Qiju Dihuang Decoction for Hypertension: A Systematic Review and Meta-Analysis

Objective To systematically evaluate the efficacy of Chinese herbal medicine Qiju Dihuang Decoction (QDD) for hypertension. Methods A comprehensive literature search of randomized controlled trials using QDD to treat hypertension was conducted in 7 electronic databases, including Chinese databases. Subjects and abstracts of the trials were read in NoteExpress for preliminary screening, and the full text was read for further screening. The data extraction table was made for the selected 19 trials, and risk of bias was assessed by using the Cochrane collaboration tool, followed by data analysis using Rev Man 5.3. Results The antihypertensive efficacy of QDD is 1.45 times that of antihypertensive drugs and 1.56 times that of conventional therapies, which can also reduce the endothelin level. QPAD exhibits an antihypertensive effect, and its clinical efficacy is 1.34 times and 1.61 times that of antihypertensive drugs, which can not only significantly lower the diastolic blood pressure but also reduce the 24 h mean ambulate blood pressure. At the same time, it can decrease the TCM syndrome score, inhibit the inflammation, protect the renal function, reduce the insulin resistance, and improve the life quality of patients. Conclusion QDD can effectively reduce blood pressure and improve the life quality of patients with hypertension, which plays a certain role in preventing hypertension complications. However, due to the methodological deficiencies, more rigorous randomized controlled trials will be needed in the future to provide stronger evidence.


Introduction
Hypertension is a common clinical cardiovascular disease with systemic arterial pressure increase as the main sign, which not only causes headache, dizziness, and other clinical symptoms but also damages important organs such as the heart, brain, kidney and eyes, and it further produces multiple system lesions or dysfunction [1]. Its high morbidity and mortality bring physical and mental suffering to patients [2]. In recent years, hypertension has become a global public health problem involving over one billion people worldwide [3,4]. Patients with hypertension require a long-term medication with diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists that are widely used. However, they frequently cause some contraindications and adverse reactions, such as irritant dry cough, hyperkalemia, sexual dysfunction, and renal deterioration, which seriously affects the life quality of many patients. And after using these drugs, about half of patients cannot effectively control their blood pressure [5]. Traditional Chinese medicine (TCM) is often used to treat patients with hypertension [6,7], which can not only achieve good clinical efficacy but also may reduce the adverse reactions. Moreover, there are also certain advantages that TCM is applied for treating the complications of hypertension. Hypertension belongs to vertigo or headache in TCM. e first treatises on "vertigo" and "headache" appeared in Inner Canon of Yellow Emperor (Huang Di Nei Jing in Chinese). TCM believes that the onset of hypertension is mainly due to wind, phlegm, deficiency, blood stasis, and other diseases caused by the wind dizzy internal movement, phlegm and blood stasis, and Qi and blood block or Qing-qiao loss of nourishing, which results in the imbalance between Qi and blood and Yin and Yang. erefore, the nature of hypertension is usually described as deficiency in origin and excess in superficiality.
Qiju Dihuang Decoction (QDD), recorded in the Qing Dynasty Measles Complete Book (Ma Zhen Quan Shu in Chinese), is one of the most commonly used TCM formulae for the syndrome of "liver and kidney Yin deficiency," mainly used for vertigo, tinnitus, eyes acerbity photophobia, and vision dim [8,9]. QDD is composed by 8 kinds of herbs, including Lycii Fructus (Gouqizi, fruit from Lycium barbarum L.), Chrysanthemi Flos (Juhua, inflorescence from Chrysanthemum morifolium Ramat.), Rehmanniae Radix Praeparata (Shudihuang, root tuber from Rehmannia glutinosa Libosch.), Dioscoreae Rhizoma (Shanyao, rhizome from Dioscorea opposita unb.), Corni Fructus (Shanzhuyu, pulp from Cornus officinalis Sieb. et Zucc.), Moutan Cortex (Mudanpi, velamen from Paeonia suffruticosa Andr.), Poria (Fuling, sclerotium from Poria cocos Schw. Wolf ), and Alismatis Rhizoma (Zexie, tuber from Alisma orientale Sam. Juzep.). Gouqizi and Shudihuang can benefit the kidney Yang and nourish essence, Juhua can clear the liver and improve the vision, Shanyao can tonify the spleen and nourish the kidney, Shanzhuyu can nourish the kidney and liver, Mudanpi can clear away the liver-fire, Fuling can induce diuresis with bland drug, and Zexie can infiltrate to remove dampness and turbidity. Pharmacological studies have found that QDD can improve the liver fat metabolism, reduce the capillary permeability, enhance the immunity, diminish the inflammation, delay the senility, and decrease the alloxan caused by high blood glucose. QDD contains many chemical components such as cycloene terpenes, flavones, cholines, and vitamin [10,11]. As an effective drug, QDD is widely used for the treatment of hypertension and related complications by combining with other Chinese herbal medicines. Some animal experiments proved that QDD could not only reduce blood pressure and blood lipids [12] but also lowers the ratio of middle level of renal arteriolus and lumen diameter in spontaneously hypertensive rats [13], so as to regulate renal vascular remodeling and to improve renal blood flow [14], which plays a protective role in the kidney. At the same time, by improving the ultrastructure of endothelial cells, it can regulate the mitochondrial membrane potential and calcium ion concentration of cells, affect the proliferation of endothelial cells [15], regulate the NO-NOS system, and reduce the damage of vascular endothelial cells [16]. Although there are some systematic reviews and meta-analyses on Chinese herbal medicines for the treatment of hypertension, most of them only reported the antihypertensive effect of Chinese herbal medicines and the changes in blood pressure before and after treatment and did not touch upon the life quality of patients and the prevention of complications. So far, only some studies have shown that QDD can be used alone or in combination with other TCM formulae to treat hypertension and other related diseases, but the clinical indicators and antihypertensive effects in these studies are different. In addition, the efficacy of QDD in the treatment of hypertension has not been systematically assessed. erefore, this study was designed to evaluate the effect of QDD on hypertension patients' blood pressure, life quality, renal function, and insulin resistance as well as the potential mechanism of lowering blood pressure.

Data and Methods
is study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [17].

Literature Search.
Randomized controlled trials (RCTs) that evaluated the effect of QDD for hypertension were searched in the following 7 electronic databases: the Chinese National Knowledge Infrastructure (CNKI, from 1980 to 2020), Chinese Biomedical Literature Database (CBM, from 1978 to 2020), Wanfang Database (from 1998 to 2020), Weipu Database (from 1989 to 2020), PubMed (from 1959 to 2020), and Web of Science (from 1986 to 2020) and Springerlink (from 1996 to 2020). We used the following terms "blood pressure" OR "high blood pressure" OR "hypertension" OR "essential hypertension" OR "primary hypertension" OR "gao xue ya" OR "xue ya" AND ("Qiju Dihuang decoction" OR "Qijudihuang decoction" OR "Qi ju di huang decoction" OR "Qijudihuang tang" OR "Qiju dihuang tang" OR "Qi ju di huang tang" OR "Qijudihuangtang" AND "clinical trial" OR "randomized controlled trial" OR "randomized controlled trial" OR "lin chuang yan jiu" OR "lin chuang shi yan". No restriction on language was applied.

Intervention and Control Measures.
e intervention measures in the treatment group should be QDD alone or in combination with other antihypertensive treatments. And, the control group should be other antihypertensive treatments or placebo, such as conventional therapy, conventional antihypertensive drugs, and lifestyle interventions (CADLI). However, trials involving qigong, TAI Chi, acupuncture, moxibustion, massage, and cupping as common interventions will be excluded. Evidence-Based Complementary and Alternative Medicine

Studies.
is study included a randomized controlled trial using QDD to treat hypertension in the experimental group. Studies were excluded if (a) they were not random; (b) no control group was used; (c) the experimental design was not rigorous and statistical methods are inappropriate; (d) it was on the indeterminacy of measurement index outcome criterion; (e) they failed to obtain effective analysis data; (f ) they were animal experiments; (g) they were plagiarized.

Data Extraction.
Two researchers independently screened the titles and abstracts of potential eligible studies, and then they retrieved and reviewed the full text of the possible studies based on the inclusion and exclusion criteria and extracted the data. If there was disagreement, they agreed through discussion or submitted it to a third party for evaluation. Data extraction table mainly included the basic information of the study (author's name, title of the study, year of publication, country/region, and publication status), study characteristics (sample size, source of cases, age, gender distribution, diagnostic criteria, and inclusion and exclusion criteria), intervention and control measures (dosage form, dose, and duration), research methodology (random scheme generation, allocation hiding, blind method, incomplete result data, selective reporting, other biases, and loss of follow-up), and outcome measures.

Assessment of Literature Quality.
According to the Cochrane collaboration tool, two reviewers independently evaluated the methodological quality of each included study. It comprised the following seven aspects: random sequence generation, allocation concealment, blind method, incomplete result data, selective reporting, and other biases [18]. e quality evaluation results of each item can be divided into three grades: "low risk," "high risk," and "unclear." When necessary, the consensus on this issue was studied with the help of a third party.

Statistical
Analysis. Statistical analysis was performed using Rev Man 5.3 software. e results of a single study were firstly described. e binomial variables were described by using relative risk (RR) and 95% confidence interval (CI), and the continuous variables were described by mean difference (MD) and 95% CI to describe the effect value of the intergroup comparison. Heterogeneity was judged on the basis of the results of I 2 test. I 2 > 50% indicated that the heterogeneity of inter-study was significant, and the random effect model was adopted. And, the fixed effect model was adopted when I 2 < 50% [19]. Subgroup analysis was conducted by different treatment methods in the control group. Inverted funnel plots were used to determine potential publication bias when more than 10 studies were included in the meta-analysis.

Results of Our Literature
Search. Based on the retrieval strategy, 383 potential relevant literatures on the treatment of hypertension by QDD were preliminarily searched in 7 databases, and 244 literatures were retrieved after 139 copies were removed. After reviewing the titles and abstracts, 189 articles were excluded because they did not comply with the inclusion criteria and 55 articles initially met the intended criteria. After reading the full text, 19 eligible studies were included for meta-analysis [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. e flow chart of literature retrieval and screening is shown in Figure 1. Table 1 summarizes the basic characteristics of the 19 trials. All the trials were conducted in China. A total of 2043 patients with hypertension were included. Sample sizes ranged from 60 to 333. In the treatment group, QDD alone was used in 7 trials, then QDD plus antihypertensive drugs (QPAD) was used in 11 trials, and QDD plus CADLI (QPCADLI) was used in 1 trial. Table 2 lists the detailed information of QDD ingredients used in 19 trials. For control conditions, 16 trials were treated with antihypertensive drugs, and conventional therapy was used in 2 trials; additionally, CADLI was used in 1 trial. All 19 included trials reported the efficacy of QDD in the treatment of hypertension. Antihypertensive effects and blood pressure were the primary outcomes. 14 trials reported antihypertensive effects [21-25, 27-29, 32, 34-38], and 11 reported blood pressure [20-23, 26, 29-31, 33, 37, 38]. In terms of secondary outcome indicators, clinical effects were described in 2 trials [26,31] and TCM syndrome score was described in 1 trial [31]; furthermore, life quality was described in 2 trials [26,31], and 24 h ambulatory blood pressure was described in 1 trial [34]. e change of Ang II was described in 2 trials [20,36], and ET was described in 1 trial [20]; in addition, ISI and INS were described in 1 trial [30]. e changes of mA1b, β 2 -MG, and NAG were described in 1 trial [33], and HsCRP was described in 1 trial [36]. All included trials reported treatment duration ranging from 1 to 6 months. Table 3 summarizes the methodological quality of the 19 included trials. e risk of bias in the trials was assessed by using the criteria in the Cochrane Handbook for Systematic Reviews of Interventions [18]. Although randomization was announced in all of the included trials, 6 trials reported random sequence generation methods, including random number table [20,28,29,32,35] and the order of treatment [23]. However, no details were found in the domains of random allocation concealment, blinding of Evidence-Based Complementary and Alternative Medicine participants, personnel and outcome assessors, and selective outcome reporting.

Clinical Effects.
Clinical effect was determined by the TCM syndrome score. e clinical symptoms were significantly alleviated, and the TCM syndrome score was decreased by > 70% after treatment, indicating an obvious effect. At the same time, the TCM syndrome score was decreased by 50∼70% for improvement. No improvement or aggravation of symptoms and a reduction of TCM syndrome score below 50% is invalid. Obvious effect was used as an indicator of clinical efficacy. Two trials [26,31] described clinical effects, and meta-analysis revealed that QPAD was 1.61 times higher than antihypertensive drugs in clinical efficacy of hypertension (2 trials, n � 172; RR: 1.61; 95% CI: 1.12 to 2.31; p � 0.01; Figure 4).

TCM Syndrome
Score. e scoring method of TCM syndromes refers to the guiding principles for clinical research of new Chinese medicine [40]. According to the degree of clinical manifestations, the scores are zero, one, two, and three points respectively; moreover, the lower the score, the better the effect. Only one trial [31] reported TCM syndrome scores before and after treatment, suggesting that QPAD significantly reduced the scores in patients compared with antihypertensive drugs (1 trial, n � 72; MD: −3.00; 95% CI: −3.61 to −2.39; p < 0.00001).

Life
Quality. SF-36 was used to evaluate the life quality of patients. And, the higher the score, the higher the life quality.
INS level was also reported by the same trial as ISI, revealing that the reduction in INS was obviously greater for QPAD than that of antihypertensive drugs alone (1 trial, n � 60; MD: −2.30; 95% CI: −3.23 to −1.37; p < 0.00001).

Adverse Reactions.
No adverse reactions were reported in all trials.
3.14. Evaluation of Publication Bias. Since fewer than 10 trials were included in each subgroup, publication bias could not be adequately analyzed.

Discussion
TCM has certain advantages and characteristics in the treatment of hypertension. In recent years, the classic TCM formulae for treating hypertension have attracted much attention [41][42][43]. However, most studies only reported the antihypertensive effect but did not concern the effect of TCM on the life quality of patients and the prevention of complications. erefore, our study aimed to systematically evaluate the efficacy of QDD on blood pressure, life quality, renal function, insulin resistance, and other aspects of patients with hypertension as well as the potential hypertensive mechanism. And, it would provide a better evidence for hypertensive patients, policymakers, and clinicians.
is systematic review and meta-analysis contained 19 trials and 2043 patients with hypertension, which evaluated the efficacy of QDD in the treatment of hypertension, including QDD vs. antihypertensive drugs, QDD vs. conventional therapy, QPAD vs. antihypertensive drugs, and QPCADLI vs. CADLI. In summary, this study has identified that QDD can significantly reduce the blood pressure, improve the antihypertensive efficiency, show an obvious -8.20 [-11.19, -5      lowering effect on TCM syndrome score, inhibit the inflammation, protect the kidney function, reduce the insulin resistance, and improve the life quality of patients. And, reduction of Ang II and ET levels is possibly one potential antihypertensive mechanism of QDD. Patients with long-term hypertension will lead to a variety of pathophysiological changes, which will not only cause headache, chest tightness, palpitations, and other symptoms but also may involve various organs and cause different complications. erefore, hypertension is a major predisposing factor for many high-risk diseases. Many studies have also showed that the treatment of hypertension can play a preventive role in the occurrence of cardiovascular and cerebrovascular diseases [44]. Effective and stable control of blood pressure can significantly reduce the incidence of coronary heart disease by around 20-25%, 35-45% lower incidence of cerebral apoplexy, and heart failure in lower rates up to 50% [45]. Compared with the current prevalence trend of hypertension, if hypertension can be effectively controlled, the number of deaths from cardiovascular and cerebrovascular diseases in adults will be decreased by 564 100 until 2030 [46]. Controlling blood pressure to target levels is the basis of preventing cardiovascular and cerebrovascular diseases in patients with hypertension, so effectively lowering blood pressure is the most critical task for treatment of hypertension. All the trials included in the meta-analysis involved measures of the antihypertensive effect of QDD. We found that both QDD alone and in combination with antihypertensive drugs can remarkably reduce diastolic blood pressure and improved the antihypertensive effect. And, the choice of QDD treatment is one of the effective ways for patients with "liver and kidney Yin deficiency" hypertension. In addition, compared with antihypertensive drugs, QPAD can significantly reduce the mean systolic blood pressure and diastolic blood pressure at 24 h as well as the standard deviation of systolic blood pressure, which suggested that the combination of QDD and antihypertensive drugs is a more optimal choice for patients who cannot effectively improve the fluctuation of blood pressure by only taking antihypertensive drugs.
is study also discovered the potential mechanism of QDD for the reduction of blood pressure and the prevention of complications. Ang II vascular remodeling is one of the important pathological changes in the pathogenesis of hypertension, such as vascular smooth muscle proliferation, apoptosis, and other lesions, which will damage vascular walls, decrease vascular compliance, and lead to the imbalance of vascular active substances and disorder hemodynamic, all of which will lead to increase blood pressure. And, it was also reported to regulate the constriction of arterioles throughout the body and increase blood pressure [47]. In addition, when vascular endothelial cells are dysfunctional, vasomotor substances (such as ET) and growth -promoting factors are released abnormally, then blood vessel will narrow and peripheral resistance will increase, which also can promote blood pressure of patients [48]. e results of our study showed that QDD could significantly inhibit ET and also has an obvious lowering effect on Ang II when being combined with antihypertensive drugs. erefore, antihypertensive effect of QDD might attribute to inhibit the Ang II and ET release, protect the vascular endothelial cell function, and reduce the vascular remodeling. Insulin resistance was the pathophysiological basis of multiple complications in some patients with hypertension [49]. And, there was a significant correlation between insulin resistance and essential hypertension, which is one of the important causes of primary hypertension. erefore, the current hot issue in hypertension field is how to reasonably lower blood pressure and improve insulin resistance [50]. In our systematic review, QPAD can not only increase ISI and decrease insulin resistance but also significantly reduce the INS, which provides a reliable evidence for the prevention of hypertension complications. In addition, the kidney is an organ which can expel excess metabolites through the urine and prevent proteins and blood cells from leaking out of the blood vessels. However, chronic high blood pressure may cause the protein to leak into the urine, which can damage the filter system of kidney. If the blood pressure has not been well controlled for a long time, an irreversible structural damage will be caused, which may give rise to renal impairment and even chronic renal failure. e main renal complication of hypertension is renal arteriosclerosis [51]. erefore, the treatment of hypertension should also pay attention to the changes in renal function. In our metaanalysis, QDD showed a significant lowering effect on mA1b, β 2 -MG, and NAG, which proved that QDD could certainly prevent renal complications of hypertension.
e Shudihuang extract has a bilateral effect on blood pressure [56]. Diosgenin from Shanyao ( Figure 6(c)) has obvious effects on reducing the occurrence of cardiovascular and cerebrovascular diseases because it can effectively decrease calcium overload in cardiomyocytes and regulate related signaling pathways [57]. Water extract of Shanzhuyu has an antihypertensive effect [58]. Total iridoid glycosides have a certain protective effect on the vascular endothelium of the heart and thoracic aorta, and its active component morroniside ( Figure 6(d)) can prevent the injury of vascular endothelial cells by increasing the activity of SOD [59]. Paeonol from Mudanpi ( Figure 6(e)) has obvious protective effect on blood vessels, which is mainly related to lowering blood lipid and inhibiting atherosclerosis. Paeonol can also significantly increase serum NO level and decrease plasma ET content [60]. Furthermore, Zexie water extract can reduce blood pressure by dilating blood vessels. Zexie terpenoids can not only inhibit the release of norepinephrine by the sympathetic Evidence-Based Complementary and Alternative Medicine nerve but also block Ca 2+ , so it can significantly lower the blood pressure [61]. Alisol A (Figure 6(f )), alisol B ( Figure 6(g)), and alisol B 23-acetate ( Figure 6(h)) can inhibit Ang II and reduce blood pressure [62]. In addition, the increase in blood pressure caused by the constriction of the aorta via the adrenal glands in the body can be offset by their vasodilation effect [63], and elevated blood pressure caused by the secretion of angiotensin can also be inhibited by alisol [61].
Hypertension belongs to vertigo or headache in TCM, and it often follows other symptoms according to its complex etiology. So, its treatment should consider the alleviation of some relative symptoms. Our research results showed that QPAD could significantly decrease the TCM syndrome score of patients and improve the life quality of patients. So, it has an obvious effect on reducing the clinical symptoms.
With the accelerating pace of our life, the incidence of hypertensive patients increases year by year and shows a trend of becoming younger [64]. erefore, in addition to providing low-salt and low-fat diet, regular work, rest, and other health guidance to patients, it is particularly important to find appropriate drugs and optimized therapeutic scheme. Although antihypertensive drugs have been improved continuously in recent years, their adverse reactions cannot be avoided till now.
ere are various ways of treating hypertension by TCM, such as herbs, acupuncture, acupoint application, cupping, and foot bath. e multitarget of TCM exactly reflects the characteristics and advantages of integrated intervention. In recent years, many formulae have shown good antihypertensive effect [65][66][67][68][69]. Since hypertension has a very complicated pathological process, integrated TCM and chemical medicine treatment may be a better choice [70]. Our research results showed that QDD alone can significantly reduce the blood pressure, improve the antihypertensive effect, and inhibit the ET biological activity. Moreover, when combined with chemical medicine, QDD can also stabilize blood pressure fluctuations, decrease TCM syndrome score, inhibit inflammation, protect kidney function, reduce insulin resistance, and improve life quality of patients. erefore, QDD combined with antihypertensive drugs is recommended to treat patients with hypertension of "liver and kidney Yin deficiency." Although the effects of QDD on hypertension were evaluated using a meta-analysis, there were some limitations. Firstly, though all of 19 included trials reported randomization, only 6 trials had the random number table. In 19 trials, one used a medical order and the rest of the test randomness was not clear. However, all trials had some deficiencies such as random allocation concealment, blinding of participants, personnel and outcome assessors, or selective outcome reporting. Secondly, no publication bias had been evaluated, because the number of trials included in each subgroup was too small (no more than 10). And, regarding the efficacy of QPAD for SBP, there was a greater heterogeneity among the 7 included trials. irdly, there are still 9 trials using modified QDD that does not exactly reflect the effect of QDD. Fourthly, QDD is widely used in the treatment of ophthalmic diseases in the clinic [8], but no outcome indicators related to ophthalmology have been reported in the included trials, so the efficacy of prevention and treatment of hypertensive ophthalmic complications remains unclear. Fifthly, the adverse reactions of QDD on hypertension are unknown, because it is not shown in the included trials.

Conclusion
In summary, this study identified that QDD can significantly reduce the blood pressure of hypertension patients and improve the antihypertensive effects; furthermore, it shows a significant ET-lowering effect. Combining with antihypertensive drugs, it can also exhibit an obvious reduction on TCM syndrome score and average blood pressure of 24 h, Ang ?, INI, mA1b, β 2 -MG, NAG, and HsCRP level. At the same time, QDD can improve the effect of insulin resistance and patients' life quality. However, due to some less standard design of the included randomized controlled trials, more long-term, randomized and double-blind clinical trials will be needed in the future to provide stronger evidence for the treatment of hypertension with QDD.