Chronic heart failure (CHF) is a complex clinical syndrome, a severe stage of various heart diseases, with a high morbidity and a 5-year survival rate similar to that of malignant tumors. Despite rapid medical advances and advances in various therapeutic options, the incidence of heart failure will continue to grow in the near future and is emerging as the most important cardiovascular condition of the 21st century.The treatment of CHF has changed significantly since the 1990s: from short-term hemodynamic/pharmacological measures to long-term, reparative strategies aimed at altering the biological properties of the failing heart. The goal of heart failure treatment is not only to improve symptoms and quality of life, but more importantly, to target the mechanisms of myocardial remodeling and to prevent and slow its progression, thereby reducing the rate of death and hospitalization in heart failure. Cardioplegia injection is a new national class II Chinese medicine marketed in 2006, and basic research has confirmed that it can promote the inward flow of calcium ions in cardiomyocytes and increase myocardial contractility, as well as dilate coronary arteries, inhibit myocardial peroxidative damage, and protect the vascular endothelium, among other things. In this study, we observed the clinical efficacy of cardioplegia injection on patients with chronic heart failure and evaluated its safety through a multicenter, randomized, double-blind, placebo-controlled study. Data and Methods 1. Diagnostic Criteria The diagnostic criteria of chronic heart failure refer to the diagnostic criteria formulated in the Guidelines for Clinical Research of New Chinese Medicines, the Diagnostic and Therapeutic Guidelines for Chronic Heart Failure in China, and the Diagnostic and Therapeutic Guidelines for Adults in the United States of America with Chronic Heart Failure (2009 Revised Edition). Cardiac function staging referred to the criteria set by the “U.S. Guidelines for the Diagnosis and Treatment of Chronic Heart Failure in Adults (2009 Revision)”. The grading of cardiac function refers to the 1994 criteria of the American Heart Association of New York. The criteria for identification of Chinese medicine symptoms were formulated with reference to the Guidelines for Clinical Research of New Chinese Medicines (2002 Trial Version). Qi and Yang deficiency, blood stasis and internal obstruction syndrome Primary symptoms: shortness of breath and wheezing, swelling, palpitations. Secondary symptoms: coldness, cold limbs, blue lips and nails. Dark tongue, thin white moss or petechiae, astringent or nodding pulse. If at least two of the primary symptoms and one or more of the secondary symptoms are present, the syndrome can be recognized by combining the tongue and pulse. Inclusion and exclusion criteria Inclusion criteria: meet the diagnostic criteria of chronic heart failure in western medicine; cardiac function ACC/AHA (American College of Cardiology/American Heart Association) stage C, New York Heart Association (NYHA) class II-III; meet the identification criteria of qi and yang deficiency and blood stasis in Chinese medicine; and voluntarily sign the informed consent form. Exclusion criteria: recent myocardial infarction, recent aorto-coronary artery bypass grafting or incisive endoluminal coronary angioplasty, etc.; patients with severe impairment of hepatic function (AST/ALT>3 ULN, TBIL>3 ULN), severe impairment of renal function (Cr>265 μmol/L); severe aortic stenosis, severe valvular insufficiency, obstructive cardiomyopathy; known allergy to cockroach or allergy to cardioplegia injection; positive skin test; pregnancy, breastfeeding, and pregnancy planning; mental abnormality or doctor’s opinion that it is not suitable to participate in the clinical study. Exclusion Criteria: For those who have been selected for this trial and belong to one of the following conditions, they will be treated as excluded cases: (1) misdiagnosis; (2) misnomer; (3) total absence of medication; (4) total absence of record after medication. Withdrawal criteria: (1) withdrawal decided by the investigator. Subject withdrawal from the trial is defined as the enrolled subject’s decision, based on the investigator’s judgment, to withdraw the case from his/her trial if the condition that makes it inadvisable to continue the trial arises during the course of the trial. (1) the condition worsened or deteriorated during the test, emergency measures must be taken; (2) the test, the subject has some comorbidities, complications or special physiological changes, it is not suitable to continue to undergo the test; (3) the use of prohibited drugs in the test program. (2) The subject withdraws from the trial. According to the provisions of the informed consent, the subject has the right to withdraw from the trial in the middle of the trial, or the subject has not explicitly proposed to withdraw from the trial, but no longer accepts the medication and testing and lost the visit. 3. General information The eight hospitals, including Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine (with the consent of the hospital’s ethics committee), Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Xi’an Hospital of Traditional Chinese Medicine, the First Hospital affiliated to Heilongjiang University of Traditional Chinese Medicine, the Second Hospital affiliated to Heilongjiang University of Traditional Chinese Medicine, the Central People’s Hospital of Siping, the First People’s Hospital of Chongqing, and the Affiliated Hospital of Changchun University of Traditional Chinese Medicine, were collected from February 2012 -February 2014 cardiovascular outpatient and inpatient, all patients were eligible for chronic heart failure stage C, NYHA classification II~III, Chinese medicine identification of qi and yang deficiency, blood stasis and internal obstruction, which met the inclusion criteria and exclusion criteria. 240 cases were planned to be enrolled, and 235 cases were actually entered into FAS and SS analysis. Sample size calculation method: the sample size calculation of the superiority test was carried out according to the statistical method. The total effective rate of graded improvement of cardiac function (apparent rate + effective rate) was used as the main index, and after checking the literature, the total effective rate of basic treatment was about 65%, and it was estimated that the total effective rate of basic treatment plus cardiovascular injection was 95%, and the test level α was set at 0.025, the degree of certainty 1 – β = 0.8, and the threshold value was 15%, then the minimum sample size of each group to satisfy the statistical requirements was 96 cases, taking into account not more than 20% of the dropout rate, 116 cases in each of the test group and control group. This trial is intended to include 240 patients, 120 cases each in the test group and control group. This number of cases meets the statistical requirements. Comparison of demographic data such as age, sex ratio, disease duration, duration of the current episode, systolic blood pressure, diastolic blood pressure, heart rate and NYHA classification between the two groups at the time of enrollment did not show any statistically significant difference (P>0.05). 4, Treatment Methods The study was a randomized, double-blind, placebo-controlled, multicenter design methodology with a superiority trial. A randomized arrangement of 240 subjects (i.e., random coding table) was generated using block group randomization method with the help of SAS 9.1.3 statistical software given the number of seeds. All subjects who met the enrollment criteria were assigned drugs and enrolled in the order of visit and drug numbering order, and each subject was allowed to participate in only 1 trial. Drug allocation was strictly in accordance with the order of visit and the order of drug numbering, and the drugs were not to be selected randomly or allocated to the investigators in segments. All patients were given standard medications for the treatment of chronic heart failure, such as diuretics, angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, vasodilators, and cardiotonic drugs. Patients treating other diseases such as abnormal liver and renal function, dyslipidemia, diabetes and other combined medications should be selected by the investigator according to the patient’s specific situation and the dose used, and the detailed record of medication information. After meeting the enrollment conditions, cardioplegia injection (Yunnan Tengchong Pharmaceutical Factory, drug lot numbers: 110937, 120228, 130272) was given. Skin test was performed before the initial administration of the drug, and the drug was administered after the result was negative. Cardioplegia injection (specification: 2 mL, 100 mg) was injected intravenously at 5 mg/kg body weight each time (with 0.9% sodium chloride injection or 5% dextrose injection 200 mL, titration rate of 20-40 drops/min), and was administered twice daily, with an interval of more than 6 h between two doses. Or give cardioplegia injection simulant (Yunnan Tengchong Pharmaceutical Factory, specification: 2 mL, 100 mg), each time 5 mg/kg body weight intravenous drip (plus 0.9% sodium chloride injection or 5% dextrose injection 200 mL, drip rate of 20-40 drops/min), twice a day, two times between more than 6 h; drug batch No.: 110938. treatment cycle of 5 days. After the blinding, it was divided into the control group (standard treatment plus cardioplegia injection simulant) and the treatment group (standard treatment plus cardioplegia injection). 5. Observation indexes and efficacy evaluation The following observation indexes were examined once before and once after 5 days of drug administration. 5.1 Cardiac function grading The efficacy indexes are graded according to NYHA grading method to evaluate the efficacy of cardiac function. The evaluation criteria are: (1) obvious effect: heart failure is basically controlled or cardiac function is improved by more than 2 grades; (2) effective: cardiac function is improved by 1 grade but less than 2 grades; (3) cardiac function is improved by less than 1 grade; (4) deterioration: cardiac function is deteriorated by 1 grade or more. Total effective rate = (obvious effect + effective)/total number of cases × 100%. 5.2 6 min walking distance Used to evaluate the effect of test drugs on exercise tolerance in patients with chronic heart failure. A straight line distance of up to 30.5 m (100 ft) is drawn on a flat surface with a chair at each end as a marker. The patient moves back and forth at his or her own pace during this period, while a tester on the sidelines chimes in every 2 min and records any discomfort (shortness of breath, chest tightness, chest pain) that the patient may experience. If the patient can not hold on, the test can be suspended or discontinued. 6 min after the end of the walking distance is calculated, and the absolute value of the change is judged as an evaluation index of the efficacy of the treatment. 5.3 Echocardiographic efficacy indexes Compare the left ventricular ejection fraction (LVEF) of the two groups before and after treatment, and evaluate the effect of the test drug on the left ventricular systolic function of patients with chronic heart failure. American HP5500 cardiac color Doppler echocardiography machine was used, and LVEF was measured before and after treatment respectively. 5.4 Evaluation of TCM evidence points Referring to the “Guidelines for Clinical Research of New Traditional Chinese Medicines”, 2002 trial version [6] was formulated. Qi and yang deficiency with internal obstruction of blood stasis: primary symptoms: (1) shortness of breath and wheezing; (2) swelling; (3) palpitations; secondary symptoms: (1) fear of cold and cold limbs; (2) bruises on the lips and nails; tongue and pulse: dull tongue, thin white moss or petechiae, and astringent or nodding pulse. At least two of the main symptoms and one or more of the secondary symptoms can be recognized in combination with the tongue and pulse. (2) Significant effect: zero or ≥70% reduction in symptom points after treatment; (2) Effective: ≥30% reduction in symptom points after treatment; (3) Ineffective: <30% reduction in symptom points after treatment; (4) Exacerbation: the points after treatment exceed the points before treatment. The formula (nimodipine method) is: efficacy index = [(pre-treatment points - post-treatment points) ÷ pre-treatment points] × 100%. 5.5 Safety index Observe vital signs, adverse events (such as rash, itching, dizziness, headache, chills, fever, nausea, vomiting, pain at the injection site, vascular irritation, palpitations, allergic asthma, respiratory distress, laryngeal edema, anaphylactic shock, or even death, etc.), and carry out blood and urine routines, liver and renal functions, and routine 12-lead electrocardiogram. 5.6 Adherence analysis Compare whether the patients in the two groups use the test drugs on time and according to the dosage, and do not use the drugs and foods prohibited in the protocol. Drug adherence should be 80%~120%, adherence = actual dosage/should dosage×100%. 6.Statistical methods Data were analyzed using SAS 9.1.3 statistical analysis software. The main efficacy data set was the FAS analysis population. Measurement data were described using ± s. Paired t-tests were used before and after treatment, and changes before and after treatment were compared using analysis of variance (ANOVA). Count data were described using frequencies (constitutive ratios), and changes before and after treatment in each group were compared using the χ2 test or nonparametric tests (CMH method). Data on adverse events and adverse reactions were analyzed using SS. p < 0.05 was considered statistically significant. Discussion Heart failure is the result of initial myocardial injury from any cause (e.g., myocardial infarction, cardiomyopathy, hemodynamic overload, inflammation, etc.), which causes structural and functional changes in the myocardium, and ultimately leads to low ventricular pumping and/or filling function. The main manifestations are dyspnea, weakness and fluid retention. Chronic heart failure is a progressive condition that can continue to develop on its own once it has started, even in the absence of new myocardial damage and in a clinically stable stage. Chronic heart failure is a common and frequent clinical condition. In the adult population of developed countries, about 1-2% of patients have heart failure, and the prevalence of people aged 70 years and older is as high as 10% or more. The basic mechanism leading to the development of heart failure is myocardial remodeling. The clinical manifestations are neuroendocrine activation and decreased cardiac function. Because the more specific symptoms (i.e., telangiectasia and paroxysmal nocturnal dyspnea) are rare, the diagnosis of early heart failure may be difficult, and objective tests are essential for the diagnosis of heart failure. Multivariate analyses have shown that a decrease in LVEF and a sustained increase in BNP plasma concentration can help determine the prognosis and survival in heart failure.LVEF is significant for the diagnosis and treatment of heart failure not only because of its prognostic significance, with lower LVEF being associated with poorer survival, but also because an improvement in LVEF after treatment indicates an improved prognosis for heart failure. In the interventional treatment of CHF, purely Western medical treatment still can not completely stop the progression of heart failure, and can not effectively reduce the morbidity and mortality of patients, and the number of heart failure patients in China and the United States is increasing every year. According to the survey, the number of CHF patients in the United States is growing at a rate of 550,000 new patients per year. China's adult heart failure patients are also on the rise year by year. Therefore, more methods and tools are needed to intervene in the occurrence and development of heart failure. Cardiolone Injection is a compound peptide preparation extracted from cockroach, the main components of which are diuretic peptide, active amino acids, nucleotides, inosine, etc. It was approved as a national class II new Chinese medicine in 2006. Yang Jing et al. showed that cardioplegia injection not only significantly relieved the symptoms of heart failure in the elderly, but also significantly reduced the level of BNP. Huang Fang et al. added cardioplegia injection on the basis of conventional heart failure drug therapy, and the results showed that LVEF was significantly higher than that of the control group, and NT-proBNP level of the treatment group was significantly lower than that of the control group, suggesting that it is beneficial to improve the prognosis of heart failure in the elderly. This trial used a randomized, double-blind, placebo-parallel-controlled design to evaluate the efficacy and safety of Cardiovascular Lung Injection in the treatment of chronic heart failure (qi and yang deficiency, stasis and blood internal obstruction syndrome). The results showed that, among the whole population, the total effective rate of cardiac function efficacy, the total effective rate of Chinese medicine symptom efficacy, the decrease value and decrease rate of Chinese medicine symptom score compared with the pre-treatment, the increase distance of 6-min walking test compared with the pre-treatment, and the increase value of LVEF compared with the pre-treatment of the treatment group were all significantly better than those of the control group (P<0.05)< span="">, which indicated that cardiofibrillum injection treatment improved the cardiac function of patients with chronic heart failure compared with that of placebo (p<0.05). The side effects are similar to those of placebo, and the long-term application is safe and reliable, which is a useful supplement for the treatment of patients with chronic heart failure.