Efficacy and Safety of Chinese Medicinal Herbs for the Treatment of Hyperuricemia: A Systematic Review and Meta-Analysis

Background. Chinese medicinal herbs may be useful for the treatment of hyperuricemia, but there has been no systematic assessment of their efficacy and safety. Objectives. To systematically assess the efficacy and safety of Chinese medicinal herbs for the treatment of hyperuricemia. Methods. Six electronic databases were searched from their inception to December 2015. Randomized controlled clinical trials (RCTs) were included. Cochrane criteria were applied to assess the risk of bias. Data analysis was performed using RevMan software version 5.2. Results. Eleven RCTs with 838 patients were included. There was no significant difference in serum uric acid between Chinese medicinal herbs and traditional Western medicine (SME: 0.19, 95% CI: −0.04 to 0.43; p = 0.10). In terms of overall efficacy, the Chinese medicinal herbs were significantly superior to Western medicine (RR: 1.11; 95% CI: 1.04 to 1.17; p = 0.0007). The Chinese medicinal herbs were better than Western medicine in reducing the adverse reactions (RR: 0.30; 95% CI: 0.15 to 0.62; p = 0.001). And all these funnel plots showed unlikelihood of publishing bias. Conclusions. The results indicate that Chinese medicinal herbs may have greater overall efficacy with fewer adverse drug reactions, although the evidence is weak owing to the low methodological quality and the small number of the included trials.


Introduction
Hyperuricemia (HUE) is a metabolic disease caused by a purine metabolic disturbance that leads to excessive production of uric acid, which is the pathogenic basis for gout. It has been reported that 18.8% of patients with HUE developed gout during a 5-year follow-up period [1]. Studies also show that, in addition to its association with gout, HUE is a strong risk factor for atherosclerosis [2], hypertension [3], and metabolic syndrome [4], which may include obesity, hyperlipidemia, and diabetes mellitus [5].
Rapid economic development in China has led to changes in the daily diet, specifically, an increased rate of high-purine diets, thereby increasing the prevalence of HUE. According to a meta-analysis conducted in 2011, the prevalence of HUE in China was 21.6% among men and 8.6% among women [6], while, in 2010, in the United States, it was 12.7% overall [7]. The many potential complications of HUE may lead to greatly increased healthcare costs. Therefore, it is extremely important to understand HUE not only in China but also around the world.
Because both excess production and decreased excretion of uric acid contribute to HUE, two types of hypouricemic drugs are commonly used for the treatment. Uricosuric drugs (i.e., probenecid and benzbromarone) that reduce the serum uric acid concentration (SUA) by increasing the renal excretion of uric acid and xanthine oxidase inhibitors (i.e., allopurinol) that decrease serum uric acid by inhibiting uric acid synthesis have been the mainstays of conventional HUE treatment [8]. Although these treatments have very good results as hypouricemic agents, they may be associated with gastrointestinal reactions, liver and kidney damage, and other adverse effects [9,10], and, in rare cases, allopurinol has been associated with reactive hepatitis and fulminant 2 Evidence-Based Complementary and Alternative Medicine hepatic failure [11]. Therefore, long-term treatment may not be advisable.
In traditional Chinese medicine (TCM), HUE belongs to the arthromyodynia disease category. Chinese medicinal herbs are administered orally as a liquid formulation prepared by chopping or crushing herbs into a thick powder, immersing the powder in water, boiling, and filtering [12], which has long been used for the treatment of HUE in China and has been associated with positive and unique clinical effects.
In the past decade, many studies have compared Chinese medicinal herbs with traditional Western medicine in the treatment of HUE. However, the treatment protocols and evaluation methodologies of these studies are different [24], which greatly limit their clinical applicability [25]. Therefore, a systematic review to evaluate the efficacy and safety of Chinese medicinal herbs in the treatment of HUE would be of great importance, and, to our knowledge, no such systematic review has been undertaken. We therefore designed this systematic review to investigate the efficacy and safety of Chinese medicinal herbs in the treatment of HUE.

Eligibility Criteria.
Randomized controlled clinical trials (RCTs) in humans were included in this review. According to our study design, the included studies should focus on the effect of the Chinese medicinal herbs (single or compound) in comparison with Western medicine only. Outcome measures should include at least one essential outcome, such as SUA and overall efficacy.

Patients.
In accordance with published diagnostic criteria, HUE [26] is diagnosed on the basis of SUA levels of up to 416 mol/L in men or 357 mol/L in women, with all other serum and uric influencing factors excluded. All patients included in the study had confirmed diagnoses of HUE. Pregnant women and patients with cancer or blood diseases were excluded.

Databases and Search Strategy.
Original research articles were searched from 6 electronic databases from their inception to December 2015: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Database (VIP), the China National Knowledge Information Database (CNKI), and Wanfang. The journal languages were restricted to Chinese and English.
We used the following search strategy: ("hyperuricemia") AND ("traditional Chinese medicine" OR "Chinese medicine", "traditional" OR "zhong yi xue" OR "Chinese Traditional Medicine" OR "Traditional Medicine", "Chinese" OR "Drugs", "Chinese Herbal" OR "herbal medicine" OR "Chinese medicine practice") AND ("control" OR "comparison" OR "controlled trial") in the English databases and ("hyperuricemia" AND "Chinese Herbal" AND "comparison") in the Chinese databases.

Endpoint Indicators.
Enumeration data of the efficacy were graded into 4 categories according to the standards of the Guiding Principles for the Clinical Research of New TCM [27]: cure, SUA decreased to normal level; markedly effective, the rate of decrease of SUA was equal to or more than 30%; effective, the rate of decrease of SUA was 5% to 30%; and ineffective, the rate of decrease of SUA was less than 5%. The rate of decrease of SUA is equal to (SUA before intervention minus SUA after intervention) divided by SUA before intervention ⋅ 100%. Enumeration data for effective treatment were counted in each group based on the categories of cured, markedly effective, and effective. Measurement data included SUA as a primary indicator.

Study Identification.
Three investigators participated in the data extraction from all publications included in the study. Data including the first author, publication year, total number of cases included in the experimental and control groups, intervention methods, and endpoint evaluation indicators were recorded. Two reviewers (LJP and CSQ) independently screened the title and abstract of the searched studies. Full text of the studies that potentially met the eligibility criteria were obtained, and the potentially relevant references were retrieved according to predefined eligibility criteria. One investigator (LJP) performed the initial data extraction, and a second investigator (CSQ) subsequently reexamined each article and verified the results. Differences were resolved by discussion with the third investigator (SYX) in order to reach consensus. And the original author was contacted if the results could not come to an agreement.

Quality
Assessment. The quality of the included studies was assessed independently by two reviewers (LZP and LSZ) using the Cochrane Collaboration tool for assessing the risk of bias [28]. When there were inconsistencies, a third reviewer (CSQ) participated in the assessment and consensus was reached by discussion. The Cochrane-recommended domains that were considered were selection bias, which is a measure of adequate sequence generation and allocation concealment; performance bias, which evaluates blinding of participants and personnel; detection bias, which checks for blinding of outcome assessment; attrition bias, which checks for incomplete outcome data; reporting bias, which indicates selective outcome reporting; and other bias, which covers other sources of bias including baseline imbalance and fraudulent outcomes. Each of these indicators was scored as low risk of bias, high risk of bias, or unclear [29].

Data Analysis.
We calculated the index and the standard error (SE ) values of SUA for each RCT before using RevMan. The index and SE values of SUA were continuous, and the standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. Enumeration data (overall efficacy and adverse reactions) were evaluated by relative risk (RR) and 95% CI. Statistical heterogeneity was assessed using a Chi-square test or by calculating Higgins 2 values [29]. The proper effect models were chosen in accordance with the results: when 2 is less than 50%, fixed effects models were chosen, and when 2 is more than 50%, a random effects model was applied [30]. Sensitivity analysis was used to explore the source of heterogeneity. The Full-text articles for more detailed evaluation, n = 35 Eligible articles with usable information fulfilling all inclusion criteria, n = 11 Studies included in quantitative synthesis (meta-analysis), n = 11 94 records were excluded because of duplication, according to title, author names, and year 260 articles were excluded by reading their abstract: animal experiments, n = 80; compliance with other complications, n = 57; narrative reviews, n = 45; irrelevant intervention, n = 78 Duplicate publication = 3; incomplete statistical results, n = 10; lack of diagnosis criteria, n = 6; unqualified control intervention, n = 5

Description of Studies.
The study selection flowchart is presented in Figure 1. A total of 389 records were identified through the database searches. After removing duplicates, 295 studies remained for eligibility screening; 284 of them were ultimately excluded, including 80 that were based on animal experiments, 57 that complied with other complications, 45 that were narrative reviews, 78 that considered irrelevant interventions, 3 that were duplicate publications, 10 that had incomplete statistical results, 6 that did not meet the diagnostic criteria, and 5 that had unqualified control interventions. Thus, 11 articles met the inclusion criteria, and 11 were included in the meta-analysis [13][14][15][16][17][18][19][20][21][22][23].

Overall Efficacy of the Chinese Medicinal Herbs. Nine
RCTs were analyzed, including 654 patients (340 in the experimental groups and 314 in the control groups) ( . For all studies, the meta-analysis indicated that 2 = 43%, and a fixed effects model was adopted for the analysis. The combined RR was 1.11, and the 95% CI was 1.04 to 1.17 ( = 0.0007), indicating a significant difference between the overall efficacy of Chinese medicinal herbs and Western pharmaceuticals for the treatment of HUE (Figure 3(a)). The funnel plot showed 9 symmetric distributions of 9 experiments, indicating unlikelihood of publishing bias (Figure 3(b)).  groups) provided safety evaluation data [15-18, 21, 22]. Subgroup meta-analysis showed statistical significance in the allopurinol subgroups (RR: 0.31 and 95% CI: 0.15 to 0.65; = 0.002). The meta-analysis showed that 2 for all 6 studies was 29%, and the analysis was performed using a fixed effects model. The combined RR value was 0.30 and the 95% CI was 0.15 to 0.62 ( = 0.001), indicating that, among the studies included, there were fewer adverse      reactions in patients using Chinese medicinal herbs (Figure 4(a)). The funnel plot showed 6 symmetric distributions of 6 experiments, indicating unlikelihood of publishing bias (Figure 4(b)).

Methodological
Quality. Among 11 included RCTs, 8 reported no significant differences at baseline between patients in the Chinese medicinal herbs groups and those in the Western medicine groups. Only 3 trials described a randomization technique (random sequence generation using a random number table), while 8 did not describe the randomization technique and 10 failed to describe concealed random allocation. Although only 1 trial had a double-blind design, the outcome measurements of other 9 trials relied on objective indicators that were not expected to be influenced by lack of blinding ( Figure 5).

Sensitivity Analysis.
The results of sensitivity analysis were relatively stable through performance from a fixed effects model to a random effects model (Figures 2-4).

Discussion
This systematic review included 11 RCTs with 838 total patients comparing Chinese medicinal herbs with Western medicine for the treatment of HUE. The outcome measures included change in SUA values, overall efficacy, and adverse reactions. Our analysis showed that Chinese medicinal herbs and traditional Western medicine had a similar effect for reducing SUA values, but, in terms of overall treatment efficacy and adverse reactions, there were significant advantages for the Chinese medicinal herbs.
The above results showed that it could not just observe SUA values, but overall treatment efficacy should be considered in order to systematically assess the efficacy and safety of Chinese medicinal herbs for the treatment of hyperuricemia. The enumeration data of the efficacy were graded into 4 categories according to the standards of the Guiding Principles for the Clinical Research of New TCM, which were advantageous to the standardization of TCM research. However, it needs more argumentation and research to get internationally recognized [31]. Therefore, no definitive conclusion can be drawn that Chinese medicinal herbs have greater overall efficacy than Western medicine. And additional studies will be needed in the future.
The results indicate that Chinese medicinal herbs have a positive therapeutic effect with fewer adverse drug reactions. We believe that the main reason for the efficacy of Chinese medicinal herbs in the treatment of HUE relates to the active ingredients of these extracts [32]. The bulbs of pseudobulb cremastra seu pleiones, which is an ingredient of decoctions used by Li [17], Zhang et al. [23], and others, contain colchicine [33]. In addition, the Chinese medicinal herbs used by Zhou [13], Yu [15], Tan et al. [16], and Li [17] contain glabrous greenbrier rhizome (Table 1), which has astilbin as an active ingredient. Astilbin has been associated with increased renal blood flow and has shown anti-inflammatory and analgesic actions. Plantago contains the active ingredient aucubin [34], which Chen [14], Tan et al. [16], Li [17], and     Zhang et al. [23] believe has a significant effect toward facilitating urine production and promoting the excretion of urea and chloride [35]. Moreover, other herbs have been used, such as seven-lobed yam rhizome [36], jobstears seed [37], and radix achyranthis bidentatae [38], all of which enhancing additional functions including promotion of uric acid excretion, reduction of platelet accumulation resulting in improved microcirculation, and anticoagulant function. The actions of these ingredients contribute to reductions in SUA and amelioration of potential side effects during treatment.
Traditional Western medicines such as allopurinol, probenecid, and benzbromarone have been cornerstones in the treatment of HUE and gout for decades [39]. Allopurinol is an analogue of hypoxanthine, which inhibits xanthine oxidase. In most patients, it is well tolerated. However, about 2% of patients will develop a skin rash, and allopurinol has been associated with rare life-threatening hypersensitivity syndromes at a rate of approximately 4/1000 cases [40][41][42]. Probenecid and benzbromarone, the uricosuric drugs, may lead to renal tubular aggregation of urate crystals and induce renal damage. Finally, in 2003, benzbromarone was withdrawn from the market because of serious hepatotoxicity. Although it is still marketed in several countries by other drug companies, withdrawal by the French manufacturer Sanofi-Synthélabo has greatly limited its availability around the world [43]. As per physicians practicing TCM, HUE is a condition that is caused by a congenital deficiency and a circulatory blockade. Blood stasis in combination with phlegm and exogenous pathogenic factors blocks the meridians and collaterals or even goes deep to the bone, transforms to heat, and finally causes renal damage [44]. Thus, Chinese herbal prescriptions usually contain several herbal components for dissipating blood stasis and reinforcing the kidneys, and these herbal components work synergistically [45]. For example, Tan et al. [16] and others add radix achyranthis bidentatae and Salvia miltiorrhiza Bge. to the prescription, which serves to inhibit platelet aggregation, expand small arteries, improve microcirculation, inhibit atherosclerotic lesions, ameliorate renal fibrosis, and protect the kidneys [37,46]. These benefits may be among the reasons that the active ingredients in Chinese medicinal herbs are able to effectively reduce the potentially adverse effects.
Most evaluations of Chinese medicinal herbs that reduce SUA have focused on the active ingredients of individual herbs. However, Chinese medicinal herbs are usually compounded in a liquid decoction. Because Chinese herbal formulations may contain several herbal components, the active ingredients of each should be considered [47]. Furthermore, many of the available reports concerned animal experiments, and large-scale clinical trials in humans were lacking. Therefore, additional studies in humans should be a goal in the future.
The present systematic review has limitations, mainly because of the low methodological quality and small number of the included trials. Indeed, most of the included RCTs were of poor quality. Of 11 trials, only 3 described a randomization method, only 1 had a double-blind design, and none described the calculation of the sample size. Moreover, no multicenter large-scale RCT met our inclusion criteria. The low quality of the research included in this review may lead to some overestimation of the overall efficacy of Chinese medicinal herbs in comparison to traditional Western medicines ( Figure 5). Furthermore, only 6 of the 11 RCTs described adverse reactions. Owing to insufficient descriptions, enumeration data for adverse reactions included only renal and hepatic dysfunction, skin reaction, gastrointestinal reaction, and acute arthritis. Therefore, a more rational approach for the evaluation of adverse drug reactions from Chinese medicinal herbs with the development of large-scale and welldesigned RCTs will be needed in the future.

Conclusion
The results of this review indicate that Chinese medicinal herbs have a positive therapeutic effect in the treatment of HUE and can safely reduce SUA while ameliorating adverse effects. Because of the low methodological quality and the small number of the included trials, no definitive conclusion can be drawn at this point, and these results should be interpreted cautiously. Additional large-scale, well-designed trials are needed.