The effectiveness of XZD on BP was evaluated in all of the 15 trials. Continuous BP was used in 9 trials in this meta-analysis.53–61 There were 385 patients in the XZD groups and 371 patients in the antihypertensive drugs groups, respectively. A random-effects model was used for statistical analysis according to the test of heterogeneity (SBP: chi-square = 74.80, P < 0.00001, I 2
= 89%; DBP: chi-square = 46.20, P < 0.00001, I 2
= 83%). The combined effects of these 9 independent trials showed a significant lowering effects of XZD on SBP (WMD = −6.99 mm Hg; 95% CI: −10.62 to −3.36, P = 0.0002) and DBP (WMD = −4.44 mm Hg; 95% CI: −6.45 to −2.44, P < 0.0001) in patients with hypertension when compared with antihypertensive drugs alone (Fig. 2A and B). Categorical BP was used in the other 6 trials to evaluate the efficacy of XZD.62–67 There were 321 patients in the XZD groups and 287 patients in the antihypertensive drugs groups, respectively. The categorical BP data were analyzed using a fixed-effects model according to the test of heterogeneity (chi-square = 6.05, P = 0.30, I 2
= 17%). A significant decrease on BP was identified in favor of XZD therapy after treatment when compared with the antihypertensive drugs (RR = 1.32; 95% CI: 1.21 to 1.43, P < 0.00001) (Fig. 2C).
Seven studies assessed the effectiveness of XZD on the symptoms outcomes in comparison with antihypertensive drugs.55–57,59,61,65,67 There were 349 patients in the XZD groups and 336 patients in the antihypertensive drugs groups. A fixed-effects model was applied based on the test of heterogeneity (chi-square = 8.90, P = 0.18, I 2
= 33%). The meta-analysis identified a significant improvement on the symptoms outcomes by XZD therapy compared with antihypertensive drugs (RR = 1.26; 95% CI: 1.18–1.35, P < 0.00001) (Fig. 3).
Four studies used the outcomes of lipid profile parameters to evaluate the effectiveness of XZD in hypertensive patients, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C).53,56,57,66 There were 146 patients in the XZD groups and 144 patients in the antihypertensive drugs groups. Pooled analysis demonstrated a significant lipid-lowering effects of XZD therapy on TC (n = 4; WMD = −1.47 mmol/L; 95% CI: −1.99 to −0.96, P < 0.00001; heterogeneity: chi-square = 12.71, P = 0.005, I 2
= 76%), TG (n = 4; WMD = −1.04 mmol/L; 95% CI: −1.62 to −0.45, P = 0.0005; heterogeneity: chi-square = 14.31, P = 0.003, I 2
= 79%), and LDL-C (n = 1; WMD = -0.60 mmol/L; 95% CI: −0.94 to −0.26, P = 0.0005; heterogeneity: not applicable), beyond HDL-C (n = 3; WMD = 0.14 mmol/L; 95% CI: −0.06 to 0.33, P = 0.17; heterogeneity: chi-square = 4.62, P = 0.10, I 2
= 57%) when compared with the antihypertensive drugs (Fig. 4).
There was only 1 trial evaluating the effect of XZD with antihypertensive drugs alone on the outcome of serum HCY level.60 There were 52 patients in the XZD group and 51 patients in the antihypertensive drugs group. Pooled result was statistically significant in favor of XZD therapy (WMD = −5.90 μmol/L; 95% CI: −6.67 to −5.13, P < 0.00001; heterogeneity: not applicable) (Fig. 5).
The effects of XZD on the hemorheology outcomes, including high shear blood viscosity, moderate shear blood viscosity, low shear blood viscosity, plasma viscosity, hematocrit, and fibrinogen, were reported in 2 trials.57,61 There were 63 patients in the XZD groups and 62 patients in the antihypertensive drugs groups. The meta-analysis revealed significant effects of XZD for improving high shear blood viscosity (n = 2; WMD = −0.62 mPa/s; 95% CI: −0.85 to −0.40, P < 0.00001; heterogeneity: chi-square = 0.21, P = 0.65, I 2
= 0%), moderate shear blood viscosity (n = 1; WMD = −0.90 mPa/s; 95% CI: −1.16 to −0.64, P < 0.00001; heterogeneity: not applicable), low shear blood viscosity (n = 2; WMD = −1.73 mPa/s; 95% CI: −2.51 to −0.96, P < 0.0001; heterogeneity: chi-square = 0.19, P = 0.67, I 2
= 0%), plasma viscosity (n = 1; WMD = −0.12 mPa/s; 95% CI: −0.17 to −0.07, P < 0.0001; heterogeneity: not applicable), hematocrit (n = 2; WMD = −0.10 %; 95% CI: −0.13 to −0.07, P < 0.00001; heterogeneity: chi-square = 0.30, P = 0.58, I 2
= 0%), and fibrinogen (n = 1; WMD = −0.56 g/L; 95% CI: −0.97 to −0.15, P = 0.007; heterogeneity: not applicable) (Fig. 6).
Only 1 trial evaluated the effectiveness of XZD on LVMI when compared with antihypertensive drugs alone.58 There were 37 patients in the XZD group and 33 patients in the antihypertensive drugs group. A significant improvement on LVMI in favor of XZD therapy was observed after treatment (WMD = −2.80 g/m2; 95% CI: −5.50 to −0.10, P = 0.04; heterogeneity: not applicable) (Fig. 8).
The funnel plot analyses of the 9 studies comparing XZD with antihypertensive drugs on SBP and DBP were generated to detect the potential publication bias. Significant asymmetry was manifested in the Figure 9A and B.
Currently, there were clinical evidence ranged from case studies, case series, controlled trials to RCTs showing that XZD is effective in treating hypertensive patients; however, no high level of evidence such as systematic review or meta-analysis was provided for further recommendation. The purpose of this systematic review was to summarize the potential cardiovascular protective actions of XZD in patients with hypertension.
A total of 15 claimed RCTs involving 1364 hypertensive patients met the inclusion criteria in this review. In general, the pooled analyses of the current RCTs demonstrated a superior therapeutic effect of XZD as adjuvant therapy in treating hypertension. That is, XPAD is more effective in lowering BP, relieving symptoms, improving blood lipids, HCY, and hemorheology, and decreasing IMT and LVMI when compared with antihypertensive drugs alone.
The main therapeutic goal of treating hypertension are to not only reduce BP to the normal level, but also reverse cardiovascular risk factors, protect the target organs, and reduce mortality and cardiovascular events.68–70 This is a systematic review and meta-analysis on the potential role of XZD for hypertension. There were several strengths in this review. First, antihypertensive therapy is the cornerstone of hypertension treatment.71 On the basis of the guidelines on hypertension by the Eighth Joint National Committee, goal BP was <150/90 mm Hg in hypertensive persons aged ≥60 years, and goal DBP <90 mm Hg in hypertensive persons 30 to 59 years.3 Evidence also indicates that hypertensive patients could benefit from antihypertensive therapy when reaching the recommended threshold BP values. In our review, 9 trials (9/15, 60%) reported the outcomes on BP values and meta-analysis by subgroup showed that in hypertensive patients treated by XZD, the mean additional reduction in SBP was 6.99 mm Hg and DBP was 4.44 mm Hg. In the other 6 trials (6/15, 40%), the results also showed statistical significance compared with antihypertensive drugs alone. Our systematic review and meta-analysis was consistent with some prior reviews supporting use of traditional Chinese herbal formulae therapy for hypertension.72–74
Second, in some cases, the hypertension-related symptoms seriously troubled patients, although the elevated BP has been effectively controlled.75 According to the evaluation criterion in GCRNDTCM, these symptoms included headache, dizziness, insomnia, irritability, etc. We investigated the efficacy of XZD on the common symptoms in patients with hypertension in this study. Seven trials (7/15, 46.67%) were identified and the subgroup meta-analysis supported that XZD significantly improved symptoms in patients with hypertension; however, we should pay attention to that, an accurate TCM syndrome diagnosis is formed based on the collected symptoms and signs of the patients.76,77 Only 10 studies (10/15, 66.67%) reported the use of diagnostic criteria of TCM syndrome. As we know, a better therapeutic benefit might be achieved when the prescribed Chinese herbal medicine fit the TCM syndrome diagnosis.78 Therefore, we suggested that the theory of formula corresponding to syndrome in TCM should be reunderstood either in theory or in practice;79 and that both using and reporting the TCM syndrome diagnosis should be considered in further researches.
Third, the treatment goal of hypertension also includes managing the coexistent risk factors for cardiovascular disease together.68,80,81 The efficacy of XZD on blood lipids was evaluated in this study. A significant improvement on blood lipids was identified, with TC, TG LDL-C, and decreased by 1.47, 1.04, and 0.60 mmol/L, respectively. A clinically, but not statistically, significant increase in HDL-C was also observed by XZD therapy. HCY is regarded as a risk factor for hypertension and plays an important role in the development and progression of carotid atherosclerosis in hypertensive patients.82,83 Epidemiologic survey confirmed that high HCY level might increase the risk of hypertension.84 In this review, XZD significantly lowered the serum HCY level in hypertensive patients. Additionally, the hemorheology is an important biochemical index for diagnosing blood stasis syndrome and evaluating the therapeutic effects of PBCRBS-based herb and formulae in TCM.31,85–87 In our review, the hemorheology was significantly improved by XZD treatment comparing with the antihypertensive drugs alone. The results were consistent with previous meta-analysis of PBCRBS-based formulae on the outcomes of hemorheology.88 As only few studies provided data for blood lipids, HCY, and hemorheology, more clinical evidence are warranted to confirm the conclusions.
Fourth, an interesting finding of this review is the evaluation of XZD on target organ damage (TOD) in hypertensive patients. Long-term high BP induces vasculature, myocardium, and renal remodeling.89 Left ventricular hypertrophy, impaired renal function, and albuminuria are manifestations of TOD in hypertension, all of which are considered strong predictors for cardiovascular events and mortality.90–94 Therefore, current guidelines for the management of hypertension recommend that the preliminary evaluation of cardiovascular risks in hypertensive patient should focus on not only BP levels, but also TOD by measuring renal function, albuminuria, left ventricular hypertrophy, IMT, and pulse wave velocity .1,69 The effects of XZD on TOD were assessed in this systematic review and meta-analysis. A significant improvement on IMT and LVMI was identified in the XZD group compared with antihypertensive drugs alone.
Additionally, XZD treatment was well tolerated in the enrolled patients. No severe adverse events occurred in the XZD groups compared with the antihypertensive drugs groups. This systematic review suggested that XZD might be a safe TCM approach in managing hypertension; however, as only 3 trials reported the adverse events, it is still difficult to draw any definite conclusion.
Before accepting the above positive findings, the following limitations should also be considered. First, although comprehensive literature search was conducted in the 7 electronic databases, databases published in other languages except Chinese and English were not included in our study. Thus, a certain degree of potential selective bias might exist and some relevant publications of XZD might be missed.
Third, we rigorously assessed the methodologic quality of the included trials based on the Cochrane Collaboration's tool. The methodologic quality is poor, which is the inherent shortcomings in primary studies. For example, all the included studies declared that, participants were randomized into the XZD group and antihypertensive drugs group; however, only 5 trials provided the adequate sequence generation and no trials reported the concealment of allocation. Inadequate reporting and poor methodologic design might weaken the strength and credibility of the clinical evidence of XZD in this review.
In summary, XZD could improve BP, symptoms, blood lipids, HCY, hemorheology, IMT, and LVMI in hypertensive patients. Although some limitations such as potential selective bias and methodologic flaws might undermine the validity of positive findings, XZD is beneficial for hypertension treatment. From a clinical point of view, further RCTs with high-quality and long-term follow-up are recommended to generate high level of clinical evidence. Altogether, this systematic review and meta-analysis here provides an evidence-based approach to the management of hypertension and suggests XZD as a new candidate cardioprotective drug, which should be given priority for future preclinical and clinical studies.
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