Study design
This is a single-center, prospective, parallel, randomized controlled trial. Based on a computer-generated randomized number, 64 patients with HFNEF will be randomly assigned to either the treatment or control group. Patients in the treatment and control groups will be treated with a drug intervention for 2 weeks and followed up for 12 weeks. We will terminate this test when the following situations occur: 1) a serious safety incident occurred during the test; 2) there are major errors in the clinical trial protocol; 3) serious deviations occur so that it is difficult to evaluate the efficacy of the drug; and 4) the project management department cancels the test. A data monitoring committee will be established, mainly to make interim analysis and assess adverse events. The committee will review the core trial processes and documents, and discuss any amendments to the main study protocol. Any adverse event will be recorded in the CRF and reported to the data monitoring committee in a timely manner. We will provide appropriate compensation for any injured subjects. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is provided as Additional file 1.
Participants
All of the 64 patients with HFNEF will be enrolled in the Department of Cardiology, the First Teaching Hospital of Tianjin University of TCM. First, the patients will be fully introduced to the benefits and risks of the treatment. Second, the patients need to sign the informed consent on a voluntary basis. Then, the patients will be divided into the treatment (Yangying Shuxin Decoction combined with the standard treatment) or control (standard treatment) groups according to the coding sequence from the pre-set random number table. The inclusion and exclusion criteria are shown in Table 1.
Table 1. Eligibility criteria
A. Inclusion criteria
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B. Exclusion criteria
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1. Age>40 years;
2. Patients with the following symptoms and/or signs:
1)Symptoms: shortness of breath or weakness or reduced exercise endurance or dyspnea at night or orthopnoea;
2)Signs: jugular hypertension, hepatojugular reflux, galloping rhythm, cardiac hypertrophy, weight gain, peripheral edema, or pulmonary rales
3. LVEF ≥50%;
4. BNP>35pg/mL;
5. Meet at least one of the following criteria:
1)There are cardiac structural changes: left atrial enlargement (LAVI>34 ml/m2) or left ventricular hypertrophy (LVMI: male>115 g/m2, female>95 g/m2);
2)Diastolic dysfunction: E/e′≥13 and e′<9 cm/s;
6. Sign the informed consent
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1. Acute coronary syndrome, congenital heart disease, severe valvular disease, constrictive pericarditis, hypertrophic cardiomyocyte, and restrictive cardiomyopathy;
2. Patients with history of intracoronary stent implantation, permanent pacemaker, implantable defibrillator (ICD), or left ventricular assist device implantation or coronary artery bypass grafting within nearly 90 days;
3. Systolic pressure >160 mmHg or <90 mmHg at intake;
4. Chronic lung disease requiring oxygen therapy or drug intervention;
5. Cerebral infarction within 90 days;
6. Special treatments should be used for patients with comorbidities such as severe liver or renal failure and malignant tumor, which could influence the clinical treatment of HFNEF;
7. Pregnant or breastfeeding women, or women at childbearing age without reliable methods of contraception;
8. Unable to complete cardiorespiratory exercise test;
9. Poor patient compliance;
10. Participated in other studies within 2 months
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The follow-up period was 12 weeks. A full physical examination and assessment of adverse events will be performed for all participants. After the patient signs the informed consent form, we will collect general information including demographics, medical history, and concomitant medications. Two clinical controls were performed at the time of enrollment (V1) and week 2 (V2). Indicators include cardiac ultrasound, CPET, BNP, NYHA cardiac function grading, EQ-5D-5L, TCM four-diagnostic information score, syndrome judgment, blood pressure, heart rate, weight, and so on. Blood and urine samples will also be taken. During the follow-up period, the investigator will contact the participants via telephone at weeks 4 (V3), 8 (V4), and 12 (V5) to monitor the patient's blood pressure, weight, NYHA cardiac function, hospitalization/outpatient costs, and compound endpoint events to assess the patients’ quality of life. This program was prepared in accordance with the standard protocol project SPIRIT 13. The specific process of the study is shown in Table 2.
Table 2. Research access flow chart
Study phase
Items
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Screening/enrolment
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Follow-up
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Time
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Baseline
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Week 2
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Week 4
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Week 8
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Week 12
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Visit
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V1
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V2
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V3
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V4
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V5
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Confirm eligibility
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Ö
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Written informed consent
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Ö
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Data collection
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General data
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Ö
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Medical history
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Ö
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Physical examination
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Ö
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Ö
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Current medications
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Ö
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Ö
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Dispense drugs
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Ö
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Record drug recall
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Ö
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Compliance judgment
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Ö
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Observation of efficacy
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CPET
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Ö
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Ö
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Echocardiography
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Ö
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Ö
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NYHA classification
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Ö
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Ö
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Ö
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Ö
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Ö
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EQ-5D-5L
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Ö
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Ö
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|
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TCM 4 diagnostic information
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Ö
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Ö
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Chinese medical syndrome elements
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Ö
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Ö
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BNP, BUA
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Ö
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Ö
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UAlb, Cr, UAlb/Cr
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Ö
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Ö
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Endpoint event
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Ö
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Ö
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Ö
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Ö
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Hospitalization/outpatient costs
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|
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Ö
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Ö
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Ö
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Safety observation
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Ö
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Ö
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Ö
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Ö
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Ö
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Blood pressure, heart rate, weight
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Ö
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Ö
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Ö
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Ö
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Ö
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Blood tests
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Ö
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Ö
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CR, BUN, ALT
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Ö
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Ö
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Electrolyte
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Ö
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Ö
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Adverse events
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Ö
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Ö
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Ö
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Ö
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Ö
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Study completion status
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Ö
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CRF examination
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Ö
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Note: BUA: blood uric acid; UAlb: urine microalbumin; CRF: case report form.
Interventions
Other TCM preparations are not allowed during the washout period for two weeks. The patients in the treatment group will be treated with conventional western medicine combined with Yangyin Shuxin Decoction 150 ml, twice a day. All Chinese herbal medicines in Yangyin Shuxin Decoction are from the Department of Pharmacy, the First Teaching Hospital of Tianjin University of TCM. The decocting room is uniformly fried and made into a vacuum package of 150 ml. The remaining decoction will be recycled if the participants withdraw from the test midway. The patients in the control group will receive conventional western medicine treatment. The duration will be 2 weeks. Both groups will be interviewed at the following time points: enrollment (V1), week 2 (V2), week 4 (V3), week 8 (V4), and week 12 (V5) after enrollment.
The TCM theory believes that patients with HFNEF have clinical syndrome characteristics of yin deficiency, blood stasis, and internal heat.15 Each of the single-drug ingredients in Yangyin Shuxin Decoction includes a variety of compounds such as polyphenols, terpenoids, saponins, and alkaloids that are beneficial to the cardiovascular system. The relevant bioactive ingredients and potential mechanisms are shown in Table 3. These ingredients have the combined effects of improving heart and lung functions, increasing activity tolerance, improving microcirculation, and improving immunity and body antioxidants in patients with HFNEF.
Western medicine standard treatment plan is implemented according to the “China Heart Failure Diagnosis and Treatment Guide 2014”16 and “2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure”17. The Western medicine standard treatment includes health education for patients to help them establish a heart-healthy lifestyle (such as salt restriction, water restriction, weight monitoring, physical exercise, smoking cessation, alcohol withdrawal, and so om) and medication guidance and emergency management instructions. In addition, other TCMs for the treatment of cardiovascular diseases should be avoided.
Table 3. Cardiovascular effects and potential mechanisms of active ingredients
Herbs
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Bioactive ingredients
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Beneficial effects
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Potential mechanisms
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Ref.#
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Fructus corni
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Cornus officinalis saponins
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Anti-inflammatory;
protecting the cardiovascular and cerebrovascular system;
inhibiting myocardial cell apoptosis; reverse cardiac hypertrophy
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Decreasing the activity of serum CPK and LDH;decreasing the expression of P47phox and Nox4 in the myocardium
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18,19
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Radix
Ophiopogonis
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Total saponins of Ophiopogon;
Polysaccharide MDG-1 from Ophiopogon japonicas;
Ophiopogon D
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Promoting myocardial injury, healing and narrowing the infarction and necrotic areas
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Reducing malondialdehyde and free fatty acids; effects on the pituitary adrenocortical system
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20,21
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Rhizoma Polygonatum
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PP;
EE of Rhizoma
Polygonatum
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Inhibiting myocardial cell apoptosis;
enzyme inhibition, anti-inflammation, anti-oxidation
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Inhibiting the release of various enzymes;
increasing SOD activity and decreasing MDA content
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22
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Coptidis rhizoma
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Alkaloids;
berberine
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Positive inotropic action;
vasodilatation; heart cell protection; antiapoptotic
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Blocking K+ channels;
activating AMP protein activated protein kinase and P13K/Akt pathways
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23,24
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Carapax trionycis
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Trionyx sinensis polysaccharides;
Trionyx sinensis extract (TSWE)
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Resistance to hypoxia;
improving immune function
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Increasing the activity of LDH
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25
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Radix Salviae miltiorrhizae
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Terpenoids
Tanshinones
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Antiatherogenic;
cardiac cytoprotective; antioxidant; anti-inflammatory; antithrombotic
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Inhibiting the calcineurin/NFAT pathway;
antiapoptosis
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26,27
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Lumbricus
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Unsaturated fatty acid
Vaccenic acid
arachidonic acid
Platelet-like activating factor
Lumbricus peptides
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Thrombolysis and anticoagulation;
Antihypertensive;
regulation of the immune
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Reducing platelet adhesion and prolonging thrombosis;
Inhibiting ACE activity
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28
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Rhizoma pinelliae
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Alkaloids
Organic acids
Volatile oils
β-stanols
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Anti-arrhythmia;
increase coronary flow;
protecting the heart ischemia reperfusion injury and vascular endothelial cell injury
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Decreasing the activity of serum lactate dehydrogenase and phosphocreatine kinase;
Inhibiting LPS stimulates endothelial cells to secrete the inflammatory cytokines, interleukin-6 and tumor necrosis factor-alpha
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29-31
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Trichosanthes peel
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Volatile oils
amino acids
flavonoids
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Anti-myocardial ischemia;
anti-atherosclerosis;
protecting vascular endothelium;
dilating blood vessels;
resistance to hypoxia
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Enhancing free radical scavenging ability;
decreasing INOS activity and NO synthesis and free radical formation
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32
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Fructus Aurantii
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Alkaloid synephrine
N-methyltyramineflavonoids
hesperidin
Nobisexualletin
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Raising blood pressure;
anti-atherosclerosis;
inhibiting thrombosis
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Promoting-adrenalin secretion indirectly;
maintaining osmotic pressure;
inhibiting vascular sclerosis
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33
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Note: CPK: creatine phosphokinase; LDH: lactate dehydrogenase; PP: polygonatum polysaccharide; EE: ethanol extract; SOD: superoxide dismutase; MDA: malondialdehyde; AMP: adenosine monophosphate; K+: calcium ion; P13K: phosphatidylinositol 3-kinase.
Outcomes
Primary outcome: the change of Peak VO2 in cardiopulmonary exercise test .
Secondary outcomes:
▸anaerobic threshold and ventilatory equivalent for carbon dioxide (VE/VCO2) slope detected in the cardiopulmonary exercise test.
▸E/e′, LAVI, LVMI, and TR detected with ultrasonic cardiogram.
▸BNP, NYHA cardiac function grading, EQ-5D-5L, TCM four-diagnostic information score, syndrome judgment, compound endpoint events, and so on.
Security outcomes: Vital signs, some laboratory tests, and adverse events are considered as safety outcomes. Vital signs, including blood pressure and heart rate, routine laboratory tests (routine urinalysis, routine blood test, and hepatic and renal functions), and electrocardiograms, and the adverse events will be documented at each visit.
Patient and public involvement
The patients or the public were not involved in the design or in conducting, reporting, or disseminating our research.
Sample size
The sample size is computed based on the literature “Effect of If-channel inhibition on hemodynamic status and exercise capacity in heart failure with preserved ejection fraction: a randomized trial”,34 peak VO2 on day 7 is 3.0±3.6 ml/kg/min in the treatment group and 0.4±2.7 ml/kg/min in the control group. Sixty-four patients will be recruited with a single-sided alpha of 0.05, a power (1-β) of 0.90, and a dropout rate of 20%. The calculation formula is as follows35:
[See supplementary files for formula.]
Blinding
Blinding the researchers responsible for the implementation and patients included is not possible due to the particularity of dosage forms. The investigators are responsible for distributing the drugs. To ensure the reliability of the test, the personnel and statistical experts performing the outcome index evaluation will be blinded. All research team members were instructed not to communicate with the participants regarding their allocation.
Data collection and management
To assess the patients’ health status since the last visit and HFNEF-related re-hospitalization or unplanned medical conditions throughout the study period, the two groups will be contacted every 2 weeks or a month. All original data will be observed directly by clinical researchers and documented completely and timely in the case report form (CRF), including the reasons why patients cannot participate. To ensure the reliability of data, the CRF will be entered by the double-entry method. All errors will be crossed out and corrected and signed by the corresponding investigator. All these data will be locked in a separate cabinet. Only authorized investigators are permitted to access this information.
Statistical analysis
SPSS23.0 statistical analysis software will be used to calculate the test data, and descriptive statistics will be conducted for all the data. For the differences between the test groups, chi-square test will be used for the counting data. The t-test will be applied when normality (and homogeneity of variance assumptions) is satisfied, otherwise the rank sum test will be used.
The number of screened patients and reasons for exclusion will be reported, as well as protocol violations and reasons. An effectiveness analysis will be conducted using the randomized populations. Participants who have received treatment but there is no valid evaluation data will be considered as missing and will be included in the effectiveness analysis.