Effects of Three Traditional Chinese Fitness Exercises Combined with Antihypertensive Drugs on Patients with Essential Hypertension: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Objective To compare the efficacy of three different traditional Chinese exercises (Tai Chi, Baduanjin, and Wuqinxi) combined with antihypertensive drugs (AHD) on patients with essential hypertension (EH). Method Eight electronic databases were searched to identify randomized controlled trials (RCTs) comparing the effects of traditional Chinese fitness exercises combined with AHD and AHD alone. The analysis mainly consists of network meta-analysis (NMA) and pairwise meta-analysis. The Cochrane assessment tool was adopted to assess the risk of bias of included literatures. This study used STATA/SE 15.1 (StataCorp, 2017), R software (version 4.0.1), and Cochrane's Review Manager software (version 5.4) to conduct data analysis and figures generation. Results A total of 30 RCTs were included in this study, of which 16 evaluated Tai Chi plus AHD versus AHD, 11 evaluated Baduanjin plus AHD versus AHD, and 3 evaluated Wuqinxi plus AHD versus AHD. No RCT compared directly among the three traditional Chinese fitness exercises. Pairwise meta-analysis showed that Tai Chi plus AHD was significantly superior to AHD alone in reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP). BDJ plus AHD was statistically superior to AHD alone in reducing SBP, DBP, and endothelin (ET) and increasing nitric oxide (NO). NMA results indicated that Tai Chi plus AHD (WMD −12.42 mmHg, 95% CI: −15.29 to −9.55) and Baduanjin plus AHD (WMD −7.03 mmHg, 95% CI: −9.80 to −4.26) were superior to AHD, and Tai Chi was more effective than other traditional exercises in lowering SBP, Tai Chi plus AHD (WMD −7.56 mmHg, 95% CI: −10.15 to −4.96) and Baduanjin plus AHD (WMD −4.51 mmHg, 95% CI: −7.38 to −1.65) were superior to AHD in reducing DBP, Baduanjin plus AHD (WMD 4.26 μmol/L, 95%CI: 2.68 to 5.83) was statistically superior to AHD in increasing NO, and Tai Chi plus AHD (WMD −7.64 pg/ml, 95% CI: −10.46 to −4.83) and Baduanjin plus AHD (WMD −9.23 pg/ml, 95% CI: −10.85 to −7.61) were superior to AHD in lowering ET. Conclusion Compared with AHD alone, both Tai Chi plus AHD and Baduanjin plus AHD showed significant benefit in regulating SBP, DBP, and ET. Among the three traditional Chinese fitness exercises, Tai Chi may be the best as an adjunctive therapy for SBP reduction. These findings provided evidence for the therapeutic benefit of either Tai Chi or Baduanjin exercise as an adjunct therapy for patients with EH. Limited by the methodological quality and quantity of included studies, results need to be interpreted with caution, and it is necessary to carry out further high-quality RCTs on traditional Chinese fitness exercise-assisted treatment of EH in the future.


Introduction
e results of many cohort studies indicate that hypertension takes a leading role in the current global burden of cardiovascular disease and overall mortality [1,2]. Data from the Global Burden of Disease project shows that nearly 9.4 million deaths every year are due to raised blood pressure [3]. erefore, prevention of the occurrence and progress of hypertension disorders is a current global priority public health problem [4]. Pharmacotherapy of hypertension is an important tool for treatment of hypertension [5]. However, there are adverse drug reactions caused by AHD, especially in the elderly, drug-drug interactions may also increase the burden related to drugs, and adverse reactions related to AHD can lead to the suspension of drug treatment [6][7][8]. Consequently, pharmacotherapy of hypertension combined with non-pharmacological method is very important; nonpharmacological method is a complementary treatment of drug therapy and delay the need for pharmacotherapy [9]. Exercise is an important non-pharmacological method to prevent, treat, and control elevated blood pressure. Patients can better regulate blood pressure by following an appropriate fitness exercise prescription, which can promote overall health and improve quality of life; low-to moderateintensity aerobic exercise is preferred for exercise therapy [10][11][12][13][14]. e 2017 Clinical Practice Guidelines for Hypertension recommends that adults diagnosed with hypertension or elevated blood pressure follow an organized exercise program to increase physical activity [15]. ere have been some studies about exercise training practices on hypertension [10][11][12][13][14]16], but comparatively little attention has been focused on exploring traditional Chinese fitness exercises as a complementary therapy for EH, such as Tai Chi, Baduanjin, and Wuqinxi. While there have been some metaanalyses on the effects of traditional Chinese fitness exercises as an adjuvant therapy for EH [17][18][19][20][21][22][23][24][25][26], relatively scarce studies provide data from direct comparisons between these traditional Chinese fitness exercises. erefore, to address this gap, we intend to perform a network meta-analysis (NMA) to compare the effects of three different traditional Chinese fitness exercises combined with AHD with AHD alone on patients with EH. In contrast to traditional metaanalyses, which focus narrowly on a single-treatment comparison, a network meta-analysis is able to pool direct and indirect evidence, analyses all possible comparisons between all treatments for a disease, and assesses the relative merits of each treatment [27]. By means of NMA based on the frequentist framework, we could calculate surface under the cumulative ranking curve (SUCRA [28]) and the likelihood of being the best and the worst for each intervention to predict the curative effect ranking of each traditional Chinese fitness exercise, and provide direct information about the three types of traditional Chinese fitness exercises evidence.  [29], the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [30]; and (3) at least one of four interested outcome measures, which include SBP, DBP, NO, ET, and required to be documented in the literature.

Study Selection.
e retrieved literature records were managed by means of reference management software NoteExpress (version 3.2). We conducted the pilot selection of literature to make sure that the inter-rater reliability among assessors was high. Based on the inclusion and exclusion criteria, two independent researchers respectively conducted a detailed screening of titles and abstracts of reference records identified through database searching. All potential articles that meet the eligible criteria and controversial literatures were required for a full-text review. Arbitration will be carried out by the third researcher, who was responsible for resolving the confliction between the two researchers.

Data Extraction.
Extraction of data of interest was separately conducted by two independent researchers after pilot extraction. e confliction between the two researchers would be resolved by the third researcher. e following data was what we need to extract: the first author of the research, publication year, diagnostic criteria for hypertension, level of blood pressure, sample, patient characteristics (age and sex), details of interventions, and outcome measures (SBP, DBP, NO, and ET).

Risk of Bias Appraisal and GRADE Assessment.
Based on Cochrane Handbook 5.1.0 [31], two independent researchers separately reviewed the included literatures to assess the risk of bias. e methodological quality of included studies was classified as having a low, unclear, or high risk of bias. Any confliction of opinions during the appraisal process was resolved by the third researcher or panel discussion. Assessment items included the following 7 items: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome data assessment, (5) incomplete outcome data, (6) selective outcome data reporting, and (7) other bias. e Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to appraise the quality of the evidence behind the ranking of interventions from NMA [32].

Statistical Analysis
2.6.1. Pairwise Meta-Analyses. Cochrane's Review Manager software (version 5.4) was used to analyze continuous data. We use the mean difference (MD) and 95% CI for continuous variables. I 2 values were used to evaluate the statistical heterogeneity between the included studies. When there is no or low heterogeneity between studies (I 2 < 25%), we used fixed-effects model to conduct the meta-analysis. If there is substantial heterogeneity (25% < I 2 < 95%) and clinical heterogeneity was considered acceptable, we used random-effects model to conduct the meta-analysis. When the statistical heterogeneity is particularly large (I 2 > 95%) or clinical heterogeneity is particularly significant, quantitative data were not pooled.

Network Meta-Analyses.
is study used STATA/SE 15.1 (StataCorp, 2017) and R software (version 4.0.1) to conduct data analysis and figures generation. We used WMD and their associated 95% CIs to summarize results. We took into account the existence of heterogeneity among different RCTs; thus, the random-effects model was selected to combine effect sizes in this network meta-analysis. We used the node-splitting model to assess inconsistency between direct and indirect comparisons. e bias in publication and small-scale study effects were evaluated with comparison-adjusted funnel plots, which were generated using "netfunnel" command. e network geometry of three different traditional Chinese fitness exercises was shown and described with network evidence plots, which were generated using "networkplot" command. We calculated the SUCRA and likelihood of being the best and the worst for each intervention to predict the curative effect ranking of each traditional Chinese fitness exercise. e significance level for all data analyses of this network meta-analysis was predetermined at 0.05.

Results of Pairwise Meta-Analysis.
ere were no statistically significant differences in other results.

Results of Network Meta-Analysis
3.5.1. Assessment of Inconsistency. Lack of direct comparison resulted in no closed loop between different interventions, and all the included studies were 2-arm trials, so there was no need for inconsistency testing.

Publication Bias.
e bias in publication and smallscale study effects are illustrated in Figure 4. Funnel plots for the SBP, NO, and ET network were roughly symmetrical, indicating that there was no apparent bias of publication due to small-scale study effects. e asymmetrical distribution of the funnel plots for the DBP network indicated that there was a possibility of bias of publication due to small-scale study effects.
3.5.6. ET Outcome. ET was assessed in 6 RCTs (390 participants). e network evidence plot for ET is shown in Figure 5. In ET reduction, Tai Chi plus AHD (WMD −7.64 pg/ml, 95% CI: −10.46 to −4.83) and Baduanjin plus AHD (WMD −9.23 pg/ml, 95% CI: −10.85 to −7.61) were statistically superior to AHD alone; there was no statistically significant difference in other results (see Figure 6 and Table 4). According to SUCRA, the interventions to decrease ET are ranked in probability (see Table 4 and Figure 7): BDJ + AHD (91.4%) > TC + AHD (58.6%) > AHD (0%). e quality of the evidence for the ranks of the treatment was low (see Table 5).

Summary of Findings.
e results indicated that combination therapies including Tai Chi plus AHD and Baduanjin plus AHD were superior to AHD alone, and Tai Chi was more effective than other traditional exercises at lowering SBP. Compared with AHD alone, Tai Chi plus AHD and Baduanjin Plus AHD produced a statistically significant DBP reduction. Compared with AHD alone, Baduanjin plus AHD produced a statistically significant NO increment, while that of Tai Chi plus AHD was not statistically significant. In terms of ET, both Baduanjin plus AHD and Tai Chi plus AHD produced a statistically significant reduction compared with AHD alone, while the difference between the two exercise types was not statistically significant.
Due to the lack of direct comparisons, there was no closed loop between different interventions, so node splitting method was not used to detect inconsistency; besides, the overall methodological quality of included studies was low, which increased the uncertainty of the results and required careful interpretation of the results.

Clinical Implications.
According to previous research results, traditional Chinese fitness exercises (Tai Chi, Baduanjin, and Wuqinxi) as adjuvant therapy are relatively easy to learn and less intense, especially suitable for longterm training of elderly patients with EH, which can enhance the antihypertensive effect, reduce the dosage of antihypertensive drugs, and ease the economic burden [43,57,60,[62][63][64][65]. However, compared with           antihypertensive drugs, the effects of traditional Chinese fitness exercises on EH remain understudied and evidence quality hierarchy of most of literatures in this field is at lower levels, meaning that it is necessary to carry out further highquality randomized controlled trials on traditional Chinese fitness exercise-assisted treatment of EH in the future. Based on the NMA results in this study, as adjunctive kinesiotherapy for EH, Tai Chi and Baduanjin have a statistically significant benefit in reducing the levels of SBP, DBP, and ET. Baduanjin has a statistically significant benefit in increasing the level of NO, while Wuqinxi may be the least effective.
ese findings of this NMA may be useful for clinicians and health professionals to select appropriate traditional Chinese fitness exercise as an adjuntive kinesiotherapy or early intervention prescription for patients with EH.

Strength and Limitations.
ere has been an increasing number of studies on traditional Chinese fitness exercises as adjuvant therapies for EH in recent years. However, our previous study rarely directly compared the effectiveness of different traditional Chinese fitness exercises. Traditional meta-analysis cannot compare multiple interventions, but NMA can address this issue. NMA attempts to integrate decision-making evidences through evaluating relative effectiveness of two or more alternative interventions in the same situation [66]. Consequently, in this study, we not only compared the effectiveness of AHD alone with traditional Chinese fitness exercises combined with AHD, but also calculated cumulative rankings for identifying superiority among the three traditional Chinese fitness exercises using Stata program based on the frequentist framework. is work could provide guidance and information for clinicians   to choose traditional Chinese exercises as an adjunct therapy for patients with EH. However, several limitations in this NMA should be noted. First, among the included literatures, there were only three literatures about Wuqinxi as an adjuvant therapy for EH, which was less than Tai Chi and Baduanjin. e estimates for the efficacy of Wuqinxi as adjuvant therapy for EH were open to considerable uncertainty as the number of studies was small, which leads to the current evidence and potential findings that still require careful interpretation. Second, since no RCT compared directly among the three traditional Chinese fitness exercises currently, we could only use indirect evidence to compare the efficacy of three traditional Chinese exercises. If the distribution of effect modifiers between different direct comparisons is unbalanced, the associated indirect comparisons will be biased [67]. ird, due to insufficient sample size of some exercise trials, confounding factors cannot be adequately controlled, leading to relatively unreliable estimates of therapeutic effects. Fourth, the quality of evidence in this NMA was low according to GRADE criteria. erefore, if high-quality evidence is obtained, the effect ranking order of interventions and pooled effect sizes may change. Fifth, although the current review is not registered, which may lead to potential bias, we still strictly follow the steps of the system review.

Conclusions
Based on the current results, we can reach the following conclusion. Compared with AHD alone, both Tai Chi plus AHD and Baduanjin plus AHD show significant benefit in regulating SBP, DBP, and ET. Among three traditional Chinese fitness exercises, Tai Chi may be the best as an adjunctive therapy for SBP reduction. ese findings provide evidence for the therapeutic benefit of either Tai Chi or Baduanjin exercise as an adjunct therapy for patients with EH. e overall methodological quality of included studies was low, so current results need to be interpreted with caution, and it is necessary to carry out further high-quality RCTs on traditional Chinese fitness exercise-assisted treatment of EH in the future.
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 they have no conflicts of interest regarding the publication of this paper.

Authors' Contributions
Lulu Dai and Yuerong Jiang put forward the idea of this study and designed the method of this systematic review. Lulu Dai, Yuerong Jiang, and Peili Wang searched the articles, conducted data collection and extraction, and analyzed the data. Keji Chen provided guidelines for this systematic review and network meta-analysis. e authors approved the final version of the manuscript for publication.