Traditional Chinese Medicine for Coronary Heart Disease: Clinical Evidence and Possible Mechanisms

Coronary heart disease (CHD) remains a major cause of mortality with a huge economic burden on healthcare worldwide. Here, we conducted a systematic review to investigate the efficacy and safety of Chinese herbal medicine (CHM) for CHD based on high-quality randomized controlled trials (RCTs) and summarized its possible mechanisms according to animal-based researches. 27 eligible studies were identified in eight database searches from inception to June 2018. The methodological quality was assessed using seven-item checklist recommended by Cochrane Collaboration. All the data were analyzed using Rev-Man 5.3 software. As a result, the score of study quality ranged from 4 to 7 points. Meta-analyses showed CHM can significantly reduce the incidence of myocardial infarction and percutaneous coronary intervention, and cardiovascular mortality (P < 0.05), and increase systolic function of heart, the ST-segment depression, and clinical efficacy (P < 0.05). Adverse events were reported in 11 studies, and CHMs were well tolerated in patients with CHD. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammatory, anti-oxidation, anti-apoptosis, improving the circulation, and regulating energy metabolism. In conclusion, the evidence available from present study revealed that CHMs are beneficial for CHD and are generally safe.


INTRODUCTION
Coronary heart disease (CHD) incurs a huge economic burden on healthcare and society (Dunbar et al., 2018). According to the epidemiological data from 1990 to 2013, 92.94 million people were suffering from this disease, which eventually led to 8.1 million deaths (Murray et al., 2015;Roth et al., 2015). Current treatments for CHD include coronary revascularization, drug intervention, risk factor control, cardiac rehabilitation, and lifestyle improvement (Arslan et al., 2018). Among them, percutaneous coronary intervention (PCI) and coronary artery bypass grafting are the most effective (Roffi et al., 2016). However, PCI is mainly for the treatment of locally severe stenotic vessels and has limited therapeutic effect on extensive coronary stenosis and microcirculation lesions (Heusch and Gersh, 2017). Meanwhile, the prognosis of patients treated with PCI is sometimes not ideal because myocardial ischemia/reperfusion injury, no reflow, coronary dissection, stent thrombosis, and acute coronary occlusion still exist (Hausenloy and Yellon, 2013;Arslan et al., 2018). Although the technology of coronary intervention is still improving and conventional medicine is constantly updating, novel treatments that can stabilize arterial plaque, improve microcirculation, and angina symptoms; prevent acute myocardial infarction; delay the development of ischemic cardiomyopathy; ultimately reduce PCI; and improve prognosis are urgently needed.
Traditional Chinese medicine (TCM) includes herbal medicine (CHM), acupuncture, and other non-pharmacological therapies, which is a holistic approach to health and healing . CHM has been used to treat CHD for thousands of years, and in modern time, many claimed randomized controlled trials (RCT) have reported some TCM Fufang exerted the cardioprotective function (Han et al., 2008;Gao et al., 2010;Chung et al., 2013;Liu et al., 2013). However, most of these studies are poor methodological quality, leading that there is still insufficient evidence to support routine use of CHMs for CHD. Thus, the Cochrane group guidelines for clinical reviews may exclude the ''not-so-good'' studies (Chan et al., 2012). In addition, in a TCM reviewing process, researchers may need to include such high-quality studies about a medical certain issue to identify current problems and areas worthy of improvement for its future development (Chan et al., 2012). Thus, we performed a systematic review to assess the efficacy and safety of CHM for CHD according to high-quality studies with at least four domains of "yes" in Cochrane risk of bias (RoB) tool .

Search Strategy and Study Selection
Studies estimating the efficacy of CHMs in patients with CHD were systematically searched from EMBASE, PubMed, Cochrane Library, Wangfang database, China National Knowledge Infrastructure (CNKI), VIP database (VIP), and China Biology Medicine disc (CBM) from inception to the end of June 2018.
The key words were used as follows: "coronary disease OR acute coronary syndrome OR myocardial infarction OR myocardial ischemia" AND "herb OR traditional Chinese medicine OR Chinese Materia Medica. " Moreover, reference lists of potential articles were searched for relevant studies.

Inclusion and Exclusion Criteria
The inclusion criteria were prespecified as follows: (1) RCTs that investigated the efficacy and safety of CHM for CHD were included. Quasi-randomized trials, such as those in which patients were allocated according to date of birth and order of admission number, were excluded. If a three-arm design was used in a study, we extracted data only for the group(s) involving CHM and the control group(s). (2) All participants were patients with a diagnosis of CHD based on one of the following criteria: (1) The guideline of unstable or stable angina from Chinese cardiovascular association in different years, (2) the guideline of unstable or stable angina from American College of Cardiology (ACC) or American Heart Association (AHA) or European Society of Cardiology (ESC) or World Health Organization (WHO) in different years, (3) be diagnosed by coronary angiography, (4) patients after PCI, and (5) diagnostic criteria made by other authors with comparable definitions were also used. (3) The treatment interventions included CHMs used as monotherapies or adjunct with conventional medicine (i.e., antiplatelet, stable plaque, control ventricular rate) or supportive treatment (i.e., nutrition support, exercise therapy, psychotherapy). Interventions for control group were restricted to no intervention, placebo, conventional medicine, and supportive treatment. Studies comparing a CHM agent with another CHM agent were excluded. (4) The primary outcome measures were the incidence of myocardial infarction and/or the incidence of PCI and/or cardiovascular mortality and/or the level of ST-segment depression and/or indicators which represent systolic and diastolic function of the heart in cardiac ultrasound. The secondary outcome measures were clinical effective rating, and the safety of co-administration of CHM. The exclusion criteria were prespecified as follows: (1) no predetermined outcome index; (2) compared or combined with other Chinese herb medicine; (3) not randomized, doubleblind, placebo-controlled designed; (4) no control group; and (5) double publication.

Data Extraction
Two authors independently reviewed each included study and extracted following aspects of details: (1) name of first author, year of publication; (2) diagnostic criteria; (3) detail information of participants for each study, including sample size, gender composition, and mean age; (4) detail information of treatment and control group, including therapeutic drug dosage, method of administration, and duration of treatment; and (5) outcome measures and intergroup differences. The data of predetermined primary and secondary outcomes were extracted for further qualitative and quantitative syntheses. We made efforts to contact authors for further information when some records' published data were only in graphical format or not in the publication. And the numerical values were measured from the graphs by digital ruler software when response was not received from authors.

Risk of Bias in Individual Studies
The methodological quality of each included study was evaluated by two authors with the seven-item checklist recommended by Cochrane Collaboration (Higgins and Green, 2012). Only RCTs with a cumulative score of at least four points were included in our systematic review. Any disagreements from two authors were dealt with through discussion with the corresponding author (GQZ).

Statistical Analysis
The statistical analysis was conducted via RevMan version 5.3. A fixed-effects model (FEM) or random-effects model (REM) was conducted to analyze pooled effects. When the outcome measurements in all included studies in meta-analysis were based on the same scale, weighted mean difference (WMD) with 95% confidence intervals was calculated as a summary statistic, otherwise standard mean difference (SMD) was calculated.
Heterogeneity between study results was investigated based on a standard chi-square test and I 2 statistic. A fixed-effects model (I 2 < 50%) or a random-effects model (I 2 > 50%) was used depending on the value of I 2 . Funnel plots were used to visually estimate publication bias. A probability value 0.05 was considered statistically significant.

CHM Composition and Possible Mechanisms of Active Ingredients
Specific herbs in the CHM formulae were recorded. The frequency of use for particular herb was calculated and those used at a high frequency that are described in detail. Animal-based mechanism studies of active ingredients from frequently used herbs were searched. The following information was recorded for such studies: identity of active ingredients and their herbal sources, suggested mechanisms and implicated signaling pathways, first author's name and publication year of the citation, and structure of active ingredients.

Systolic and Diastolic Functions of the Heart in Cardiac Ultrasound and the Level of ST-Segment Depression in Electrocardiogram
For systolic function, five studies (Qiao et al., 2006;Qiu et al., 2009;Chen et al., 2013;Sun, 2014;Mao et al., 2016) showed CHM existed significant effect for increasing LVEF compared with control group (P < 0.05). For diastolic function, there was no study involving related indicators as outcome measure. Two studies (Qiao et al., 2006;Chen et al., 2013) showed that CHM could decrease the ventricular wall motion score compared with control (P < 0.05). In addition, meta-analysis of three studies (Chu et al., 2010;Hu et al., 2014;Sun, 2014) reported that CHM can increase degree of decline in the ST-segment compared with control (n = 473, OR = 2.51, 95% CI: 1.64∼3.83, P < 0.0001, I 2 = 0%) ( Figure 5).

Summary of Evidence
This is the first clinical systematic review of 27 high-quality RCTs involving 11,732 participants to estimate the efficacy and safety of CHMs for CHD. The evidence available from present study revealed that CHMs are beneficial for CHD and are generally safe. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammation, anti-oxidation, anti-apoptosis, circulation improvement, and energy metabolism regulation.

Limitations
First, there were still some methodological weaknesses in the primary studies although we included high-quality studies. Only nine of the 27 included studies (Lu et al., 2006;Chu et al., 2010;Wang et al., 2009;Xu et al., 2015;Zhang et al., 2015;Duan et al., 2016;Mao et al., 2016;Wang et al., 2016) reported allocation concealment, and eight included studies (Lu et al., 2006;Chu et al., 2010;Wang et al., 2009;Xu et al., 2015;Zhang et al., 2015;Duan et al., 2016;Wang et al., 2016) reported blinding during outcome assessment. It is worth noting that an average 18% more "beneficial" effect in trials with inadequate or unclear concealment of allocation compared with adequate concealment (Higgins and Green, 2012). And blinding during outcome assessment is an essential method to avoid systemic errors which existed in the outcome assessment of non-blinded studies (Higgins and Green, 2012).
Second, English and Chinese literatures were included only in present study and the absence of studies written in other languages may generate selective bias in a certain degree. Third, no included trials were reported to have been registered, and negative findings were less likely to be published, which may lead to the efficacy being overestimated.

Implications
The findings from present study indicate that CHM paratherapy is beneficial for CHD and is well tolerated. Thus, we recommended, at least to an extent, to use CHMs for CHD, especially selected case. Further study should identify specific CHM and/or indications of CHM. In addition, the findings of the most frequently used herbs such as Miltiorrhiza, pseudo-ginseng, ginseng, Radix Paeoniae rubra, Astragalus membranaceus, rhizome of Chuanxiong, leech, borneol, and safflower and their main active components should be considered as further development of herbal prescriptions and component injection for CHD.
Some methodological weaknesses still existed in the primary studies. Recommendations for further research are as follows: (1) the CONSORT 2010 statement , CONSORT for TCM (Bian et al., 2011), RCTs investigating CHM (Flower et al., 2012), and CONSORT Extension for Chinese Herbal Medicine Formulas 2017 (Cheng et al., 2017) should be abided by for the design.
(2) Clinic trials should be registered in a generally accessible database (www.clinicaltrials.com) prior to first case inclusion. It allows verification of predefined study hypothesis and end-points of the study, which would help to the 5 | Different syndromes of coronary heart disease and the classification of herbs according to syndrome differentiation therapy for different syndromes.

Syndrome
Syndrome differentiation therapy for different syndromes Representative herbs in the theory of traditional Chinese medicine mentioned in present study report of negative findings and reduce publication bias (Rongen and Wever, 2015). (3) In view of trials with insufficient statistical power that runs the risk of over estimating therapeutic efficacy (Kjaergard et al., 2001), the further studies are recommended to provide statistical information of sample size estimation. (4) In order to ensure the efficacy of TCM, the identity and quantity of the herbal preparations should be described clearly in further research. (5) The safety of TCM has been increasingly concerned by both medical workers and the public. The frequency of use for particular herb was calculated and those used at a high frequency that are described in detail in the part 3.6 and Table 3. The high-frequency herbs that we selected can ignite the treatment based on syndrome differentiation according to the herbal functions Table 5. Ginseng and Astragalus membranaceus benefit qi; Miltiorrhiza, pseudo-ginseng, Radix Paeoniae rubra, rhizome of Chuanxiong, leech, and safflower promote blood circulation for removing blood stasis; and borneol has function of resuscitation with aromatics for relieving pain. Thus, we can also deduce that the main patterns of CHD are qi deficiency and blood stasis. The selected high-frequency herbs are composed of a herbal prescription for CHD, which can be used for clinic and as a candidate for RCT.
Cardioprotection by anti-inflammation, antioxidant, antiapoptosis, and circulation improvement for myocardial I/R injury  was an innovative strategy for antagonizing the injurious biochemical and molecular events that eventually resulted in irreversible ischemic injury (Wu and He, 2010). The included preclinical trials presented the main active components of the most frequently used herbs that performed antiinflammatory, anti-oxidation, anti-apoptosis, energy metabolism regulation, and circulation improvement mechanisms in multiple models of I/R injury through multiple signal pathways, including the PI3K/Akt signaling pathway, AMPK/Akt/PKC pathway, PI3K/Akt/mTOR pathway, mitochondrial-dependent apoptotic pathway, P38MAPK pathway, eNOS phosphorylation, and p-JNK-NF-kappaB-TRPC6 pathway. Further studies of CHM for CHD should explore the multi-drug, multitarget signal pathway using novel techniques such as network pharmacological approach.

Conclusion
The findings from present study indicate that CHMs are beneficial for CHD and are generally safe. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammatory, anti-oxidation, antiapoptosis, circulation improvement, and energy metabolism regulation mechanisms.