Xuefuzhuyu decoction for hyperlipidemia: a systematic ... fileJTCM| August15,2014|Volume34|Issue4| LiaoJQetal./SystematicReview (LDL-C), is an independent risk factor for atherosclero-sis.

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JTCM |www. journaltcm. com August 15, 2014 |Volume 34 | Issue 4 |August 15, 2014 |Volume 34 | Issue 4 |

Online Submissions: http://www.journaltcm.com J Tradit Chin Med 2014 August 15; 34(4): [email protected] ISSN 0255-2922

© 2014 JTCM. All rights reserved.

SYSTEMATIC REVIEW

Xuefuzhuyu decoction for hyperlipidemia: a systematic review andMeta-analysis of randomized clinical trails

Jiangquan Liao, Jiaxing Tian, Tengfei Li, Weijiang Song, Weihan Zhao, Jinhang Duaa

Jiangquan Liao, Jiaxing Tian, Weijiang Song, WeihanZhao, Graduate School, Beijing University of Chinese Medi-cine, Beijing 100029, ChinaTengfei Li, Department of Cardiovascular, Beijing Hospitalof Traditional Chinese Medicine, Beijing 100010, ChinaJiangquan Liao, Jinhang Du, Cardiovascular IntegrativeMedicine Department, China-Japan Friendship Hospital, Bei-jing 100029, ChinaSupported by National Natural Science Foundation of Chi-na (the Inflammatory Mechanism of Renal Damage in Hy-perlipidemia Rat After Myocardial Ischemia and the Inteven-tion of Activating Blood and Dissolving Stasis. No. 81072924)Correspondence to: Prof. Jinhang Du, Cardiovascular Inte-grative Medicine Department, China-Japan Friendship Hos-pital, Beijing 100029, China. [email protected]: +86-18810383273Accepted: August 27, 2013

AbstractOBJECTIVE: To evaluate the efficacy and safety ofXuefuzhuyu decoction for hyperlipidemia.

METHODS: Randomized clinical trials on hyperlip-idemia treated by Xuefuzhuyu decoction, eitheralone or with Western Medicine, were searched inelectronic databases. Databases searched were:MEDLINE, Allied and Complementary Medicine Da-tabase, EMBASE, The Cochrane Library 2013 (Issue4), China National Knowledge Infrastructure Data-base, Chinese Biomedical Literature Database, andWanfang Database up to 2 May, 2013. Study selec-tion, data extraction, quality assessment, and dataanalysis were conducted according to the Co-chrane standards.

RESULTS: Six randomized clinical trials involving

748 patients (373 patients in the treatment group,375 patients in the control group) were included inthe analysis. The studies were of low methodologi-cal quality. Meta-analysis indicated that the effectof Xuefuzhuyu decoction on hyperlipidemia wasbetter than that in the control group [n=748, OR=5.07, 95% CI (3.40, 7.58), P<0.01]. Weighted meandifferences in total cholesterol, low-density lipopro-tein cholesterol, triglycerides, and high-density li-poprotein cholesterol were ﹣0.79, ﹣0.74, ﹣0.44,0.16, respectively, and Meta-analysis revealed thatthe treatment group was better than the controlgroup with 95% CI (﹣1.21, ﹣0.36), (﹣0.94, ﹣0.55),( ﹣ 0.77, ﹣ 0.11), (0.04, 0.27), respectively (all P<0.05). Some adverse events in evaluated studieswere recorded.

CONCLUSION: Xuefuzhuyu decoction may be ef-fective for treating hyperlipidemia. The studies weanalyzed were of low methodological quality,which indicates that the above findings should beconsidered cautiously. Therefore, more strictly de-signed large-scale randomized clinical trials areneeded to evaluate the efficacy of Xuefuzhuyu de-coction in hyperlipidemia.

© 2014 JTCM. All rights reserved.

Key words: Hyperlipidemias; Medicine, Chinese tra-ditional; Treatment outcome; Meta-analysis; Re-view; Xuefuzhuyu decoction

INTRODUCTIONHyperlipidemia, including elevated serum total choles-terol (TC) and low-density lipoprotein cholesterol

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Liao JQ et al. / Systematic Review

(LDL-C), is an independent risk factor for atherosclero-sis. It can lead to coronary heart disease and ischemicstroke.1,2 The first phase of National Health and Nutri-tion Examination Survey (NHANES Ⅲ) (1988-1991)indicated that 49% of adult Americans have a TC≥5.2 mmol/L (200 mg/dL).3 An update of NHANES Ⅲfrom 1999-2000 reported that adult Americansage-standardized TC is 5.27 mmol/L (203 mg/dL).4

Therefore, prevention and treatment of hyperlipidemiais very important. Common lipid-lowering drugs usedin clinic at present include Hydroxy methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins),phenoxy aromatic acids (fibrates), nicotinic acid and itsderivatives, and other types of lipid-lowering drugs. Allof the main lipid-lowering drugs, such as statins and fi-brates, have certain side effects. Moreover, the combi-nation of statins and fibrates has a high risk of side ef-fects such as muscle damage and liver damage.More than 2000 plants are used in traditional herbalor alternative medical systems and some may providerelief to patients with cardiovascular diseases, especiallythose with hyperlipidemia and ischemic heart disease.In China, Japan, and other areas in Asia, the usage ofherbs is based on Traditional Chinese Medicine(TCM) theory. Syndrome and disease differentiationare important to TCM. Therefore, hyperlipidemia inTCM is considered a blood stasis syndrome. Hyperlip-idemia including hemodynamic changes and arterialplaque caused by hyperlipidemia, should be treated byactivating blood and dissolving stasis.5 Xuefuzhuyu de-coction, which originated in the Qing Dynasty, is con-sidered one of the most effective decoctions for activat-ing blood and dissolving stasis related to the cardiovas-cular and cerebrovascular systems. The clinical use ofXuefuzhuyu decoction may improve blood circulation,and relieve the symptoms of angina or other cardiovas-cular diseases.6 Some studies indicate that Xuefuzhuyudecoction is effective on hyperlipidemia. Therefore, asystematic review of clinical trials related to Xuefu-zhuyu decoction and hyperlipidemia are reported inthis study.

MATERIALS AND METHODS

Inclusion criteria for studiesRandomized controlled trials (RCTs) or quasi-RCTs,either in English or Chinese, regardless of journal, allo-cation concealment, or blinding method, were includ-ed in our analysis.

Inclusion and exclusion criteria for participantsPatients with hyperlipidemia were included regardlessof their age, sex, or race if the diagnosis of hyperlipid-emia was made by "Screening and management of lip-ids"7 or any other reasonable criteria. Patients with dia-betes, hypothyroidism, nephrotic syndrome, liver andgallbladder disease that could lead to secondary hyper-

lipidemia were excluded. Those with severe heart, liver,or kidney disease, or severe infection were also exclud-ed.

Primary and secondary outcomesThe primary outcome was lipid-lowering efficacy. Sec-ondary outcomes were TC, LDL-C, triglyceride (TG),and high-density lipoprotein cholesterol (HDL-C) lev-els.

Outcome measurementEfficacy evaluation criteria were determined accordingto "Chinese Adult dyslipidemia Prevention Guide"8

and other guidelines. "Effective" was considered TCdecreased >10% , TG decreased >20% , or one of thelipid indexes was restored to normal after intervention."Invalid" was considered TC decreased <10%, TG de-creased <20% , or none of the lipid indexes were re-stored to normal after intervention. "Worsened" wasconsidered when TC or TG increased >10%, or otherlipid indexes exceeded normal after intervention.

Literature searchThe following electronic databases were searched sincethe beginning of the database to 2 May, 2013: MedicalLiterature Analysis and Retrieval System Online, Alliedand Complementary Medicine Database, ExcerptaMedica Database, The Cochrane Library 2013 (Issue4), and three Chinese Databases: China NationalKnowledge Infrastructure Database, Chinese Biomedi-cal Literature Database, and Wanfang Database. Thesearch terms used were "Xuefuzhuyu", "lipid", "hyper-lipidemia", "dyslipidemia", "hypercholesterolemia",and "hypertriglyceridemia". Various combinations ofthe search terms were used depending on the database.The type of publication was clinical study. Two review-ers (Weijiang Song and Weihan Zhao) worked inde-pendently for inclusion of studies. Any disagreementswere resolved through discussion.

Data extraction and quality assessmentArticles were identified and selected independently bytwo reviewers (Jiaxing Tian, Beijing University of Chi-nese Medicine, and Tengfei Li, Beijing Hospital of Tra-ditional Chinese Medicine, both of them had beentrained in Beijing University of Chinese Medicine foridentifying and selecting the articles) according to theestablished inclusion criteria. The methodological qual-ity was assessed via the Cochrane Collaboration's riskof bias criteria:9 (a) whether the random method is cor-rect; (b) whether allocation concealment is used; (c)whether the blind method is used; and (d) whether lostcases are described and intent-to-treat analysis is used.If all the above quality standards were "adequate," itwas unlikely that there would be any biases. However,if one criterion was "not clear," there was a moderateprobability of corresponding bias. If one criterion was"inadequate" or "not used," there was a high probabili-

412



ty of corresponding bias. Discrepancies were resolvedby consensus through discussion between the two re-viewers and, if needed, by asking for further evaluationfrom the other two reviewers (Jiangquan Liao, BeijingUniversity of Chinese Medicine, and Jinhang Du, Chi-na-Japan Friendship Hospital).10

Statistical analysisThe mean changes in TC, LDL-C, TG, and HDL-Ccompared with baseline were calculated in the Xuefu-zhuyu decoction and control arms. These changes wereused to assess the differences between the interventionand control groups. The odd risk (OR) of data was cal-culated if the variables were dichotomous data. Theweighted mean difference (WMD) was calculated if thevariables were continuous data. A 95% confidence in-terval (CI) was also calculated from the data using theCochrane Collaboration's software.11

RESULTS

Study descriptionA total of 105 articles were identified. After screeningthe titles and abstracts,26 potentially relevant studieswere found. After detailed evaluation of the full text,20

some articles were excluded. Most articles were exclud-ed because hyperlipidemia was only a complication, orlipids were not the main evaluating indexes. One arti-cle was excluded because it claimed that it was a RCT,but was actually a cohort study using healthy peoplewithout intervention as the control group. One articlewas excluded because it only reported differences be-tween the treatment and control groups after treat-ment. Eventually, six articles met our inclusion criteria

(Figure 1). All studies were RCTs from China. Three14,16,17

of the included trials used Xuefuzhuyu decoction plussimvastatin as the treatment group and simvastatin asthe control group. Two studies12,13 used Xuefuzhuyu de-coction alone as treatment and inositol nicotinate tab-lets as the control group. One trial15 used Xuefuzhuyudecoction alone as the treatment group and Xuezhi-kang capsule (a Chinese patent medicine extractedfrom red yeast rice which can reduce lipids) as the con-trol group. Detailed data of all the included researchare summarized in Table 1.

Quality assessmentAll studies mentioned randomization but none de-scribed detailed randomization methods. Five showedno significant differences in baseline. None mentionedallocation concealment, blinding methods, or inten-tion-to-treat. Therefore, all six studies had high proba-bilities of selection bias, performance bias, or measure-ment bias (Table 2).

Efficacy evaluationAll six studies12-17 compared efficacy between the treat-ment group and the control group after intervention.The treatment group scored significantly higher thanthe control group [n=748, OR=5.07, 95% CI (3.40,7.58), P<0.01]. Three14,16,17 of the studies used Xuefu-zhuyu decoction plus unspecified lipid-lowering drugsas the treatment group while three12,13,15 used Xuefu-zhuyu decoction alone as treatment. All of the sub-groups showed that the treatment group was more ef-fective than the control group [n=401, OR=5.49, 95%CI (3.02, 9.98), P<0.01 and n=347, OR=4.74, 95%CI (2.76, 8.14), P<0.01]. The efficacy evaluation intwo studies12,13 is different from other studies. "Effec-tive" should be classified until one or more lipid index-es reached normal.12,13 Compared with other includedstudies, this might lead to false "invalid" findings. Thetotal outcome did not interfere with the results after ex-cluding the two studes12,13 because the treatment groupstill scored higher than the control group [n=579, OR=5.48, 95% CI (3.43, 8.75), P<0.01] (Figure 2).In the subgroup Xuefuzhuyu decoction plus lipid-low-ering drugs, Xuefuzhuyu decoction was combined withconventional lipid-lowering drugs in the treatmentgroup compared with only conventional lipid-loweringdrugs in the control group. In the subgroup Xuefu-zhuyu decoction alone, Xuefuzhuyu decoction wasused alone in the treatment group compared with con-ventional lipid-lowering drugs in the control group.

Index evaluationFour studies14-17 compared the effect of lowering TC be-tween the treatment and control groups. The treat-ment group was significantly more effective than thecontrol group [n=439, WMD=﹣0.79, 95% CI (﹣1.21,﹣ 0.36)]. Both of the subgroups, Xuefuzhuyu decoc-tion plus lipid-lowering drugs and Xuefuzhuyu decoc-Figure 1 Flow chart of trial selection process

Initially identified publications (n=105)

Publications excluded through screeningthe title and abstract (n=76)·Not relevant to hyperlipidemia (n=28)·Not clinical trial (n=48)

Articles further evaluated by full text (n=26)

Excluded publications after reading thefull text (n=20)·Hyperlipidemia is only a complicationor lipids is not the main evaluating index(n=15)·Lack of detailed data (n=1)·Case reports or cohort study (n=4)

Researches included in the systematic review (n=6)

413



tion alone, showed effectiveness in lowering TC [n=275, WMD=﹣0.85, 95% CI (﹣1.35, ﹣0.34) and n=164, WMD=﹣0.57, 95% CI (﹣0.98, ﹣0.16)]. Thedifferences exist in the test for subgroups differences(P<0.05 but P>0.01). In these four studies, only one14

did not apply syndrome differentiation on the includ-ed patients to adjust the usage of herbal medicines.However, the patients were regarded as having bloodstasis because the inclusion criteria included blood sta-sis. Additionally, the usage of Xuefuzhuyu decoction inone14 study was based on syndrome differentiation.Both the Xuefuzhuyu decoction plus lipid-loweringdrugs and the Xuefuzhuyu decoction alone were moreeffective than the control groups for lowering TC (Fig-ure 3).Only two studies14,16 recorded a comparison of LDL-Cbetween the treatment group and the control group af-ter intervention. The treatment group was significantlymore effective than the control group in loweringLDL-C [n=158, WMD= ﹣ 0.74, 95% CI ( ﹣ 0.94,﹣0.55)]. Both of the studies used Xuefuzhuyu decoc-tion plus simvastatin as treatment group and simvas-tatin alone as control group. One16 study used syn-drome differentiation and added certain herbal medi-cines based on the differentiation. One other study14 alsoused differentiation. However, one14 was not as effectiveas the other16 (WMD=﹣0.57, 95% CI (﹣1.09, ﹣0.05)]vs [WMD=﹣0.77, 95% CI (﹣0.98, ﹣0.56)], and statis-tically the heterogeneity was low (P>0.05). This indi-cates that the confidence of the data integration wasvalid, and Xuefuzhuyu decoction plus simvastatin ismore effective than simvastatin alone in loweringLDL-C (Figure 4).Four studies14-17 compared the effect of lowering TG be-tween the treatment group and the control group. Thetreatment group was significantly more effective than thecontrol group in lowering TG [n=439, WMD=﹣0.40,95% CI (﹣ 0.59, ﹣ 0.20)]. In the subgroup Xuefu-zhuyu decoction plus lipid-lowering drugs as treat-ment, one14 study did not show a significant differencein lowering TG between the treatment and controlgroups. However, meta-analysis showed that Xuefu-zhuyu decoction plus lipid-lowering drugs was more ef-fective than lipid-lowering drugs in lowering TG (het-erogeneity: P>0.05). All three studies14,16,17 in the sub-group Xuefuzhuyu decoction plus lipid-lowering drugsused simvastatin as the conventional lipid-loweringdrug. Simvastatin usually lowers TC and LDL-C. Us-ing TG-lowering drugs like fenofibrate could enhancethe investigation of Xuefuzhuyu decoction for TG-low-ering effectiveness. However, hyperlipidemia is alwaysa combination of varying degrees of hypercholesterol-emia and hypertriglyceridemia, and the combinationof statins and fibrates could increase the chances side ef-fects. Therefore, the lowering of TG after combinationof Xuefuzhuyu decoction and simvastatin indicatesthat Xuefuzhuyu decoction could be an adjuvant or re-placement therapy for hyperlipidemia.Ta

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414



The subgroup that used Xuefuzhuyu decoction aloneas treatment group, used Xuezhikang capsule as a con-trol group. Xuezhikang capsule is a Chinese patentmedicine mainly extracted from red yeast rice. Clinicaltrials and experimental research has shown that Xuezhi-kang capsule has certain lipid-lowering effects.18,19 Onestudy15 used syndrome differentiation, and showed thatXuefuzhuyu decoction alone was more effective thanXuezhikang capsule at lowering TG [n=164, WMD=﹣0.88, 95% CI (﹣1.51, ﹣0.25)]. This indicates theimportance of syndrome differentiation (Figure 5).Four studies14-17 compared the effect on increasingHDL-C between the treatment group and the controlgroup. The treatment group was more effective thanthe control group in significantly increasing HDL-C[n=439, WMD=0.16, 95% CI (0.04, 0.27)]. Three-

studies14,16,17 used Xuefuzhuyu decoction plus lipid-low-ering drugs as a treatment group, while one15 used Xue-fuzhuyu decoction alone as a treatment group. The for-mer subgroup showed that there was no statistical dif-ference between the treatment group and the controlgroup [n=275, WMD=0.15, 95% CI (﹣0.04, 0.34)].However, there was tendency for Xuefuzhuyu decoc-tion plus lipid-lowering drugs to exceed lipid-loweringdrugs in increasing HDL-C. After data integration ofboth subgroups, the difference is statistically significant(Figure 6).

SecurityTwo14,16of all studies listed safety reports. Both studiesused Xuefuzhuyu decoction plus lipid-lowering drugsin the treatment group. In the treatment group, four

Study

Hong B et al200012

Tian YF200113

Lei WN200614

Wang XY200915

Zeng XG201116

Qiu J 201217

Randomsequencegeneration

NMT

NMT

NMT

NMT

NMT

NMT

Allocationconcealment

NMT

NMT

NMT

NMT

NMT

NMT

Blinding ofparticipants, personneland outcome assessors

NMT

NMT

NMT

NMT

NMT

NMT

Incompleteoutcome data

NMT

NMT

NMT

NMT

Mentioned

NMT

Selectivereport bias

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Othersources of

bias

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Grade ofrisk of bias

Ca

Ca

Ca

Ca

Ca

Ca

Table 2 Quality assessment of evaluated studies

Notes: NMT: not mentioned. aHigh probability of occurrence of the corresponding bias.

Figure 2 Meta-analysis of efficacy

415

JTCM |www. journaltcm. com August 15, 2014 |Volume 34 | Issue 4 |


out of 79 patients who received Xuefuzhuyu decoctionplus simvastatin had gastrointestinal discomfort, onehad fatigue, and one had headache and dizziness. Inthe control group, 79 patients received simvastatin,and 15 had gastrointestinal discomfort, 12 had head-ache and dizziness, and one had fatigue.

Follow-upNone of these RCTs included follow-up.

DISCUSSIONBased on the results, Xuefuzhuyu decoction may beable to treat hyperlipidemia with no significant side ef-fects. However, all of the studies in this review had lowmethodology quality and the sample sizes were small.These studies lacked the details of randomization, allo-cation concealment, and blinding methods, which leadto inability to judge whether the study was conductedproperly. There were no multi-center or large-scale ran-

Figure 5 Meta-analysis of TGTG: triglyceride. Xuefuzhuyu decoction group vs control group, it shown significant effect in lowering TG.

Figure 3 Meta-analysis of TCTC: total cholesterol. Both the test for overall and subgroups indicated that treatment group was better than control group.

Figure 4 Meta-analysis of LDL-CLDL-C: low-density lipoprotein cholesterol.

416



domized clinical trials about Xuefuzhuyu decoction intreating hyperlipidemia. Therefore, the use of Xuefu-zhuyu decoction for hyperlipidemia is not adequate.According to this systematic review, Xuefuzhuyu decoc-tion could enhance the effectiveness of lipid-loweringdrugs. Moreover, Xuefuzhuyu decoction showed effec-tiveness in lowering TG, which provides more flexiblechoices in treatment protocols for hyperlipidemia. Theapplication of syndrome differentiation based on TCMtheory is very important in the usage of Chinese herbalmedicines. According to this systematic review, Xuefu-zhuyu decoction could be used in hyperlipidemia pa-tients with different syndromes based on the guidanceof accurate differentiation. The methodological qualityof these clinical trials for Xuefuzhuyu decoction shouldbe improved. Evaluating the efficacy of Xuefuzhuyu de-coction on hyperlipidemia requires more strictly de-signed large-scale randomized clinical trials.

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Figure 6 Meta-analysis of HDL-CHDL-C: high-density lipoprotein cholesterol. Xuefuzhuyu decoction group vs control group. After data integration of both sub-groups, the difference is statistically significant.

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Xuefuzhuyu decoction for hyperlipidemia: a systematic ... fileJTCM| August15,2014|Volume34|Issue4| LiaoJQetal./SystematicReview (LDL-C), is an independent risk factor for atherosclero-sis.

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