Cardiovascular disease (CVD) is the leading cause of mortality all over the world. Despite advances in prevention and treatment over the past 20 years, CVD remains a leading cause of death and disability. The emergence of CVD as a leading cause of morbidity and mortality in China, in large part, is a result of the rapid economic growth and associated sociodemographic change that has occurred over the past few decades [
Complementary and alternative medicine (CAM) refers to a series of medical and health care practices and products that are not an integral part of conventional medicine due to insufficient proof of their safety and effectiveness [
Zhen Gan Xi Feng Decoction (ZGXFD), a traditional Chinese herbal formula containing twelve commonly used herbs (achyranthes root, ruddle, dragon bone, oyster shell, plastrum testudinis, white peony root, radix scrophulariae, radix asparagi, fructus toosendan, raw malt, artemisia capillaris Thunb, and glycyrrhiza), is widely used to treat hypertension-related symptoms in clinical practice for centuries in China. Recent researches showed that ZGXFD could contribute to blood pressure control. The mechanism of the prescription maybe related to calming liver, suppressing liver yang hyperactivity, and nourishing kidney yin in Chinese medicine. Biochemically, ZGXFD also showed good effect in decreasing the concentrations of angiotensin in plasma and myocardium, reducing the endothelin content in brain and improving PPAR
Currently, ZGXFD used alone or combined with antihypertensive drugs has been widely used as an alternative and effective method for essential hypertension treatment in China. And until now a number of clinical studies of ZGXFD reported the effectiveness ranging from case reports and case series to controlled observational studies and randomized clinical trials. However, there is no critically appraised evidence such as systematic reviews or meta-analyses on potential benefit and safety of ZGXFD for essential hypertension to justify their clinical use and their recommendation. Understanding the effect of ZGXFD on blood pressure, quality of life (QOL) and cardiovascular risk factors could be valuable for the management of essential hypertension. The present paper aims to evaluate the beneficial and harmful effects of ZGXFD for treatment of essential hypertension in randomized trials.
The literature searches were conducted in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (August, 2012), PubMed, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and searched the reference list of retrieved papers. All of those searches ended on August 15, 2012. Ongoing registered clinical trials were searched in the website of Chinese clinical trial registry (
All the randomized controlled trials (RCTs) of all the prescriptions based on “Zhen Gan Xi Feng Decoction” compared with antihypertensive drugs in patients with hypertension were included. RCTs combined ZGXFD with antihypertensive drugs compared with antihypertensive drugs, and all the modified ZGXFD were included as well. There were no restrictions on population characteristics, language, and publication type.
The primary outcome measure was blood pressure (BP), and the secondary outcome measure was TCM syndrome and symptom differentiation (TCM-SSD) scores. The criteria “significant effective, effective, or not effective” were also included in the outcome measurement. Duplicated publications reporting the same groups of participants were excluded.
Two authors conducted the literature searching (X. J. Xiong and X. C. Yang), study selection (X. J. Xiong and W. Liu), and data extraction (X. J. Xiong and X. Du) independently. The extracted data included authors and title of study, year of publication, study size, age and sex of the participants, details of methodological information, name and component of Chinese herbs, treatment process, details of the control interventions, outcomes (e.g., blood pressure), and adverse effects for each study. Disagreement was resolved by discussion and reached consensus through a third party (J. Wang).
Methodological quality of trials was assessed using 7 criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0 (X. J. Xiong and B. Feng) [
RevMan 5.1 software provided by Cochrane Collaboration was used for data analyses. Dichotomous data were expressed as relative risk (RR) and continuous outcomes as weighted mean difference (WMD), both with 95% confidence intervals (CI). Meta-analysis was performed if the intervention, control, and outcome were the same or similar. The statistical heterogeneity was presented as significant when
After primary search of 5 databases, 229 trials were screened out from electronic and manual searches (Figure
Characteristics and methodological quality of included studies.
Study ID | Sample | Diagnosis standard | Intervention | Control | Course (week) | Outcome measure |
---|---|---|---|---|---|---|
Guo et al. |
129 | Hypertension diagnostic criteria (unclear); GCRNDTCM | ZGXFD | Captopril | 4 | BP; TCM-SSD; side effect |
Mao 2005 |
70 | 1999 WHO -ISH GMH; GCRNDTCM | Modified ZGXFD | Indapamide | 3 | BP; TCM-SSD |
Luo 2008 |
45 | CGMH-1999; GCRNDTCM | ZGXFD | Captopril | 2 | BP; TCM-SSD |
Liu and Zhong |
120 | CGPMHBP-2004; GCRNDTCM | Modified ZGXFD plus benazepril | Benazepril | 3 | BP; TCM-SSD |
Li and Zheng |
166 | Hypertension diagnostic criteria (unclear); TCM diagnostic criteria (unclear) | Modified ZGXFD | Captopril | 4 | BP; side effect |
Zhou 2000 [ |
300 | Hypertension diagnostic criteria (unclear); TCM diagnostic criteria (unclear) | Modified ZGXFD plus nitrendipine | Nitrendipine | 4 | BP; side effect |
Study selection process.
The 6 RCTs involved 830 patients with essential hypertension. There was a wide variation in the age of subjects (18–87 years). Six (6) trials specified three diagnostic criteria of hypertension, one trial [
The interventions included all the prescriptions based on “Zhen Gan Xi Feng Decoction” alone and ZGXFD with antihypertensive drugs. The controls included antihypertensive drugs alone. Four trials [
The total treatment duration ranged from 2 weeks to 4 weeks. The variable prescriptions are presented in Table
Composition of formula.
Study ID | Formula | Composition of formula |
---|---|---|
Guo et al. 2002 [ |
ZGXFD | Achyranthes root, ruddle, dragon bone, oyster shell, plastrum testudinis, white peony root, radix scrophulariae, radix asparagi, fructus toosendan, raw malt, artemisia capillaris thunb, and glycyrrhiza. |
Mao 2005 [ |
Modified ZGXFD | Achyranthes root 30 g, ruddle 30 g, uncaria 30 g (put in later), dragon bone 15 g, oyster shell 15 g, plastrum testudinis 15 g, white peony root 12 g, radix scrophulariae 12 g, radix asparagi 12 g, fructus toosendan 9 g, raw malt 20 g, artemisia capillaris thumb 9 g, and glycyrrhiza 6 g. |
Luo 2008 [ |
ZGXFD | White peony root 30 g, radix asparagi 15 g, achyranthes root 30 g, ruddle 30 g, dragon bone 30 g, oyster shell 30 g, plastrum testudinis 25 g, radix scrophulariae 15 g, fructus toosendan 10 g, raw malt 10 g, artemisia capillaris thumb 15 g, and glycyrrhiza 10 g |
Liu and Zhong 2008 [ |
Modified ZGXFD plus benazapril | White peony root 15 g, radix asparagi 15 g, plastrum testudinis 15 g, oyster shell 15 g, fructus toosendan 6 g, ruddle 30 g, achyranthes root 30 g, radix scrophulariae 15 g, dragon bone 15 g, artemisia capillaris thumb 6 g, raw malt 6 g, and glycyrrhiza 5 g. Severe headache plus chrysanthemum 10 g; insomnia plus pearl shell 15 g and caulis polygoni multiflori 15 g; vexation plus gardenia 10 g and scutellaria baicalensis georgi 10 g; severe phlegm-heat plus pinellia pedatisecta schott 6 g and fritillaria cirrhosa 10 g. |
Li and Zheng 2012 [ |
Modified ZGXFD | Radix scrophulariae 15 g, ruddle 30 g, white peony root 15 g, achyranthes root 30 g, radix asparagi 15 g, dragon bone 15 g, oyster shell 15 g, raw malt 6 g, artemisia capillaris thumb 6 g, plastrum testudinis 15 g, fructus toosendan 6 g, and glycyrrhiza 3 g. Vexation plus plaster stone; abundant sputum plus pinellia pedatisecta schott and bamboo bark; slow-weak pulse plus prepared radix rehmanniae and pulp of cornus; diarrhea remove plastrum testudinis and ruddle, plus halloysitum rubrum; insomnia plus coptis chinensis, rehmanniae radix and caulis polygoni multiflori; severe headache plus abalone shell; severe dizziness plus gastrodia elata. |
Zhou 2000 [ |
Modified ZGXFD plus nitrendipine | White peony root 20 g, radix asparagi 10 g, plastrum testudinis 5 g, oyster shell 30 g, abalone shell 20 g, ruddle 80 g, magnetite 30 g, achyranthes root 10 g, radix scrophulariae 15 g, salvia miltiorrhira 30 g, and panpax notoginseng 10 g. Severe headache plus antelope horn; insomnia plus pearl shell and caulis polygoni multiflori; vexation plus gardenia and scutellaria baicalensis georgi; severe phlegm-heat plus pinellia pedatisecta schott and fritillaria cirrhosa. |
The methodological quality of the included trials was assessed to be generally low according to the predefined quality assessment criteria in Table
Quality assessment of included randomized controlled trials.
Included trials | Sequence generation | Allocation concealment | Blinding of participants personnel and outcome assessors | Incomplete outcome data | Selective outcome reporting | Other sources of bias | Risk of bias |
---|---|---|---|---|---|---|---|
Guo et al. 2002 [ |
Table of random number | Unclear | Unclear | No | No | Unclear | Unclear |
Mao 2005 [ |
Table of random number | Unclear | Unclear | Yes | No | Unclear | Unclear |
Luo 2008 [ |
Unclear | Unclear | Unclear | Yes | No | Unclear | High |
Liu and Zhong 2008 [ |
Unclear | Unclear | Unclear | Yes | No | Unclear | High |
Li and Zheng 2012 [ |
Unclear | Unclear | Unclear | Yes | No | Unclear | High |
Zhou 2000 [ |
Unclear | Unclear | Unclear | Yes | No | Unclear | High |
Four trials [
Analyses of blood pressure.
Trials | Intervention ( |
Control ( |
RR [95% CI] |
|
|
---|---|---|---|---|---|
ZGXFD versus antihypertensive drugs | |||||
ZGXFD versus captopril | 1 | 54/68 | 40/61 | 2.02 [0.92, 4.46] | 0.08 |
Modified ZGXFD versus indapamide | 1 | 40/47 | 19/23 | 1.20 [0.31, 4.61] | 0.79 |
ZGXFD versus captopril | 1 | 22/24 | 18/21 | 1.83 [0.28, 12.19] | 0.53 |
Modified ZGXFD versus captopril | 1 | 78/86 | 65/80 | 2.25 [0.90, 5.64] | 0.08 |
| |||||
Meta-analysis | 4 | 194/225 | 142/185 | 1.93 [1.14, 3.25] | 0.01 |
| |||||
ZGXFD plus antihypertensive drugs versus antihypertensive drugs | |||||
Modified ZGXFD plus benazapril versus benazapril | 1 | 56/60 | 47/60 | 3.87 [1.18, 12.68] | 0.03 |
Modified ZGXFD plus nitrendipine versus nitrendipine | 1 | 183/200 | 72/100 | 0.07 [0.00, 1.22] | 0.07 |
| |||||
Meta-analysis | 2 | 239/260 | 119/132 | 1.03 [0.47, 2.25] | 0.93 |
Analyses of systolic blood pressure.
Trials | MD [95% CI] |
|
|
---|---|---|---|
ZGXFD versus antihypertensive drugs | |||
ZGXFD versus captopril | 1 | −10.94 [−15.64, −6.24] | <0.00001 |
Modified ZGXFD versus indapamide | 1 | −0.74 [−6.72, 5.24] | 0.81 |
| |||
Meta-analysis | 2 | −7.05 [−10.74, −3.35] | 0.0002 |
Analyses of diastolic blood pressure.
Trials | MD [95% CI] |
|
|
---|---|---|---|
ZGXFD versus antihypertensive drugs | |||
ZGXFD versus captopril | 1 | −8.42 [−10.98, −5.86] | <0.00001 |
Modified ZGXFD versus indapamide | 1 | −0.52 [−4.67, 3.63] | 0.81 |
| |||
Meta-analysis | 2 | −6.24 [−8.42, −4.07] | <0.00001 |
Analyses of TCM-SSD Scores.
Trials | Intervention ( |
Control ( |
RR [95% CI] |
|
|
---|---|---|---|---|---|
ZGXFD versus antihypertensive drugs | |||||
ZGXFD versus captopril | 1 | 59/68 | 44/61 | 2.53 [1.03, 6.21] | 0.04 |
Modified ZGXFD versus indapamide | 1 | 45/47 | 17/23 | 7.94 [1.46, 43.24] | 0.02 |
ZGXFD versus captopril | 1 | 23/24 | 15/21 | 9.20 [1.00, 84.26] | 0.05 |
| |||||
Meta-analysis | 3 | 127/139 | 76/105 | 3.78 [1.82, 7.85] | 0.0004 |
| |||||
BBTD plus antihypertensive drugs versus antihypertensive drugs | |||||
modified ZGXFD plus benazapril versus benazapril | 1 | 56/60 | 47/60 | 3.87 [1.18, 12.68] | 0.03 |
| |||||
Meta-analysis | 1 | 56/60 | 47/60 | 3.87 [1.18, 12.68] | 0.03 |
Two trials [
The number of trials was too small to conduct any sufficient additional analysis of sensitivity, subgroup, and publication bias.
Three out of six trials mentioned the adverse effect [
Currently, more and more systematic reviews (SRs) and meta-analysis have been conducted to assess the efficiency of Chinese herbal medicine for essential hypertension [
Firstly, all the six trials included in this paper had risk of bias in terms of design, reporting, and methodology. Only two randomized controlled trials (RCTs) [
Second, there was lack of knowledge for the final indicator at endpoint. As we know, the primary goal of essential hypertension treatment is to reduce mortality or prevent progression to severe complications. However, all the included trials only reported the outcomes such as blood pressure and symptom improvement. None of the trials reported the mortality rate or the incidence of complications. Future RCTs of ZGXFD with appropriate design need to be carried out to measure the mortality and morbidity of hypertension.
Third, our review found inadequate reporting on adverse events in the included trials. Only two of the six trials reported the adverse effect of ZGXFD or modified ZGXFD briefly, providing limited information. One trial [
Fourth, publication and other biases may play an important role in the review. Only trials published in China could be identified and included after conducting comprehensive searches. We tried to avoid language bias and location bias; however, potential publication bias could not be excluded totally. Almost all the RCTs claimed positive effect of ZGXFD though some of them turned out to be negative when analyzed by standard statistical techniques using risk ratios or mean differences. We have conducted extensive searches for unpublished material, but no unpublished “negative” studies were found.
In summary, the reported effectiveness and safety of ZGXFD for essential hypertension cannot be taken as confirmative conclusion. Due to poorly designed and low-quality methodology, the evidence is still inconclusive. We hope that further RCTs with better research methods as a good approach to evaluate the effectiveness will be needed in ZGXFD for essential hypertension clinical study.
All authors declare that they have no conflict of interests.
X. Xiong, X. Yang, B. Feng, W. Liu, H. Li, J. Ma, X. Du, P. Wang, K. Su, F. Chu, G. Zhang, and X. Li contributed equally to this paper.
The current work was partially supported by the National Basic Research Program of China (973 Program, no. 2003CB517103) and the National Natural Science Foundation Project of China (no. 90209011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.