Zhi-Hao Luo, Yu Lai, Yun-Tao Liu, Xia Yan, Da-Wei Wang,3?

1. The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120

2. Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120

3. Shunde Hospital of Guangzhou University of Chinese Medicine, Shunde 528300

Keywords:

ABSTRACT

1. Introduction

Acute myocardial infarction was a clinically life-threatening critical cardiovascular disease. It was characterized by high morbidity and high mortality. It was mainly manifested by chest tightness, chest pain, palpitations, and palpitation. Heart failure was often associated with acute myocardial infarction[1]. Clinical data show that in acute myocardial infarction, heart failure occurs in about 8.7% of people[2]. When the two diseases occur at the same time, the 5-year mortality rate was as high as 55% or more, and it was increasing year by year[3]. Heart failure often results in ventricular filling and impaired ejection capacity. Most of the current treatments include diuretics, vasodilation, and inhibition of myocardial remodeling[4].

Neoactivin (recombinant human brain natriuretic peptide, rhBNP) was a new drug for the treatment of heart failure. It had a similar mechanism of action as BNP. It had become the drug of choice for the treatment of heart failure in western developed countries, and it has been included in our guide[5]. Its role was mainly to improve heart function through diuresis, sodium drainage, vasodilation, inhibition of myocardial remodeling, secretion of aldosterone and endothelin, anti-sympathetic nervous system, etc[6, 7], and without causing arrhythmias[8]. The current effectiveness and safety of neoactivin in the treatment of acute myocardial infarction and heart failure need to be improved. This study retrieves RCTs in this regard since the database was built. Systematic review of eきcacy and safety in this area.

2.Clinical data

Inclusion criteria: (1) Literature type: Randomized controlled clinical trial (RCT)； (2) Patients: Patients diagnosed with acute myocardial infarction (AMI) and concomitant heart failure； (3) Intervention measures: Control group: Western medicine routine treatment, Including emergency thrombolytic therapy or interventional therapy, oxygen inhalation, diuretics, anticoagulant drugs, antiarrhythmia, antiplatelet aggregation, myocardial ischemia improvement, cardiac strengthening drugs, etc. Therapy group: Western medicine conventional treatment + neoactivin. The load was preliminarily statically pushed (5 μg / kg), followed by 0.0075 μg / (kg · min) for 72 h. (4) Outcome observation: Total eあective rate, left ventricular end diastolic diameter (LVDd), left ventricular ejection fraction (LVEF), brain natriuretic peptide precursor (NT-ProBNP), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP), etc. Exclusion criteria: (1) The study design was unreasonable and a non-randomized controlled clinical trial； (2) Animal experiments, reviews, retrospective studies, etc；(3) Chinese and English literature published repeatedly.

2.1.Search methods and strategies

Computer retrieval from the database construction to December 2019, Published documents in the China Knowledge Network (CNKI), Wanfang, VIP, CBM, PudMed, Cochrane databases. The search terms were "neobiotin", "acute myocardial infarction", "heart failure"； And English "Acute myocardial infarction", "Heart failure", "Recombinant human brain natriuretic peptide".

2.2.Screening literature and quality evaluation criteria

Screening by two researchers, exclusion of non-conforming articles as required, and inclusion of eligible studies； According to Jadad scoring criteria； The included articles were randomized, whether there were blind methods, distribution hidden, and lost followup. In addition, according to Cochrane bias risk assessment tools, the evaluation was divided into low risk, high risk and unknown risk. The screening and quality evaluation of the two researchers' documents were completed independently of each other, and if there were diあerences, the third researcher would evaluate them.

2.3.Data extraction

Main contents: Basic information of the patient, intervention method, sample size, clinical efficiency, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd), brain natriuretic peptide precursor (NT-ProBNP), heart rate (HR) , Systolic blood pressure (SBP), diastolic blood pressure (DBP) and adverse reactions.

2.4.Statistical analysis

Count data uses odds ratio (OR), measurement data uses weighted mean difference (WMD), and both use 95% confidence interval (CI). Analysis was performed using RevMan5.3 software. The heterogeneity of the included literature was tested and its size was assessed by I2. If I2＞ 50%, the heterogeneity between the studies was large, so the random analysis model was used for meta analysis. If I2≤ 50%, the heterogeneity between studies was small, and the fixedeあect model was used for meta-analysis. Sensitivity analysis was performed by excluding the included studies one by one to observe whether the results were stable. If the number of documents included in the main indicators was ≥ 10, the bias can be analyzed by using an inverted funnel chart.

3.Results

3.1.Literature search

Preliminary screening results: 67 articles in Wanfang Database, 44 articles in Weipu, 143 articles in CNKI, and 30 articles in CBM. Screening of literature across databases. Removed 30 articles from Wanfang, 22 from Weipu, 20 from CNKI, and 15 from CBM. The remaining 97 papers were integrated, 67 similar papers were removed, 30 papers were included, and 30 full-text readings were read. Finally, 23 Chinese literatures were included in a total of 2024 patients. The literature search process is shown in Figure 1.

Fig 1 Literature screening process

3.2.Included study characteristics and literature quality evaluation

A total of 23 articles were included in 2024 patients. The 23 articles included had Jadad scores of 1 to 3, and the overall quality evaluation was poor. Randomized groupings reported in allliterature, random number table reported in four literatures[9-12]. There had two literatures reported random computer grouping[13, 14]. No other literature reports specific random allocation methods； None of the literature had reported blindness； None of the literature reported whether to implement allocation hiding； The number and reason for withdrawal were not reported in the literature. The basic characteristics of the included studies were shown in Table 1.

Tab 1 Basic characteristics of involved literature

3.3.Evaluation of included research quality

The evaluation is divided into the following aspects: (1) Random method: In this study, 23 studies appeared "random", and 6 studies used the correct random method ("computer random" method and "random number table" method). The rest of the studies did not mention specific random methods, which were rated as "Unknown risk".(2) Assign hidden: None of the 23 studies was mentioned and rated "unknown risk".(3) Subject's blind method and results evaluator's blind method: It was not mentioned in this study and was rated as "Unknown Risk". (See Figure 2).

Fig 2:Assessment of the bias risk of the included studies

3.4.Meta Analysis

3.4.1.Comparison of total effective rate after treatment

There had 19 articles reported total eあectiveness[2, 9-14, 16, 18-22, 24-26, 29-31],a total of 1666 cases, heterogeneity was I2= 0%, indicating no heterogeneity, which was analyzed by a fixed effect model. Results: The experimental group was more eあective than the control group in total effective rate, and the difference was statistically significant (OR = 4.30, 95% CI [3.26, 5.67], P ＜0.00001, Z = 10.30), as shown in Figure 3.

Fig 3 Forest plot of therapeutic eあects after application of neoactivin

3.4.2.Improve LVEF after treatment

There had 17 articles reported on LVEF[2, 11, 12, 15-19, 21, 23-27, 29-31],a total of 1380 cases, the heterogeneity test results showed I2 = 84%, indicating heterogeneity, it used random eあects model analysis. Results: With the improvement of LVEF, the experimental group was better and the diあerence was significant (OR = 1.58, 95% CI [1.27, 1.90], P ＜0.00001, Z = 9.81), see Figure 4.

Fig 4 LVEF comparison forest map after application of new biotin

3.4.3.Improve LVDd after treatment

There had 8 articles reported on LVDd[15-17, 24-27, 30],a total of 778 cases, the heterogeneity test results showed I2= 93%, indicating heterogeneity, it used random eあects model analysis. Results: With the improvement of LVDd, the experimental group was better and the diあerence was significant (OR = -0.91, 95% CI [-1.50, -0.33], P = 0.002, Z = 3.04), as shown in Figure 5.

Fig 5 LVDd contrast forest map after application of neoactivin

3.4.4.Improve CO situation after treatment

There had 4 articles reporting improvements on CO[11, 16, 18, 29], a total of 350 cases, the heterogeneity test results showed I2 = 89%, indicating heterogeneity, it used random eあects model analysis. Results: In the case of CO improvement, the experimental group was better and the diあerence was significant (OR = 1.24, 95% CI [0.55, 1.94], P = 0.0005, Z = 3.49), see Figure 6.

Fig 6 CO contrast forest map after application of neoactivin

3.4.5.Improve NT-ProBNP after treatment

There had 13 articles reported improvement of NT-ProBNP[2, 9, 12, 16, 18, 19, 21, 23, 25-27, 30, 31], a total of 1194 cases, the heterogeneity test results showed I2= 98%, indicating heterogeneity, it used random eあects model analysis. Results: With the improvement of NT-ProBNP, the experimental group was better and the diあerence was significant (OR = -4.37, 95% CI [-6.21, -3.25], P ＜0.00001, Z = 6.26), see Figure 7.

Fig 7 NT-ProBNP comparison forest map after application of neoactivin

3.4.6.Improve heart rate after treatment

There had 12 articles reported improving heart rate[2, 11-16, 19, 21, 23, 28, 31], a total of 1016 cases, the heterogeneity test results showed I2 = 0%, indicating no heterogeneity, it used a fixed eあect model analysis. Results: The experimental group was more eあective than the control group in improving heart rate, and the diあerence was statistically significant (OR = -13.70, 95% CI [-14.95, -12.46], P ＜0.00001, Z = 21.62), as shown in Figure 8.

Fig 8 Heart rate comparison forest after applying new biotin

3.4.7.Improve SBP after treatment

There had 9 articles reported improving SBP[2, 13-15, 19, 21, 23, 28, 31], a total of 680 cases, the heterogeneity test results showed that I2 = 91%, indicating heterogeneity, it used random eあects model analysis. Results: With the improvement of SBP, the experimental group was better and the diあerence was significant (OR = -12.38, 95% CI [-17.98, -6.79], P ＜0.00001, Z = 4.34), as shown in Figure 9.

Fig 9 SBP contrast forest map after application of new biotin

3.4.8.Improve DBP after treatment

There had 6 articles reported improving DBP[2, 13, 14, 19, 21, 31], a total of 460 cases, the heterogeneity test results showed I2 = 0%, indicating no heterogeneity, it used a fixed eあect model analysis. Results: The experimental group was more effective than the control group in improving DBP, and the diあerence was statistically significant (OR = -7.42, 95% CI [-8.53, -6.30], P ＜0.00001, Z = 13.03), see Figure 10.

3.4.9.Adverse reactions

There had 7 studies [9, 11, 18, 21, 23, 29, 31] reported the occurrence of adverse reactions during the treatment of neoactivin. The main adverse reactions during the period were the following: hypotension, dizziness, headache, nausea, and palpitations. The symptoms could be relieved after adjusting the medication rate or stopping the medication. No serious cardiovascular events occurred. Heterogeneity is I2= 63%, indicating heterogeneity, and analyzed by random eあects model. Results: In terms of adverse reactions, the diあerence was not statistically significant (OR = 0.95, 95% CI [0.29, 3.16], P = 0.94, Z = 0.08), indicating that the clinical application of neovivin was safe, see Figure 11.

Fig 11 Forest map of adverse reactions

3.5.Sensitivity analysis

Based on the total eあective rate of neoactivin in the treatment of acute myocardial infarction with heart failure and the improvement of LVEF and NT-ProBNP, the results were analyzed one by one. The results showed that the removal of any one of the literatures had no eあect on the results, indicating that the results were stable.

3.6.Post Bias Evaluation

Using the standard error of OR as the vertical axis and OR as the horizontal axis, a funnel plot was drawn for the total eあective rate of clinical eきcacy. The chart shows that left-right symmetry is not completely consistent, indicating that the article may have publication bias, as shown in Figure 12.

Fig 12 Funnel chart of clinical eきcacy

4. Discussion

Acute myocardial infarction combined with heart failure had a higher morbidity and mortality in the clinic, and its 5-year survival rate was similar to that of malignant tumors. The main cause of this was myocardial infarction, which causes abnormal cardiac function and decreased cardiac output, which leads to acute stasis and insuきcient blood supply, and that leads to excessive activation of the renin-angiotensin-aldosterone system (RAAS). The current treatment goal was to reduce the area of myocardial infarction, and the prevention and treatment of complications was the key. Although the current popularity and improvement of cardiac interventional techniques had significantly improved the survival rate of AMI, the incidence of heart failure had also increased significantly. BNP was a natural antagonist of RAAS. It had the functions of urination, sodium diuresis, vasodilation, inhibition of myocardial fiber proliferation, and improvement of myocardial ischemia and hypoxia[32]. However, when AMI occurs, the amount of BNP secretion decreases, which cannot eあectively antagonize the overactive neuroendocrine system in the antibody. Neoactivin was an endogenous peptide, which can antagonize the neuroendocrine system, diuretic and sodium excretion, dilate blood vessels, and delay cardiac remodeling[33]. It can supplement the advantages of insuきcient BNP in the body, regulate the neuroendocrine system, and protect the heart.

This study analyzes the efficacy and safety of neoactivin in the treatment of acute myocardial infarction and heart failure. Finally, 23 articles are included. The results suggested that the neoactivin group is more effective than conventional western medicine treatment, especially in effective, LVEF , LVDd, NT-ProBNP, HR, SBP, DBP, etc. In the adverse reactions, the difference between the two groups is not statistically significant, indicating that the drug is safe； However, the limitations of this study exist. Only six specific randomized methods have been reported in the literature. The risk of selective bias is also high, and no implementation method of allocation concealment has been reported in the literature； Unreported blindness may lead to higher bias； And the literature is all positive, perhaps because articles with positive results are easy to publish, which will cause publication bias.

In summary, this study summarized the significant effect of neoactivin in the treatment of acute myocardial infarction with heart failure, and no significant adverse reactions were found. However, the literatures included in this study were all Chinese, and the English literatures were not retrieved. There may be literature selection bias and the quality of the literatures is low. The above may aあect the accuracy of the research results. It is recommended to pay attention to random methods, blind methods, and allocation concealment in future clinical studies, and look forward to multicenter, large-sample related clinical studies to verify the results of this study.