Ischemic Stroke: A Systematic Review and Meta-Analysis

Objective. To investigate the correlation between traditional Chinese medicine (TCM) body constitution and ischemic stroke (IS). Methods. Literature search was conducted in databases includingWanfang database, Chongqing VIP, China National Knowledge Infrastructure, Embase, and PubMed from inception to November 16, 2020. Observational studies evaluating the association between TCM body constitution and IS were included for analysis. .e distribution of body constitutional types in IS patients was pooled into meta-analysis. .e correlation between constitution and IS was presented by the odds ratio (OR) and 95% CI through the comparison between IS and the general population. Results. 41 studies involving 11,211 participants were included. Among the nine constitution types, qi-deficiency constitution (QDC), phlegm-dampness constitution (PDC), and blood stasis constitution (BSC) are the common types, accounting for 25% [0.22, 0.29], 23% [0.20, 0.29], and 17% [0.13, 0.22], respectively, in IS patients. .e proportion of PDC and QDC among IS patients is 2.34 times and 3.47 times higher than that in the general population, respectively (OR and 95% CI: 2.34 [1.39, 3.94], 3.47 [1.61, 7.50], respectively). Conclusion. PDC and QDC are the common constitutions in IS patients and may have a potential correlation with the incidence of IS. Due to the low or moderate quality of included studies, more well-designed prospective studies are warranted to further evaluate the relationship between TCM constitutions and IS.


Introduction
Stroke is the second most mortal disease globally.Ischemic stroke, a sudden functional loss caused by the cut-off of the bloodstream to the brain, is the most common type that accounts for over 85% of all cases [1].Every year, about 6 million people die from stroke globally, and even worse, the illness, disability, and premature death caused by stroke will double by 2035 [2].e recurrence rate within a decade is as high as 39.2% [3][4][5].On the one hand, the treatment and rehabilitation of stroke will bring huge economic burden to the society, but on the other hand the current therapeutic approaches are insufficient for reducing deaths caused by stroke.Prevention of stroke is of great significance to the family and the society.Risk factor management is important for preventing stroke.In studies focusing on stroke risk factors, the Framingham Stroke Scale is currently the most widely used stroke risk assessment tool in western countries [6].However, it overestimated the risk of stroke in Chinese [7].Besides, these studies focus on defining risk factors of stroke, without providing a clear definition of the high-risk group of stroke [8].
In traditional Chinese medicine, preventative treatment before the disease onset has been practiced for thousands of years.TCM theory states that Chinese medicine has a great advantage in the preventive treatment of disease.TCM constitution identification is the effective approach of "treating disease before onset."[9] e TCM constitution is a relatively stable and integrated intrinsic feature of physiological function, morphological structure, and psychological state formed by innate endowment and acquired disposition.e TCM constitution can be classified into nine basic types: yang-deficiency constitution (YADC), qi-deficiency constitution (QDC), qi stagnation constitution (QSC), phlegm-dampness constitution (PDC), yin-deficiency constitution (YIDC), damp-heat constitution (DHC), blood stasis constitution (BSC), balance constitution (BC), and inherited special constitution (ISC).Among these, BC is normal constitution and all the others are biased constitutions.People with different constitution have different characteristics in physiological manifestation, pathological state and morbidity tendency, and so on.For instance, the BC, formed by the harmony of yin, yang, qi, and blood, is characterized by ruddy complexion, vigorous energy, and moderate posture.People with BC can adapt to the environment easily and are unlikely to suffer from diseases.
ere are emerging clinical studies focusing on TCM constitution and its correlation with IS.
ese studies provide a basis for investigating the clinical distribution of TCM constitution in IS patients.However, no systematic review is found among existing studies.us, a summary is needed to incorporate the existing literature.To provide solid evidence for clinical and scientific research based on larger sample, a meta-analysis is conducted on the above studies.

Searching Strategy
2.2.1.Literature Search.We collected clinical literatures on the association between TCM constitution and IS from databases such as Wanfang Database, Chongqing VIP, China National Knowledge Infrastructure, Embase, and PubMed.e literature is either in English or in Chinese.
e dates range from the day when the database was founded to November 16, 2020.e keywords are "ischemic stroke," "constitution," and "Chinese medicine."For Chinese databases, searching strategies are "ischemic stroke + constitution" in title or abstract, and "Chinese medicine" in full text.For English databases, search strategies are ((ischemic stroke) AND constitution AND (TCM OR Chinese medicine)).

Exclusion.
(1) e basic characteristic of patients are not reported (gender, age etc.).( 2) e results' data reported are deficient.3. Research reports share the same patient samples.
2.4.Literature Screening and Data Extraction.All papers are first screened by title/abstract in line with the eligibility criteria on NoteExpress software.ose that pass the initial screen are checked throughout.en, only those that pass the two screenings are used for data extraction.Each paper is screened and extracted by two investigators independently, and the results are cross-checked in every step.In the case of divergence in cross-check, the checked paper will be examined by the 3rd investigator for the final decision.e main extract data include researcher's name, study type, period and region, participant source, sample size, age, gender, constitution results, and measures of quality control.

Quality Evaluation.
e Unit States Agency for Healthcare Research (AHRQ) publishes standards to evaluate cross-sectional study [11], including 11 items with the highest mark of 11. e items include observation period, eligibility criteria, research object continuity, data source, and quality control.As for the mark, 0-3 is considered as low quality, 4-7 as medium quality, and 8-11 as high quality.e Newcastle-Ottawa scale (NOS) recommends case-control study and cohort study [12], containing 11 items in 3 prospects.
e NOS mainly evaluates the comparability between groups, population selection, and evaluation of exposure factors.Its highest mark is 9, and any mark over 6 is considered as high quality.
2.6.Statistical Analysis.Two meta-analysis sets are constructed based on the 41 studies included.

Analysis Dataset 1.
e analysis dataset 1 is a metaanalysis of the association between TCM constitution and IS.
is part aims to explore the risk TCM constitution in IS. e meta-analysis is conducted on the studies that report distribution of TCM constitution in both IS patients and general population.ReviewManager (version 5.3) software is used for the meta-analysis.e effect values are described by odds ratio (OR) and 95% confidence interval (95%CI).I 2 is defined as the heterogeneity of the meta-analysis.If the heterogeneity is low (I 2 ≤ 25%), the fix effect model will be chosen; if the heterogeneity is high (25% < I 2 < 75%), the random effect model will be chosen; if the heterogeneity is much higher (I 2 ≥ 75%), qualitative description will replace meta-analysis.

Analysis Dataset 2.
e analysis dataset 2 is a metaanalysis of the distribution of TCM constitution in IS patients.is part aims to explore the total rate of different TCM constitution types in patients.
e meta-analysis is conducted on the studies that report distribution of different constitution types in IS patients.
e data of studies in analysis 2 is featured with that they only provide the number 2 Evidence-Based Complementary and Alternative Medicine of people and events in one group.At present, Review-Manager, a commonly used meta-analysis software, cannot achieve single-rate meta-analysis.In this analysis, R version 3.2.2 is used for this meta-analysis.e results are shown by total ratio of different TCM constitution types in IS population and its 95% CI.When the heterogeneity is much higher, the subgroup analysis will be conducted according to region, gender, and related factors.3.

Meta-Analysis 2: Meta-Analysis of the Distribution of TCM Constitutions in IS Patients.
e meta-analysis is conducted on each TCM constitution type of IS patients report as an index.Among the 41 studies, 1 case-control study of PDC only covers the proportion of PDC, and the other 40 studies report data on the proportion of various types of TCM constitution.erefore, 41 studies are included in the meta-analysis of PDC. e results show that these studies are highly heterogenous.Considering the particularity of the cross-sectional study in the field of TCM constitution (see Section 4.3), the random effect model is used for meta-analysis.PDC, QDC, and blood stasis constitution (BSC) accounts for more than 15% of all.e results of meta-analysis are shown in a forest map, and the rest of the TCM constitutions less than 15% are listed in a table.
e results are shown in Figure 4.
PDC.In total, 41 articles report PDC's distribution in IS patients .Heterogeneity is tested among all studies (I 2 � 96%, P < 0.01) and random-effects model is used.Metaanalysis finds that rate � 23% and 95% CI is [0.20, 0.29].e results are shown in Figure 5.
BSC.In total, 40 articles report blood stasis constitution's distribution in IS patients .Heterogeneity is tested out among the studies (I 2 � 98%, P < 0.01) and randomeffects model is used.Meta-analysis finds that rate � 17% and 95% CI is [0.13, 0.22].e results are shown in Figure 6.
Other TCM Constitutions.In total, 40 articles that report YADC, YIDC, DHC, QSC, BC, and ISC's distribution in IS patients .Meta-analysis finds the rate is lower than 15%.e detailed results are shown in Table 3.  [15,20,21,24,25,32,37,45,48,51].No gender difference is found in the distribution of PDC in IS patients (OR: 1.09, 95% CI: 0.72-1.65P � .68), in that of QDC (OR: 1.18, 95% CI: 0.77-1.81,P � 0.46), and neither in that of BSC (OR: 0.78, 95% CI: 0.42-1.46,P � .43). e results find that BC tops all, accounting for 32.14% among all.And QDC, DHC, and YADC are ranked in the top three in terms of biased constitutions, accounting for 13.42%, 9.08%, and 9.04%, respectively.In this meta-analysis, QDC has the highest proportion (25%) in all TCM constitution types, close to the proportion of BC in the general population, much higher than the proportion of QDC in the general population (13.42%).Similarly, PDC and BSC are like so. e BC only accounts for 7%.erefore, it is advised to identify the constitution before the onset of the disease, and health education is an effective way to prevent the high-risk group from turning into bias constitution such as QDC, PDC, and BSC.In addition, identifying the bias constitution earlier could promote the return of bias constitution to BC through TCM therapies, which is of great significance to prevent the occurrence of IS.

Discussion
In terms of the regional distribution proportion of TCM constitutions, the PDC and BSC occupy the highest proportions in Northeast China, followed by North China, Central South China, and East China.
e QDC is most common in North China, followed by East China, Northeast China, and Central South China.e difference in distribution among regions is related to the climate, water, and dietary habit.TCM emphasizes the harmony between people and nature.So, this study may be closely related to climatic and dietary factors.
e environment in North and Northeast China is colder and drier than the East and Central South China, and people in North and Northeast China prefer salty food and spirit.So, PDC and BSC have higher proportion there, while the climate in North and East China is warmer but not hot, moister but not humid.Besides, the food is light in these regions.So the proportion of QDC there is higher than that in the Northeast and the Central south China.Further studies need to be done to explore other reasons.
In terms of the proportion of gender distribution of TCM constitution, the proportion of PDC, QDC, and BSC is the same in males and females in this study.is is possibly because QDC, PDC, and BSC are the main constitution of IS, and the pathological mechanism results in the same constitution regardless of gender.

Methodological Problems in the Studies of TCM Constitution in IS Patients.
is study discovers many methodological problems through quality evaluation.e international reporting standard for observational studies statement (Strengthening the Reporting of Observational Studies in Epidemiology, STROBE) has not been applied for  Evidence-Based Complementary and Alternative Medicine format reports in any research included [55].e reporting rate of each item is pretty low according to the evaluation standard of AHRQ cross-sectional study.Very few studies report the quality control measures clearly, which may lead to bias in the research results.e studies are highly heterogenous (I 2 value is larger) from the meta-analysis of TCM constitution distribution.
From the perspective of research design, these studies do not contain enough basic information, including but not limited to the time range, the approach to including subjects, the methodological details of constitution identification, nationality, age, gender, body mass index, blood glucose, blood lipids, blood pressure, rejection rate, and funding status.In the statistical analysis of data, some studies omit Evidence-Based Complementary and Alternative Medicine the correlation between TCM constitutions and gender, age, disease degree, and other related factors.e individual studies find three or more types of mix constitution, or indicate the proportion of balanced constitution in the subjects is 0. is is because the researchers neglect that the TCM constitution scale should be based on the feelings of the past year, which leads to confusion on TCM constitution and TCM syndrome.

Limitations of the Study.
is study analyzes the distribution proportion of different TCM constitutions in IS patients, and the correlation among region, gender, and TCM constitution.However, it fails to study the correlation between TCM constitution and nationality, occupation, age, marital status, course of disease, biochemical index, TCM syndrome, and other factors in IS patients, as it lacks data report in the original literature.
is, it is more difficult to figure out the factors affecting TCM constitution.
e results are likely to be biased due to the high heterogeneity of the cross-section studies in the meta-analysis, which is related to many factors of each study such as the region, sample size, diagnostic criteria, and measurement methods.However, TCM constitution theory believes that the differences in constitution are due to region and gender.And the features of TCM constitution are reflected in the results of the national norm [54].Hence, to describe the overall TCM constitution distribution features of IS patients in China, this study analyzes the data of original literature comprehensively and categorizes them by region and gender for more accurate results.Wangkai [32] Zouzhi et al. [44] Total (95% CI) Total events Heterogeneity: tau 2 = 0.22; chi 2 = 12.63, df = 4 (P = 0.01); I 2 = 68% Test for overall effect: Z = 3.20 (P = 0.001) Total (95% CI) Total events Heterogeneity: tau 2 = 0.60; chi 2 = 18.40, df = 5 (P = 0.002); I 2 = 73% Test for overall effect: Z = 3.16 (P = 0.002)  e results suggest that the groups most in need of IS prevention are qi-deficiency, phlegm-dampness, and blood stasis constitution.Some effective prevention measures are health education, lifestyle, and TCM intervention.
e TCM constitution could be applied for the clinical treatment of ischemic stroke (QDC, PHC, BSC, and other types).e differentiated treatment is offered based on the TCM constitution, and the conformational effect between TCM constitution and syndrome.
e process could improve the research plan quality though peer review.A general population control group could be organized for the cross-sectional study to compare the differences in TCM constitution between groups, so as to examine the TCM constitution closely related to the disease.As advised, a case-control study or prospective cohort study should be carried out for the possible high-risk TCM constitution of a disease.is is to identify the causal relationship between the TCM constitution and the disease, especially true for heavy chronic disease like stroke.For a thorough analysis of the factors influencing TCM constitution, interference factors shall be controlled in line with the international norms of observational research methodology of quality evaluation.

Conclusions
e meta-analysis of 11,211 subjects finds that PDC, QDC, and BSC types are the main TCM constitutions in IS patients, QDC and PDC are risk factors for IS, and QDC is most closely related to IS.It is suggested that the future clinical observation research on the correlation between TCM constitutions and diseases should improve research quality, comprehensively explore the factors influencing TCM constitution, and thoroughly study the association between constitution and disease.ereby, it could provide valuable reference for the clinical diagnosis and treatment of differentiated syndrome and diseases and adopt relevant implementation and reporting norms of evidence-based medicine.

2. 3
.1.Inclusion.(1) All clinical studies (including crosssectional studies, case-control studies, and cohort studies) in Chinese or English on TCM constitution and ischemic stroke correlation are included.(2) All patients in studies should be clearly diagnosed with ischemic stroke.(3) TCM constitution recognition: TCM constitution is recognized by "classification and determination of TCM constitution" norm report by China Correlation of Chinese Medicine (CACM) in 2009 [10].

Figure 1 :
Figure 1: Flow diagram and results of literature searching.

Figure 3 :
Figure 3: Meta-analysis of PDC's distribution in IS and the general population.

Table 1 :
e basic characteristics and quality score of studies included.
Figure 2: Meta-analysis of QDC's distribution in IS and the general population.

Table 2 :
Meta-analysis of other TCM constitutions' distribution in IS and the general population.

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Table 3 :
Meta-analysis of rate of other TCM constitutions in IS patients.