A systematic review and meta-analysis of clinical research on treating angina pectoris of coronary heart disease with traditional Chinese medicine to promote blood circulation and remove blood stasis
Introduction
Coronary heart disease (CHD), also known as coronary atherosclerotic heart disease, is a heart disease which occurs when blood vessels narrow due to atherosclerosis and myocardial ischemia (1). Due to the insufficient blood supply of coronary artery, there is a sharp transient ischemia and hypoxia in myocardium, which result in the symptoms of palpitations, fatigue, chest pain, accompanied by systemic fever, panic, vomiting (2). At present, the treatment of angina pectoris is mainly focusing on dilating blood vessels, improving myocardial ischemia, inhibiting platelet aggregation, and resolving arteriosclerotic plaques. However, long-term drug treatment can entail side effects such as liver and kidney injury (3).
Traditional Chinese medicine (TCM) therapy has its unique advantages in the treatment of CHD related symptoms of angina pectoris, from the traditional Chinese medicine knowledge, angina pectoris belongs to the cognitive category of “chest obstruction” and “heartache”, and its final pathogenesis is heart blood stasis. Therefore, promoting blood circulation to remove blood stasis should be its main treatment (4). A study (5) applied the combination of TCM and conventional Western medicine in the treatment of angina pectoris, achieving encouraging results. Another study (6) divided 102 angina pectoris patients into two groups, one with the treatment of a special Chinese herb decoction, the other with the treatment of nifedipine, isosorbide dinitrate, and enteric solubility aspirin, the result showed no significant difference in terms of angina pectoris symptoms improvement, the cardiac function index and the blood lipid index for the Chinese decoction group even better. A large number of such kind of randomized controlled studies (RCTs) have been conducted, but these studies have variable quality and a lack of systematic review. In this study, a systematic review and meta-analysis of such studies were conducted to investigate the therapeutic effect of TCM in the treatment of angina pectoris of CHD, all of which had the intervention through oral TCM administration and most of them based on the treatment of conventional medicine like phospholipid, βreceptor blocker, or calcium channel blocker. We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-2233).
Methods
Databases
PubMed, Embase, CBM (China Biology Medicine Database) and Web of Science were selected as the database sources for literature in this study.
Search strategy
The keywords “traditional Chinese medicine”, “decoction”, “TCM”, “angina pectoris”, and “coronary heart disease” were used to search literature published in the above-mentioned databases from 2010.1 to 2021.8.
Inclusion and exclusion criteria of literature
Inclusion criteria
The inclusion criteria for the meta-analysis were as follows: (I) single-center or multi-center RCTs; (II) the study participants had CHD and a definite diagnosis of angina pectoris; (III) the study participants were divided into a control group and an intervention group for comparative analysis; the intervention group was treated with a combination of TCM for promoting blood circulation and removing blood stasis (including decoction, pills, capsules, etc.) and Western medicine, and the control group was treated with conventional treatment (including simvastatin, isosorbide mononitrate, aspirin, or other commonly used Western medicines).
Exclusion criteria
The exclusion criteria for studies were as follows: (I) observational studies, investigations, guidelines, reviews, case analyses, and other studies; (II) studies with a sample size of less than 40; (III) studies without observation indicators, or studies with outcomes of incomplete or conflicting data.
Literature screening
Two retrieval personnels checked the database search results independently, remove the repetitive literatures. Preliminary screening was performed according to the inclusion and exclusion criteria by reading the abstracts of the RCTs. Then the full texts of the potentially eligible RCTs were read. Finally, the eligible studies were included for meta-analysis after quality evaluation.
Literature quality evaluation
The Jadad scoring criteria (7) were used to evaluate the quality of the included RCTs, and studies with fewer than 3 points were excluded. The evaluation process was independently carried out by two researchers. In cases of conflicting opinion, a third researcher was invited to participate as an arbitrator.
Data extraction
The full texts were read by a researcher, who extracted data, including interventions, total number, grouping, characteristics of study participants, and outcome measures, and entered them into an Excel sheet.
Outcome measures
All outcome measures were collected from the included articles and are shown in Table 1.
Table 1
| Author | Year | Outcome measures | Safety |
|---|---|---|---|
| Ma et al. (8) | 2021 | The effective rate of angina pectoris, frequency of attacks, glyceride consumption, inflammatory factors, endothelial vascular function | No reports |
| Lei et al. (9) | 2019 | Improvement of angina pectoris and blood lipid level | No reports |
| Zhi et al. (10) | 2015 | The effective rate of angina pectoris hemorheological level, the Seattle Angina Questionnaire (SAQ) | No reports |
| Hu et al. (11) | 2010 | Efficacy of angina pectoris, blood lipid level | No reports |
| Liang (12) | 2020 | Effective rate of angina pectoris, the Seattle Angina Questionnaire (SAQ) | No reports |
| Li et al. (13) | 2019 | Seizure frequency, hemorheological parameters, myocardial enzyme spectrum parameters | No reports |
| Huang et al. (14) | 2018 | Comprehensive response rate, frequency and duration of angina pectoris | No reports |
| Liu et al. (15) | 2018 | Treatment response rate and adverse reaction rate | Adverse events |
| Shi et al. (16) | 2018 | Treatment response rate and adverse reaction rate | Adverse events |
Statistical methods
The RevMan 5.3.5 software (issued by the Cochrane Collaboration) was used to perform a comprehensive analysis to investigate the efficacy, the frequency of angina pectoris attack, blood lipid level, quality of life score, and other indicators after angina pectoris treatment. All percentage data were converted to the actual number of objects. Binary statistics were reported as OR and 95% CI, and continuous statistics were reported as SMD and 95% CI. Differences were considered statistically significant with P<0.05.
Literature bias risk and heterogeneity
The RevMan 5.3.5 software was used to assess the bias risk of the included RCTs. The studies were assessed in the following six aspects: the generation of sequences, classification concealment, blinding method, outcome measures, selective reporting, and other biases. The bias risk was included in the calculation of the final statistics and the preparation of forest plots. I2 analysis and Q check were performed to assess the heterogeneity of the included studies. Heterogeneity was indicated by I2>50% or P<0.1, in which case the random-effects model was used. In the absence of heterogeneity, the fixed-effects model was used. When heterogeneity existed between studies, eliminating literature one by one to find which caused the heterogeneity. The fixed-effects model and random-effects model switch were used to conduct the sensitivity analysis, if the result showed both no significant difference, the results were stable. Funnel plots were used to represent publication bias.
Results
Literature screening results
In this study, 117 studies were initially screened. According to the inclusion and exclusion criteria, and the literature quality evaluation, 9 studies involving 824 patients were finally included in the meta-analysis, as shown in Figure 1. The basic characteristics of the included studies are shown in Table 2.
Table 2
| Author | Year | Number (T/C) | Male (T/C) | Mean age (years) (T/C) | Intervention group treatment | Control group treatment | Observation period (days) | Jadad score |
|---|---|---|---|---|---|---|---|---|
| Ma et al. (8) | 2021 | 47/46 | 29/27 | 61.3/60.7 | TCM + Western medicine | Western medicine | 56 | 4 |
| Lei et al. (9) | 2019 | 20/20 | 10/9 | 63.6/61.3 | TCM + Western medicine | Western medicine | 42 | 5 |
| Zhi et al. (10) | 2015 | 52/52 | 30/29 | 56.6/56.5 | TCM + Western medicine | Western medicine | 40 | 6 |
| Hu et al. (11) | 2010 | 60/60 | 36/32 | 55.4/53.2 | TCM + Western medicine | Western medicine | 60 | 6 |
| Liang (12) | 2019 | 21/21 | 11/10 | 65.9/63.6 | TCM + Western medicine | Western medicine | 90 | 5 |
| Li et al. (13) | 2019 | 63/63 | 31/29 | 68.3/70.5 | TCM + Western medicine | Western medicine | 56 | 4 |
| Huang et al. (14) | 2018 | 36/35 | 22/21 | 52.6/51.5 | TCM + Western medicine | Western medicine | 60 | 5 |
| Liu et al. (15) | 2018 | 69/69 | 36/34 | 61.3/62.9 | TCM + Western medicine | Western medicine | 14 | 6 |
| Shi et al. (16) | 2018 | 45/45 | 25/26 | 48.3/48.3 | TCM + Western medicine | Western medicine | 60 | 6 |
T represents the intervention group; C represents the control group. TCM, traditional Chinese medicine.
Literature bias and quality assessments
As shown in Figure 2 and Figure 3, the quality of the 9 articles included in this study was evaluated according to the Cochrane Random Intervention Evaluation System. The random sequence generation method was not explained in 1 study; the classification concealment was unclear in 1 study; the blinding method was unclear in 1 study; the outcome index data was incomplete in 1 study; and for 1 study, there was unknown bias. Nevertheless, the overall risk of bias of the 9 articles was low.
Meta-analysis results
Effective rate
Of the 9 articles finally included, Li et al.’s study (13) did not report effective rate indicator, so only 8 articles were elected into the synthesis. The results showed that the 8 articles exhibited statistical homogeneity (I2=25%, P=0.23), and the effective rate of the intervention group was greater than that of the control group [OR =3.20, 95% CI: (2.09, 4.90)], the statistical value was Z=5.35, P<0.00001, and the difference was statistically significant. These results indicated that the TCM + conventional Western medicine group exhibited a significantly greater therapeutic effect than the conventional Western medicine treatment group (Figure 4).
Angina attack frequency (times)
Three studies reported the frequency of angina pectoris attack as an outcome indicator. Meta-analysis showed revealed statistical heterogeneity between the 3 studies (I2=59%, P=0.09), so the random-effects model was used. Angina attack was less frequent in the intervention group than the control group [SMD =−1.85, 95% CI: (−2.29, −1.41)], the statistical value was Z=8.22, P<0.0001, and the difference was statistically significant. These results indicated that TCM + conventional Western medicine had a significantly lower frequency of angina pectoris attack in patients comparing to the conventional Western medicine (Figure 5).
Analysis of other indicators
As shown in Table 3, meta-analysis of other indicators showed that after treatment with TCM + conventional Western medicine, the serum total cholesterol concentration was lower, the duration of each angina attack was shorter, and the quality of life was better than that after treatment with conventional Western medicine alone, and the differences were statistically significant (all P<0.05). However, no statistical significance was observed for other indicators.
Table 3
| Outcome measures | No. of articles | Effect size | P value | Model |
|---|---|---|---|---|
| Serum TC | 3 | −0.53 (−1.21, −0.31) | 0.007 | Random effects; P<0.1; I2=65% |
| TG | 3 | −0.42 (−0.84, −0.03) | 0.352 | Random effects; P<0.1; I2=78% |
| HDL-C | 3 | −0.63 (−0.99, −0.12) | 0.449 | Random effects; P<0.1; I2=56% |
| LDL-C | 3 | 0.19 (0.08, 1.55) | 0.241 | Random effects; P<0.1; I2=76% |
| Duration of each angina attack (min) | 2 | −2.63 (−3.65, −1.22) | 0.021 | Random effects; P<0.1; I2=55% |
| SAQ | 2 | 3.54 (1.31, 4.58) | 0.001 | Fixed effects; P<0.1; I2=15% |
TC, total cholesterol; TG, triacylglycerol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SAQ, the Seattle Angina Questionnaire.
Adverse reaction rate
As shown in Figure 6, only 2 studies reported the adverse reactions in the two treatment groups: Liu et al. (15) reported the occurrence of abnormal blood glucose and liver function damage, while Shi et al. (16) reported the occurrence of muscle spasm, arthralgia, and hepatitis in both groups. Meta-analysis revealed that the homogeneity of the two studies was good (I2=0%, P=0.41). The statistical effect size obtained by the fixed-effects model was [OR =0.48, 95% CI: (0.21, 1.08)] and the statistical effect value was Z=1.78, P=0.08; however, the difference was not statistically significant.
Analysis of publication bias
The funnel plot in Figure 7 shows uneven distribution between the two subgroups, suggesting the presence of publication bias.
Discussion
The development of CHD may be related to a variety of factors such as sex, age, underlying diseases, drinking habits, and excessive obesity, all of which may lead to abnormal lipid metabolism. Such abnormality can damage the vascular endothelium and promote plaque formation and growth, resulting in stenosis and ischemic cardiomyopathy (17). In this systematic review and meta-analysis, 9 RCTs were included and a total number of 824 patients were involved. The results showed that the use of TCMs combining with conventional drugs for promoting blood circulation and removing blood stasis had the advantages of reducing the frequency of angina pectoris attacks, shortening the attack time, improving the therapeutic effect, reducing serum total cholesterol, and improving patient quality of life after treatment. Meanwhile, the two treatment approaches had equivalent efficacy in reducing the patients’ blood lipids. Two of the nine studies reported on adverse reactions after treatment, and there was no significant difference in the incidence rate of adverse reactions between the two treatment methods which meant the TCM treatment won’t add adverse reactions. The results of this study were consistent with those of the meta-analysis of Huang et al. (18), which included several (not reported) RCTs of TCMI (traditional Chinese medicine injection), but in this study, the experimental group interventions were administered through oral path, the results showed both administrating paths were effective.
The treatment of angina pectoris is mainly aimed at improving myocardial ischemia, reducing the frequency of attacks, and preventing the occurrence of myocardial infarction. Conventional medicines, such as nitrates, can improve the myocardial oxygen supply, protect myocardial cells, reduce the cardiac load, and delay the occurrence of cardiovascular disease. However, some patients cannot take conventional medicines for a long time due to insufficient drug tolerance (19).
Medicinal plant materials used in TCM, such as Panax notoginseng, Salvia miltiorrhiza, Hawthorn, Polygonum multiflorum, and Lonicera japonica, have been proved by modern pharmacology to regulate thrombosis, possess anti-oxidation and anti-aging properties, promote blood circulation, and remove blood stasis, ultimately helping to eliminate myocardial stasis and achieve the purpose of eliminating angina pectoris (20). Furthermore, TCMs have milder side effects than conventional medicines, making them more suitable for the long-term treatment of angina pectoris.
Also there are other TCM treatments clinically confirmed effective, a meta-analysis (21) of 12 RCTs showed that acupuncture therapy could serve as an adjunctive treatment of angina pectoris and contribute to the symptoms improving.
However, there were some limitations to this study. For instance, although the Jadad scores of the 9 included articles were all above 3, but in some articles, the blinding or allocation concealment was unclear, which may have impacted on the results. Furthermore, although the 8 studies showed statistically homogeneity during synthesizing, the funnel plot showed uneven distribution, which suggested there might be the presence of publication bias.
Also, since few of the included studies reported indicators as blood lipid level, quality of life, and adverse events, only 2 or 3 literatures included during synthesis for these indicators, which might lead to unaccuracy of the results.
Individual studies reported indicators as serum inflammatory factor level, endothelial vascular function, or the hemorheological level, but no synthesis was performed due to few articles. Therefore, more RCTs are needed and included to investigate the effect of TCM on such indicators.
Furthermore, the formulas and compositions of the TCMs used in the 9 included RCTs differed, and there was no uniform standard for the conventional Western medicine treatment, which may have produced inconsistency when the two groups were compared. Still, more high-quality studies are needed to continue in-depth discussion regarding the therapeutic effect of TCM on angina pectoris of CHD.
Conclusions
In this meta-analysis of the therapeutic effect of TCMs for promoting blood circulation and removing blood stasis on angina pectoris in patients with CHD, 9 studies involving 824 patients were included. The results showed that the application of TCM in the treatment of angina pectoris can improve the therapeutic effect, reduce the frequency of angina pectoris, shorten the attack time, reduce serum total cholesterol, and improve the quality of life after treatment; however, it has no significant effect on reducing blood lipids.
Acknowledgments
Funding: Natural Science Foundation of Zhejiang Province (grant No. LGF20H270013).
Footnote
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-2233
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-2233). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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(English Language Editor: J. Reynolds)
