Meta-Analysis of the Effect of Honghua Injection in the Treatment of Coronary Heart Disease Angina Pectoris

Objective To evaluate the effectiveness of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris. Methods Computer extensively searched PubMed, Cochrane Library, Embase, China Biomedical Archives (SinoMed), China Knowledge Network (CNKI), Chinese Journal Full-text Database (VIP), Wanfang Data Knowledge Service Platform (Wanfang), and collected randomized controlled trials (RCTs) of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris. Use Review Manager5.3 software for meta-analysis. Results 21 RCTs were included, involving 1894 participants. Meta-analysis shows that honghua injection combined with western medicine can significantly improve the clinical efficacy (OR = 4.03, 95% CI[2.96,5.49]), electrocardiographic efficacy (OR = 3.39, 95%CI[2.44, 4.70]), can significantly reduce total cholesterol (TC) levels (MD = −0.39, 95% CI[−0.47, −0.31]), triacylglycerol (TG) levels (MD = −0.45, 95% CI[−0.51, −0.39]), increase high-density lipoprotein cholesterol (HDL-C) levels (MD = 0.29,95%CI[0.26,0.32]), reduce low-density lipoprotein Cholesterol (LDL-C) levels (MD = −0.59, 95%CI[−0.79, −0.38]). Five articles reported adverse reactions. Conclusion Honghua injection combined with western medicine is more effective than western medicine alone in patients with coronary heart disease angina pectoris. More multicenter, large sample, high-quality RCTs are needed to provide evidence.


Introduction
According to a survey by the World Health Organization (WHO), one cause of global lifespan reduction is coronary atherosclerotic heart disease (CHD), referred to as coronary heart disease [1]. With economic developing, people's living habits have changed and the population is aging, the risk factors of coronary heart disease are becoming increasingly prominent. According to estimates, as of 2018, there were about 11 million patients with coronary heart disease in China [2], and the mortality rate continues to rise, becoming a major disease threatening human health. Epidemiological studies have shown that the overall prevalence of coronary heart disease is on the rise, the patient population tends to be younger, and the number of acute attacks is increasing year by year [3]. Coronary heart disease has many complications and dangerous diseases. If it is acute, it can develop into myocardial infarction, and in severe cases, it can cause sudden death. erefore, it is particularly critical to study its clinically effective treatment.
In the field of modern medicine, Coronary heart disease is usually caused by a single risk factor called "dyslipidemia," and the main factors that cause dyslipidemia are genetics, lifestyle, certain diseases (such as thyroid dysfunction and kidney disease) and medications [4].he treatment of coronary heart disease often uses antiplatelet drugs, calcium antagonists, and other drugs, and symptomatic treatments such as anticoagulation, lipid regulation, blood pressure reduction, and vasodilation can significantly alleviate the clinical symptoms of patients. e effect of functional improvement is limited, and adverse drug reactions are prone to occur [5]. Traditional Chinese medicine believes that the pathogenesis of coronary heart disease is based on the right deficiency, and it is a process of intermixing with Yin and cold, blood stasis, qi stagnation, phlegm obstruction and other evils [6]. Clinical observations have shown that, compared with simple chemical treatment, using the appropriate treatment plan of traditional Chinese medicine preparations combined with conventional chemical drugs has a significant effect, and it has a better effect in improving the quality of life of patients and reducing side effects [7].
Honghua injection is an injection made by processing and extracting honghua. It is a clear liquid from yellowish red to reddish brown. At present, it has been widely used in various diseases, such as hypertension, coronary heart disease, pulmonary heart disease, cerebral infarction, diabetes, chronic renal failure, and primary dysmenorrhea [8]. Relevant studies have shown that honghua injection has the effects of improving blood concentration, anticoagulation, and improving microcirculation [9], and the pharmacological effects of honghua for promoting blood circulation, clearing menstruation, removing blood stasis and relieving pain are the expansion of blood vessels and anti-myocardial ischemia, lowering blood lipids, exciting the uterus, anticoagulation, anti-thrombosis, and other effects [10,11].
Relevant clinical trials have initially shown that honghua injection combined with western medicine can improve the treatment effect of coronary heart disease angina pectoris. However, it has not been systematically evaluated in the world. In this study, methods such as meta-analysis were used to systematically evaluate the effectiveness of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris, which is convenient to guide clinical use. e Chinese search terms are "coronary atherosclerotic heart disease," "coronary heart disease," "coronary syndrome," "angina pectoris," "honghua injection," "safflower injection" and "random." e English search terms are "coronary disease," "coronary artery disease," "random," "Honghua injection," "Honghua injection" and so on.

Inclusion Criteria.
(1) e type of research is RCT. (2) e subjects of the study are patients who meet the domestic and foreign consensus criteria for diagnosing coronary heart disease angina pectoris, regardless of age and gender. (3) e control group is treated with conventional western medicine, and the test group is treated with honghua injection on the basis of the control group. (4) e language is Chinese or English.
(2) Documents for which data cannot be extracted. (3) In addition to honghua injection and conventional western medicine, the treatment group also used other traditional Chinese medicine injections. (4) e treatment group used honghua extract and other similar products.

Outcome Indicators
(1) Clinical efficacy. It meets the "Criteria for Evaluating the Curative Effect of Coronary Heart Disease Angina Pectoris and ECG." Significant effect: After treatment, the patient's ECG returned to normal or almost normal or reached the standard of marked effect, or the symptoms of angina pectoris disappeared or the number of angina pectoris was reduced by more than 80%, nitroglycerin consumption was reduced by more than 80%, or the main clinical symptoms improved within 10 days or the chest pain symptoms disappeared or Reduced by 90%; Effective: After treatment, the patient's angina pectoris symptoms were significantly relieved, the number of angina pectoris was reduced by more than half, nitroglycerin consumption was reduced by 50% to 80%, the ECG improvement reached the effective standard or the main clinical symptoms improved within 10 to 20 days, or chest pain symptoms Improved by more than 50%; ineffective: After treatment, the patient's angina pectoris symptoms are not improved or even worsened, the ECG is the same as before treatment or worse than before treatment, or the number of angina pectoris episodes, nitroglycerin consumption is reduced by less than 50%, or chest pain symptoms are not improved. (2) Efficacy of ECG. It meets the "Criteria for Evaluating the Efficacy of Coronary Heart Disease Angina Pectoris and ECG." Markedly effective: ST-segment after treatment, T wave returned to normal or roughly normal range; effective: ST-segment of ECG after treatment increased by more than 0.05 mV compared to before treatment but did not reach the normal level, the inverted T wave changes in the main lead became shallow or changed two-way; ineffective: After treatment, the ECG is similar to that before treatment or the ST segment is lower than before treatment by more than 0.05 mV, and the T wave is deepened or not improved.

Data Extraction.
Two researchers independently screened the literature, extracted data, and cross-checked according to preset inclusion and exclusion criteria. If there is any objection, the third researcher will discuss and resolve it through negotiation. Establish an Excel data extraction table, which mainly includes: the source of the included literature (name of the first author, year of publication), sample size, general information of participants (such as gender, age, etc.), intervention measures, treatment process and outcome indicators.

Bias Risk Assessment. Use the Cochrane Risk of Bias
Tool to assess the risk of bias for each study. e tool considers the following factors: (a) the random sequence generation method used; (b) the allocation concealment method used; (c) the blinding method used (participants and personnel); (d) the blinding method used (result evaluator); (e) incomplete result reporting; (f ) selective reporting of research results and (g) other possible sources of bias. Each entry is judged as low risk, high risk, or unclear risk of bias.

Statistical
Analysis. RevMan 5.3 software was used for statistical analysis of the included literature research data, and the count data used risk ratio (RR) or odds ratio (OR), continuous variable data was expressed as mean difference (MD), and 95% CI indicated that the difference was statistically significant. If I 2 ≦ 50%, it indicates that the heterogeneity is small, and the fixed effects model (FEM) is used; If I 2 > 50%, it indicates that the heterogeneity is large, first determine the reason for the heterogeneit, conduct a sensitivity analysis to eliminate the possible source of the heterogeneity, if the heterogeneity is still large, then use the random effects model (REM). Or use subgroup analysis for further analysis. Figure 1, 561 documents were initially retrieved, of which 290 studies were eliminated as duplicates. After screening by title, abstract, and full text, a total of 21 studies were included in this metaanalysis ( Figure 1).

Risk of Bias in the Included Literature.
Nineteen studies [13-22, 29, 30, 32] only described "random grouping" and were considered unclear risk, and 1 study was included in the group order odd and even numbers were randomly divided into treatment group and control group, which were considered high risk. One study was divided into treatment group and control group according to the random number table, which was considered low risk. None of the included studies described allocation concealment and blinding, so they were assessed as unclear risks. e included studies reported that the outcome data was complete and there was no selective reporting, so the reporting bias was evaluated as low risk. None of the included trials described whether there were other potential biases, so the risk was determined to be unclear. e results of the risk of bias assessment are shown in Figure 2.

Clinical Efficacy.
Meta-analysis results showed that there was no heterogeneity among the 17 studies (P � 0.99 9, I 2 � 0%), so the fixed effects model was used, and the difference was statistically significant (OR � 4.03, 95%CI [2.96, 5.49], P < 0.00001), indicating that the clinical effect of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris is better than that of the western medicine treatment group ( Figure 3).

Efficacy of ECG.
Eleven studies have reported the efficacy of ECG.After the heterogeneity test, the heterogeneity among the studies were small (I 2 � 27%, (P � 0.18), so a fixed-effect model was used.
e results showed that honghua injection combined with western medicine was better than the control group in improving the efficacy of ECG, and the difference was statistically significant (OR � 3.39, 95%CI [2.44, 4.70], P < 0.00001) (Figure 4).

TC.
Four studies reported TC.After the heterogeneity test, the heterogeneity among the studies is small (I 2 � 4%, (P � 0.37), so the fixed effects model was used, and the difference was statistically significant (MD � -0.39, 95%CI [−0.47, −0.31], P < 0.00001) indicates that the TC levels of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris is better than that in the western medicine treatment group ( Figure 5).

TG.
Four studies reported TG.After the heterogeneity test, there was no heterogeneity between the studies (I 2 � 0%, (P � 0.95), so the fixed effects model was used, and the difference was statistically significant (MD � −0.45, 95%CI [−0.51, −0.39], P < 0.00001) indicates that the TG levels of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris is better than that in the western medicine treatment group ( Figure 6).

HDL-C.
4 studies reported HDL-C.After the heterogeneity test, there was no heterogeneity between the studies (I 2 � 0%, (P � 0.47), so the fixed effects model was Evidence-Based Complementary and Alternative Medicine used, the difference was statistically significant (MD � 0.29,95% CI [0.26, 0.32], P < 0.00001), indicating that the HDL-C levels of honghua injection combined with western medicine is better than that of the western medicine treatment group (Figure 7).
3.4.6. LDL-C. 4 studies reported LDL-C.After the heterogeneity test, the heterogeneity between the studies was relatively large (I 2 � 86%, P < 0.0001). e sensitivity was analyzed, Excluding the literature one by one for heterogeneity test, the results show that the heterogeneity was still large, so the random effects model was used, and the difference was statistically significant (MD � −0.59, 95%CI [−0.79, −0.38], P < 0.00001) (Figure 8).

Discussion
Inflammation is one of the main causes of coronary plaque. Myocardial infarction (heart attack) is a common manifestation of CAD. CAD can lead to cardiovascular complications to a large extent. e role of oxidative stress or inflammation predisposes atherosclerotic plaques to rupture, leading to CV events (CAD), so inflammation is likely to be a driver of CAD and atherosclerotic plaque development [33,34]. e types of coronary heart disease included in this meta-analysis include unstable angina, acute myocardial infarction, and coronary heart disease myocardial ischemia. e control group used conventional western medicine for   Evidence-Based Complementary and Alternative Medicine the clinical treatment of coronary heart disease angina pectoris, such as statins, aspirin, enteric-coated tablets, nitrates, etc. e frequency of administration was mostly once a day, up to three times a day. e treatment group was honghua injection plus the control group. Outcome indicators include not only short-term key efficacy indicators but also physical and chemical indicators. e results of this meta-analysis showed that the efficacy of honghua injection combined with western medicine in the treatment of coronary heart disease angina pectoris is better than that of western medicine alone, which is manifested in significantly improving clinical efficacy, electrocardiogram, and blood lipid indicators. At present, the clinical treatment of coronary heart disease angina pectoris also pays more attention to the combination of Chinese and western medicine, which has the advantages of small toxic side effects and obvious therapeutic effects.

Limitation.
(1) According to the scores of the Cochrane Risk Evaluation Form, the quality of the studies included in In the observation group, there were 2 cases of facial flushing, 2 cases of nausea and vomiting, 1 case of headache, 1 case of arrhythmia, 1 case of recurrent myocardial infarction, 1 case of post-infarction angina pectoris; control group had 3 cases of nausea and vomiting, 1 case of diarrhea, and 3 cases of heart rhythm disorders, 3 cases of recurrent myocardial infarction, 2 cases of post-infarction angina, and 2 cases died  List Consistency Included studies (year of first author's name) √ Sample size (T/C) √ Gender (male/female) (T/C) √ Average age (years) (T/C) √ Interventions (T/C) √ Course of treatment (T/C) √ Outcome indicators(T/C) √ this study is not high. Most of the random methods only describe "random" without specifying the specific random allocation method; and all studies did not mention whether blinding and allocation concealment were used. (2) Since only a few of the included literature mentioned adverse reactions, the safety evaluation of honghua injection needs to be studied. (3) e number of studies on a single outcome indicator is too small (for example, only 4 studies are included), and there is no subgroup analysis for indicators with heterogeneity to explore the source of heterogeneity. (4) e studies involved in this study have not been followed up for long-term.
Future trial design needs to increase the sample size, design strict randomized controlled trials, adopt appropriate randomization methods, and increase the use of blinding and allocation concealment methods in trials; improve the strength of research evidence, objectively report negative results, and ensure the statistics. e authenticity of the data provides a large amount of reliable data support for the treatment of coronary heart disease angina pectoris to better guide clinical practice (Tables 3 and 4).