Effectiveness and safety of electroacupuncture combined with conventional drugs in the treatment of stable angina pectoris in coronary artery disease: A systematic evaluation and meta-analysis

Background: The objective of this study is to systematically evaluate the clinical effectiveness and safety of electroacupuncture combined with conventional drugs in the treatment of stable angina pectoris. Methods: Computer searches of 3 Chinese literature databases (CNKI, VIP, WangFang) and 4 English literature databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science), all searched from the time of database construction to October 2022. Two researchers were selected to independently perform literature screening, data extraction, and risk of bias evaluation, and meta-analysis of the included studies was performed using RevMan 5.3 software. Results: A total of 7 publications with a total of 1042 patients were included, and electroacupuncture combined with conventional drug therapy compared with drug therapy alone was effective in improving clinical symptoms of angina pectoris (relative risk [RR] = 1.19, 95% CI = [1.09, 1.31], P = .0002), clinical treatment efficiency of electrocardiography (RR = 1.34, 95% CI = [1.19, 1.50], P = .00001), visual analog score (VAS) (mean deviation = 0.07, 95% CI = [−0.11, 0.25], P = .44), and Seattle Angina Scale (mean deviation = 4.91, 95% CI = [2.91, 6.91], P < .00001) were better than conventional drug therapy, while the number of adverse events in the intervention group was lower than that in the control group. One of the outcome indicators with greater heterogeneity was tested by sensitivity analysis, and each outcome indicator was found to be more robust. The risk of bias evaluation of each outcome indicator using funnel plots suggested the possibility of publication bias. Conclusion: The current study results found that electroacupuncture combined with conventional drugs can significantly improve the clinical symptoms of patients with stable angina pectoris compared with conventional drug therapy, with a low incidence of adverse reactions, but the number of high-quality literature with rigorous study design protocols is currently low, which may cause bias in the results of this study, so the above conclusions need to be further verified through clinical trials.


Introduction
Stable angina is a clinical syndrome in which patients with coronary artery disease experience acute, temporary ischemia or hypoxia of myocardial tissue due to physical exertion, emotional stimuli, and other external triggers, resulting in chest pain or chest discomfort. [1] According to epidemiological findings, cardiovascular disease deaths account for the first cause of total deaths worldwide, of which 80% of cardiovascular disease deaths are caused by coronary heart disease (CHD), resulting in Pang et al. • Medicine (2023) 102:7 Medicine about 9.14 million deaths worldwide. [2] According to the latest epidemiological studies, CHD is now the leading cause of death among the global population and has become one of the most urgent public health problems. [3] At present, modern medical treatment of CHD mainly adopts the methods of controlling risk factors, standardizing drug intake, intervening in lifestyle and rebuilding blood flow, which can achieve certain efficacy. However, the economic burden, decreased drug tolerance, and drug side effects arising from long-term drug therapy are limitations, so it is necessary to seek natural, safe and effective complementary alternative therapies for the treatment of stable angina. [4] Acupuncture is an effective and safe traditional nonpharmacological treatment for cardiovascular diseases, which has been widely used in the prevention and treatment of CHD because of its clinical efficacy and low adverse effects. Clinical studies have shown that electroacupuncture combined with acupuncture has good efficacy in the treatment of angina pectoris in CHD, which can significantly reduce the symptoms of angina pectoris, improve myocardial ischemia, and promote the recovery of cardiac function. In addition, the study on the efficacy mechanism of electroacupuncture found that electroacupuncture can inhibit the production of inflammatory factors in rats, and reduce chronic pain and other complications while effectively promoting the recovery of neurological function. The use of acupuncture in the early stage of the disease can improve the therapeutic effect, shorten the course of the disease, control the progress of the disease, and improve the quality of life of patients . In addition, electroacupuncture has the unique advantages of being economical, safe, and without significant side effects, which can reduce the economic burden of patients and is worthy of clinical promotion and application. However, the quality of existing studies also varies, and there is a lack of a more complete systematic evaluation of evidence-based medicine. Therefore, this study systematically evaluates the clinical effectiveness and safety of electroacupuncture for stable angina pectoris in coronary artery disease and provides a reference basis and reference for clinical and research purposes.

Registration of selected topics
This system evaluation is registered on PROSPERO (registration number CRD42022364351) and was analyzed according to the Preferred Reporting Items for System Evaluation and Meta-Analysis (PRISMA) guidelines.

Search strategy
Pudmed, cochrane library, Embase, Web of Science, CNKI, WangFang, VIP, and CBM were searched by computer to find information about electroacupuncture combined with conventional drugs for the treatment of The literature related to randomized controlled trials on the treatment of stable angina pectoris in coronary artery disease. The literature was searched from the date of database creation to October 6, 2022. All searches were performed using a combination of subject terms and free words, and were supplemented by manual searches for relevant systematic evaluations. The Chinese search terms were "electroacupuncture," "electroacupuncture therapy," "coronary atherosclerotic heart disease stable angina," "coronary heart disease stable angina," and "coronary heart disease stable angina," "stable angina," "angina pectoris," "randomized controlled trial," and "randomized controlled trial." The English search terms consisted of subject terms and free words, "Stable angina," "Anginas, Stable," "Chronic Stable Angina ", "Stable Angina Pectori," "Stable Angina Pectoris," "randomized controlled trial," "controlled clinical trial," "randomized," "placebo." Taking PudMed as an example, the search strategy is shown in Table 1.

Inclusion and exclusion criteria
2.3.1. Inclusion criteria. Type of study: all published randomized controlled trials on electroacupuncture combined with conventional drugs for stable angina pectoris, without limiting the randomized protocol, without limiting whether blinding was used in the study, and without limiting the language. Study subjects: Western medicine diagnosis was in accordance with the Nomenclature and Diagnostic Criteria for Ischemic Heart Disease promulgated by the International Society of Cardiology and the World Health Organization in 1979. [5] Chinese medicine diagnosis and evidence-based typing conformed to the Chinese Diagnostic and Efficacy Criteria for Diseases and the Guidelines for Clinical Research on New Chinese Medicines, and there were no obvious complications or contraindications to electroacupuncture treatment. Age, gender and race of patients with stable angina pectoris of CHD were not restricted. [6] Interventions: patients in the intervention group were treated with conventional western drugs (nitrates, aspirin, β-blockers, angiotensin-converting enzyme inhibitors and other drugs, ensuring that both groups remained consistent when conventional treatment was involved). Combined electroacupuncture treatment (electroacupuncture machine was used for electrical stimulation after the milli-needle was pierced into the acupuncture point; the selection of acupuncture points, the implementation of the technique, the retention time, the duration of treatment, and the specification and manufacturer of the selected needle and electroacupuncture instrument were not limited).

Risk of bias evaluation
Risk of bias evaluation of the literature was performed using the assessment tool recommended by the Cochrane Centre for Evidence-Based Assessment for: randomization scheme, implementation of allocation concealment scheme, implementation of blinding, completeness of outcome data, selective reporting bias, other sources of bias. The literature was evaluated by 2 researchers independently, with further discussion or third-party assessment in case of disagreement.

Statistical analysis
In this paper, Rev Man 5.3 software (Version 5.3, http://ims. cochrane.org/revman/download) was applied to analyze the data from the literature, and the data were statistically analyzed using Relative Risk (RR) and Mean Deviation for counting units and measurement units, respectively, where the effect models were chosen: Fixed-effect model: when the consistency of the study results was high (P > .10), both effect sizes were expressed by 95% CI, and when P > .05, the difference was not statistically significant; when P < .05, the difference was statistically significant. Randomeffects model: This model was used when there was heterogeneity in the study, but the differences were not clinically significant. The reasons for the existence of heterogeneity were also analyzed and described, and subgroup analysis was performed when necessary.

Basic characteristics of the included literature
Six of the included literature were randomized controlled trials, with baseline information for the control and intervention groups described in the text and all comparable, with 6 studies describing specific randomization methods, 2 studies mentioning blinding of subjects, 1 study mentioning shedding data, 1 study mentioning allocation concealment, and Cochrane Collaboration Network risk of bias assessment of the literature (Tables 2 and 3 and Fig. 2).

Efficacy in improving clinical symptoms of angina pectoris.
A total of 4 [7,8,13,14] studies reported the outcome index of angina treatment efficacy, and the clinical heterogeneity test was performed for these 4 studies (I 2 = 0%, P = .89), and the results of the heterogeneity test suggested that the heterogeneity of the above 4 studies was small, so the fixed-effects model was used to combine the effect sizes, and the results of the Meta-analysis showed that the RR = 1.19, 95% CI = [1.09, 1.31], P = .0002 < 0.05, the difference was statistically significant, as shown in the figure, which implies that the intervention group was more effective than the control group in improving clinical symptoms of angina pectoris (Fig. 3).

Electrocardiographic clinical treatment efficiency.
A total of 3 [9,12,14] research studies reported the outcome index of ECG treatment efficiency, and high heterogeneity was found in the above 3 studies by heterogeneity test (I 2 = 83%, P = .003), so Meta-analysis was performed using random effects model, and the results showed that RR = 1.34, 95% CI = [1.19, 1.50], P = .00001, and the difference was statistically significant, suggesting that the intervention group using electroacupuncture combined with western medicine treatment was better than the control group using western medicine treatment alone in terms of improvement of patients' electrocardiograms (Fig. 4).

3.3.3.
Visual analogue score. Two [10,11] studies reported visual analogue scores as an outcome indicator in patients with stable angina, and before Meta-analysis, baseline period agreement tests were performed for both studies, and the results were as follows: there was no heterogeneity in the baseline period effect sizes for VAS scores in the 2 studies (I 2 = 0%, P = .33), so the fixed-effects model was chosen to combine effect sizes, as seen in the forest plot of Figure 5, which showed that the intervention group patients had better VAS scores than control patients after treatment, but it was not statistically significant (Z = 0.77, P = .44 > 0.05), suggesting that although electroacupuncture combined with conventional drug treatment could reduce VAS scores, the reduction did not reach statistical significance, that is, from a statistical point of view, there was no significant difference between electroacupuncture combined with conventional drug treatment compared with conventional drug treatment (Fig. 5).

Seattle Angina
Scale score. Two [9,10] studies reported Seattle Angina Scale score (SQA) as an outcome index, and since the results of the baseline period agreement test of the above 2 studies suggested no heterogeneity in the effect size (I 2 = 0%, P = .82), Meta-analysis was performed using a fixed-effects model, and the results suggested that the SQA score of patients in the intervention group after electroacupuncture combined with conventional western drug therapy was higher than that of the control group of conventional western drug-treated patients (Z = 4.82, P < .00001), and the difference was statistically significant, suggesting that electroacupuncture combined with conventional drug treatment could significantly improve patients' angina symptoms (Fig. 6).

Sensitivity analysis
Sensitivity analysis of the 3 [7,10,13] studies using ECG clinical treatment efficiency as an outcome indicator using a single study-by-study exclusion method showed that Meta-analysis heterogeneity decreased when Wang B study was excluded (I 2 = 0%, P = .40). Sensitivity analysis using the same method for  the 2 studies using the SQA as an outcome indicator revealed no change in meta-analytic heterogeneity.

Publication bias analysis
The funnel plot was used to analyze the publication bias for improving the clinical symptom efficiency of angina pectoris, the clinical treatment efficiency of electrocardiography, the VAS and the SQA, and the results showed that the left-right distribution of the clinical symptom efficiency of angina pectoris (Fig. 7), the clinical treatment efficiency of electrocardiography (Fig. 8) and the SQS funnel plot were symmetrical (Fig. 9), and the left-right distribution of the VAS funnel plot was asymmetrical (Fig. 10), suggesting the possibility of publication bias.

Related adverse reactions
3.6.1. Adverse drug reactions. Two [10,11] studies reported adverse drug-related information for stable angina relief. Drug-related adverse reactions were mainly abdominal pain, chest tightness, dyspnea, and heart failure, but there were no serious adverse events.
3.6.2. Electroacupuncture adverse reactions. One [9] study reported 2 cases of acupuncture-related adverse events during the study. Acupuncture-related adverse events mainly included dizziness and local pain, and no other serious adverse events were observed.    3.6.3. Serious adverse events. One [8] study reported 1 subject died 9 days after enrollment due to acute myocardial infarction (Table 4).

Discussion
Clinical trials and mechanism of action studies at home and abroad have shown that acupuncture treatment improves microcirculation by improving several blood rheological indicators such as fibrinogen, plasma viscosity, red blood cell pressure and aggregation index in patients with angina pectoris, [15] thereby reducing the frequency of angina attacks, [16] decreasing the degree of angina pain, improving clinical symptoms and ECG of angina pectoris, [16] and improving the quality of life of patients with angina pectoris. [17] Electroacupuncture, as a new physical therapy measure, [18] uses pulsed current to unblock the meridians and qi and blood at the acupuncture site on the basis of acupuncture to obtain qi, regulate the function of the internal organs, promote blood circulation, and thus achieve relief of patients' angina symptoms. [15] The present study was conducted to explore the effectiveness and safety of electroacupuncture in the treatment of angina pectoris in CHD by systematically evaluating previous articles on electroacupuncture in the treatment of angina pectoris in CHD, [18] to find evidence-based medical evidence on electroacupuncture in the treatment of angina pectoris in CHD, and to further provide a basis for clinical and scientific research. [19] A total of 7 randomized controlled trials of electroacupuncture combined with conventional drugs for the treatment of stable angina were included in this study to evaluate 5  outcome indicators of clinical efficiency, ECG clinical treatment efficiency, VAS, SQA, and incidence of adverse effects of electroacupuncture combined with conventional drugs in patients with stable angina. From the current evidence, electroacupuncture combined with conventional drug therapy is significantly more effective than conventional drug therapy alone, especially in improving clinical symptoms of angina pectoris, improving patients' ECG performance, reducing the frequency of angina pectoris episodes, and reducing the number of angina pectoris episodes, while possessing safety and economic characteristics.
This study found large heterogeneity in some of the outcome indicators, which, upon further investigation, may be due to the following reasons: the study groups included in this study were all from China, the study groups were homogeneous, and there were differences in age, gender, disease duration, sample size, treatment drugs, duration of treatment, and outcome indicators among the populations included in different studies, making the studies not on a uniform baseline, which may have an impact on the analysis results.
The study has certain limitations, mainly in the following areas: the low quality of the literature included in the study, the small sample size, no multicenter, large-sample randomized controlled studies or real-world studies, the inconsistent efficacy indicators used across studies, the lack of blinding and allocation concealment methods in most trials, the treatment of excluded and dislodged cases not clearly reported, and the lack of a rigorous scientific design. In addition, there was a lack of

Conclusions
Current research evidence suggests that electroacupuncture combined with conventional drugs can significantly reduce the frequency of angina attacks, decrease the degree of angina pain, improve angina clinical-related symptoms and ECG, and improve the quality of life of patients with angina compared with drug therapy alone. Due to the small number and low quality of literature included in the study, the authenticity and reliability of this study urgently need more standardized design, rigorous multicenter, large-sample randomized controlled trials and real-world studies to verify. It is recommended that future clinical trials on electroacupuncture for stable angina pectoris should use high-quality clinical trial designs and be implemented with reference to international standards as much as possible, such as using the Cochrane Risk of Bias Assessment Tool and Consort to design and evaluate trial protocols and allocation concealment methods, and improving baseline patient data and efficacy evaluation indexes with reference to international standards, in order to reduce various potential risks of bias. to reduce the potential risk of bias and improve the quality of studies related to electroacupuncture for stable angina pectoris.