Effect of Xuezhikang, an Extract From Red Yeast Chinese Rice, on
Coronary Events in a Chinese Population With Previous
Myocardial Infarction
Zongliang Lu, MD, PhDa, Wenrong Kou, MDa, Baomin Du, MDb, Yangfeng Wu, MDc, Shuiping Zhao, MD, PhDd, Osvaldo A. Brusco, MDe, John M. Morgan, MDf, and David M. Capuzzi, MD, PhDf,* on behalf of the Chinese Coronary Secondary Results of well-controlled prospective clinical trials showed the efficacy of lipid-lowering
therapies in the reduction of cardiovascular (CV) events in western populations, but they were
not reported with a Chinese population. This multicenter study was conducted to determine the
effects of Xuezhikang (XZK), a partially purified extract of red yeast rice, on lipoprotein and
CV end points in Chinese patients who experienced a previous myocardial infarction. Nearly
5,000 of these patients with average low-density lipoprotein cholesterol levels at baseline were
randomly assigned either to placebo or to XZK daily for an average of 4.5 years. The primary
end point was a major coronary event that included nonfatal myocardial infarction and death
from coronary heart disease. Frequencies of the primary end point were 10.4% in the placebo
group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and
45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by
30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density
lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels.
In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary
events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and
was 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 therapy the reduction of recurrent cardiovascular (CV) events in a of patients with circulatory disorders in China for centuries.
multicenter study of Chinese patients with average levels of These extracts can decrease plasma lipids in animal models low-density lipoprotein (LDL) cholesterol.
and have been used in several countries, including theUnited States. Lovastatin, the first statin drug approved by Study medication, design, and patients:
regulatory authorities, was extracted from yeast rice. Xu-ezhikang (XZK), produced by the Beijing WBL Peking The study medication consisted of 300-mg capsules of University Biotech Co. Ltd (WPU) (Beijing, Peoples Re- XZK, each containing the combination of lovastatin, also public of China), is a partially purified extract of red yeast termed monoclonin K (2.5 to 3.2 mg/capsule); a small Chinese rice with multiple components. Results of smaller quantity of lovastatin hydroxyl acid; as well as ergosterol clinical trials indicated that red yeast rice preparation can alter plasma lipoproteins The primary aim of The study protocol was approved by the data and safety this study was to evaluate the long-term efficacy of XZK in monitoring 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 carried Fuwai Hospital, Peking Union Medical College, Chinese Academy of out with 4,870 patients (age 18 to 70 years) each with a Medical Science; bWBL Peking University Biotech Co. Ltd, Beijing;cPeking University Health Science Center; dThe Second Xianya Hospital documented previous myocardial infarction (MI) in 65 Chi- of Central South University, Peoples Republic of China; eTexas A&M nese hospitals. During the prior 60 months, all eligible School of Medicine, Corpus Christi, Texas; fLankenau Institute for Med- patients had to have incurred an MI that met appropriate ical Research, Wynnewood, Pennsylvania. Manuscript received June 8, diagnostic criteria, including increased serum creatine ki- 2007; revised manuscript received and accepted February 18, 2008.
nase. Other entry criteria were total cholesterol 170 to 250 Members of the Chinese Coronary Secondary Prevention Study Group mg/dl and triglycerides Յ400 mg/dl. Patients with LDL cholesterol levels Ͼ180 mg/dl at screening could be retested This study was supported by the Chinese National Scientific and after 4 weeks of dietary therapy. Patients who met entry Technological Projects, Peoples Republic of China, and sponsored by WPL criteria at screening underwent a 4-week diet control period Peking University Biotech Co. Ltd (WPU), Beijing, Peoples Republic of during which all lipid-lowering agents were discontinued.
*Corresponding author: Tel: 610-645-8426; Fax: 610-645-2205.
Patients taking other necessary medications unlikely to alter plasma lipoproteins at stable doses for 4 prior weeks were 0002-9149/08/$ – see front matter 2008 Elsevier Inc. All rights reserved.
The American Journal of Cardiology ( Table 1Baseline characteristics of patients in the placebo and Xuezhikang(XZK) groups Figure 1. Kaplan-Meier curves for the proportion of patients without primary events in the XZK and placebo groups.
domization and biannually thereafter. The primary study end point was the occurrence of a major coronary event that consisted of nonfatal MI or death from coronary or cardiac causes. Secondary end points included total CV mortality, total all-cause mortality, need for coronary revasculariza- tion, and change in lipoprotein lipids. Plasma samples were drawn from properly fasted study subjects and obtained at baseline, 6 to 8 weeks after randomization, and at 6-month Statistical analysis: Treatment effects of XZK were an-
alyzed using the prespecified primary end point of majorcoronary events. Based on published about 2,350 Data are expressed as mean Ϯ SD or percent.
HDL ϭ high-density lipoprotein.
intention-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 placebo permitted to continue those medications at the same dos- group after 5 years at p Ͻ0.05 (2 tailed) with a 15% dropout ages. Patients were randomly assigned at a 1:1 ratio into the rate. Data for baseline patient characteristics and efficacy XZK and placebo groups. Lipid levels measured after the and safety were summarized using descriptive statistics and 4-week dietary period were used as baseline.
analyzed using the chi-square test. Numerical data were Patients with any of the following concomitant condi- presented as mean Ϯ SD and 95% confidence interval and tions at the screening visit of significant CV disorders, analyzed using the t test. Clinical end points of the trial were including clinically uncontrolled arrhythmias, cardiac val- calculated based on prespecified definitions. Baseline data vular disease, unstable angina, congestive heart failure, were monitored and processed using Powerbuilder software planned interventions, systolic blood pressure Ͼ180 mm Hg (Synbase, Berkeley, California). Cumulative incidence or diastolic blood pressures Ͼ110 mm Hg, and New York curves were generated using the Kaplan-Meier method for Heart Association class III or worse congestive heart fail- the major end points in both study groups. SPSS 11.5 ure; history of completed stroke; uncontrolled diabetes mel- software (SPSS Institute, Chicago, Illinois) was used for litus with fasting plasma glucose Ͼ200 mg/dl; clinically significant 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 to This trial was carried out from May 1996 to December 2003 study participation; premenopausal women of childbearing in 65 hospitals in China, led by the Cardiovascular Institute potential; or history of alcohol or narcotic substance abuse and Fuwai Hospital at the Chinese Academy of Medical Sciences. Patients (3,986 men, 884 women) were randomly Eligible patients were randomly assigned into 1 of the 2 assigned at a ratio of 1:1 into the XZK (n ϭ 2,429) and groups for twice-daily treatment with XZK 600 mg or placebo (n ϭ 2,441) groups. The study plan was to enroll placebo, administered orally for an average of 4.5 years.
4,700 patients with 2 interim analyses as prespecified and to Clinical visits were set at 6- to 8-week intervals after ran- discontinue the study upon detection of a significant differ- Coronary Artery Disease/Effects of Xuezhikang on Coronary Events Table 2Events according to study group (intention-to-treat population) CI ϭ confidence interval.
* Intention-to-treat population.
† Difference between the placebo and XZK groups.
ence for the primary end point between the drug-treated and patients. A significant (p Ͻ0.01) 4.2% increase in high-density placebo groups. Because the second interim analysis lipoprotein cholesterol was observed in the XZK group, with showed p Ͻ0.05 for the primary end point, the study was no change in the placebo group. No treatment-related serious discontinued in June 2003. Mean duration of treatment was adverse events or deaths were reported during the study period, and XZK appeared to be well tolerated by patients. Total The XZK and placebo treatment groups were well adverse experiences and discontinued participation because of matched at baseline for plasma lipids, concomitant medica- these or all causes were similar in both groups. Mild transient tions, CV risk factors, and other baseline characteristics gastrointestinal side effects were reported similarly in both Mean LDL cholesterol was 129 mg/dl in both groups. Changes in laboratory findings did not differ between groups at baseline, and 98% of patients completed the study.
the 2 treatment groups. Minor occasional and transient in- Patients treated with XZK showed a highly significant (p creases in serum transaminase and creatine kinase were ob- Ͻ0.001) 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 produced Discussion
striking relative and absolute decreases of, respectively,45% and 4.7% in major coronary events compared with Most large clinical trials with statin therapy examined the placebo. These improved outcomes in XZK-treated patients impact of about a 25% to 40% fall in LDL cholesterol on increased progressively during the course of the trial the occurrence of CV events and mortality. This relation Treatment with XZK during a 4-year period appeared to appears to be greater in patients with rather high levels of have prevented 47 major (17 fatal, 30 nonfatal) coronary LDL cholesterol. The first placebo-controlled multicenter events. Moreover, the XZK-treated group experienced trial with a statin showed a significant decrease in both highly significant relative decreases of 62% in the occur- all-cause mortality and CV events in simvastatin-treated rence of nonfatal MI and 32% in fatal coronary events patients with increased serum However, be- These patients also experienced a highly signif- cause patients with coronary atherosclerosis commonly icant decrease of about 1⁄3 in both CV and total mortality compared with those treated with placebo. Patients treated more information is needed to develop strategies to iden- with XZK also experienced a 1⁄3 decrease in the need for tify and treat these patients effectively.
coronary revascularization, which was 2.8% compared with This trial was designed to test the efficacy and safety of 4.2% in placebo-treated patients. No significant differences XZK in a Chinese patient population with previous MI and were observed for other measures, except for deaths caused average levels of LDL cholesterol to test the impact of this by cancer 29 patients experienced cancer-related therapy on recurrent coronary events. Results showed that death in the placebo group compared with 13 in the XZK- treatment of this study population with XZK produced pro- found changes in both lipoprotein lipids and the number of XZK produced significant decreases in levels of total and recurrent coronary events. The decrease in these events found LDL cholesterol and triglycerides and increases in high-den- in the present study appear to exceed those reported with statin sity lipoprotein cholesterol compared with placebo monotherapy in a similar trial of western patients enrolled in These differences were significant (p Ͻ0.05) by 6 to 8 weeks the Cholesterol and Recurrent and other statin tri- after randomization, and were maintained over the study du- ration. Treatment with XZK also produced a significant (p However, comparisons of results, treatments, and out- Ͻ0.001) decline in plasma total cholesterol of 13% from base- comes in this and other studies require very cautious inter- line compared with only a 2% decrease in the placebo group.
pretation. Although the 2 populations differed in several LDL cholesterol was diminished significantly by 20% in the respects, the potentially greater impact of XZK in Chinese XZK-treated group compared with 3.5% in placebo-treated patients reported in this trial should not be interpreted to The American Journal of Cardiology ( stem solely from the baseline characteristics of the popula-tion tested. The greater effect of XZK may be caused at least in part by the potential properties of its nonstatin compo-nents. XZK has several ingredients, of which the lovastatincomponent, although quantitatively predominant, is un-likely to account solely for the favorable plasma lipid- lowering and the rather striking CV benefit found. Thus, itis likely that components other than lovastatin in XZK, such as lovastatin hydroxy acid, plant sterols, isoflavones, and isoflavone glycosides, also likely contributed to However, this issue requires additional study. It is important to acknowledge that the various components of XZK prep-arations have not as yet been adequately isolated, analyzed,and characterized for their consistency, stability, and indi- vidual pharmacologic and other properties and, therefore, In conclusion, this study showed that long-term treatment with XZK significantly decreased the recurrence of coronary events and total mortality in Chinese patients with average levels of LDL cholesterol. Moreover, treatment with XZK significantly improved plasma lipoprotein lipids and was safeand well tolerated by these study participants. However, future use of this product will depend on the separation, identification,characterization, and development of a carefully formulated preparation of red yeast rice. Additional studies of its proper- ties and therapeutic potential are necessary.
Investigators: Fuwai Hospital (Y.S. Xu, D.F. Gu, X. Jia, Z.
Chen, J.L. Sun, J. Chen); Peking University Shougang Hos- pital (X.H. Yu, J.H. Wang, N. Wang, R.P. Zheng, S.H.
Zhang); Heilongjiang Yichun Forrest Industry Central Hos- pital (C.X. Liu, L.H. Sun, Y.C. Zhao, Y. Lin, J.B. Huang); Capital Medical University Beijing Chaoyang Hospital(D.Y. Hu, X.C. Yang, Y.Z. Liu, M.M. Gao, P. Zhang); Liaoning People’s Hospital (C.X. Deng, Y. Liu, Z.Q. Li, Y.Q. Shi, T.S. Hu); Chongqing Medical University First Hospital (Y.Z. Chen, S. Tan, W.R. Zhao, G.L. Deng, W.J.
Huang); Hebei Baoding Second Hospital (J.C. Zhang, H.
Yu, Q.S. Shi, X.Z. Wang, B. Jiang); Shangdong University Qilu Hospital (X.R. Pan, L. Li, P.L. Pu, M.Q. Shu, Q.L.
Xu); Peking University First Hospital (J.H. Zhang, W.H.
Ding, L. Li, J.J. Yang, J.L. Su); Anshan Steel Company Tiedong Hospital (W.D. Zhao, X. Liu, L.J. Li, J.F. Yang, Q.S. Wang); Institut of Cardiology, Tianjing Medical Uni- versity Second Hospital (T.G. Huang, L.F. Li, L.J. Zhou); Peking University Third Hospital (J.X. Guo, W.H. Li, Z.P.
Li); Beijing Fangshan First Hospital (X.G. Zhang, X.M.
Peng, Y.W. An); Xi’an Jiaotong University First Hospital (J. Shu, L.T. Ma, H. Ge, M.J. Zhang, Z.R. Lv); Beijing Haidian Hospital (J.H. Li, J.W. Yang, L. Zhang); Jiangsu People’s Hospital (Y.L. Cheng, J.G. Chen, C.W. Zhou, H.H. Zhang); Harbing Medical University First Hospital (Y.L. Huang, X.F. Qu, J.J. Li, H. Guo); Shangdong Dezhou Hospital (G.X. Wang, S.Z. Hao, S.J. Li, H.S. Chang); Bei- jing Military Area General Hospital (S.M. Zhou, H.Q. Li- ang, S.J. Cao, J.G. Liu); Shanxi Hanzhong People’s Hospi- tal (J. Yang, M.Y. Zhao, Y. Lv, S.L. Xu); Central South University Xiangya Second Hospital (Z.L. Wang, S.P.
Zhao, X.P. Li, X.L. Luo); Beijing Jiangong Hospital (Y.P.
Coronary Artery Disease/Effects of Xuezhikang on Coronary Events Li, Y. Lei); Liaoyang Central Hospital (S.Q. Fan, L.H.
Data collection group: Y.F. Wu, X.G. Wu, J.L. Wang.
Wang, L.J. Zhao, Y.C. Zhao); Beijing Chuiyangliu Hospital(S.W. Xue, J. Li, S.Y. Xu, Y.G. Cao); Fudan University Clinical quality control: Z.L. Lu, W.R. Kou, B.M. Du,
Zhongshan Hospital (B.G. Tong, W. Wang, S.K. Xu); Shanxi University First Hospital (H.Z. Chen, W.L. Guo,L.J. Wang, X.M. Yan); Peking Union Medical Collage Monitoring offices: National Center for Cardiovascular
Hospital (X.F. Jing, C.H. Wang, B.X. Tang, H. Bai); Qing- hai Medical Collage Hospital (L. Li, Y. Liu, Y.P. Li, F.
Mei); Shandong Liaocheng Second People’s Hospital (K.Z.
Writing committee: Z.L. Lu, S.P. Zhao, Y.F. Wu, B.M.
Yuan, Y. Zhang, Y.R. Sun, L. Chen); Shanxi Cardiovascu- Du, S. Li, J.M. Morgan, D.M. Capuzzi.
lar Hospital (S.R. Xue, J.P. Wang, B. Li, Z.M. Liu); CapitalMedical University Beijing Friendship Hospital (L.H. Shen, Associate laboratory and quality control for serum lipid
J.R. Liang, Y. Zhang, Y.L. Song); Tianjing Medical Uni- measurement: Ministry of Health Institute of Gerontology.
versity General Hospital (Y.M. Sun, Z. Wang, Y.H Xu.,W.J. Zhang); Shandong Dezhou People’s Hospital (R.Q.
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(Zusammenfassung der Merkmale des Arzneimittels) 1. BEZEICHNUNG DES ARZNEIMITTELS Ixel 25 mg - Kapseln 2. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG Jede Hartkapsel enthält 25 mg Milnacipran-Hydrochlorid, entsprechend 21,77 mg Milnacipran freie Base. Die vollständige Auflistung der sonstigen Bestandteile siehe Abschnitt 6.1. 3. DARREICHUNGSFORM Hartkapsel Rosa Oberteil und Unterteil, mit Auf

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