A Systematic Review of Xuezhikang, an Extract from Red Yeast Rice, for Coronary Heart Disease Complicated by Dyslipidemia

Objective. This systematic review aims to evaluate the benefit and side effect of Xuezhikang for coronary heart disease (CHD) complicated by dyslipidemia. Methods. All randomized clinical trials (RCTs) with Xuezhikang as a treatment for CHD combined with dyslipidemia were considered for inclusion. Data extraction and analyses and quality assessment were conducted according to the Cochrane standards. Results. We included 22 randomized trials. Xuezhikang showed significant benefit on the incidence of all-cause deaths, CHD deaths, myocardial infarction, and revascularization as compared with placebo based on conventional treatment for CHD. It remarkably lowered total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) as compared with the placebo or inositol nicotinate group, which was similar to statins group. Xuezhikang also raised high-density lipoprotein cholesterol (HDL-C) compared to placebo or no intervention, which was similar to Inositol nicotinate and slightly inferior to statins. The incidence of adverse events did not differ between the Xuezhikang and control group. Conclusions. Xuezhikang showed a comprehensive lipid-regulating effect and was safe and effective in reducing cardiovascular events in CHD patients complicated by dyslipidemia. However, more rigorous trials with high quality are needed to give high level of evidence.


Introduction
Coronary heart disease (CHD) is one of the most serious diseases with high incidence and mortality. Dyslipidemia contributes greatly to the formation and progression of atherosclerosis (AS), which plays a dominant role in leading to CHD. Patients with CHD are also commonly complicated with dyslipidemia. Modulating dyslipidemia actively, especially lowering low-density lipoprotein-cholesterol (LDL-C) by statins, has been demonstrated to be very crucial to prevent AS and reduce the morbidity and mortality of CHD. Most recently, the updated ESC/EAS guidelines for management of dyslipidemia [1] further highlighted the aggressive lipid-lowering strategy in subjects with documented coronary vascular disease (CVD) or previous myocardial infarction (MI). However, the application of statins might be restricted by the adverse effect on the liver function and creatine kinase, especially in patients with old age, multiple comorbid diseases, high-dose statins, or a combination lipidlowering therapy. Thus it is of great clinical significance to find an effective but safer alternative therapy in CHD patients complicated by dyslipidemia.
Xuezhikang is a partially purified extract of fermented red yeast rice (Monascus purpureus). It is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace element, and so forth. The health enhancing qualities of this yeast have been introduced and used in China for over two thousand years. At latest systematic review indicated the beneficial effects of Xuezhikang in the treatment of hyperlipidemia [2]. Therefore, Xuezhikang has been recommended in a guideline for China adult dyslipidemia prevention [3]. Recently, clinical benefits of Xuezhikang were also found in CHD patients combined with dyslipidemia in some randomized controlled trials [4][5][6]. This systematic review aims to evaluate the benefit and side effect of Xuezhikang, a potential 2 Evidence-Based Complementary and Alternative Medicine Table 1: Definition of dyslipidemia or treatment goal of patients with CHD or equivalents on serum lipid level.

Inclusion Criteria. Randomized controlled trials (RCTs)
comparing Xuezhikang with placebo, no intervention, or established lipid-lowing agents in English or Chinese were considered. Quasirandomized trials were excluded, and the duration of the intervention was no less than four weeks. Participants of all age with CHD complicated by dyslipidemia meeting with at least one of the current or past definitions or guidelines of CHD [including acute coronary syndrome (ACS)] [7][8][9][10][11][12][13] and dyslipidemia (treatment goal as the lower limit, see Table 1) [14][15][16][17][18][19][20] were considered. Those who did not introduce diagnostic criteria in the text but stated patients with definite CHD or dyslipidemia were also included. Secondary dyslipidemia, high serum lipid level after meal, serious heart failure, and serious hepatic or renal failure were excluded. Outcome measures include primary outcomes (including all-cause mortality, CHD mortality, incidence of MI, revascularization, and rehospitalization for unstable angina) and secondary outcomes [including serum total cholesterol (TC), triglyceride (TG), LDL-C, and-high density lipoprotein cholesterol (HDL-C)].

Search Strategy.
Two reviewers searched the following databases up to September 2011 independently for the identifications of trials (publication or nonpublication): The Cochrane Library, Pubmed, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese VIP Information (VIP), and Wanfang Databases. We used the terms as follows: coronary heart disease, CHD, coronary artery disease, angina pectoris, myocardial infarction, acute coronary syndrome, cardi * , and Xuezhikang, red yeast rice, monascus. Because of different characteristics of various databases, MeSH terms and free text terms were used regardless of the report types in full text, title, keyword, subject terms, or abstract.

Data Extraction and Quality Assessment.
Two reviewers (Shang QH, Liu ZL) independently extracted data according to a data extraction form made by the authors. Disagreements were resolved by consensus or consultation from a third reviewer (Liu JP). The methodological quality of trials was assessed independently using criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.0.1 (Shang QH, Liu ZL) [20]. We contacted with the authors if there was any doubt in randomization and blinding method. The items included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. We judged each item from three levels ("Yes" for a low of bias, "No" for a high risk of bias, "Unclear" otherwise), and then we assessed the trials and categorized them into three levels: low risk of bias (all the items were in low risk of bias), high risk of bias (at least • Number of the two groups was not clear (n = 1) • The participants did not meet the inclusive criteria (n = 112) one item was in high risk of bias), unclear risk of bias (at least one item was in unclear).

Description of Included Trials. 22 RCTs (23 papers)
6520 Participants were included (3264 in intervention group and 3256 in control group). Two of the trials did not report the gender, and 4905 male and 1538 female were included in the other 20 trials. A total of 7 criteria of CHD (including ACS) were selected, but 6 trials did not introduce criteria of CHD but mentioned "patients with CHD were eligible to include." 3 criteria of dyslipidemia were used for 11 trials, and the other 11 trials only reported the serum lipid levels, which were categorized to dyslipidemia according to the previous and current definitions and guidelines Table 1. One trial [4] included patients with MI; five of the trials [5,27,28,34,39] included patients with unstable angina; two of the trials [6,38] included patients with ACS; three of the trials [21,22,31] included patients with stable angina. The other 11 trials [23-26, 29, 30, 32, 33, 35-37] did not introduce the types of CHD or all types were included.
Patients in 19 trials prescribed Xuezhikang 600 mg QD (regulation was conducted for adverse events), one trial used Xuezhikang 600 mg TID if the serum TC or TG still higher 4 Evidence-Based Complementary and Alternative Medicine after having been prescribed for 6 weeks (600 mg BID in previous 6 weeks) [30], one trial [37] prescribed Xuezhikang 300 mg TID, and one trial [31] prescribed Xuezhikang 1200 mg QN. The duration of treatment ranged from 4 weeks to 7 years.

Methodological Quality of Included Trials.
According to the criteria introduced above, no trial was evaluated as having a low risk of bias. Only one trial of the 22 trials reported the method to generate the allocation sequence (random number table) in the paper [6]. After we contacted with the authors, six trials announced a correct method for allocation sequence [4-6, 31, 33, 35]. One trial was assessed as having adequate concealment [35]. Two trials applied doubleblinding [4,35], and two trials used single-blinding but did give us objective to be blinded [25,37]. One trial blinded the outcome assessors [4]. One trial reported prior sample size estimation and mentioned intention-to-treat analysis [4]. Five trials reported information on withdrawal/dropout [4,6,22,29,32]. 18 trials [4-6, 22-27, 29, 31-33, 35-39] provided baseline data for the comparability among groups. The results of the assessment of risk of bias are presented in a "risk of bias summary" figure produced by Revman 5.1 automatically Figure 2. (Tables 3 and 4) 3.3.1. All-Cause Mortality. There was only 1 trial [4] reported the all-cause mortality in the comparisons of Xuezhikang and conventional therapy versus placebo and conventional therapy [RR 0.67; 95% CI 0.54 to 0.83; 1 trial, n = 4870].

Incidence of MI.
There were 3 studies reporting CHD events in 3 different comparisons. Compared with placebo on the basis of conventional therapy, Xuezhikang showed a reduction of morbidity of MI (RR 0.39; 95% CI 0.28 to 0.55; 1 trial, n = 4870) [4]. Compared with simvastatin on the basis of conventional therapy, Xuezhikang showed no significant difference (RR 0.95; 95% CI 0.30 to 3.05; 1 trial, n = 84) [28]. In comparisons of Xuezhikang and simvastatin and conventional therapy versus simvastatin and conventional therapy, Xuezhikang showed no effect in reducing incidence of MI (RR 0.20; 95% CI 0.01 to 3.96; 1 trial, n = 48) [27].

Serum TC Level.
There were 21 studies that reported the level of total cholesterol  [21, 23-25, 28, 31, 37, 39]. Since there was significant heterogeneity in the comparison, we examined the data carefully and found that data of two trials deviated from the others. After looking over the papers, one of the two trial [26] with an unclear conventional therapy and the other used Xuezhikang 300 mg tid in the whole trial [37]. Sensitive analysis was used and got a similar conclusion (MD 0.02 mmol/L; 95% CI −0.03 to 0.06; 6 trial, n = 489) after excluded the two trials [26,37].

Serum TG Level.
There were 20 studies that reported the level of TG (see Table 4), but one trial only reported the serum lipid level of the treatment group [30]. (1)

Serum LDL-C Level.
There were 21 studies that reported the level of LDL-C (see Table 4), but one trial only reported the serum lipid level of the treatment group [30].  [21, 23-25, 28, 31, 37, 39]. Because there was significant heterogeneity in the comparison, we examined the data carefully and found that data of two trials deviated from the others. After looking over the papers, one of the two trials [26] with an unclear conventional therapy and the other used Xuezhikang 300 mg tid in the whole trial [37].    (1))

Serum HDL-C Level.
There were 19 studies that reported the level of HDL-C (see Table 4), but one trial only reported the serum lipid level of the treatment group [30].
(3) There was a lower effect on serum HDL-C level of Xuezhikang comparing to statins on the basis of conventional therapy (MD −0.10 mmol/L; 95% CI −0.19 to −0.01; 8 trial, n = 633) [21, 23-25, 28, 31, 37, 39]. Because there was significant heterogeneity in the comparison, we examined the data carefully and found that data of one trials deviated from the others. After looking over the papers, we found that the trial used Xuezhikang 300 mg tid [37]. Sensitive analysis was used and got a similar conclusion (MD −0.10 mmol/L; 95% CI −0.11 to −0.08; 7 trial, n = 553) after excluded the trial [37]. (4) Compared with no treatment on the basis of

Publication Bias.
A funnel plot analysis of the 8 trials in comparison of Xuezhikang and conventional therapy versus conventional therapy on serum TC level was conducted and shown in Figure 3.

Adverse Events.
There were 17 trials that reported adverse events (Ads); see Table 5. 4 of the 17 trials [5,24,33,37] indicated no Ads in the duration of treatment, and 2 trials [23,34] only introduced that there was no difference of the two groups. The most commonly reported Ads in the 10 trials were intestinal disturbance (abdominal distension, constipation, and diarrhea), dizziness, high serum alanine aminotransferase (ALT), high serum creatine kinase (CK), high serum creatinine, high blood urea nitrogen (BUN), and skin itch. All of Ads were not significantly different between the Xuezhikang group and control group. One trial [4] reported that there was significant difference between the two groups on sexual dysfunction (P = 0.0253) in the paper, but after we import the data into Revman 5.  39), and there was no significant difference between the two groups, this trial also reported death in other reason, which was introduced in allcause mortality, and the difference between the two groups was not significant.

Discussion
This systematic review included 22 randomized trials and a total of 6520 participants. Xuezhikang showed significant benefit on the incidence of all-cause deaths, CHD deaths, myocardial infarction, and revascularization as compared with placebo or no intervention based on conventional treatment for CHD. It remarkably lowered TC, TG, and LDL-C as compared with the placebo or inositol nicotinate group, which was similar to statins group. Xuezhikang also significantly raised HDL-C compared to placebo or no intervention, which was similar to inositol nicotinate and slightly inferior to statins. The incidence of adverse events did not differ between the Xuezhikang and control group. The results showed the comprehensive lipid-regulating effect of Xuezhikang and indicated that it was safe and effective in reducing cardiovascular events in CHD patients complicated by dyslipidemia.