Effect of Tongqiao Huoxue Decoction Combined with Western Medicine on Ischemic Stroke: A Systematic Review

Objective We conducted a systematic review and meta-analysis to systematically evaluate the curative effect of Tongqiao Huoxue Decoction (TQHXD) combined with Western medicine treatment (WMT) on Ischemic Stroke (IS). Methods Randomized controlled trials (RCTs) of TQHXD in the treatment of IS by computer retrieval of PubMed, Embase, Web of Science, Chinese Biomedical Literature Service System, CNKI, Wanfang Database, and Weipu Database. The retrieval time was taken from the establishment of the database to July 30, 2020. Two researchers, respectively, conducted a strict evaluation of the quality of the literature and extracted the data which were then entered in the RevMan5.3 software for meta-analysis. Results 40 articles were listed, which involved 3260 patients. Meta-analysis results show that TQHXD combined with WMT can significantly reduce patients' NIHSS score, serum hypersensitivity C-reactive protein (hs-CRP), plasma viscosity, serum fibrinogen, serum total cholesterol, and serum triglycerides and improve patients' ADL-Barthel scoring and treatment efficiency. However, there is no evidence that TQHXD combined with the WMT  group can significantly decrease the incidence of adverse events. Conclusion The therapeutic effect of TQHXD combined with the WMT  group was significantly better than that of the WMT  alone group. For the treatment of patients with IS, TQHXD combined with WMT is worthy of application and promotion.


Introduction
Depending on the latest report from the World Health Organization, stroke is the second leading cause of death worldwide [1]. In 2016 alone, approximately 5.5 million people died of a stroke [2]. China is one of the countries with the heaviest stroke burden in the world. e latest census results showed that the incidence of stroke disease in China is about 1.6%, of which Ischemic Stroke (IS) accounts for 21.4% [3]. Evidence-based medicine research results [4] showed that most ischemic strokes are caused by blood clots blocking cerebral blood vessels. Elevated plasma fibrinogen is an important pathogenic factor of cerebrovascular diseases [5], and its increased content will cause plasma viscosity to rise, increase red blood cell and platelet aggregation, increase whole blood viscosity, and promote thrombosis, which leads to ischemia Sexual events. Bushi's studies have shown that thrombin activity is generally enhanced in patients with ischemic cerebrovascular disease and their high-risk groups [6]. Animal experiments [7] found that in the ischemic center of the rat model of middle cerebral artery occlusion, the activity of thrombin was considerably increased, and the expression of the prothrombin gene was upregulated. In vitro experiments [8] have shown that the nonproteolytic activity of thrombin could activate microglia and enhance microglia phagocytosis, thereby causing damage to neurons [9].
According to the symptoms and manifestations of IS, Chinese medicine believes that its onset is mainly caused by poor blood circulation [10,11], so treatments that promote blood circulation are typically used for treatment. Tongqiao Huoxue Decoction (TQHXD) is derived from Wang Qingren's book Medical Forest Correction. Wang believed that it has the effects of promoting blood circulation, relieving pain, and refreshing. Studies [12] found that highdose TQHXD could significantly improve the neuromotor function of rats with IS, increase serum NO and ET-1 levels, and reduce brain tissue Glu and Asp levels. TQHXD [13] may alleviate the neurological deficit in rats with cerebral ischemia and reperfusion by promoting the expression of neurotrophic factors in brain tissue and inhibiting lipid peroxidation. It can be seen that by looking for a suitable entry point, TQHXD combined with Western medicine treatment (WMT) can exert a beneficial effect. At present, a large number of clinical trials have confirmed the clinical efficacy of TQHXD in the treatment of IS. However, due to the different quality and sample size of the research, it lacks strong convincing power and lacks evaluation research on systematic safety and effectiveness. In order to provide an evidence-based reference for clinical medication, this article collects the published literature of TQHXD for the treatment of IS to conduct a systematic review.

Research Registrations.
We log in to PROSPERO official website (https://www.crd.york.ac.uk/PROSPERO/) to register a protocol for meta-analysis; the number of successful registration is CRD42020147688.

Types of Studies Included in the Study.
Only clinical randomized controlled trials (RCTs) of TQHXD combined with WMT in the treatment of IS are included.

Research Objects Included in the Study.
Patients with general clinical signs and symptoms of IS, excluding other diseases [14], are included. e course of the disease is within 2 weeks.

e Main Intervention Measures Are Included in the Study.
e treatment group was TQHXD combined with the WMT group, the control group was the WMT group, and the two groups were both treated without acupuncture, cupping, massage, and other rehabilitation methods.

Research Exclusion Criteria.
e exclusion criteria are as follows: the type of study does not correspond to nonrandomized controlled study, the intervention measures of the study do not match, the study is repeated, and the study does not contain 9 kinds of outcome indicators.

Data Extraction and Quality
Evaluation. e documents retrieved from each database were entered into the CNKI-Estudy software to eliminate duplicates, read the title and abstract according to the PICOS principle, and then read the full text and finally determined to be included in the study. e quality evaluation relates to the Cochrane risk bias assessment tool. e obtained documents are provided and the quality was evaluated by two staff members (Lan Li and Ruo-meng Ma). Any differences during the period will be arbitrated by a third member (Da-yuan Zhong).
2.9. Statistical Analysis. RevMan5.3 software was used for data analysis. Binary variables use Odds Ratio (OR) and Relative Risk (RR); continuous variables use standard deviation (MD) as effective indicators. Using t 2 and Chi 2 statistics to analyze the heterogeneity between the studies, if I 2 ≤50%, it indicates that the heterogeneity between the studies is small, and then the fixed-effects model is used.
Otherwise, it indicates that the heterogeneity is large, and the random-effects model is used.

e Search Results and the Basic Characteristics of the Included Studies.
A total of 40 RCTs meeting the criteria were included , involving 3260 patients. e literature search and inclusion flow chart is shown in Figure 1.
e basic characteristics of the included studies are shown in Table 1.

Hypersensitive C-Reactive Protein.
ere are 7 studies [18,21,28,30,31,43,47] that reported the index of highsensitivity C-reactive protein. e heterogeneity test showed that there are significant differences in heterogeneity among the 7 studies, so the random-effects model was used for meta-analysis. e results ( Figure 5) showed that the TQHXD combined with the WMT group was significantly different from the group of WMT alone (MD � 1.89, 95% CI (1.14, 2.64), P < 0.00001).

Serum Total Cholesterol.
ere are 4 studies [19,25,26,28] that reported serum total cholesterol indicators. e heterogeneity test results showed that there are none significant differences in heterogeneity among the four studies. erefore, a fixed-effects model was used for metaanalysis.

Triglycerides.
ere are 5 studies [19,25,26,28,30] that reported triglyceride indicators. e heterogeneity test results showed that there are significant differences in heterogeneity among the 5 studies. erefore, a randomeffects model was used for meta-analysis. e results (Figure 9) showed that the TQHXD combined with the WMT group was significantly different from the WMT group alone (MD � 0.47, 95% CI (0.22, 0.71), P < 0.00002).

Incidence of Adverse Reactions.
ere are 10 studies [17, 20-22, 25-27, 29, 30, 42] that reported the incidence of adverse reactions. e heterogeneity test results showed that there are none significant differences in heterogeneity among these 10 studies, so the fixed-effects model was used for meta-analysis. e results ( Figure 11) showed that the TQHXD combined with the WMT group and the WMT group were not significantly different from each other (RR � 1.38, 95% CI (0.80, 2.40), P � 0.25).

Analysis of Publication Bias.
e effectiveness of 29 studies [16, 17, 19, 20, 22-24, 29-37, 42-46, 48-55] was evaluated by the funnel chart, and the results showed that the funnel chart has good symmetry, as shown in Figure 12, which means that there is no publication bias in the study.

Discussion
IS is a common cause of death and acquired disability [56]. Its pathogenesis is mainly due to slow blood flow, changes in blood composition, and increased blood viscosity on the basis of arteriosclerosis.
e key factor for treatment is improving blood circulation in the ischemic area as soon as possible, eliminating secondary edema, and restoring the normal metabolism and nerve function of brain cells. e current treatment for this IS is mainly through intravenous drug thrombolysis, arterial thrombolysis, nonstent mechanical thrombectomy, and stent mechanical thrombectomy treatment [57]. Among them, intravenous drug thrombolytic treatment time is stricter (3-4.5 h in acute cerebrovascular occlusion), the recanalization rate of large artery occlusion is low, and the treatment effect is relatively poor. e cerebral infarction secondary to acute cerebrovascular occlusion is mostly caused by the formation of a large number of thrombi on the basis of cerebral artery stenosis. Even if the blood vessel is unblocked again after simple thrombolysis, the problem of obvious vascular stenosis will remain, and reocclusion is prone to occur [58]. Moreover, thrombolytic drugs could easily cause intracranial hemorrhage. e incidence of intracranial hemorrhage by intravenous thrombolysis is about 6.4% and that of arterial thrombolysis is close to 10%. is makes the condition worse, so the effect of treatment is not particularly ideal [59,60]. erefore, it is necessary to find more effective drugs to treat it. After thousands of years of development, Chinese medicine has left many classic prescriptions such as TQHXD and Buyang Huanwu Decoction, which have been used in the clinical treatment of human IS. Traditional Chinese medicine believes that the onset of IS is closely related to poor blood circulation and that blood stasis is both a pathological product and a pathogenic factor [11]. Modern physicians' understanding of the pathogenesis of IS by blood stasis and treatment methods for promoting blood circulation has become unified [61]. Poor blood circulation is considered to be the main cause of the disease, and the clinical application of the blood circulation method is effective. Significantly. TQHXD has the effects of promoting blood circulation, relieving pain, and resuscitating. It has been widely used in the treatment of brain injury diseases such as IS.
Meta-analysis is a statistical method that combines the effect size of the included studies of the same kind into a quantitative indicator. e combination can increase the sample size and improve the effectiveness of the test. Based on the meta-analysis method, this study combined 40 RCTs of TQHXD combined with WMT in the treatment of IS. e results showed that TQHXD combined with WMT in the treatment of IS can significantly reduce the patient's NIHSS score, serum Sensitive C-reactive protein, plasma viscosity, serum fibrinogen, serum total cholesterol, and serum triglycerides which can improve the ADL-Barthel score of patients and the effective rate of treatment. But there is no CNKI n = 128 Wanfang database n = 143 Weipu database n = 104 PubMed n = 0 Embase n = 0 Web of Science n = 1 Other ways n = 0      Evidence-Based Complementary and Alternative Medicine cerebral infarction. Tao Fei's study [63] shows that reducing blood TC, TG, and LDL can prevent and reduce the occurrence of stroke. e existing research results show that TQHXD combined with WMT has an effect on fibrinogen, plasma viscosity, serum total cholesterol, triglycerides, and other indicators, thereby playing a therapeutic effect on IS. Du Yong's study [64] found that gavage of TQHXD can significantly increase the relative expression of LC3II/I, MnSOD, COXIV, and Bcl-2 protein in rats with brain injury and reduce the relative expression of p62 and cleaved caspase-3 protein. e amount indicates that the effect of TQHXD may be related to the activation of mitochondrial autophagy and inhibition of cell apoptosis. e results of adverse reaction analysis showed that there were 28 adverse events in the TQHXD combined with the WMT group and 20 cases in the WMT group. e adverse reactions were mainly dizziness, fatigue, loss of appetite, nausea and vomiting, abdominal pain, and diarrhea. e adverse reaction symptoms were manifested between the two groups, and the difference was not statistically significant (P > 0.05). erefore, it is not believed that the addition of TQHXD will increase the risk of adverse events. In summary, TQHXD combined with WMT has a good effect, which is worthy of application and promotion.  Figure 6: e forest diagram comparing TQHXD combined with WMT and WMT to compare fibrinogen.

Conclusion
In summary, the safety and effectiveness of TQHXD combined with WMT in the treatment of IS still require a large number of RCTs with double-blind trials to verify. However, all studies of TQHXD combined with WMT in the treatment of IS were collected comprehensively, and the clinical efficacy of TQHXD combined with WMT in the treatment of IS was evaluated objectively. erefore, the results of this study still have certain clinical guiding significance.
Data Availability e data used in this article are obtained from public databases. e process including the literature, data extraction, and calculation are all described in the article. If necessary , the first author Da-yuan Zhong (13751728424@163.com) or the corresponding author Yi-hui Deng (644138330@ qq.com) can be contacted to obtain data.  Figure 11: e forest diagram of TQHXD combined with WMT and WMT to compare the incidence of adverse reactions. Evidence-Based Complementary and Alternative Medicine