Meta-analysis of the effectiveness of traditional Chinese herbal formula Zhen Wu Decoction for the treatment of hypertension

Objectives Zhen Wu Decoction (ZWD), a famous classic herbal formula documented in traditional Chinese medicine (TCM), is widely available in China for treating hypertensive patients with kidney yang deficiency and fluid retention syndrome. This systematic review aims to evaluate the effectiveness and safety of ZWD for hypertension. Methods Cochrane Central Register of Controlled Trials, PubMed, Embase, the Chinese National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Chinese Biomedical Literature Database, and the Wanfang Database were searched from their inception to November 2014. Randomised controlled trials of ZWD used alone or in combination with antihypertensive drugs against placebo, no intervention or antihypertensive drugs in hypertensive patients were identified. Two assessors independently reviewed each trial. The Cochrane risk of bias assessment tool was used for quality assessment. Results Seven trials involving 472 hypertensive patients were identified. Compared with antihypertensive drugs, ZWD showed no significant effects in lowering blood pressure (BP) (n=177; risk ratio (RR) 1.06; 95% CI 0.87 to 1.28; p=0.58); however, ZWD plus antihypertensive drugs (ZPAD) significantly lowered systolic BP (n=80; weighted mean difference (WMD) −14.00 mm Hg, 95% CI −18.84 to −9.16 mm Hg; p<0.00001), diastolic BP (n=80; WMD −8.00 mm Hg, 95% CI −11.35 to −4.65 mm Hg; p<0.00001), and BP (n=215; RR 1.21, 95% CI 1.08 to 1.37; p=0.001). TCM symptoms and syndromes were significantly improved by either ZWD (n=177; RR 1.58, 95% CI 1.28 to 1.95; p<0.0001) or ZPAD (n=215; RR 1.30, 95% CI 1.14 to 1.49; p=0.0001). Adverse effects were not reported. Conclusions This systematic review revealed no definite conclusion about the application of ZWD for hypertension due to the poor methodological quality, high risk of bias, and inadequate reporting on clinical data. More rigorously designed trials, especially addressing continuous BP and adverse effects, are warranted.


INTRODUCTION
Hypertension remains one of the major modifiable risk factors associated with cardiovascular morbidity and mortality, affecting more than 60 million individuals in the USA and totalling nearly one billion worldwide. 1 2 The primary prevention and management of hypertension and blood pressure (BP) related diseases has become a global public health challenge. 3 4 Tremendous progress have been made in the application of renal denervation therapy, combination antihypertensive and lipid-lowering therapies, and evidence-based guideline recommendations for stepwise, multidrug regimens released by the Eighth Joint National Committee ( JNC 8) and other authorities. [5][6][7] However, despite the availability of multiple antihypertensive agents with distinct pharmacologic classes and single-pill combination pharmacotherapy, goal BP is not achieved in large numbers of hypertensive patients and the control rates of hypertension among different age groups remain suboptimal. 2 8 Therefore, there is an unmet need for new Strengths and limitations of this study ▪ Zhen Wu Decoction (ZWD), a famous classic herbal formula in traditional Chinese medicine, is often prescribed for patients with hypertension. ▪ This is the first systematic review addressing the effectiveness and safety of ZWD for the treatment of hypertension. ▪ The strength of this review is the comprehensive and unbiased literature searches in seven electronic databases without limitations on language or publication status. ▪ The included trials were of small sample size and at high risk of bias. ▪ This review revealed no definite conclusion about the application of ZWD for hypertension.
approaches for the treatment of hypertension. Currently, a revival of interest in complementary and alternative medicine (CAM) for the treatment of hypertension has attracted widespread attention. [9][10][11] A large number of systematic reviews and meta-analyses have been performed to summarise the growing number of randomised controlled trials (RCTs) addressing the effectiveness and safety of CAM for hypertension. [12][13][14][15][16][17][18][19][20][21][22][23] In 2013, the American Heart Association summarised the BP-lowering efficacy of several commonly used CAM approaches with an evidence-based classification of recommendations for their implementation in clinical practice. 24 Among various CAM therapies, Chinese herbal medicine (CHM) has been used in traditional Chinese medicine (TCM) to treat symptoms related to hypertension for over 2500 years. [25][26][27] Previous studies have shown that kidney yang deficiency and fluid retention syndrome is a common syndrome of hypertension, which is usually characterised by aversion to cold, cold limbs, weakness, fatigue, dizziness aggravated by change in body position, tinnitus, thirst without a desire to drink or not being thirsty, chest distress, palpitation, gastric distension, abdominal distension, poor appetite, lumbar heaviness, heaviness in the lower extremities, oedema, daytime sleepiness, dysuria, swollen tongue with greasy fur, and deep-weak-slow pulse. 28  . According to the records by Dr Zhang, kidney yang deficiency and fluid retention syndrome could be significantly improved by ZWD, which happens to be consistent with our studies. [26][27][28][29] Over the past six decades, accumulating data from case reports, cases series, non-controlled trials, and RCTs have generally yielded consistent findings regarding the BP-lowering and symptoms-improving effects of ZWD, either used alone or in combination with antihypertensive drugs, for the management of hypertension. [30][31][32] However, no meta-analyses have been conducted to summarise these research studies and many questions about the potential role of ZWD remain unanswered. The purposes of this study are to: (a) evaluate the efficacy of ZWD compared with placebo, no intervention, or antihypertensive drugs; (b) assess the efficacy of ZWD plus antihypertensive drugs (ZPAD) compared with antihypertensive drugs; and (c) estimate the safety of ZWD.

METHODS
This study complied with the Preferred Reporting Items for Systematic Review and Meta-analyses Statement (PRISMA). 33

Study selection
Types of studies All the RCTs reporting the application of ZWD for the treatment of hypertension were involved without limitations on language or publication.

Types of participants
All the participants enrolled in this study had to meet at least one of the current or past diagnostic criteria of hypertension and kidney yang deficiency and fluid retention syndrome. 5 Patients with severe respiratory disease, acute infectious disease, severe heart disease, severe liver disease, or tumour were excluded. If the trials did not elaborate the definitions of hypertension and TCM syndrome but simply stated that the included subjects were hypertensive patients with kidney yang deficiency and fluid retention syndrome, they were also included. No limitations on gender, age, or ethnicity of the participants were set.

Types of interventions
Patients were randomised into either a ZWD group or a control group. RCTs comparing ZWD versus placebo, no intervention, or antihypertensive drugs were included. Trials comparing ZPAD against antihypertensive drugs were also included. The antihypertensive drugs had to be given identically to both groups. If trials included other co-interventions such as another herbal formula, acupuncture, cupping, moxibustion, massage, yoga, qigong, Tai Chi, and aromatherapy, they were excluded. Treatment duration was required to be at least 2 weeks.

Types of outcome measures
The primary outcomes were defined as categorical or continuous BP, and secondary outcomes were TCM symptoms and syndromes. As shown in tables 1 and 2, the efficacy of ZWD on categorical BP and TCM symptoms and syndromes were classified into three grades based on the evaluation criteria from the Guidelines of Clinical Research of New Drugs of Traditional Chinese Medicine (GCRNDTCM). There is no restriction on language or publication status. The search terms for literature searching were: ('hypertension' OR 'high blood pressure' OR 'blood pressure' OR 'gao xue ya' OR 'xue ya') AND ('zhen wu decoction' OR 'zhenwu decoction' OR 'zhen wu tang' OR 'zhenwu tang' OR 'zhenwutang') AND ('clinical trial' OR 'randomized controlled trial' OR 'randomised controlled trial').

Data extraction
The eligible studies were screened by two reviewers independently based on the titles and the abstracts. They were then further assessed for the final analysis. Some important information from primary trials were extracted, including first author's name, country, year of publication, age, gender, number of hypertensive patients, details of interventions for ZWD and control groups, the composition of ZWD or modified ZWD, co-interventions, outcome measures, the duration of treatment, and adverse effects related to ZWD. Disagreements were resolved by discussion between all of the reviewers.

Assessment of risk of bias
Two reviewers independently evaluated the risk of bias of each study using the assessment tool from the Cochrane Handbook. 34 The criteria consisted of the following seven items: (1) sequence generation (selection bias); (2) allocation concealment (selection bias); (3) blinding of participants and personnel ( performance bias); (4) blinding of outcome assessments (detection bias); (5) incomplete outcome data (attrition bias); (6) selective reporting (reporting bias); and (7) other sources of bias (from Chapter 8: assessing risk of bias in included studies).

Data analysis
Studies were combined according to the outcome measure, types of interventions, and controls. Meta-analysis was performed using Review Manager (V.5.2 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). The weighted mean difference (WMD) with 95% CI was used for continuous BP, while the risk ratio (RR) with 95% CI was adopted in categorical BP and TCM symptoms and syndromes. Heterogeneity was assessed by visual inspection of forest plots, p values, and I 2 statistics; p<0.10 and I 2 >50% indicated a substantial level of heterogeneity. Because no significant clinical heterogeneity was identified in this review, a fixed effect model was applied. A value of p<0.05 was considered to be statistically significant. Figure 1 shows the process of study selection and identification. A total of 154 potentially relevant articles were initially screened in the seven electronic databases based on our literature searching strategy. After removing 102 duplicates, 52 articles were identified for further analysis. Through screening the titles and abstracts, 28 articles were excluded because they were literature reviews, expert opinions, commentaries, case reports, case series, non-clinical trials, or animal research. The remaining 24 full-text articles were then assessed for eligibility.  Of them, 17 articles were excluded for the following reasons: participants did not meet the inclusion criteria (n=11), no control group (n=4), and intervention included other medical therapies (n=2). Ultimately, seven studies were assessed to be eligible in our review. [35][36][37][38][39][40][41] Study characteristics The basic characteristics of the seven included randomised trials are summarised in table 3. A total of 472 hypertensive patients were enrolled, with 248 in the treatment group and 224 in the control group. All of these trials were carried out in China and all the participants involved were Chinese. All studies were of small sample size, ranging from 40 to 80 participants. Four diagnostic criteria of hypertension were reported: two trials used the Chinese Guidelines for the Management of Hypertension-2004 (CGMH-2004); 35 41 one trial used the WHO/International Society of Hypertension (ISH) Guidelines for the Management of Hypertension-1999 (WHO/ISH GMH-1999); 36 one trial used the GCRNDTCM; 37 and one trial used the Internal Medicine-2004 (IM-2004). 39 Three trials declared the diagnostic criteria of kidney yang deficiency and fluid retention syndrome by GCRNDTCM. [35][36][37] All the studies used a two-arm design (one treatment group vs one control group). For interventions, patients in the treatment group received either ZWD (n=3) [35][36][37] or ZPAD (n=4). [38][39][40][41] The different compositions of ZWD or modified ZWD are presented in table 4. Patients in the control group received antihypertensive drugs, including extended release nifedipine tablets, captopril, hydrochlorothiazide, valsartan, and amlodipine.

Study identification
The BP outcomes were reported in all of the studies: six trials used categorical BP 35-37 39-41 and one trial used continuous BP. 38 TCM symptoms and syndromes were reported in six trials. 35-37 39-41 The duration of the treatment ranged from 2 weeks to 1 month.

Risk of bias within studies
As shown in figure 2, the risk of bias in all of the included studies was assessed as high. Although randomisation was declared in all the trials, only one trial described the method to generate the allocation sequence (random number table). 38 Because none of the studies reported how they concealed allocation, the risk of bias was assessed as high. Only one trial reported blinding of participants and personnel, 36 and none of the other studies reported whether double-blinding was done so the risk of bias was evaluated as high. All studies had a low risk of bias for incomplete outcome data. The risk of bias of selective outcome reporting and other sources were assessed as unclear because no protocols or other information could be obtained from the primary authors via email, telephone or fax.    figure 3D), with no significant heterogeneity (χ 2 =0.76; p=0.69; I 2 =0%).

Adverse effects
Adverse effects monitoring was not reported in all the included trials.

Summary of evidence
This meta-analysis provides a quantitative synthesis of the clinical efficacy of ZWD for the treatment of hypertension by integrating outcomes from seven clinical

Limitations
This review had the following limitations. Cochrane risk of bias criteria was used to evaluate the methodology of the included trials. 34 Poor methodological design was commonly seen in the clinical trials of CAM. 42 Despite a comprehensive and unbiased literature search of seven electronic databases without language and publication restrictions, no randomised, double-blind, placebocontrolled trials could be identified. In this review, all the trials had flaws in terms of random sequence generation, allocation concealment, double-blinding, and reporting. Therefore, we could not rule out the potential for selection, performance and/or detection bias completely. Additionally, inadequate reporting on dropout or withdrawal, the small sample size, and the limited number of included studies were also identified in this review, which might weaken the strength of the positive conclusions. Similar poor methodological quality of primary studies was also confronted in other systematic reviews and meta-analyses of CHM for hypertension. 12 13 16 19 43-46 It has been one of the major challenges for CAM researchers to establish its place in the evidence-based treatment of hypertension. 28 47-49 Another limitation of this review is the inadequate reporting on BP outcomes. Although the efficacy of ZWD on BP was reported in all the included trials, continuous BP was reported in only one trial 38 and categorical BP was used in the other six trials. Without a detailed BP reduction value, it is impossible to recommend this conclusion for researchers worldwide. Indeed there are some difficulties in evaluating the efficacy of TCM by continuous BP because the application of categorical BP was authoritatively recommended by the China Food and Drug Administration (available at http://www.sda.gov.cn) in GCRNDTCM. However, continuous BP could be reported in further studies simultaneously.
Last but not least, inadequate reporting on adverse effects was identified in this review. CHM is becoming increasingly popular among patients with cardiovascular diseases worldwide, 50-52 but recently concerns have emerged over its safety and potential interaction with conventional western medicine. [53][54][55] As no information about adverse effects could be obtained, it was not possible to carry out a systematic review on these effects. We hope that the adverse effects of ZWD or ZPAD will be monitored and reported in detail in the future.

CONCLUSION
This systematic review revealed no definite conclusion about the application of ZWD for the treatment of hypertension due to the poor methodological quality, high risk of bias, and inadequate reporting on clinical data. More rigorously designed RCTs, especially addressing continuous BP and adverse effects, are warranted.