiveness and safety of GXST for the treatment of CHF with ejection fraction decrease (< 50%) caused by CHD. There are also some limitations in this study. Firstly, this experiment will be conducted in five provinces of China. Whether similar effects are obtainable to other regions and ethnic groups remain uncertain. Secondly, this study is only 52 weeks in duration; further data on long-term clinical effect and safety are needed. Thirdly, GXST used in this trial is designed for the treatment of CHF with blood stasis syndrome; thus, the findings may not be applicable to other CHF syndromes. Abbreviations CHF Chronic Heart failure; TCM Traditional Chinese medicine; GXST Guanxinshutong capsule; CHM Chinese herbal medicine; CFDA China Food and Drug Administration; CHD coronary heart disease; 6MWT 6 min walk test; NYHA New York Heart Association; MLHFQ Minnesota heart failure quality of life scale; AEs Adverse events; eCRF Electronic case report forms; SAS Statistical Analysis System; ACEI Angiotensin converting enzyme inhibitors; LVEF Left ventricular ejection fraction; GC-MS Gas chromatography-mass spectrometer; LC-MS Liquid chromatograph-mass spectrometer; 2D-DIGE Two-dimensional difference gel electrophoresis; MALDI-TOF-MS Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry; IPA ingenuity pathway analysis; SAP statistical analysis plan; FAS full analysis set; SAS safety analysis set; PPS per protocol set; ITT intention to treat; LOCF last observation carried forward; EDC electronic data management system; GCP Good Clinical Practice; eCRF electronic case report form SD standard deviation; CPED Cardiopulmonary exercise test. Declarations Ethics approval and consent to participate Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University has approved this study (No. 2019-Y-003-02), and all participate centers will receive approval from their local ethics committee. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding This project is supported by the National Natural Science Foundation of China (No.81630105), the National Key R&D Program of China (2017YFC1700400, 2017YFC1700403). Authors' contributions HW, SH, and FW designed the study. YW and JX contributed equally to the article, who conceptualized the study design and wrote the manuscript. LZ, JY modified the manuscript. YP, YH, and CL are responsible for the quality control of the test drug. LD, YX, JC, HZ, and LY participated in the modification of this protocol. 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Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975. https://doi.org/10.1002/ejhf.592. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239.https://doi.org/10.1016/j.jacc.2013.05.019. Chinese Society of Cardiology，Editorial board of Chinese Journal of Cardiology. Guidelines for diagnosis and treatment of heart failure in China 2014. Chin J Cardiol. 2014;42(2):3-10. Booth RA, Hill SA, Don-Wauchope A, Santaguida PL, Oremus M, McKelvie R, et al. Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review. Heart Fail Rev. 2014; 19(4): 439-451. https://doi.org/1007/s10741-014-9445-8. Roberts E, Ludman AJ, Dworzynski K, Al-Mohammad A, Cowie MR, McMurray JJ, et al. The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting. BMJ. 2015;350:h910. https://doi.org/10.1136/bmj.h910. Li WK. Clinical observation on the treatment of chronic heart failure with the combination of traditional Chinese and Western Medicine. J Pract Med Techn. 2008;(10):1317-1318. Lai WW, Zhao WA, Chen GZ, Lin WQ, Xu CX, CAI KX, et al. Observation on the therapeutic effect of Yiqi Huoxue formula combined with sakubatrevalsartan on patients with chronic heart failure. Chin J Moder Appl Pharm. 2019;36(18):2312-2316. Liu T, Ma LP. Curative effect observation of the treatment of refractory heart failure with Qiliqiangxin capsule and Xinmailong injection. World Latest Med Infor. 2019; 19(52):248+268. Chinese Rehabilitation Medical Association Professional Committee of Cardiovascular Diseases, Committee of Cardio-Cerebral-Vascular Diseases of GSC. Chinese expert consensus on cardiac rehabilitation for patients with chronic stable heart failure. Chin J Cardiol. 2014;42:714–20. Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of Chinese Journal of Cardiology. Chinese guidelines for the diagnosis and treatment of heart failure 2014. Chin J Cardiol. 2014;42:98–122. Zhao N, Guo ZX, Zhao X, Zhao LB. Chemical constituents and pharmacological action of Salvia miltiorrhiza. J Fore Med. 2007;(04):155-160. Chen XR, Lu JB, Shi HP. New progress in the pharmacological study of Salvia miltiorrhiza. Chin J Hosp. 2001;(01):44-45. Zhou J, Gao SP, Mei XL. Research progress of Mongolian medicine Guangzao. Strait Pharm J. 2017;29(06):1-5. Zhu JD, Yuan DJ, Lin XY. Current situation of pharmacological research and clinical application of Caryophylli flos. Chin J Pharm Econ. 2013; (01):32-35. Contributions to the literature This study is a double-blind, placebo-controlled trial of Guanxinshutong capsule as add-on therapy, provides a strategy with the combination of Chinese and western medicine in chronic heart failure patients. This is a pilot study to explore the efficacy and safety of Guanxinshutong capsule on chronic heart failure with ejection fraction decrease, provides a preliminary basis for expanding the scope of application of Guanxinshutong capsule. This study will apply metabolomics and proteomics examination to explore the therapeutic biomarkers and pharmacodynamic material basis of Guanxinshutong capsule in treating chronic heart failure, provides a novel ideas for precision treatment. 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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-13309","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":331966,"identity":"3da1a801-4acc-4a63-8ded-3903183b9c2f","order_by":1,"name":"Yu Wang","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":331967,"identity":"849bc9d9-5792-423e-a68e-834d4e211d18","order_by":2,"name":"Jiaping Xu","email":"","orcid":"","institution":"Zhejiang Chinese Medical 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Wan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYBACAwbGBjCDn5n58ANitTSC9Ui2s6UZEKkFao3BeR4FCaK0mLMfbn/wcUdt4ubDPED9NTbRBLVY9iQ2Ns48czxx22HeAw8YjqXlNhB02IHExmbetmO52w7zJRgwNhwmQsv5hxAtm5t5DCSI03IDbEtN7gZm4rU8bJw5s+1A/YzDwEBOIMov59MffPjYVmfM33/48IMPNTaEtUDBYQiVQKRyEKgjQe0oGAWjYBSMOAAAHnZGxoNenwoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4459-8246","institution":"Zhejiang Chinese Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hai-tong","middleName":"","lastName":"Wan","suffix":""}],"badges":[],"createdAt":"2020-02-04 16:20:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.22735/v1","doiUrl":"https://doi.org/10.21203/rs.2.22735/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":458810,"identity":"30dfde56-0233-4783-8848-729810eab060","added_by":"auto","created_at":"2020-02-06 17:37:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":242963,"visible":true,"origin":"","legend":"CONSORT flow diagram for GXST clinical trial.","description":"","filename":"figure1.PNG","url":"https://assets-eu.researchsquare.com/files/27815ed7-a721-4b9a-8dd8-e5d66849b488/v1/figure 1.PNG"},{"id":15666036,"identity":"b28fe573-8eea-477c-a203-2e8f44136d4d","added_by":"auto","created_at":"2021-11-18 13:34:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":719325,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-13309/v1/9661d8df-5971-4ff5-af68-050b385c9c78.pdf"},{"id":458809,"identity":"e67a29d4-fdf7-4eab-9a26-a2b028ab80cf","added_by":"auto","created_at":"2020-02-06 17:37:31","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":130048,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.doc","url":"https://assets-eu.researchsquare.com/files/27815ed7-a721-4b9a-8dd8-e5d66849b488/v1/SPIRIT checklist.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEfficacy and safety of Chinese herbal medicine \u003cem\u003eGuanxinshutong \u003c/em\u003ecapsule for the treatment of chronic heart failure with ejection fraction decrease (\u0026lt;50%) caused by coronary heart disease: study protocol for a randomized controlled trial\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eChronic Heart failure (CHF) is a complex clinical syndrome characterized by decreased cardiac output, insufficient organ perfusion and venous congestion due to cardiac dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. And it is a global epidemic, affecting about 26\u0026nbsp;million people worldwide, with more than 1\u0026nbsp;million hospitalized people in the United States and Europe each year [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In China, it is estimated that 4.5\u0026nbsp;million aged from 35 to 74 suffered from CHF, and with the growing aging of population and changes of lifestyle, the incidence of common cardiovascular diseases such as hypertension, coronary heart disease (CHD), and CHF continues to rise [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. CHF has resulted in a growing economic and public health burden on individuals, their families and society and calls for new therapies, as well as prevention.\u003c/p\u003e \u003cp\u003eCurrently, angiotensin converting enzyme inhibitors (ACEI), β-blockers and aldosterone receptor antagonists are called \"Golden Triangle\", which are listed as the standard and basic treatment for CHF. According to 2018 China HF diagnosis and treatment guidelines, \"Golden Triangle\" should be used for CHF as soon as possible without waiting for the poor curative effect of the combined use of ACEI and β-blockers or the left ventricular ejection fraction (LVEF) must be less than 35% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the improvement of the curative effect results in more side effects, such as electrolyte disorder, the increase of serum creatinine, and even renal function impairment. Furthermore, due to the contraindications, side effects, and unsatisfied relief of symptoms, the compliance of patients receiving conventional drug treatment needs to be improved. Therefore, it is crucial to develop supplementary therapeutic approaches for the treatment of CHF.\u003c/p\u003e \u003cp\u003eTCM has been widely and successfully used in treating cardiovascular diseases in China for more than 2000\u0026nbsp;years and has great advantages in less harmful side effects, high safety, and ideal effects. As early as the Han Dynasty, CHF was classified as \u0026ldquo;palpitation\u0026rdquo; or \u0026ldquo;heartache\u0026rdquo; according to its symptoms. Based on thousands of years clinical practice, TCM has accumulated many experiences in the treatment of CHF, currently, CHM combined with western routine therapy have shown promising benefits in controlling symptoms, reducing mortality, improving cardiac function and promoting life quality in patients with CHF [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Within the framework of TCM theory, all the related symptoms, signs, tongue appearances and pulse feelings at a certain stage of disease are summarized as a syndrome (\u0026lsquo;\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eZheng\u003c/span\u003e\u0026rsquo; in TCM) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Syndrome is not only the core of TCM theory but also the base of definite diagnosis and effective therapies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In TCM, patients with CHF can be divided into varied syndromes, and according to previous data the syndrome of \u0026lsquo;blood stasis\u0026rsquo; is the most common and important subtype[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGuanxinshutong capsule (GXST), which is commonly used to treat CHD in China, was developed by Shaanxi Buchang Pharmaceutical Co., Ltd, and approved by China Food and Drug Administration (CFDA) for the treatment of CHD in 2002 (approval number Z20020055). GXST consists of five herbal medicines (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and was reported to promote blood circulation, remove blood stasis and relieve pain [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Experimental studies showed that GXST inhibited the ventricular remodeling process through increasing mitochondrial productivity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], repressing the expression of matrix metalloprotein 9, angiotensin receptors 1 and extracellular regulated protein kinases 2 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and transforming growth factor-β/Smad signaling pathway [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and finally to treat patients with CHF. A clinical trial with 61 patients reported that compared to conventional treatment, combination with GXST could significantly increase LVEF and cardiac output and reduce end-systolic and diastolic volume in acute myocardial infarction patients with CHF [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Meanwhile, in our previous clinical study, GXST exerted obvious effect on CHF (unpublished data) which implied it might be the potentially promising CHM for the treatment of CHF. However, current data of GXST as complementary therapy in CHF are insufficient, and the present clinical trials are limited in the methodology and sample size. Therefore, in this study, we conduct a large-scale, multi-center, double-blinded clinical trial to investigate the efficacy and safety of GXST in CHF caused with ejection fraction decrease (\u0026lt;\u0026thinsp;50%) by CHD.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eComponents of GXST (intervention drug)\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMain composition\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eChinese Pinyin\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eLatin scientific name\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003ePlant part\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eChoerospondiatis Fructus\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eGuang Zao\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eChoerospondiatis Fructus\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eFruit\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSalvia miltiorrhiza\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eDan Shen\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eSalvia miltiorrhiza Bunge\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eRhizome\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eClove\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eDing Xiang\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eCaryophylli Flos\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eFlower\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBorneol\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eBing Pian\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eBorneolum Syntheticum\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eResin\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTabasheer\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eTian Zhu Huang\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eConcretio Silcea Bambusae\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eResin\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eIn this trial, we aim to assess the efficacy and safety of GXST for CHF with ejection fraction decrease (\u0026lt;\u0026thinsp;50%) caused by CHD.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign and settings\u003c/h2\u003e \u003cp\u003eThis study is a prospective, randomized, double-blind, placebo-controlled, multicenter, superior trial.\u003c/p\u003e \u003cp\u003eResearchers must explain to participants the trial properties, purpose, potential benefits and risks, alternative treatment options, and the rights of participants under the Helsinki declaration, Participants fully understand and voluntarily sign the informed consent. After the participants have enrolled and signed the informed consent, participants will be randomized in a 2:1 ratio to the intervention group and the placebo group. The trial will be conducted by 11 medical centers throughout China (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and a total of 480 participants will be recruited. This trial consists of 1-week baseline period, 12-week intervention period and 40-week follow-up period. A flow diagram of the study procedures is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \n\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eResearch setting\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCode\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipating hospitals\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eSecond Affiliated Hospital of Zhejiang Chinese Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eZhoukou Central Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003ePingdingshan First People's Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eHangzhou First People's Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eFenyang Hospital of Shanxi Province\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eThe\u0026nbsp;Affiliated\u0026nbsp;Hospital\u0026nbsp;of Liaoning\u0026nbsp;University\u0026nbsp;of\u0026nbsp;Traditional\u0026nbsp;Chinese\u0026nbsp;Medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eLishui Traditional Chinese Medicine Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eFirst\u0026nbsp;People's\u0026nbsp;Hospital\u0026nbsp;of\u0026nbsp;Huzhou\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003ePizhouTraditional Chinese Medicine Hospital\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eZhumadian Central Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.657596371882086%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"89.3424036281179%\"\u003e\n \u003cp\u003eFirst Affiliated Hospital of Xinxiang Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\n\n\n \u003ch2\u003eStudy population\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria are as follows: (1) meet the diagnosis of CHD [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and CHF[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; (2) meet the diagnostic criteria of blood stasis syndrome in TCM [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; (3) aged 40 to 80, both male and female; (4) NYHA class II\u0026thinsp;~\u0026thinsp;III; (5) LVEF\u0026thinsp;\u0026lt;\u0026thinsp;50% (by two-dimensional echocardiographic Simpson method); (6) course of disease\u0026thinsp;\u0026ge;\u0026thinsp;3 months, stable condition in recent 1 month or receiving routine treatment with stable doses more than 1 month; (7) plasma NT-proBNP\u0026thinsp;\u0026ge;\u0026thinsp;125\u0026nbsp;ng/L; (8) volunteer, understand and sign informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003eThe exclusion criteria for recruitment of participants into the study are: (1) acute coronary syndrome occurred in the past 1 month; (2) plan to take cardiac surgery during the trial; (3) with severe diseases like cardiogenic shock, acute myocarditis, uncontrollable malignant arrhythmia, hypertrophic obstructive cardiomyopathy, pulmonary embolism or severe valvular disease requiring surgery; (4) uncontrolled hypertension with systolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;180\u0026nbsp;mmHg, diastolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;110\u0026nbsp;mmHg, or hypotension\u0026thinsp;\u0026lt;\u0026thinsp;90/50\u0026nbsp;mmHg; (5) with severe liver or kidney dysfunction or active liver disease, or AST, ALT\u0026thinsp;\u0026ge;\u0026thinsp;3 times the upper limit of normal; (6) psychiatric patients, or patients with severe depression, or a history of alcohol or drug abuse; (7) pregnant women, or breast-feeding women, or those who are trying to get pregnant during the trial; (8) with allergic constitution, or be allergic to test drug; (9) with previous or present tumor history, or with precancerous lesions confirmed by pathological examination; (10) participate in other clinical studies 3 months before this trial.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRandomization, allocation concealment mechanism and blinding\u003c/h2\u003e \u003cp\u003eParticipants are randomized to the intervention group or the placebo group in a 2:1 ratio using the Central Randomization System to achieve computerized randomization in blocks of 6, stratified by center. The random sequence will be placed in an envelope and subsequently sealed. According to the randomization number, the statistician will send the envelope directly to the Shaanxi Buchang Pharmaceutical Co., Ltd for the labeling of the invention and placebo drugs. All researchers, subjects, physicians, drug administrators and dispensing nurses will be blinded until the study is completed. The blinding codes can't be broken until all the clinical data are entered into eCRF database and locked, except subjects experience an SAE or need to be rescued in an emergency situation. Once unblinded, the cases will withdraw from the study, and researchers should report the reasons to the inspector within 24\u0026nbsp;h and the precise cause, date, treatment situation, and results should be recorded in eCRF.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eEligible patients will be randomly allocated to the intervention group and the placebo group, both of which are given conventional therapies.\u003c/p\u003e \u003cdiv id=\"FPar1\" renderingstyle=\"Style2\" class=\"FormalPara\"\u003e \u003ch2\u003eIntervention group\u003c/h2\u003e \u003cp\u003eGXST, 0.3\u0026nbsp;g/capsule, op, 3capsules/time, thrice daily;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"FPar2\" renderingstyle=\"Style2\" class=\"FormalPara\"\u003e \u003ch2\u003ePlacebo group\u003c/h2\u003e \u003cp\u003ecapsule stimulants, 0.3\u0026nbsp;g/capsule, op, 3capsules/time, thrice daily.\u003c/p\u003e \u003c/div\u003e \u003cp\u003eThe GXST and capsule stimulants are both provided by Shaanxi Buchang Pharmaceutical Co. Ltd. The capsule stimulant's primary content is starch and dextrin, adding food colorants and flavoring agents, and achieves a smell, color, taste, and texture comparable to GXST. After the treatment, the packaging will be returned to the researches.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003ePrimary and secondary outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome is the difference in 6 MWT [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The secondary outcomes are as follows: (1) changes in NT-proBNP; (2) improvement in heart function assessed by NYHA classifications [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (3) improvement of MLHFQ [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; (4) improvement in echocardiographic parameters of left ventricular end-diastolic diameter and LVEF; (5) incidence rate of clinical endpoint events (rehospitalization for CHF acute aggravation, cardiogenic death, and all-cause death); (6) improvement of blood stasis syndrome symptom scale score. According to the degree of the symptoms from normal, mild, moderate to severe, the scores of 0, 2, 4 and 6 will be given respectively of the primary symptoms and signs, and 0, 1, 2 and 3 of the secondary symptoms and signs. The higher the score, the severer the symptoms. The patient with syndrome scores decreasing by more than 70% are considered as effective cases, which will be counted as a percentage of all cases. The details of items to be measured and the time window of data collection are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\n\n\u003cp\u003e\u003cstrong\u003eTable 3. Study schedule\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eStudy phase Time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.34841628959276%\"\u003e\n \u003cp\u003eBaseline period\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" width=\"34.61538461538461%\"\u003e\n \u003cp\u003eIntervention period\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.027149321266968%\"\u003e\n \u003cp\u003eFollow-up period\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.532846715328468%\"\u003e\n \u003cp\u003eVisit 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.883211678832115%\"\u003e\n \u003cp\u003eVisit 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.613138686131386%\"\u003e\n \u003cp\u003eVisit 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.343065693430656%\"\u003e\n \u003cp\u003eVisit 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"22.62773722627737%\"\u003e\n \u003cp\u003eevery 4 weeks until 52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.830188679245282%\"\u003e\n \u003cp\u003e-7～0 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.11320754716981%\"\u003e\n \u003cp\u003e4 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.056603773584907%\"\u003e\n \u003cp\u003e8 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e12weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline data collection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eInclusion/exclusion criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eDemographic data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eGet the central random number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003ePrevious history、medical history and allergies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eConcomitant disease and treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSafety evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eVital signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003ePhysical examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eBlood routine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eUrine routine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eBlood biochemistry\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eMyocardial Zymogram and troponin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eECG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eChest X-ray or CT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eUrine pregnancy test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEfficiency evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e6MWT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eNT-proBNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eNYHA class\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eMLHFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e\u0026nbsp;Echocardiographic parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eBlood stasis syndrome symptom scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eClinical endpoint events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther work\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eDispense drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eRecovery and record of study drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eMetabolomics and proteomics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eRecord AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eConcomitant medications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.009049773755656%\"\u003e\n \u003cp\u003eEvaluate the adherence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.34841628959276%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.085972850678733%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.538461538461538%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.990950226244344%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.027149321266968%\"\u003e\n \u003cp\u003e×\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CT-computed tomography, 6MWT-6 min walk test, NYHA class classification of the New York Heart Association heart function, MLHFQ Minnesota Heart Failure Quality of Life Scale, AE adverse event.\u003c/p\u003e\n\n\n\n\u003ch2\u003eSafety outcomes\u003c/h2\u003e \u003cp\u003eSafety outcomes include vital signs (temperature, heart rate, breathing, and blood pressure), image examinations (X-ray or CT), laboratory examinations (blood and urine test, blood biochemistry test, myocardial zymogram, and troponin test, and urine pregnancy test) and AEs. AEs will be recorded throughout the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eMetabolomics and proteomics\u003c/h2\u003e \u003cp\u003e50 subjects are randomly selected and blood samples are taken for metabolomics and proteomics examination to explore the therapeutic biomarkers and pharmacodynamic material basis of GXST in treating CHF.\u003c/p\u003e \u003cp\u003eMetabolomics: gas chromatography-mass spectrometer (GC-MS) and liquid chromatograph-mass spectrometer (LC-MS) techniques are used to detect the chemical and biological fingerprints, describe the possible metabolic pathways, and identify biomarkers of GXST for the treatment of CHF.\u003c/p\u003e \u003cp\u003eProteomics: two-dimensional difference gel electrophoresis (2D-DIGE) method is used to establish the protein patterns; Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) is applied to identify differentially expressed proteins; bioinformatics is used to analyze the biological functions of differentially expressed proteins; String analysis and ingenuity pathway analysis (IPA) are applied to establish the protein network and explore the pharmacodynamic material basis of GXST for the treatment of CHF.\u003c/p\u003e \u003ch2\u003eData Management\u003c/h2\u003e \u003cp\u003eThe data management will be performed by the department of Medical Statistics, First Hospital of Peking University with electronic data management system (EDC). According to the requirements of Good Clinical Practice (GCP) and research plan, two researchers entry electronic case report form (eCRF) accurately, timely, completely and normatively. Clinical research associate adopt system automatic and manual logic verification to check the consistency of eCRF data and source data, and issues questions online at any time in case of any problem. After all subjects have completed the trial, all medical records have been entered into EDC, and the primary researcher, sponsor, statistical analyst and data management personnel review and confirm the data, then the data will be locked and submitted to the statistician for statistical analysis by the administrator. After the data is locked, data can be corrected in the statistical analysis program after confirmation, and if there is exact evidence to prove that it is necessary to unlock, the researcher and the sponsor need to sign relevant documents. After the trial, the data management report will be written according to the actual implementation of the project.\u003c/p\u003e \u003cp\u003eIn this study, due to CHM is added to the basic treatment of western medicine, which can guarantee the rights and therapeutic effects of patients, no data monitoring committee is established. Personal information about potential and enrolled participants will be protect confidentiality before, during, and after the trial, and researchers should keep the data for five years after the termination of the clinical trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe formula for calculating the sample size is as follows, which is based on the superior clinical trial sample size estimation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The sample size is driven by the expected improvement in 6MWT. Referring to previous clinical researches [\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], we assumed that the improvement in 6MWT is 30 meters, and the combined standard deviation (SD) is 100 meters in this study. Given a type I error rate of α\u0026thinsp;=\u0026thinsp;0.025, a power of 80% (type II error rate of β\u0026thinsp;=\u0026thinsp;0.2), considering of 20% possible dropout rate, a total of 470 patients need to be allocated. For the convenience of randomization, the final sample size was 320 cases in the intervention group and 160 cases in the placebo group, total of 480 cases.\u003c/p\u003e\n\u003cp style=\"text-align: center;\"\u003e\n \u003cimg src=\"data:image/png;base64,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\" style=\"width: 276px;\"\u003e\n\u003c/p\u003e\n\n\u003cp\u003eIn this formula k is the ratio between two sample cases, δ is the expected improvement in 6MWT, σ is the combined SD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis plan (SAP) will be specified before data analysis. The statistical analysis will be performed by the department of Medical Statistics, First Hospital of Peking University using SAS software version 9.4 (or higher version). The full analysis set (FAS) includes patients who received allocated treatment and provided assessable outcome data. The safety analysis set (SAS) includes patients who received allocated treatment at least once. The per protocol set (PPS) includes patients who received allocated treatment and for whom planned outcome data as per the protocol are available. According to the intention-to-treat (ITT) principle, the FAS is used for the primary endpoint, and the FAS and PPS are used for the important secondary and other secondary endpoints. For quantitative data, we will calculate the mean, SD, median, minimum, maximum, interquartile range, and for classified data, we will describe various cases and percentages.\u003c/p\u003e \u003cp\u003eInter-group comparisons will be analyzed by appropriate methods according to the type of data, independent t-test (homogeneity of variance, normal distribution) or Mann-Whitney-Wilcoxon test (nonnormal distribution) will be used for comparison of quantitative data, chi-square test or Fisher's exact test (if chi-square test is not applicable) will be used for classified data, and Wilcoxon rank-sum test or Cochran-Mantel-Haenszel test will be used for ranking data. Paired t-test will be applied to assess the difference of outcome before and after treatment in the same group. Significance will be assumed at a \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003ep\u003c/span\u003e level of less than 5%. The superiority of the GXST group to the placebo group in terms of 6MWT will be examined with a superiority of 30 metres. The last observation carried forward (LOCF) method is used for missing values.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eAny AEs that occur during the observation period must be recorded. AEs within one week after the end of the trial are recorded by the patient's initiative reporting method. The development of AEs will also be observed until all the AEs disappear. The classification and coding of AEs are formulated with reference to Common Terminology Criteria for AEs 4.03.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eQuality control of the intervention\u003c/h2\u003e \u003cp\u003eIn order to further ensure the quality of this trial, a multi-center trial Coordination Committee and the general director are set up to implement and solve related problems. The Coordination Committee includes the leaders of each center and the head of sponsor, and all passes pre-clinical training. All staff including the operators, researchers, physicians, data collectors, and analyzers can fully understand the purpose and content of the trial. This trial is inspected by the CFDA, sponsor and clinical research organization throughout the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eEthics and dissemination\u003c/h2\u003e \u003cp\u003eThis study has approved by the Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (No. 2019-Y-003-02), and all participate centers will receive approval from their local ethics committee. All data will be recorded in eCRF and imported into public clinical trial management platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.medresman.org\u003c/span\u003e\u003c/span\u003e) and posted on Chinese Clinical Trial Registry within 6 months after completion of the trial. Study results will be published in academic conferences and peer-reviewed journals.\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eCHF is a global public health problem. According to the 2018 China Cardiovascular report [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], hypertension and CHD are the main causes of HF. An analysis of the predisposing factors of 426 elderly patients with HF suggests that CHD is the leading cause of HF, accounting for 43.2% [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. GXST was approved by CFDA for the treatment of CHD in 2002. Experimental studies and small-sample clinical trials have confirmed that GXST could reduce the symptoms of the patients with CHF [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, we choose CHF with ejection fraction decrease (\u0026lt;\u0026thinsp;50%) caused by CHD as the inclusion criteria.\u003c/p\u003e \u003cp\u003eCurrently, there are three methods for the assessment of functional capacity and exercise tolerance in patients with HF. First, the self-assessed or physician-reported categorization of patients\u0026rsquo; physical status which is mainly dependent on the patients\u0026rsquo; perceives. Second, peak oxygen consumption, which is a maximal symptom-limited exercise test (cardiopulmonary exercise test; CPET), will explain the reason of dyspnea and fatigue based on the assessment of all systems involved in physical activity. However, because of the demand for special equipment and trained personnel, it is unavailable in some hospital settings. Third, submaximal exercise tests including 6MWT, which is well-tolerated by patients. 6MWT is a simple and inexpensive test that requires no special equipment and advanced training for physicians and assesses the submaximal level of functional capacity of patients while walking on a flat barrier-free corridor in a period of 6\u0026nbsp;min [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. NT-proBNP, as an important biomarker of cardiac function, is recommended for the diagnosis, screening, differential diagnosis, severity and prognosis evaluation of HF [\u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In this study, we choose 6MWT as the primary outcome and NT-proBNP as the secondary outcome. In order to reduce the possible differences caused by the detection of each center, metabolomics, proteomics, and NT-proBNP adopt centralized detection methods. The samples are tested in the Central Laboratory of Zhejiang Chinese Medical University.\u003c/p\u003e \u003cp\u003eTCM has developed for thousands of years and is one of the positive signs of globalization in the world. An increasing proofs demonstrates that integrative medicine, combined with TCM and western medicine, emerges as an optimal approach for achieving better effectiveness in patients with CHF [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. According to the TCM theory and syndrome differentiation, blood stasis syndrome is the core pathogenesis of CHF [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and GXST play an important role in promoting blood circulation and removing blood stasis and is optimal for treating CHF. As the principal active components, \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003esalvia miltiorrhiza\u003c/span\u003e and \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003echoerospondiatis fructus\u003c/span\u003e were showed to perform the function of microcirculation improvement, vascular endothelial cells protection, anti-arrhythmia, and antioxidation [\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eCaryophylliflos\u003c/span\u003e was effective in anticoagulation, antiplatelet aggregation and antithrombotic [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. However, whether GXST as the supplementary therapy is better than western medicine alone in patients with CHF still requires confirmation by large sample, multicentre and randomized controlled clinical trials. This study is a multicentre, double-blinded, placebo-controlled clinical trial with the hope of verifying the effectiveness and safety of GXST for the treatment of CHF with ejection fraction decrease (\u0026lt;\u0026thinsp;50%) caused by CHD.\u003c/p\u003e \u003cp\u003eThere are also some limitations in this study. Firstly, this experiment will be conducted in five provinces of China. Whether similar effects are obtainable to other regions and ethnic groups remain uncertain. Secondly, this study is only 52 weeks in duration; further data on long-term clinical effect and safety are needed. Thirdly, GXST used in this trial is designed for the treatment of CHF with blood stasis syndrome; thus, the findings may not be applicable to other CHF syndromes.\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic Heart failure;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTraditional Chinese medicine;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGXST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGuanxinshutong capsule;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChinese herbal medicine;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCFDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChina Food and Drug Administration;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecoronary heart disease;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e6MWT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e6\u0026nbsp;min walk test;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNYHA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNew York Heart Association;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMLHFQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMinnesota heart failure quality of life scale;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse events;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic case report forms;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStatistical Analysis System;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACEI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAngiotensin converting enzyme inhibitors;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVEF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeft ventricular ejection fraction;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGC-MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGas chromatography-mass spectrometer;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLC-MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLiquid chromatograph-mass spectrometer;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e2D-DIGE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTwo-dimensional difference gel electrophoresis;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMALDI-TOF-MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMatrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eingenuity pathway analysis;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estatistical analysis plan;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efull analysis set;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esafety analysis set;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eper protocol set;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eITT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintention to treat;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLOCF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elast observation carried forward;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelectronic data management system;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGood Clinical Practice;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelectronic case report form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation;\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPED\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCardiopulmonary exercise test.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University has approved this study (No. 2019-Y-003-02), and all participate centers will receive approval from their local ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is supported by the National Natural Science Foundation of China \u0026nbsp;(No.81630105), the National Key R\u0026amp;D Program of China (2017YFC1700400, 2017YFC1700403).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHW, SH, and FW designed the study. YW and JX contributed equally to the article, who conceptualized the study design and wrote the manuscript. LZ, JY modified the manuscript. YP, YH, and CL are responsible for the quality control of the test drug. LD, YX, JC, HZ, and LY participated in the modification of this protocol. PZ, JY designed the method for statistical analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgement\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCoronel R, de Groot JRD, van Lieshout JJ. Defining heart failure. Cardiovasc Res. 2001; 50(3):419-422. https://doi.org/1016/S0008-6363(01)00284-X.\u003c/li\u003e\n\u003cli\u003eTan LB, Williams SG, Tan DK, Cohen-Solal A.So many definitions of heart failure: Are they all universally valid? A critical appraisal. Expert Rev Cardiovasc Ther. 2010; 8(2):217. https://doi.org/1586/erc.09.187.\u003c/li\u003e\n\u003cli\u003eAmbrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: Lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63(12):1123-1133. https://doi.org/10.1016/j.jacc.2013.11.053.\u003c/li\u003e\n\u003cli\u003eGuo DF, Huang GY, Wu XG, Duan XF, He J, Whelton PK, et al. Epidemiological survey and prevalence of heart failure in China. Chin J Cardiol. 2003;(01):6-9.\u003c/li\u003e\n\u003cli\u003eHuo ST, Gao RL, Liu LS, Zhu ML, Wang W, Wang YJ, et al. Summary of China cardiovascular disease report 2018. Chin Circul J. 2019;34(03):209-220.\u003c/li\u003e\n\u003cli\u003eHeart Failure Group of Chinese Society of Cardiology, Editorial Board of Chinese Journal of Cardiology. Guidelines for diagnosis and treatment of heart failure in China. Chin J Cardiol. 2018;46(10):760.\u003c/li\u003e\n\u003cli\u003eXu BL, Xu XG. Clinical research progress of chronic heart failure treated by traditional Chinese Medicine. Clin J Chin Med. 2011;3(23):27-28.\u003c/li\u003e\n\u003cli\u003eJiang M, Zhang C, Zheng G, Guo H, Li L, Yang J, et al. Traditional Chinese medicine zheng in the era of evidence-based medicine: A literature analysis. Evid Based Complement Alternat Med. 2012;2012:409568. https://doi.org/10.1155/2012/409568.\u003c/li\u003e\n\u003cli\u003eXu H, Chen KJ. Integrative medicine: The experience from china. J Altern Complement Med. 2008;14(1):3-7. https://doi.org/1089/acm.2006.6329.\u003c/li\u003e\n\u003cli\u003eCui XL, Mao JY, Wang XL, Wang HX, Li GZ, Liu HW, et al. Expert investigation and analysis of Traditional Chinese Medicine Syndromes of heart failure. J Shanghai Univ Tradi Chin Med. 2009;23(02):31-33.\u003c/li\u003e\n\u003cli\u003eZhang Y, Wang Y, Li H, Wang SY, Tian M, Gong LH. Effect of guanxin shutong capsule on ATP metabolism in rats with heart failure. Word J Integ Tradi \u0026amp; West Med. 2016;(11):1523-1525.\u003c/li\u003e\n\u003cli\u003eZhang Y, Liu XN, Wang Y, Wang SY, Gong LH. Effect of guanxin shutong capsule on myocardial energy metabolism in rats with chronic heart failure. J Tradi Chin Med. 2015;56(23):2054-2057.\u003c/li\u003e\n\u003cli\u003eZhang Y, Liao JD, Wang C, Liu Y, Gong LH, Gao SS. Effect of guanxin shutong capsule on MMP-9 in myocardium of rats with chronic heart failure. J Shanghai Univ Tradi Chin Med. 2012;(6): 83-85.\u003c/li\u003e\n\u003cli\u003eZhang Y, Wang C, Gong LH, Liao JD, Gao SS. Effect of guanxin shutong capsule on at 1 and erk 2 in chronic heart failure rats. Inter J Tradi Chin Med. 2013;35(1): 37-39.\u003c/li\u003e\n\u003cli\u003eFang HL, Liu F, Han NJ, Niu R, Zhao M, Chen YF. The study of the mechanism of guanxin shutong capsule inhibits TGF-\u0026beta;/Smad signal pathway and improves the isoproterenol induced cardiac remodeling in rats. Tradi Chin Drug Res \u0026amp; Clin Pharm. 2019;5:516-522.\u003c/li\u003e\n\u003cli\u003eLi F. The therapeutic effect of guanxin shutong capsule combined with clopidogrel on patients with acute myocardial infarction and heart failure. J Med Theor \u0026amp; Pract. 2019;32(08):1150-1151.\u003c/li\u003e\n\u003cli\u003eInterventional cardiology, atherosclerosis and coronary heart disease group of Chinese Society of Cardiology, Thrombus prevention and treatment Committee of cardiovascular physician branch of Chinese Medical Doctor Association. Guidelines for diagnosis and treatment of stable coronary heart disease. Chin J Cardiol. 2018;46(9):680-694.\u003c/li\u003e\n\u003cli\u003eZhang ZS. Congestive heart failure. Scientific and Technical Documentation Press；\u003c/li\u003e\n\u003cli\u003eZheng SY. Guidelines for Clinical Research of New Drugs in TCM. China Medical Science Press；\u003c/li\u003e\n\u003cli\u003eHolland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, et al. An official european respiratory society/american thoracic society technical standard: Field walking tests in chronic respiratory disease.Eur Respir J.2014;44(6):1428-1446. https://doi.org/1183/09031936.00150314.\u003c/li\u003e\n\u003cli\u003eThe Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed.Boston: Mass: Little, Brown and Co; 1994.\u003c/li\u003e\n\u003cli\u003eRector TS, Cohn JN. Assessment of patient outcome with the minnesota living with heart failure questionnaire: Reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan multicenter research group. Am Heart J. 1992;124(4): 1017-1025.https://doi.org/10.1016/0002-8703(92)90986-6.\u003c/li\u003e\n\u003cli\u003eWan X, Zh L, Liu JP. Estimation of sample size in clinical studies: (1) clinical trials. J Tradi Chin Med. 2017;48:504\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eFan LH, Zhang GZ. Clinical observation on 45 cases of acute coronary syndrome treated by guanxin shutong capsule combined with conventional Western Medicine. J Tradi Chin Med \u0026amp; Pharm. 2012;18(11):33-35.\u003c/li\u003e\n\u003cli\u003eDu XF. Clinical effect of guanxin shutong capsule combined with conventional Western Medicine on patients with acute coronary syndrome. J Jilin Med. 2014;35(34):7653-7654.\u003c/li\u003e\n\u003cli\u003eWu ZJ, Huang XX, Chen J. Clinical observation of guanxin shutong capsule combined with Western Medicine in the treatment of angina pectoris of coronary heart disease. J New Chin Med. 2015;47(01):43-44.\u003c/li\u003e\n\u003cli\u003eGuo DQ, Li P. Clinical observation of guanxin shutong capsule in the treatment of unstable angina pectoris. Chin J Clinic. 2013;41(12):37-38.\u003c/li\u003e\n\u003cli\u003eNa KX, Zhang GY, Tian J, Qin H, Ma LQ, Yu P.An analysis of the predisposing factors of 426 elderly patients with HF. Chin J Med. 2008;43(6):41-42.\u003c/li\u003e\n\u003cli\u003ePonikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891\u0026ndash;975. https://doi.org/10.1002/ejhf.592.\u003c/li\u003e\n\u003cli\u003eYancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147\u0026ndash;239.https://doi.org/10.1016/j.jacc.2013.05.019.\u003c/li\u003e\n\u003cli\u003eChinese Society of Cardiology，Editorial board of Chinese Journal of Cardiology. Guidelines for diagnosis and treatment of heart failure in China 2014. Chin J Cardiol. 2014;42(2):3-10.\u003c/li\u003e\n\u003cli\u003eBooth RA, Hill SA, Don-Wauchope A, Santaguida PL, Oremus M, McKelvie R, et al. Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review. Heart Fail Rev. 2014; 19(4): 439-451. https://doi.org/1007/s10741-014-9445-8.\u003c/li\u003e\n\u003cli\u003eRoberts E, Ludman AJ, Dworzynski K, Al-Mohammad A, Cowie MR, McMurray JJ, et al. The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting. BMJ. 2015;350:h910. https://doi.org/10.1136/bmj.h910.\u003c/li\u003e\n\u003cli\u003eLi WK. Clinical observation on the treatment of chronic heart failure with the combination of traditional Chinese and Western Medicine. J Pract Med Techn. 2008;(10):1317-1318.\u003c/li\u003e\n\u003cli\u003eLai WW, Zhao WA, Chen GZ, Lin WQ, Xu CX, CAI KX, et al. Observation on the therapeutic effect of Yiqi Huoxue formula combined with sakubatrevalsartan on patients with chronic heart failure. Chin J Moder Appl Pharm. 2019;36(18):2312-2316.\u003c/li\u003e\n\u003cli\u003eLiu T, Ma LP. Curative effect observation of the treatment of refractory heart failure with Qiliqiangxin capsule and Xinmailong injection. World Latest Med Infor. 2019; 19(52):248+268.\u003c/li\u003e\n\u003cli\u003eChinese Rehabilitation Medical Association Professional Committee of Cardiovascular Diseases, Committee of Cardio-Cerebral-Vascular Diseases of GSC. Chinese expert consensus on cardiac rehabilitation for patients with chronic stable heart failure. Chin J Cardiol. 2014;42:714\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eChinese Society of Cardiology of Chinese Medical Association, Editorial Board of Chinese Journal of Cardiology. Chinese guidelines for the diagnosis and treatment of heart failure 2014. Chin J Cardiol. 2014;42:98\u0026ndash;122.\u003c/li\u003e\n\u003cli\u003eZhao N, Guo ZX, Zhao X, Zhao LB. Chemical constituents and pharmacological action of Salvia miltiorrhiza. J Fore Med. 2007;(04):155-160.\u003c/li\u003e\n\u003cli\u003eChen XR, Lu JB, Shi HP. New progress in the pharmacological study of Salvia miltiorrhiza. Chin J Hosp. 2001;(01):44-45.\u003c/li\u003e\n\u003cli\u003eZhou J, Gao SP, Mei XL. Research progress of Mongolian medicine Guangzao. Strait Pharm J. 2017;29(06):1-5.\u003c/li\u003e\n\u003cli\u003eZhu JD, Yuan DJ, Lin XY. Current situation of pharmacological research and clinical application of Caryophylli flos. Chin J Pharm Econ. 2013; (01):32-35.\u003c/li\u003e\n\u003c/ol\u003e\n"},{"header":"Contributions to the literature","content":"\u003cul\u003e\n\u003cli\u003eThis study is a double-blind, placebo-controlled trial of Guanxinshutong capsule as add-on therapy, provides a strategy with the combination of Chinese and western medicine in chronic heart failure patients.\u003c/li\u003e\n\u003cli\u003eThis is a pilot study to explore the efficacy and safety of Guanxinshutong capsule on chronic heart failure with ejection fraction decrease, provides a preliminary basis for expanding the scope of application of Guanxinshutong capsule.\u003c/li\u003e\n\u003cli\u003eThis study will apply metabolomics and proteomics examination to explore the therapeutic biomarkers and pharmacodynamic material basis of Guanxinshutong capsule in treating chronic heart failure, provides a novel ideas for precision treatment.\u003c/li\u003e\n\u003c/ul\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Guanxinshutong capsule, Chronic heart failure, Coronary heart disease, Chinese medicine, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.2.22735/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.22735/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground \u003c/p\u003e\u003cp\u003eChronic Heart failure (CHF) is a global epidemic and common cardiovascular disease with high mortality and poor prognosis, which bring heavy burdens to society and family. Traditional Chinese medicine (TCM) has been extensively used in China as an adjunct treatment for CHF. Guanxinshutong capsule (GXST), approved by the China Food and Drug Administration (CFDA) in 2002 (No. Z20020055), is commonly used Chinese herbal medicine (CHM) for the treatment of coronary heart disease (CHD) currently. Both experimental research and small-sample clinical trials have shown that GXST could attenuate CHF. However, the effects of GXST on CHF as an adjunct therapy are lack of high-quality clinical evidence. This study is a large-scale, multi-center, double-blinded clinical trial to explore the efficacy and safety of GXST in CHF with ejection fraction decrease (\u0026lt;50%) caused by CHD. \u003c/p\u003e\u003cp\u003eMethods \u003c/p\u003e\u003cp\u003eThis study is a multi-center, randomized, double-blind, placebo-controlled clinical trial. After 1week baseline period, a total of 480 participants will be randomly assigned to the intervention group and placebo group in ratio 2:1. Based on routine medications, the intervention group will be treated with GXST while the control group will be treated with placebo (both 0.3g/capsule, op, 3 capsules/time, thrice daily) for 12 weeks, and then be followed-up for another 40 weeks. The primary outcome is the effect of 6 min walk test (6MWT). The secondary outcomes include NT-proBNP, classification of the New York Heart Association (NYHA) heart function, Minnesota heart failure quality of life scale (MLHFQ), echocardiographic parameters, blood stasis syndrome symptom scale and clinical endpoint events. Metabolomics and proteomics will also be assessed. Adverse events (AEs) will be monitored throughout the trial. All the data will be recorded in electronic case report forms (eCRF) system database and analyzed in accordance with a predefined statistical analysis plan. Ethical approval of this trial has been granted by the Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (ID: 2019-Y-003-02). Written informed consent of patients will be required. The results will be disseminated to the public through peer-reviewed journals and academic conferences.\u003c/p\u003e\u003cp\u003e Discussion \u003c/p\u003e\u003cp\u003eThis study integrates the advantages of TCM and western medicine in the treatment of CHF, the result of this study will offer the efficacy and safety evidence of GXST on CHF with ejection fraction decrease (\u0026lt;50%).\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Chinese herbal medicine Guanxinshutong capsule for the treatment of chronic heart failure with ejection fraction decrease (\u0026lt;50%) caused by coronary heart disease: study protocol for a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-02-06 17:37:30","doi":"10.21203/rs.2.22735/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3fbd75d1-6fa1-4c2f-8c30-f7978788b50b","owner":[],"postedDate":"February 6th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56232,"name":"Cardiac \u0026 Cardiovascular Systems"},{"id":56233,"name":"Internal Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":[],"versionCreatedAt":"2020-02-06 17:37:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-13309","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-13309","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}