Traditional Chinese Medicine for Essential Hypertension: A Clinical Evidence Map

We systematically retrieved and summarised clinical studies on traditional Chinese medicine (TCM) for the prevention and treatment of essential hypertension (EH) using the evidence map. We aimed to explore the evidence distribution, identify gaps in evidence, and inform on future research priorities. Clinical studies, systematic reviews, guidelines, and pathway studies related to TCM for the prevention and treatment of EH, published between January 2000 and December 2019, were included from databases CNKI, WanFang Data, VIP, PubMed, Embase, and Web of Science. The distribution of evidence was analysed using text descriptions, tables, and graphs. A total of 9,403 articles were included, including 5,920 randomised controlled studies (RCTs), 16 guidelines, expert consensus and path studies, and 139 systematic reviews (SRs). The articles publishing trend increased over time. This study showed that the intervention time of TCM was concentrated at 4–8 weeks, mainly through Chinese herbal medicine (CHM) for the prevention and treatment of elderly hypertension and the complications. A Measurement Tool to Assess Systematic Reviews (AMSTAR) scores of the included reviews ranged from 2 to 10. Most of the SRs had a potentially positive effect (n = 120), mainly in 5–8 score. Primary studies and SRs show potential benefits of TCM in lowering blood pressure, lowering the TCM syndrome and symptom differentiation scores (TCM-SSD scores), improving the total effective rate, and reducing the adverse events. The adjunctive effect of TCM on improving the total effective rate, lowering the blood pressure, lowering the TCM-SSD scores, and lowering the adverse effects was only supported by low-quality evidence in this research. The evidence map was used to show the overall research on TCM for the treatment of EH; however, due to the existing problems of the primary studies, the current research conclusion needs further research with higher quality and standardisation.


Introduction
Hypertension has become a primary global disease and is an important global public health challenge [1]. According to literature, in 2000, 26.4% of adults worldwide suffered from high blood pressure. It is estimated that by 2025, 29.2% of people in the world will suffer from high blood pressure [2].
ere is currently an upward trend of the hypertension prevalence and mortality rates among Chinese residents and it is predicted that by 2030, the annual economic burden of not well known due to the adverse effects and intolerance of antihypertensive drugs that the patients currently face [5].
erefore, more attention must be given to complementary and alternative medical treatments. Systematic reviews (SRs) have shown that traditional Chinese medicine (TCM) has a significant effect on lowering blood pressure but there is little research on its underlying intervention mechanisms [6,7].
As an evidence integration method, evidence mapping can integrate evidence of various study types under a research topic and comprehensively demonstrate the problems in the research topic, thereby depicting a complete picture of the research field [8][9][10]. Several evidence mapping reports have been published on the Chinese medical fields such as acupuncture, Tai Chi, massage, and angelica; however, they only included randomised controlled studies (RCTs) and SRs [11][12][13][14]. However, the clinical evidence for the prevention and treatment of hypertension by TCM is unclear. erefore, this study used an evidence map to systematically find relevant literature (observational studies, RCTs, SRs, guidelines, and expert consensus) on the clinical prevention and treatment of essential hypertension, in order to better understand the distribution of evidence in this field, identify gaps in evidence, and provide potential information for priority areas.

Database and Search Strategies.
e literature searches were conducted using PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and WanFang data. e search was restricted from January 1, 2000, to December 31, 2019. We searched the Chinese database using "hypertension". e retrieval subjects are limited to TCM, integrated Chinese and Western medicines, TCM internal medicine, surgery of Chinese medicine, gynaecology of Chinese medicine, paediatrics of Chinese medicine, and other TCM-related subjects. English database retrieval was divided into two parts. e search terms for the first retrieval included: ("hypertension" OR "blood pressure, high" OR "blood pressures, high" OR "high blood pressure" OR "high blood pressures") AND ("medicine, Chinese traditional" OR "traditional Chinese medicine" OR "traditional medicine, Chinese" OR "Chinese medicine, traditional" OR "herbal medicine" OR "drugs, Chinese herbal" OR "herbal formula" OR "Chinese herbal medicine" OR "Chinese herb therapy" OR "Chinese herb" OR "herb therapy" OR "herbal remedy" OR "acupuncture"). e second retrieval search term was "hypertension" + hypertension-related formulas and nondrug therapy that frequently appeared in the meta-analysis in the Chinese database; the two retrievals were combined. e literature searched included academic journals, graduation theses, and conference papers.

Inclusion Criteria.
e inclusion criteria were as follows: (1) Type of study: RCTs, nonrandomised controlled trials (non-RCTs), cohort studies, case-control studies, cross-sectional studies, real-world studies (RWS), systematic reviews, meta-analyses, expert consensus, guidelines, and clinical pathway studies on TCM intervention for hypertension (2)  Can't answer," or "Not applicable" was assigned according to judgement criteria of AMSTAR. e number of "yes" was counted as the total AMSTAR score. A score of 4 or less was considered low quality, a score of 5 to 8 was medium quality, and a score of 9 or more was high quality [15,16]. Based on the SRs' clinical effectiveness, it was further divided into 4 categories: "evidence of no effect," "unclear evidence," "evidence of a potentially positive effect," and "evidence of a positive effect" [13]. e category "evidence of no effect" meant that the effect of the control group is equal to or better than that of the TCM observation group. "Unclear evidence" meant that the result of a systematic review of similar contents is controversial, or the evidence is summarised as inconclusive by the original study's author. "Evidence of a potentially positive effect" referred to the systematic review of all included clinical studies, combined results, and statistical evidence to show effectiveness but the lack of basic and auxiliary evidence made it difficult to produce positive and reliable conclusions. "Evidence of a positive effect" meant that statistics showed that TCM therapy had a significant effect and that the authors of the systematic review had no major doubts regarding the current evidence and recommend the therapy.

Data Analysis and Presentation.
EXCEL 2013 was used to integrate and process the data. e data summary and analysis are shown as text and charts. e distribution of the development trend is depicted as a line chart, the distribution of category proportions as a pie chart, and the distribution of evidence as bubble plots and heatmap.

Description of the Included Trials.
e initial search retrieved 55,197 articles from the six databases. After removing duplicates, 39,162 trials were identified. After screening the titles and abstracts, 10,302 trials were retained. By browsing the full-text articles, we further excluded 899 records. In the end, 9,403 studies were reviewed, including primary studies (n � 9,243), systematic reviews (n � 144), and guidelines, expert consensus, and path studies (n � 16) ( Figure 1).

Trends in Publication
Year of Clinical Studies. A total of 9,403 studies were included from January 2000 to December 2019. e number of studies showed an overall rising trend with a peak in 2018 at home and 2015 abroad, respectively (see Figure 2). e TCM role is increasingly being suspected in the prevention and treatment of hypertension, both in China and worldwide.

Research on Syndrome and Constitution.
A total of 848 clinical studies on TCM syndromes of hypertension were included, of which the syndrome distribution ranked first with a total of 162; others included hypertension syndromes and clinical indicators in young and middle-aged people (n � 4) [20][21][22][23], syndromes in elderly hypertension (n � 124), hypertension stages and grades (n � 9) [24], four diagnosis information and TCM syndromes (n � 1) [25], and TCM syndromes and clinical indicators in grade 3 hypertension (n � 2) [26,27]. Regarding comorbidity, there were 2 cases of hypertension with arrhythmia, 22 cases of atherosclerosis, 9 cases of a cerebral haemorrhage, 19 cases of cerebral infarction, and 32 cases of diabetes. Studies on the correlation between syndromes and clinical indicators mainly involved indicators such as homocysteine, blood lipid, blood glucose, vascular function, and inflammation. A total of 245 studies on the TCM constitution of hypertension were included, of which there were 12 constitution and syndrome types, mainly involving the phlegm-dampness syndrome [28]. As the syndrome type and constitution articles involved more than 100 kinds of clinical indicators, only the first 36 indicators were shown (see Figure 3). e bubble plot shows the syndrome and constitution and mainly on a wide range of hypertension and elderly patients with hypertension; however, there are few studies on prehypertension and hypertension grades.
Studies of CHM injection and oral traditional Chinese medicine preparations showed that the evaluation indexes of hypertension were mostly related to complications. e total effective rate, BP, brain function evaluation indicators, and safety index of TCM injection had a high degree of attention, shown in red. Blood coagulation and TCM-SSD scores had low attention, shown in blue. e total effective rate, clinical symptoms, BP, and safety index of oral Chinese medicine preparation were highly relevant in the clinical studies. e indicators of blood coagulation, hemorheology, and brain function received little attention, and the research directions were generally consistent.

Investigation of the Application of TCM Prevention and
Treatment Schemes. RWS found that the 30,034 hypertension patients in 16 AAA-grade hospitals were mainly treated with intravenous drugs, among which the 3 traditional Chinese medicine preparations, the Danhong injection, Shuxue Ning injection, and Ginkgo Biloba extract, were used more than 10% of the total drugs used [19]. e Beijing Hospital found that Liuwei Dihuang pill had the highest comprehensive ranking for the use and frequency of CPM from 2008 to 2010 [29]. Regarding CHM decoction, a cohort study involving 154,083 people in Taiwan from 2003 to 2009 showed that about 80% of patients used traditional Chinese medicine at least once. Tianma Gouteng decoction and salvia miltiorrhiza were the most frequently used Chinese medicine [18]. From 1996 to 2005, the main herbal medicine types for hypertension in the Beijing area were tonify deficiency medicine, levelling liver and calming wind drugs, heatclearing drugs, blood-activating and stasis-eliminating compound, and damp-clearing drugs [30]. Similarly, the study found that in the past 30 years, the first 5 effective treatments were activating the blood and dissolving stasis, xifeng antispasmodic, benefit qi and blood, smooth liver yang, and removal of pathogenic heat from the blood [31]. In summary, there was a consistent use of medication for hypertension prescriptions. Evidence-Based Complementary and Alternative Medicine traditional Chinese medicine preparations and 1,170 articles used the analysis intervention duration, most of which were concentrated in a 4-8 week period (n � 547, 46.8%), of which only 3 articles of more than 42 months of intervention were present in the strongly exposed group [32][33][34], suggesting that the research time limit of TCM intervention in hypertension was generally shorter (Figure 7).
According to the AMSTAR scale evaluation, the most qualified item, 9, had 138 SRs. However, 137 SRs did not provide the preliminary design scheme, 106 reviews did not consider the retrieval and inclusion of the grey literature, 70 SRs did not perform a comprehensive literature search, 29 SRs did not properly apply the scientific quality of the included studies to the derivation of conclusions, 31 SRs did not assess and document the scientific quality of the included studies, 138 SRs did not provide the list of included and excluded research literature, 40 SRs did not assess the likelihood of publication bias assessment, and 117 SRs did not provide a conflict of interest statement. One review met 10 criteria [40] and nine reviews met 9 criteria [6,7,[41][42][43][44][45][46][47]. e authors considered these 10 systematic reviews to be of high quality. A total of 94 systematic reviews were of moderate quality and met the 8 AMSTAR criteria (n � 19), 7 criteria (n � 27), 6 criteria (n � 27), and 5 criteria (n � 21). e other 35 systematic reviews were of the lower quality and met 4 criteria (n � 14), 3 criteria (n � 10), or 2 criteria (n � 11).

CHM plus Antihypertensive Drugs versus Antihypertensive Drugs.
e pooled results of the largest review (24 RCTs, 4502 participants) showed a high number of participants with reduced blood pressure (relative risk (RR) 1.28; 95% confidence interval (CI) 1.21, 1.36, P < 0.001; 8 RCTs (RR: 1.12; 95% CI 1.06, 1.39, P < 0.001; 5 RCTs)). However, the authors cautioned evidence of a potentially positive effect due to the poor quality of the included RCTs [41]. Fifteen studies reported significant effects of xuefu zhuyu decoction combined with antihypertensive drugs (15 RCTs, 1364 participants) for lowering the blood pressure compared to the control group (P < 0.05). e author suggested that xuefu zhuyu decoction for hypertension should be prioritised for future preclinical and clinical studies [6]. e Liuwei Dihuag pill (6 RCTs, 555 participants) and jian ling decoction combined with antihypertensive drugs were more effective in controlling the blood pressure [43,46]. In contrast, 2 SRs showed no significant difference [42,47] RCTs) compared to the antihypertensive drugs alone. Compared to no intervention, qigong significantly reduced SBP and DBP (P < 0.05) [44]. One Cochrane review concluded that the clinical evidence for short-term and sustained BP-lowering effect by acupuncture was unclear (quality � 10) [40].

TCM-SSD Scores
3.13.1. CHM versus Antihypertensive Drugs. One SR showed a significant effect of CHM for lowering the TCM-SSD scores compared to the antihypertensive drugs [7].

CHM plus Antihypertensive Drugs versus Antihypertensive Drugs.
Two SRs showed a significant effect of CHM combined with antihypertensive drugs for lowering the TCM-SSD scores compared to the antihypertensive drugs [41,46].
3.14. Adverse Events. Of the 139 SRs, there was an outcome measure of adverse effects in 77 SRs, which included gastrointestinal reaction, dizziness, headache, cough, and nausea [41,49]. In summary, all of these SRs indicated that the side effects in the TCM adjuvant therapy group were  generally less than or lighter than those in the Western medicine group.

Guidelines, Consensus, and Clinical Pathway Studies.
A total of 16 papers were retrieved on the treatment of hypertension guidelines, consensus, and clinical pathway of TCM research, including the TCM treatment for hypertension and its complications and consensus (n � 10), consensus recommendation on the application for CPM of hypertension (n � 1) [161], the optimisation path of TCM clinical program (n � 4), and the nursing clinical path (n � 1) [162]. In 2019, more than 70% of the experts recommended 6 types of CPM: the Tianma Gouteng decoction, qiju dihuang capsule, jinguishenqi pill, gingko leaf tablets, niuhuang jiangya pill, and banxia tianma pill to help non-TCM practitioners to select appropriate CPM according to the TCM symptoms. In addition, multicentre RWS found that the 7 common syndromes under the TCM diagnosis and treatment guidelines for hypertension, including liver fire flaming upward syndrome, yin deficiency and yang hyperactive syndrome, blood stasis and internal obstruction, phlegm and dampness, deficiency of qi and blood, deficiency of kidney essence, and chong and ren imbalance, only accounted for 58.38% of the common syndromes. Further, adding the phlegm and blood stasis mutual settlement syndrome is recommended and so it cancels the chong and ren imbalance [163]. Guidelines and path research guide the treatment of EH in TCM and also guide the treatment of complications such as acute cerebral haemorrhage and depression.

Discussion
In this study, an evidence map was used to systematically sort the literature on hypertension in the past 20 years. Compared to the previous evidence mapping studies that only included RCTs or SRs [11][12][13][14], the current study mainly focussed on the diversified research types (observational studies, interventional studies, secondary studies, and RWS), intervention measures (CHM and nondrug therapy), and the analysis contents (TCM prevention and treatment schemes, intervention time, study outcomes, adverse reactions, etc.) has been expanded to provide a comprehensive description of the clinical problem. It shows the volume and field of available research and highlights areas where published meta-analysis has reported positive results and identified gaps in evidence.

Advantages of TCM in the Prevention and Treatment of
Hypertension. For hypertension prevention and treatment by TCM, the key areas to target are lowering BP, lowering the TCM-SSD scores, improving the clinical symptoms, and protecting the target organs. e adverse events in the TCM paratherapy group were generally less than those in the control group. A total of 120 SRs found that CHM and nondrug therapy had potential active effects for the treatment of hypertension, 16 SRs showed unclear evidence, and 3 SRs showed active effects. Regarding complications, damage to the heart, brain, and kidney target organs accounted for more than 50% of the studies, and TCM had a good effect on the dissipation of the hypertensive cerebral haematoma, stroke score, proteinuria, and left ventricular hypertrophy. Meanwhile, the evaluation of TCM clinical programs showed that TCM combined with Western medicine can enhance clinical effectiveness and reduce adverse events. Regarding clinical symptoms, it had an improved effect on the main symptoms of vertigo, headache, and systemic symptoms. Based on the study of guidelines and pathways, TCM syndromes and CPM (tianma gouteng decoction qiju dihuang capsule, jingui shenqi pill, gingko leaf tablets, niuhuang jiangya pill, and banxia tianma pill) have been put forward for clinical application.

Future Focus on TCM Prevention and Treatment of
Hypertension. TCM intervention for prehypertension is still insufficient. At present, only 3 SRs have been published, including nondrug therapy (17 RCTs, quality � 6) [160], CHM (8 RCTs, quality � 5) [137], and CHM (5 RCTs, quality � 8) [51]. In the future, greater focus should be placed on improving prevention and treatment during early hypertension, including prehypertension, grade 1 hypertension, and youth hypertension, and additional research should be carried out on specific clinical indicators and mechanisms. It is also important to investigate in emotion, obesity, and other hypertension risk factors by CHM and nondrug therapy.

Limitations and Implications.
In general, a summary of the findings of included SRs and clinical studies showed that TCM paratherapy for EH has better efficacy and safety than the control group. e research evidence on the risk factors, quality of life, emotional and psychological, early intervention, duration of intervention, and adverse events is weak. However, there are several limitations to the present study. First, the evidence map provides only a broad overview of the research areas and cannot provide definitive answers regarding the effectiveness of an intervention. e specific control of clinical indicators requires more detailed and targeted research. Second, the evidence map did not establish the reporting guidelines and did not avoid overlap between the included studies across reviews. ird, the quality of the methodology of most SRs was low (25.2%) to moderate (67.6%), which directly influences the reliability of the results. Fourth, literature types, heterogeneity, and complex intervention measures in the included studies only elucidate the efficacy and safety at a macroscopic level. e improvements for further evidence map are as follows [164,165]. In terms of data sources, a complementary search of the clinical registration platform and references should be additionally conducted. Regarding content extraction, one should further focus on the retrieval according to the priority areas to further improve accuracy. To avoid unrecognised individual literature due to a large number of retrieved literature and the problem of splitting the same research results, topic selection of TCM literature should focus on specific clinical problems, avoid extensive titles, and prevent the result from being too complex for an explanation. Finally, one should review the evidence base with standard evidence synthesis methods (i.e., systematic Evidence-Based Complementary and Alternative Medicine review), improve the methodological quality of SRs themselves, and encourage prospective registration of SRs.

Conclusion
e conclusion of the SRs and primary studies highlight TCM's advantages as adjunctive therapy for improving hypertension. Similarly, the development trend of CHM and nondrug therapy for the prevention and treatment of hypertension is relatively good, which reflects the diverse TCM prevention and treatment measures for hypertension. However, clinical research evidence needs to be treated with caution because of methodological flaws. In the future, studies with larger sample sizes, standardisation, and higher quality are required to provide further scientific evidence for TCM in treating hypertension.
Data Availability e datasets used during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors' Contributions
Yue Liu and Fengqin Xu conceived the idea, designed the study, and interpreted the data together and are the cocorresponding authors. Yan Zhang, Biqing Wang, Chunxiao Ju, and Lu Liu conducted the literature searches, evaluated the risk of bias of each study, and wrote the manuscript together. Jun Mei and Ying Zhu helped to revise the manuscript.