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Effect of Xuezhikang, an Extract From Red Yeast Chinese Rice, onCoronary Events in a Chinese Population With PreviousMyocardial Infarction
Zongliang Lu, MD, PhD
a
, Wenrong Kou, MD
a
, Baomin Du, MD
b
, Yangfeng Wu, MD
c
,Shuiping Zhao, MD, PhD
d
, Osvaldo A. Brusco, MD
e
, John M. Morgan, MD
f
, andDavid M. Capuzzi, MD, PhD
f,
* on behalf of the Chinese Coronary SecondaryPrevention Study Group
Results of well-controlled prospective clinical trials showed the efficacy of lipid-loweringtherapies in the reduction of cardiovascular (CV) events in western populations, but they werenot reported with a Chinese population. This multicenter study was conducted to determine theeffects of Xuezhikang (XZK), a partially purified extract of red yeast rice, on lipoprotein andCV end points in Chinese patients who experienced a previous myocardial infarction. Nearly5,000 of these patients with average low-density lipoprotein cholesterol levels at baseline wererandomly assigned either to placebo or to XZK daily for an average of 4.5 years. The primaryend point was a major coronary event that included nonfatal myocardial infarction and deathfrom coronary heart disease. Frequencies of the primary end point were 10.4% in the placebogroup and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-densitylipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels.In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronaryevents and the occurrence of new CV events and deaths, improved lipoprotein regulation, andwas safe and well tolerated. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:1689 –1693)
Extracts of red yeast rice have been widely used for therapyof patients with circulatory disorders in China for centuries.These extracts can decrease plasma lipids in animal modelsand have been used in several countries, including theUnited States. Lovastatin, the first statin drug approved byregulatory authorities, was extracted from yeast rice. Xu-ezhikang (XZK), produced by the Beijing WBL PekingUniversity Biotech Co. Ltd (WPU) (Beijing, Peoples Re-public of China), is a partially purified extract of red yeastChinese rice with multiple components. Results of smallerclinical trials indicated that red yeast rice preparation canalter plasma lipoproteins effectively.
The primary aim of this study was to evaluate the long-term efficacy of XZK inthe reduction of recurrent cardiovascular (CV) events in amulticenter study of Chinese patients with average levels of low-density lipoprotein (LDL) cholesterol.
Study medication, design, and patients:
The study medication consisted of 300-mg capsules of XZK, each containing the combination of lovastatin, alsotermed monoclonin K (2.5 to 3.2 mg/capsule); a smallquantity of lovastatin hydroxyl acid; as well as ergosteroland some other components.The study protocol was approved by the data and safetymonitoring and regional ethics committees of each studysite, and informed consent forms were signed by all enrolledpatients before study initiation. This randomized, double-blind, placebo-controlled, parallel-group study was carriedout with 4,870 patients (age 18 to 70 years) each with adocumented previous myocardial infarction (MI) in 65 Chi-nese hospitals. During the prior 60 months, all eligiblepatients had to have incurred an MI that met appropriatediagnostic criteria, including increased serum creatine ki-nase. Other entry criteria were total cholesterol 170 to 250mg/dl and triglycerides
400 mg/dl. Patients with LDLcholesterol levels
180 mg/dl at screening could be retestedafter 4 weeks of dietary therapy. Patients who met entrycriteria at screening underwent a 4-week diet control periodduring which all lipid-lowering agents were discontinued.Patients taking other necessary medications unlikely to alterplasma lipoproteins at stable doses for 4 prior weeks were
a
Fuwai Hospital, Peking Union Medical College, Chinese Academy of Medical Science;
b
WBL Peking University Biotech Co. Ltd, Beijing;
c
Peking University Health Science Center;
d
The Second Xianya Hospitalof Central South University, Peoples Republic of China;
e
Texas A&MSchool of Medicine, Corpus Christi, Texas;
f
Lankenau Institute for Med-ical Research, Wynnewood, Pennsylvania. Manuscript received June 8,2007; revised manuscript received and accepted February 18, 2008.Members of the Chinese Coronary Secondary Prevention Study Groupare listed in the Appendix.This study was supported by the Chinese National Scientific andTechnological Projects, Peoples Republic of China, and sponsored by WPLPeking University Biotech Co. Ltd (WPU), Beijing, Peoples Republic of China.*Corresponding author: Tel: 610-645-8426; Fax: 610-645-2205.
E-mail address:
capuzzid@mlhs.org (D.M. Capuzzi).0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. www.AJConline.orgdoi:10.1016/j.amjcard.2008.02.056
permitted to continue those medications at the same dos-ages. Patients were randomly assigned at a 1:1 ratio into theXZK and placebo groups. Lipid levels measured after the4-week dietary period were used as baseline.Patients with any of the following concomitant condi-tions at the screening visit of significant CV disorders,including clinically uncontrolled arrhythmias, cardiac val-vular disease, unstable angina, congestive heart failure,planned interventions, systolic blood pressure
180 mm Hgor diastolic blood pressures
110 mm Hg, and New York Heart Association class III or worse congestive heart fail-ure; history of completed stroke; uncontrolled diabetes mel-litus with fasting plasma glucose
200 mg/dl; clinicallysignificant renal or hepatic diseases; active malignancy,excluding nonmelanoma skin cancer; any other uncon-trolled clinical condition that may alter plasma lipids or beconsidered to pose an undue risk or contraindication tostudy participation; premenopausal women of childbearingpotential; or history of alcohol or narcotic substance abusewere excluded from this study.Eligible patients were randomly assigned into 1 of the 2groups for twice-daily treatment with XZK 600 mg orplacebo, administered orally for an average of 4.5 years.Clinical visits were set at 6- to 8-week intervals after ran-domization and biannually thereafter. The primary studyend point was the occurrence of a major coronary event thatconsisted of nonfatal MI or death from coronary or cardiaccauses. Secondary end points included total CV mortality,total all-cause mortality, need for coronary revasculariza-tion, and change in lipoprotein lipids. Plasma samples weredrawn from properly fasted study subjects and obtained atbaseline, 6 to 8 weeks after randomization, and at 6-monthintervals.
Statistical analysis:
Treatment effects of XZK were an-alyzed using the prespecified primary endpoint of majorcoronary events. Based on published data,
about 2,350intention-to-treat patients per group was sufficient to have90% power to detect a mean 20% decrease in coronaryevents in the treatment group compared with the placebogroup after 5 years at p
0.05 (2 tailed) with a 15% dropoutrate. Data for baseline patient characteristics and efficacyand safety were summarized using descriptive statistics andanalyzed using the chi-square test. Numerical data werepresented as mean
SD and 95% confidence interval andanalyzed using the
t
test. Clinical end points of the trial werecalculated based on prespecified definitions. Baseline datawere monitored and processed using Powerbuilder software(Synbase, Berkeley, California). Cumulative incidencecurves were generated using the Kaplan-Meier method forthe major end points in both study groups. SPSS 11.5software (SPSS Institute, Chicago, Illinois) was used forstatistical analysis.
Results
This trial was carried out from May 1996 to December 2003in 65 hospitals in China, led by the Cardiovascular Instituteand Fuwai Hospital at the Chinese Academy of MedicalSciences. Patients (3,986 men, 884 women) were randomlyassigned at a ratio of 1:1 into the XZK (n
2,429) andplacebo (n
2,441) groups. The study plan was to enroll4,700 patients with 2 interim analyses as prespecified and todiscontinue the study upon detection of a significant differ-
Figure 1. Kaplan-Meier curves for the proportion of patients withoutprimary events in the XZK and placebo groups.Table 1Baseline characteristics of patients in the placebo and Xuezhikang(XZK) groupsVariable Placebo (n
2,441) XZK (n
2,429)Age (yrs)Men 58.0
9.7 58.1
9.9Women 62.6
7.4 62.9
6.7Men 82% 82%Women 18% 18%Body mass index(kg/m
2
)24.7
2.8 24.8
2.9Blood pressure(mm Hg)Systolic 129
18 129
17Diastolic 80
10 80
10CV risk factorsSmoking 35% 34%Hypertension 55% 56%Diabetes 12% 13%Medication useAspirin 95% 95%
Blocker 55% 57%Calcium channelblocker37% 36%Converting-enzymeinhibitor50% 49%Nitrate 92% 91%Plasma lipid levelsmmol/l (mg/ dl)Total cholesterol 5.38
0.83 (208
25) 5.35
0.67 (207
26)LDL cholesterol 3.34
0.78 (129
29) 3.34
0.65 (129
28)HDL cholesterol 1.19
0.36 (46
15) 1.19
0.39 (46
15)Triglycerides 1.85
0.83 (164
74) 1.85
0.86 (164
77)Data are expressed as mean
SD or percent.HDL
high-density lipoprotein.1690
The American Journal of Cardiology (www.AJConline.org)
ence for the primary end point between the drug-treated andplacebo groups. Because the second interim analysisshowed p
0.05 for the primary end point, the study wasdiscontinued in June 2003. Mean duration of treatment was4.5 years.The XZK and placebo treatment groups were wellmatched at baseline for plasma lipids, concomitant medica-tions, CVrisk factors, and other baseline characteristics(Table 1). Mean LDL cholesterol was 129 mg/dl in both
groups at baseline, and 98% of patients completed the study.Patients treated with XZK showed a highly significant (p
0.001) decrease in frequency of major coronary events,with 10.4% in the placebo group compared with 5.7% in theXZK-treated group. Thus, treatment with XZK producedstriking relative and absolute decreases of, respectively,45% and 4.7% in major coronary events compared withplacebo. These improved outcomes in XZK-treated patientsincreased progressively during the course of the trial (Figure1). Treatment with XZK during a 4-year period appeared tohave prevented 47 major (17 fatal, 30 nonfatal) coronaryevents. Moreover, the XZK-treated group experiencedhighly significant relative decreases of 62% in the occur-rence of nonfatal MI and 32% in fatal coronary events(Table 2). These patients also experienced a highly signif-
icant decrease of about
1
⁄
3
in both CV and total mortalitycompared with those treated with placebo. Patients treatedwith XZK also experienced a
1
⁄
3
decrease in the need forcoronary revascularization, which was 2.8% compared with4.2% in placebo-treated patients. No significant differenceswere observed for other measures, except for deaths causedby cancer (Table 2); 29 patients experienced cancer-related
death in the placebo group compared with 13 in the XZK-treated group.XZK produced significant decreases in levels of total andLDL cholesterol and triglycerides and increases inhigh-den-sity lipoprotein cholesterol compared with placebo (Table 3).
These differences were significant (p
0.05) by 6 to 8 weeksafter randomization, and were maintained over the study du-ration. Treatment with XZK also produced a significant (p
0.001) decline in plasma total cholesterol of 13% from base-line compared with only a 2% decrease in the placebo group.LDL cholesterol was diminished significantly by 20% in theXZK-treated group compared with 3.5% in placebo-treatedpatients. A significant (p
0.01) 4.2% increase in high-densitylipoprotein cholesterol was observed in the XZK group, withno change in the placebo group. No treatment-related seriousadverseeventsordeathswerereportedduringthestudyperiod,and XZK appeared to be well tolerated by patients. Totaladverse experiences and discontinued participation because of these or all causes were similar in both groups. Mild transientgastrointestinal side effects were reported similarly in bothgroups. Changes in laboratory findings did not differ betweenthe 2 treatment groups. Minor occasional and transient in-creases in serum transaminase and creatine kinase were ob-served in both groups.
Discussion
Most large clinical trials with statin therapy examined theimpact of about a 25% to 40% fall in LDL cholesterol onthe occurrence of CV events and mortality. This relationappears to be greater in patients with rather high levels of LDL cholesterol. The first placebo-controlled multicentertrial with a statin showed a significant decrease in bothall-cause mortality and CV events in simvastatin-treatedpatients with increased serum cholesterol.
However, be-cause patients with coronary atherosclerosis commonlyhave rather modest increases in LDL cholesterol,
more information is needed to develop strategies to iden-tify and treat these patients effectively.This trial was designed to test the efficacy and safety of XZK in a Chinese patient population with previous MI andaverage levels of LDL cholesterol to test the impact of thistherapy on recurrent coronary events. Results showed thattreatment of this study population with XZK produced pro-found changes in both lipoprotein lipids and the number of recurrent coronary events. The decrease in these events foundin the present study appear to exceed those reported with statinmonotherapy in a similar trial of western patients enrolled intheCholesterol and Recurrent Events
and other statin tri-als.
However, comparisons of results, treatments, and out-comes in this and other studies require very cautious inter-pretation. Although the 2 populations differed in severalrespects, the potentially greater impact of XZK in Chinesepatients reported in this trial should not be interpreted to
Table 2Events according to study group (intention-to-treat population)Events Placebo XZK DifferencePlacebo-XZK (%)Risk *ReductionWith XZK(95% CI)p Value
†
No. of Patients Incidence (%) No. of Patients Incidence (%)Nonfatal MI 120 4.9% 47 1.9% 3% 0.38 (0.27
0.54)
0.0001Coronary disease mortality 134 5.5% 92 3.8% 1.7% 0.69 (0.52
0.88) 0.005Fatal MI 28 1.2% 19 0.8% 0.4% 0.67 (0.38
1.20) 0.19Fatal stroke 13 0.5% 12 0.5% 0.04% 0.91 (0.42
1.99) 0.85Coronary revascularization 103 4.2% 67 2.8% 1.4% 0.64 (0.47
0.86) 0.004CV mortality 149 6.1% 105 4.3% 1.8% 0.70 (0.54
0.89) 0.005Cancer mortality 29 1.2% 13 0.5% 0.7% 0.44 (0.23
0.84) 0.014Total mortality 189 7.7% 126 5.2% 2.5% 0.67 (0.52
0.82) 0.0003CI
confidence interval.* Intention-to-treat population.
†
Difference between the placebo and XZK groups.1691
Coronary Artery Disease/Effects of Xuezhikang on Coronary Events
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