Traditional Chinese medicine for ischemic heart disease: clinical manifestations and objective indicators

Background: The clinical practice of Traditional Chinese medicine (TCM) has a history of more than 2000 years. Modern clinical trials and experimental researches of TCM have been conducted for decades and provided support for the application of TCM in the prevention and treatment of ischemic heart disease (IHD). However the level of evidence and the proper application of TCM were still barely satisfactory. Methods: In this study, we divided IHD into 5 different stages, including stable angina, unstable angina, acute myocardial infarction, post myocardial infarction and chronic heart failure. Then we systematically reviewed and meta-analyzed the existing RCTs on both clinical manifestations and objective indicators, in these 5 aspects. Results: The results indicate that TCM can both improve the clinical manifestations and ameliorate the objective parameters in different courses of IHD. Some of the improvements lead to potential long-term benets. Conclusions: TCM is effective on CVD in different stages of diseases, both in improving clinical manifestations and objective indicators. To acquire more solid and comprehensive evidence of TCM in treating CVD, more rigorously designed RCTs with longer follow-up duration are warranted.

criteria. Scienti c researches of TCM were launched to elucidate the effectiveness and mechanisms of TCM. TCM, or integrative medicine has help preventing and treating diseases across the world, not just in east of Asia 9 .
Under this circumstance, it is worth to gather the evidence of TCM treating CVD, to provide faith in treating CVD with TCM as primary or alternative therapy, and help decreasing the mortality and morbidity of CVD worldwide. Here, we aim to evaluate the e cacy and potential advantages of TCM in different course of IHD. We searched for published studies of RCTs with relatively ne quality, and systematically assessed the e cacy and safety of TCM therapy for the major clinical stages of IHD, including stable angina (SA), unstable angina (UA), acute myocardial infarction (AMI), post myocardial infarction (PMI) and chronic heart failure (CHF) caused by IHD.

Methods
Search strategy and inclusion/exclusion criteria Since English and Chinese are the major publication language that TCM related researches used 10  The studies we included should meet following criteria: 1) Study participants were diagnosed as SA, UA, MI, or CHF, did or did not underwent percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or thrombolysis. 2) Study should be randomized clinical trial, which compared the e cacy and quantitative parameters of TCM medication with placebo or contemporary medication. 3) Follow-up in each study should ≥4 weeks. 4) Study quality was considerably ne, with a Jadad score 11 ≥2. We excluded studies with the following features: 1) Studies were nonrandomized or without description of randomization method. 2) Studies without de nite diagnostic criteria. 3) Studies compared different TCM medications. When 2 articles reported the results from the same research, the articles with more data was included.
We have searched and investigated other systematic reviews of TCM, most of which would exclude the studies without objective laboratory measurements or physical parameters. One of the unique characteristics of TCM is emphasizing the symptoms of diseases. The cluster and pattern of symptoms can be both the evaluation of the features of disease, and the e cacy of the TCM medication. And by the Guiding Principles for Clinical Research of New Chinese Medicines, which was drafted and published by State Drug Administration of China, most of TCM related studies evaluated the clinical e cacy with semiquantitative methods and uni ed standard. Hence we included those studies which used clinical e cacy evaluated with well-adapted standard as primary parameters.

Statistical analysis
Data were analyzed using Review Manager v5.3 12 and Microsoft excel 2016. Meta-analysis was conducted if the included studies were no less than 2. For dichotomous outcome the pooled relative risk (RR) with 95% con dence interval (CI) was used as the effect measure. For the continuous outcome, standard mean difference (SMD) was used as the effect measure. The model used to pool the data was Random effect model, since the intervention between studies were different.

General information
A ow diagram of the literature search and study selection is shown in Figure 1. We included 77 eligible studies, in which 11 were in English, 66 were in Chinese. The publication date ranged from 2006 to 2018. The participant amount in single group varied from 20 to 2441, the average amount was 79 (the average amount was 49 if one of the largest scale RCT was ruled out). A total of 12544 subjects were included in this research. The quality of the studies were considered mostly moderate, 6 of them had a Jadad score of 5, 12 of them had a Jadad score of 3 to 4, and the rest of them (60 studies) had a Jadad score of 2. Generally, there were 25 studies of SA, 18 studies of UA, 12 studies of AMI, 7 studies of PMI, and 16 studies of CHF. The detail information of included studies were listed in Table 1. TCM for Stable Angina 25 RCTs (No. 1-25 in Table 1) evaluated TCM treating SA were included and assessed. The sample size ranged from 46 to 239 participants, with average of 88.68. The intervention duration ranged from 4 to 12 weeks, with average of 6.18 weeks. The methodological quality of the included RCTs was generally low. 2 of 25 RCTs had a Jadad score of 5, and 2 had a Jadad score of 4, 2 had score of 3 and 19 had score of 2.
The major and secondary outcomes we included and assessed were clinical e cacy, angina e cacy, angina frequency, nitrates consumption, ECG e cacy, and levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglyceride (TG).
SA is now considered stable ischemic heart disease (SIHD), a stage of coronary heart disease (CHD) with certain manifestations of cardiac ischemia, the existence of cardiovascular risk factors, and the potential risk of developing into acute coronary syndromes (ACS). According to the latest guideline, the management of SA is comprised of the management of risk factors (i.e. hypertension, dyslipidemia, diabetes mellitus) and the control of ischemic symptoms 13 . The control of angina pectoris is important in the management of SA, especially to those patients without any risk factor or had taken action on the risk factors. The reduction of angina frequency, degree of pain or discomfort, consumption of nitrates compose of the clinical e cacy of SA treatment. Hence we conducted meta-analysis of clinical e cacy, angina e cacy, angina frequency and nitrates consumption in TCM treating SA.
In the meta-analysis of clinical e cacy, 20 RCTs were included, and had shown signi cant difference of RR (1.25, 95% CI, 1.17 to 1.34). Statistical heterogeneity in this model was considered low (P=0.22, I 2 =19%) ( Figure 2A). TCM had a signi cant effect in improving clinical e cacy. 11 RCTs were included in the meta-analysis of angina e cacy, and had shown signi cant difference of RR (1.23, 95% CI, 1.11 to 1.37). Statistical heterogeneity in this model was considered high (P=0.005, I 2 =60%) ( Figure 2B). 6 RCTs were included in the meta-analysis of angina frequency, the RR was -0.82 (95% CI, -1.25 to -0.39) ( Figure  2C). 5 RCTs were included in the meta-analysis of nitrate consumption, the RR was -1.13 (95% CI, -1.68 to -0.59) ( Figure 2D).These analyses indicated TCM could both ameliorate the manifestation of angina and reduce the angina frequency and consumption of nitrates, together improved the clinical e cacy of SA.
13 RCTs also paid close attention to the ECG e cacy. Meta-analysis showed signi cant improvement of TCM in ECG, with RR of 1.23 and 95% CI 1.14 to 1.33 ( Figure 2E). ECG e cacy indicated that TCM can improve stable angina in the aspect of ECG.
Dyslipidemia is one of the major risk factors of cardiovascular disease, and the levels of cholesterol in uence the strati cation of the CVD risk categories, hence affect the expectation of cardiovascular event and the treatment intensity 14 . These meta-analyses indicated that TCM can adjust the levels of cholesterol, and serve as effective therapy for SA in both clinical manifestation and risk factors.
TCM for Unstable Angina 18 RCTs (No. 26-43) evaluated TCM treating UA were included and assessed. The sample size ranged from 60 to 244 participants, with average of 103.17. The intervention duration ranged from 4 to 12 weeks, with average of 4.78 weeks. The methodological quality of the included RCTs was generally low. Only 1 of 18 RCTs had a Jadad score of 4 and 3, and the rest of them had score of 2. The major and secondary outcomes we included and assessed were clinical e cacy, angina e cacy, angina frequency, nitrates consumption, ECG e cacy, levels of LDL-C and C-reactive protein (CRP). 1 of 18 RCTs compared TCM with placebo, and the rest of them compared TCM with blank intervention, on the basis of conventional therapy, including antiplatelet, beta blocker, anticoagulant, statins, ACEI/ARB, long-or short-active nitrates, and hypotensor, hypoglycemics if necessary. 14 of 18 RCTs had reported the clinical e cacy after intervention. Meta-analysis had shown signi cant difference of RR (1.20, 95% CI, 1.12 to 1.27). Statistical heterogeneity in this model was considered moderate to high (P=0.04, I 2 =43%) ( Figure 4A). As for the angina e cacy, 6 RCTs were included in the meta-analysis and had shown signi cant difference of RR (1.25, 95% CI, 1.14 to 1.36). Statistical heterogeneity in this model was considered low (P=0.89, I 2 =0%) ( Figure 4B). The RCTs documented angina frequency and nitrates consumption were relatively fewer (2 RCTs in each comparison). Metaanalysis were conducted in these 2 comparison, and had shown signi cant difference in RR (angina frequency: -1.95, 95% CI -2.41 to -1.49, heterogeneity P=0.14, I 2 =54%; nitrates consumption: -2.12, 95% CI -3.02 to -1.22, heterogeneity P=0.004, I 2 =88%) ( Figure 4C and D). These analyses indicated TCM could improve the clinical e cacy of SA, probably by ameliorate the manifestation of angina and reduce the angina frequency and consumption of nitrates.
7 RCTs had documented the ECG e cacy after intervention. Meta-analysis showed signi cant improvement of TCM in ECG, with RR of 1.25 and 95% CI 1.14 to 1.36. Statistical heterogeneity in this model was considered low (P=0.89, I 2 =0%) ( Figure 4E). ECG e cacy indicated that TCM can improve unstable angina in the aspect of ECG.
As for the laboratory parameters, LDL-C and CRP were synthetize respectively. Meta-analysis shown signi cant difference in CRP (-1.10, 95% CI -1.64 to -0.55, with Random effect model, heterogeneity P<0.00001, I 2 =90%) ( Figure 5A) but not in LDL-C (0.12, 95% CI -0.75 to 0.99) ( Figure 5B). Meta-analyses of 2 out of 3 RCTs that LDL-C included showed no signi cant difference either. Data of other conventional cholesterol was not su cient enough for systematic review in these 18 RCTs concerning UA. The e cacy of TCM for CVD risk factors in UA needs more evidence to be proved.
TCM for AMI 11 RCTs (No. 44-54) evaluated TCM treating AMI were included and assessed. All the participants in every RCTs were diagnosed myocardial infarction with formally published criteria. The intervention time nodes were around the AMI and coronary recanalization. Respectively, 2 RCTs were 30 minutes to 2 days before recanalization; 1 RCTs were 12 to 55 days after recanalization; 8 RCTs were immediately after recanalization. The sample size ranged from 40 to 219 participants, with average of 111.18. The intervention duration ranged from 4 to 24 weeks, with average of 7.82 weeks. The methodological quality of the included RCTs was moderate. 2 of 11 RCTs had a Jadad score of 5, and 1 had a Jadad score of 4, 2 had score of 3 and 6 had score of 2. The major and secondary outcomes we included and assessed were clinical e cacy, major adverse cardiovascular events (MACE), cardiovascular death (CD) and left ventricular ejection fraction (LVEF), according to the data in RCTs we included. 7 of 11 RCTs had reported the clinical e cacy after intervention. All of them compared TCM with blank intervention, with the basis of antiplatelet, anticoagulant, beta blocker, ACEI. Participants in 1 of the RCTs underwent thrombolysis, and in another RCT, participants underwent PCI. The rest 5 RCTs used conservative treatment as described above. Meta-analysis had shown signi cant difference of RR (1.11, 95% CI, 1.05 to 1.18). Statistical heterogeneity in this model was considered low (P=0.36, I 2 =11%) ( Figure  6). This result indicated that TCM can improve the clinical e cacy of AMI.
The average follow-up duration of these RCTs were 7.82 weeks (4 to 24 weeks), hence the short-term outcomes would be the major concern of TCM intervention in these RCTs. 4 of the RCTs had documented incidence of MACE in each group after intervention. Meta-analysis showed signi cant difference of RR (0.57, 95% CI 0.47 to 0.78) ( Figure 7A). As for CD, meta-analysis also showed signi cant difference of RR (0.33, 95% CI 0.15 to 0.76) ( Figure 7B). 5 of the RCTs had also documented the LVEF after intervention. Data was pooled together and synthetized, the results favored TCM group (SMD 0.94, 95% CI 0.22 to 1.66) ( Figure 7C). Research had shown that the 30-day cardiac mortality rate in ST elevated myocardial infarction (STEMI) patients was 7.3% even underwent PCI, the 1-year cardiac mortality rate was 8.4%, with a <1.5% annual risk of successive cardiac death 15 . To reduce the short-term cardiac mortality rate in AMI patients is vital to control the over-all outcomes of MI patients. Cardiac mortality rate in TCM group is 4.1%. The results in these research indicated that TCM may be a key role in this goal.

TCM for PMI
Post myocardial infarction is usually reckoned as 4 to 8 weeks after acute myocardial infarction. If the patient survive from AMI and/or cardiac shock, malignant arrhythmia, cardiac remodeling and coronary collateral circulation establishment should be the major physiopathological process 16,17  showed that in LVEF, TCM did not achieve signi cant progression compared to blank intervention (RR 0.36, 95% CI -0.08 to 0.80) ( Figure 9A). As for MACE in PMI after intervention, the incidence rate in TCM group was 5.18%, compared to 8.04% in control group (RR 0.56, 95% CI 0.32 to 0.97) ( Figure 9B). TCM has signi cant effect on reducing incidence rate of MACE.

TCM for CHF
As more patients survive and live longer after MI, the incidence and prevalence of IHD related CHF continue to rise 19 . Cardiovascular and non-cardiovascular caused HF will have different pathologies. In patients with HF (both hospitalized and ambulatory), most deaths are due to cardiovascular causes 20 .
16 RCTs (No. 62-77) evaluated TCM treating CHF were included and assessed. All the participants in every RCTs were diagnosed IHD or previous MI with formally published criteria. The sample size ranged from 60 to 491 participants, with average of 110.69. The intervention duration ranged from 4 to 24 weeks, with average of 9.25 weeks. The methodological quality of the included RCTs was considered moderate to low. Only 1 of 16 RCTs had a Jadad score of 5 and 3, the rest 14 RCTs had score of 2. The major and secondary outcomes we included and assessed were clinical e cacy, N terminal pro B type natriuretic peptide (NT-proBNP), LVEF and 6-minute walk test (6MWT), according to the data in RCTs we included.  Figure 11B and 11C). NT-proBNP and LVEF can serve as ideal parameters in diagnosing and evaluating severity of HF, also associated with increased mortality and morbidity in patients with HF 21,22 . And the 6MWT independently predicts CHF severity, hospitalization and death 23 . TCM may ameliorate clinical symptoms and improve life quality in patients with CHF.

Discussion
Clinical e cacy, or the amelioration of symptoms, is the major purpose and evaluation of TCM intervention, according to its nautural characteristics. It is the ability to relieve clinical symptoms that makes it survive and prosper for more than 2 thousand years. Modern TCM has embraced advanced modern medicine and science for more than 2 hundred years. One of the pharmaceutical monograph named < Bencaogangmu Shiyi> (supplementto compendium of materia medica) has recorded quinine as imported product for the treatment of malaria back in 1765. In 1909, one of the famous clinical monograph named < Yixue Zhongzhong Canxilu> (practical records of traditional Chinese medicine with reference to western medicine) had presented a formula with aspirin as one of the ingredients for the treatment of u. Till mid-20th century, the clinical practice and research of real modern TCM was initially formed 24 . Interestingly, the frontier aspect of modern TCM research was CHD. Decades have passed by and we have learned that TCM can both ameliorate clinical symptoms and improve objective parameters.
More and more clinical and experimental evidence has been revealed to support the utilization of TCM as primary or complementary therapy for diseases.
The quanti cation of TCM symptoms was once obstacle for the evaluation and promotion of TCM. The Guiding Principles for Clinical Research of New Chinese Medicines (published by State Drug Administration of China in 2002) has uniformed the chaos of clinical e cacy evaluation. It was based on patient self-reported severity of various clinical symptoms to form a disease assessment scale. The symptoms used in evaluation varies in different diseases, and are most related to the concern of the diseases. With this equipment allows researchers assess the clinical e cacy in a more quantitative way, especially in some diseases which clinical manifestations play important role in the management and patient satisfaction (i.e. SA, CHF with NYHA class / cardiac function) 25,26 .
As we mentioned above, we value the clinical e cacy comparison after intervention. 'Effective' was de ned as the total score of symptoms reduced over 50% after intervention in the RCTs we included. Of all the aspects of IHD this research concerned, TCM achieved better clinical e cacy, with RR ranged between 1.14 to 1.30. The evaluation and the results of angina e cacy were similar to clinical e cacy in these analyses, and were corroborated by the analyses of angina frequency and nitrates consumption. Considering almost every RCT was conducted on the basis of conventional treatment in both TCM group and control group, it is safe to say that TCM can improve clinical e cacy as complementary to western medicine. The improvement of clinical e cacy was coincided with previous reports [25][26][27][28][29][30] .
As the clinical e cacy was improved, objective parameters were altered in these RCTs. In different stages of IHD, the secondary outcomes, or what we pay more attention to, is different. Such as in SA, patients experience occasional angina pectoris, apart from angina relieving and controlling, the management of SA is control of risk factors. Since in this research we mainly focus on the IHD, the risk factor in this aspect was dyslipidemia. Meta-analyses had shown that TCM could lower levels of TC, LDL-C, TG and increase level of HDL-C in SA. These can gain dependable bene t for patients with SA in the holistic management of IHD.
The secondary outcomes we synthesized and analyzed were affected by RCTs we included. In the aspect of UA, only LDL-C was pooled and analyzed, as seldom study documented other types of lipid. And CRP was meta-analyzed, since UA is the unstable form of atherosclerosis with increased level of in ammation 31 , CRP was tested as useful biomarker. In the aspect of AMI and PMI, MACE and CD were more important to assess the value of TCM intervention. MACE and CD are more likely to happen closer to the onset of MI 15 . It is vital to control recurrent cardiovascular events in patients experienced MI. These analyses indicated that TCM can reduce the incidence rate of MACE and CD both in acute and non-acute stage of MI.
LVEF re ects the pumping function of left ventricular. Local myocardial damage or long-term myocardium ischemia can lead to the reduction of LVEF. LVEF was documented in AMI, PMI and CHF related RCTs. Level of LVEF is one of the major diagnostic and strati cation biomarkers for HF. All-cause mortality is generally higher in HF with reduced EF (HFrEF) than HF with preserved EF (HFpEF) 32 . Compared with patients with HFpEF and patients with HFrEF, patients with HF with recovered EF (HFrecEF) had fewer all-cause, cardiovascular and HF-related hospitalizations and were less likely to experience composite end points 33 . NT-proBNP have diagnostic and prognostic value in patients with HF 34 . Reduction of NT-proBNP is associated with reduced morbidity and mortality outcomes, whereas increased NT-proBNP portends poor patient outcomes 35 . The 6MWT has important prognostic value in patients with chronic heart failure 36 . It has also been recommended to monitor the disease course and to assess the e cacy of intervention in patients with mild-to-moderate CHF 37 . Improvement of 6MWT contributed to improvement of exercise con dence in HF patients, which indicated more intention to perform exercise 38 . Meta-analyses of LVEF in AMI, and CHF, and of NT-proBNP and 6MWT in CHF had provided evidence for the TCM potential long-term protection for IHD.
Systematic review and meta-analysis of TCM are popular for years, because the screening and synthesizing process can enhance the reliability of TCM RCTs, which mostly were moderate to low quality. Previously published meta-analyses had provided bene cial evidence for single TCM medication in some aspects of IHD respectively. Some of them had also taken IHD or CHD as whole to assess the e cacy of TCM. Panpan Hao et al. 39 had evaluated TCM therapy for several CVD risk factors, atherosclerotic cardiovascular disease (ASCVD) and CHF in 1 study. They included RCTs published in the past decade with a relatively strict criteria. Subgroup analyses showed the landscape of TCM therapy in different aspects of CVD. The methodological quality of included RCTs were moderate to high, the results and conclusions of this review are considered reliable. Meanwhile they only included RCTs with objective laboratory measurements or physical examination, clinical symptoms improvement evaluation was absent from this study. In this high quality, wide spectrum systematic review of TCM therapy for CVD, it would have been intriguing to evaluate if TCM could improve clinical e cacy along with the amelioration of objective parameters. Another systematic review had also evaluated TCM in the management of some of the most important cardiovascular diseases, including hypertension, acute ischemic stroke, HF, CHD and type 2 diabetes 40 . In this study, hard endpoint was required, too. But the methodology quality was not restricted in the inclusion criteria. The results were similar to Panpan Hao et al. in certain aspects.
The purpose of our study is to evaluate the e cacy of TCM in different stages of IHD. TCM is now widely used in the treatment of CVD in the eastern Asia, with the tendency of worldwide. It is urged to demonstrate more convincing evidence for the clinical practice of TCM. We divided IHD into 5 stages: SA, UA, AMI, PMI, HF, in which TCM are usually applied and more applicable for systematic analysis. These stages represent the developing process of IHD. In stage of SA, CVD risk factors are more likely to be managed, the control of angina symptom can be a challenge in clinical practice. In stage of UA and AMI, guidelines for acute coronary syndrome are elaborate, recanalization is sometimes needed. Any approach to reduce the mortality rate is encouraged. When patient has survived MI, reducing recurrence of cardiovascular events and preserving cardiac function would be the priority in clinical practice. By the meta-analyses in this study, we have failed in locating the best breakthrough point of TCM for IHD, but have discovered that TCM should be used in all these stages of IHD as complementary medicine to better the clinical outcomes.
Studies both in English and in Chinese were screened and included. The methodology quality of RCTs we included was considered moderate, as we ruled out all the RCTs with Jadad score less than 2, those without de nite randomization method were excluded, either. Primary and secondary endpoints we included and analyzed were based on the disease features and the included RCTs.
There were some potential limitations and sources of variability to this review: 1) The individual RCTs differed in baseline characteristics, especially some baseline parameters such as NT-proBNP, LVEF, and the baseline western medication. 2) The follow-up duration was moderate to short, the sample size was relatively small. 3) Heterogeneity was considered moderate to high between studies in some of the comparison. Baseline, follow-duration and sample size inconsistence may contribute to it. 4) Most of the RCTs compared TCM with blank intervention, only a few had used placebo. TCM decoction and some patent medicine are mostly highly-scented, it is di cult to produce satisfying placebo. 5) Non-drug therapy was not included in this study, such as acupuncture and moxibustion, Taichi, massage. The combination of drug therapy and non-drug therapy would increase the Heterogeneity. To eliminate these limitations and enhance the reliability, further rigorously designed RCTs with larger scale and multiple centers are needed.

Conclusions
Our meta-analysis of data from RCTs supports the use of TCM in different stages of IHD. TCM can both improve the clinical manifestations and ameliorate the objective parameters. Some of the improvements lead to potential long-term bene ts. To acquire more solid and comprehensive evidence of TCM in treating CVD, larger scaled, multi-centered, double-blinded RCTs with reliable placebo and longer follow-up duration are warranted.  Figure 1 Flow diagram of the RCT inclusion process.     Major outcomes and LVEF comparison between TCM group and control group in AMI. A: Incidence of MACE comparison between TCM group and control group. B: Incidence of CD comparison between TCM group and control group. C: LVEF comparison between TCM group and control group.  Clinical e cacy comparison between TCM group and control group in CHF