General information
A flow 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 efficacy, angina efficacy, angina frequency, nitrates consumption, ECG efficacy, 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 symptoms13. 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 efficacy of SA treatment. Hence we conducted meta-analysis of clinical efficacy, angina efficacy, angina frequency and nitrates consumption in TCM treating SA.
In the meta-analysis of clinical efficacy, 20 RCTs were included, and had shown significant difference of RR (1.25, 95% CI, 1.17 to 1.34). Statistical heterogeneity in this model was considered low (P=0.22, I2=19%) (Figure 2A). TCM had a significant effect in improving clinical efficacy. 11 RCTs were included in the meta-analysis of angina efficacy, and had shown significant difference of RR (1.23, 95% CI, 1.11 to 1.37). Statistical heterogeneity in this model was considered high (P=0.005, I2=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 efficacy of SA. 13 RCTs also paid close attention to the ECG efficacy. Meta-analysis showed significant improvement of TCM in ECG, with RR of 1.23 and 95% CI 1.14 to 1.33 (Figure 2E). ECG efficacy indicated that TCM can improve stable angina in the aspect of ECG.
Analyses also showed that TCM can improve dyslipidemia in SA. 9 RCTs reported TC level after intervention. Meta-analysis showed that TCM can significantly lower TC in SA (SMD -1.22, 95% CI -1.58 to -0.87) (Figure 3A). 10 RCTs showed that TCM can significantly lower LDL-C in SA (-0.79, 95% CI -1.06 to -0.53) (Figure 3B). TCM can also lower TG in meta-analysis of 9 RCTs (-0.86, 95% CI -1.18 to -0.21) (Figure 3D). As for the protective cholesterol, TCM can increase the level of HDL-C, supported by the meta-analysis of 8 RCTs (0.6, 95% CI 0.27 to 0.94) (Figure 3C).
Dyslipidemia is one of the major risk factors of cardiovascular disease, and the levels of cholesterol influence the stratification of the CVD risk categories, hence affect the expectation of cardiovascular event and the treatment intensity14. 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 efficacy, angina efficacy, angina frequency, nitrates consumption, ECG efficacy, 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 efficacy after intervention. Meta-analysis had shown significant 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, I2=43%) (Figure 4A). As for the angina efficacy, 6 RCTs were included in the meta-analysis and had shown significant difference of RR (1.25, 95% CI, 1.14 to 1.36). Statistical heterogeneity in this model was considered low (P=0.89, I2=0%) (Figure 4B). The RCTs documented angina frequency and nitrates consumption were relatively fewer (2 RCTs in each comparison). Meta-analysis were conducted in these 2 comparison, and had shown significant difference in RR (angina frequency: -1.95, 95% CI -2.41 to -1.49, heterogeneity P=0.14, I2=54%; nitrates consumption: -2.12, 95% CI -3.02 to -1.22, heterogeneity P=0.004, I2=88%) (Figure 4C and D). These analyses indicated TCM could improve the clinical efficacy of SA, probably by ameliorate the manifestation of angina and reduce the angina frequency and consumption of nitrates.
7 RCTs had documented the ECG efficacy after intervention. Meta-analysis showed significant 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, I2=0%) (Figure 4E). ECG efficacy 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 significant difference in CRP (-1.10, 95% CI -1.64 to -0.55, with Random effect model, heterogeneity P<0.00001, I2=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 significant difference either. Data of other conventional cholesterol was not sufficient enough for systematic review in these 18 RCTs concerning UA. The efficacy 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 efficacy, 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 efficacy 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 significant difference of RR (1.11, 95% CI, 1.05 to 1.18). Statistical heterogeneity in this model was considered low (P=0.36, I2=11%) (Figure 6). This result indicated that TCM can improve the clinical efficacy 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 significant difference of RR (0.57, 95% CI 0.47 to 0.78) (Figure 7A). As for CD, meta-analysis also showed significant 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 process16, 17. Prompt and adequate intervention can boost the cardiac rehabilitation and prolong life expectancy18. 7 RCTs (No.55-61) evaluated TCM treating PMI were included and assessed. All the participants experienced AMI 1-12 months before inclusion, despite recanalization or not. The sample size ranged from 60 to 4870 participants, with average of 763.57 (average of 79.17 if the largest scale RCT was ruled out). The intervention duration ranged from 4 to 216 weeks, with average of 42.29 weeks (average of 13.33 if the largest scale RCT was ruled out). The methodological quality of the included RCTs was generally low. 1 of 7 RCTs had a Jadad score of 5, 1 had a Jadad score of 3, and 5 had score of 2. The major and secondary outcomes we included and assessed were clinical efficacy, angina efficacy, LVEF and MACE.
5 of 7 RCTs had reported the clinical efficacy after intervention. All of them compared TCM with blank intervention, with the basis of antiplatelet, beta blocker, statins, ACEI/ARB and nitrates. Meta-analysis had shown significant difference of RR (1.28, 95% CI, 1.15 to 1.42). Statistical heterogeneity in this model was considered low (P=0.76, I2=0%) (Figure 8A). 3 RCTs were included in the meta-analysis of angina efficacy, and had shown significant difference of RR (1.48, 95% CI, 1.23 to 1.78). Statistical heterogeneity in this model was considered low (P=0.26, I2=25%) (Figure 8B). This result indicated that TCM can improve the clinical and angina efficacy of PMI.
LVEF reflects the pumping function of left ventricular. Size of infarct myocardium, formation of ventricular aneurysm, ventricular remodeling, arrhythmia and cardiac rehabilitation are the detrimental and beneficial factors of remaining LVEF. 3 RCTs documented LVEF after intervention. Meta-analysis showed that in LVEF, TCM did not achieve significant 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 significant 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 efficacy, N terminal pro B type natriuretic peptide (NT-proBNP), LVEF and 6-minute walk test (6MWT), according to the data in RCTs we included.
13 of 16 RCTs had reported the clinical efficacy after intervention. All of them compared TCM with blank intervention, with the common basis of diuretic, Aldosterone antagonists, beta blocker and ACEI/ARB. Meta-analysis had shown significant difference of RR (1.23, 95% CI, 1.13 to 1.34). Statistical heterogeneity in this model was considered high (P=0.002, I2=61%) (Figure 10). This result indicated that TCM can improve the clinical efficacy of CHF.
6 RCTs had documented the level of NT-proBNP in each group after intervention. Meta-analysis showed significant reduction of SMD in TCM group (SMD -2.72, 95% CI -4.26 to -1.19) (Figure 11A). As for LVEF and 6MWT, 16 RCTs and 10 RCTs documented LVEF and 6MWT respectively, meta-analysis showed significant increase of SMD in TCM groups (LVEF: SMD 0.91, 95% CI 0.45 to 1.37; 6MWT: SMD 0.65, 95% CI 0.41 to 0.89) (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 HF21, 22. And the 6MWT independently predicts CHF severity, hospitalization and death23. TCM may ameliorate clinical symptoms and improve life quality in patients with CHF.