Journal of Traditional Chinese Medical Sciences (2015) 2, 71e79

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Traditional Chinese medicine for activatingblood circulation and detoxifying in unstableangina pectoris: A systematic review andmeta-analysis

Ying Zhang a,b,c, Hua Qu a,b,c, Xiaojuan Ma b,c,**, Dazhuo Shi b,c,*

a Graduate School, Beijing University of Chinese Medicine, Beijing 100029, Chinab China Heart Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing100091, Chinac Cardiovascular Diseases Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing100091, China

Received 11 December 2014; accepted 16 February 2015Available online 16 March 2016

KEYWORDSMeta-analysis;Traditional Chinesemedicine;Angina pectoris;Activating bloodcirculation;Detoxifying

Abbreviations: ABCD, activating bloodreduction of angina symptoms; ECG,syndrome; MI, myocardial infarction;Knowledge Infrastructure; VIP, ChinesFAA, frequency of angina attacks; DAAcholesterol; TG, triglyceride; HDL-C, hnecrosis factor alpha; CRP, C-reactive* Corresponding author. China Heart** Corresponding author. China Heart

E-mail addresses: abc_mxj@aliyunPeer review under responsibility o

http://dx.doi.org/10.1016/j.jtcms.202095-7548/ª 2015 Beijing University oCC BY-NC-ND license (http://creative

Abstract Objective: The purpose of this review was to evaluate the effectiveness of tradi-tional Chinese medicine for activating blood circulation and detoxifying (ABCD) in patientswith unstable angina pectoris.Methods: We performed an electronic literature search of six medical databases for relevantarticles published up to December 2014. Randomized controlled trials that compared ABCDChinese medicine (alone or alongside conventional drugs) with conventional drugs or other Chi-nese medicines alone were included. A meta-analysis was performed for the followingoutcome measures: reduction of angina symptoms, electrocardiogram improvement, bloodlipid levels, inflammatory factor levels, and plasma fibrinogen levels.Results: In total, 11 moderate- to low-quality studies involving 686 patients were included.The evidence indicated that ABCD Chinese medicine exhibited superior effectiveness inrelieving angina symptoms compared with conventional drugs [relative risk, 1.23; 95%

circulation and detoxifying; UAP, unstable angina pectoris; RCTs, randomized controlled trials; RAS,electrocardiogram; FIB, fibrinogen; CI, confidence interval; RR, relative risk; ACS, acute coronaryhs-CRP, high-sensitivity C-reactive protein; CBM, Chinese Biological Medicine; CNKI, China Nationale Scientific Journal database; WFDP, WanFang Digital Periodicals; WMDs, weighted mean differences;, total duration of angina attacks in 24 h; SRRN, stopping or reducing rate of nitroglycerin; TC, totaligh-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol (LDL-C); TNFa, tumorprotein.Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100091, China.Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100091, China..com (X. Ma), dz_shi@126.com (D. Shi).f Beijing University of Chinese Medicine.

16.01.001f Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under thecommons.org/licenses/by-nc-nd/4.0/).

72 Y. Zhang et al.

confidence interval, 1.05e1.44]; however, electrocardiogram improvement was not very sig-nificant (relative risk, 1.21; 95% confidence interval, 0.91e1.62). Moreover, ABCD Chinesemedicine exhibited superior anti-inflammatory, anticoagulant, and lipid-lowering effectscompared with other medicines.Conclusions: Within the methodological limitations of the included studies, our results suggestthat ABCD Chinese medicine is beneficial for the treatment of unstable angina pectoris.ª 2015 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This isan open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Although therapeutic strategies for coronary heart diseaseshave greatly advanced and mortality rates have decreasedin Western countries over the past few decades,1 mortalityand morbidity associated with these diseases are stillincreasing in China, where a large number of patients arediagnosed with acute coronary syndrome (ACS). ACS in-cludes unstable angina pectoris (UAP), non-ST-elevatedmyocardial infarction (MI), and ST-elevated MI, whichdescribe different degrees of myocardial ischemic states.2

UAP is the most common clinical presentation of ACS.Conventional medications for UAP include aspirin,angiotensin-converting enzyme inhibitors, beta-blockers,calcium antagonists, and nitrates.3 However, all thesedrugs may have undesirable effects. For example, aspirincan potentially increase the incidence of hemorrhage andsome patients have acquired resistance to the drug.

Traditional Chinese medicine has become a populartreatment for UAP. According to modern medical theory,platelet activation, thrombosis, and inflammation arecentral to UAP pathogenesis. In contrast, according totraditional Chinese medicine, blood stasis is at the core ofUAP development. If blood stasis is not eliminated, it re-sults in the production of toxins over time. Therefore,numerous modern medical studies have been conducted onthe use of traditional Chinese medicine for activating bloodcirculation and detoxifying (ABCD). Basic studies haverevealed that ABCD can decrease tissue damage and theexpression of inflammation-related factors in the rat modelof carotid artery thrombosis,4 inhibit the nuclear factorkappa B pathway and decrease matrix metalloproteinase-9in the aorta of apolipoprotein E knockout mice,5 decreaseserum high-sensitivity C-reactive protein (hs-CRP) levels,6

decrease apoptosis and oxidative damage to umbilicalvein endothelial cells induced by oxidized low-density li-poprotein,7 and inhibit coagulation and platelet activationin a rat model of acute MI.8

In clinical practice, ABCD Chinese medicine has beenfound to exhibit add-on effects in UAP patients; it canenhance the effectiveness of conventional medicine inrelieving angina symptoms,9e12 decrease the dosage ofnitroglycerin, and minimize adverse effects.13 However,evidence supporting or disproving these cardiovascularprotective effects has not been systematically reviewed.We therefore conducted this study to systematically andobjectively evaluate the clinical efficacy of ABCD Chinesemedicine for UAP based on a comprehensive understanding

of previous studies and meta-analyses of randomizedcontrolled trials (RCTs).

Methods

Search strategy

We performed an electronic literature search using thefollowing databases: PubMed (1989eDecember 2014), Webof Science (1990eDecember 2014), Chinese BiologicalMedicine (CBM; 1990eDecember 2014), China NationalKnowledge Infrastructure (CNKI; 1989eDecember 2014),Chinese Scientific Journal (VIP; 1989eDecember 2014), andWanFang Digital Periodicals (WFDP; 1989eDecember 2014).There were no language restrictions. We used the followingEnglish search terms alone or in combination: “traditionalChinese medicine,” “activating blood circulation anddetoxifying,” “unstable angina pectoris,” “randomizedcontrolled trials,” “controlled trials,” and “randomly.”Chinese search terms included generic names for UAP(“Bu_wen_ding_xing_xin_jiao_tong”), ABCD (Huo_xue_jie_du or Hua_yu_jie_du), frequently used herbal formulaefor ABCD (Wu_wei_xiao_du_yin, si_miao_yong_an_tang orXian_fang_huo_ming_yin), and randomized (Sui_ji).

Study selection

The inclusion criteria for studies were as follows: RCTs;inclusion of patients diagnosed with UAP according toaccepted criteria; comparison of ABCD Chinese medicine asan intervention or co-intervention (alongside conventionaldrugs for UAP) with no treatment, placebo, other types ofChinese medicines, or conventional drugs; measurement ofthe effectiveness of ABCD Chinese medicine for UAP by areduction in angina symptoms (RAS), electrocardiogram(ECG) improvement, and laboratory indices.14

Data extraction and methodological qualityassessment

Two investigators (Ying Zhang and Xiaojuan Ma) evaluatedall studies and independently extracted relevant data fromeach using a structured table. To resolve any disputes, athird investigator (Dazhuo Shi) was consulted.14 Thefollowing data were extracted: number of patients inexperimental and control groups, age, UAP diagnosticcriteria, intervention, treatment duration, and outcome

Traditional Chinese medicine in unstable angina pectoris 73

measures. Two authors independently assessed the risk ofbias in the included studies using criteria recommended inthe Cochrane Handbook for Systematic Reviews of In-terventions, version 5.1.0. This risk was judged as high forstudies that met all criteria, unclear for studies withinsufficient information for judgment, and low for studiesthat met none of the criteria.15

Statistical analysis

Dichotomous data were analyzed using relative risks (RRs)and continuous variables were analyzed using weightedmean differences (WMDs); effect sizeswere indicated by 95%confidence intervals (CIs). Statistical heterogeneity wasmeasured using the I2 statistic. Fixed-effect models wereapplied if there was no significant heterogeneity acrossstudies (I2 < 50%); otherwise, random-effects models wereapplied. All P-values were two-tailed, and the threshold forstatistical significance was set at 0.05. Cochrane Collabora-tion software (RevMan 5.2, Copenhagen, Denmark) was usedto perform statistical analyses. There is no registered pro-tocol for the present meta-analysis.

Fig. 1 Flow chart of stud

Results

Based on our inclusion criteria, we identified 1098 potentialstudies from our initial search and excluded 644 trials forduplicated publications. Subsequently, 108 potential trialswere identified, 97 of which were excluded for specificreasons (Fig. 1). Eventually, only 11 RCTs9e13,16e21 met ourinclusion criteria.

Characteristics of the included studies

The characteristics of the 11 included RCTs are listed inTable 1. The RCTs collectively involved 686 patients andwere published between 2002 and 2014. All patients wereresidents of the People’s Republic of China. Of this total,352 patients received ABCD Chinese medicine alone or incombination (experimental group). The treatment courseranged from 2 to 4 weeks, and RAS and ECG improvementwere the most common outcome measures. Serum hs-CRPand blood lipid levels were the most commonly measuredlaboratory indices.

y search and selection.

Table 1 Characteristics of the trials included in this meta-analysis.

Study Samplesize T/C

Mean age T/C Diagnosisstandard

Course(week)

Experimental group Control group Outcomemeasures

Feng et al.,2014

30/31 61.9/61.4 2007CDTGUANSTEMI

4 Xiongshaocapsule þ Huangliancapsule þ CD

Xiongshaocapsule þ CD

hs-CRP BL

Pei et al.,2012

32/32 61.94/60.36 2007CDTGUANSTEMI

3 Guizhi fulingdecoction þ Huanglianjiedu decoction þ CD

CD RAS BL hs-CRPFAA DAA

Zhang et al.,2004

45/30 58.89/58.77 1979ISFC/WHO

4 Tongmai jiedu decoction CD RAS ECG

Zhao et al.,2007

42/38 52.52/50.24 2000CDTGUANSTEMI

2 Huayu jiedu decoction CD RAS CRP SRRNTNFa

He et al.,2007

30/30 61.96/62.93 1979 ISFC/WHO 4 Huoxue jiedudecoction þ CD

CD RAS ECG hs-CRP

Chen et al.,2009

30/31 61.24/61.84 2007CDTGUANSTEMI

2 Xiongshaocapsule þ Huangliancapsule þ CD

Xiongshaocapsule þ CD

RAS ECG hs-CRPBL AE

Pan et al.,2010

38/38 58.23/57.69 GCRNDTCM 4 Qingre jiedu huoxuedecoction þ CD

CD RAS ECG hs-CRP

Gao et al.,2014

33/32 65.9/67.2 GCRNDTCM 2 Quyu jiedudecoction þ CD

CD RAS ECG hs-CRPFIB

Zeng et al.,2009

28/25 58.2/56.4 2000CDTGUANSTEMI

2 Xuebijing injection þ CD CD BL TNFa FIB

Peng et al.,2012

20/20 61/60.6 2007CDTGUANSTEMI

2 Shuxin tongbidecoction þ CD

CD RAS ECG

Wang et al.,2002

20/23 63.5/64.8 2000CDTGUANSTEMI

2 Huangqi injection þ Luotaiinjection þ Jiedu huxincapsule þ CD

CD CD62P vWF

CDTGUANSTEMI: Chinese diagnosis and treatment guidelines of unstable angina and non-ST segment elevation myocardial infarction;GCRNDTCM: Guidelines of clinical research of new drugs of traditional Chinese medicine; ISFC/WHO: International Society and Feder-ation of Cardiology/World Health Organization; hs-CRP: high-sensitivity C-reactive protein; BL: blood lipid; FAA: frequency of anginaattacks; DAA: duration of angina attack; RAS: reduction of angina symptoms; ECG: electrocardiogram; SRRN: stopping or reducing rate ofnitroglycerin; TNFa: tumor necrosis factor alpha; AE: adverse event; FIB: fibrinogen; T/C: treatment/control; CD62P: P-selectin protein;vWF: von Willebrand factor; CD: conventional drugs.

74 Y. Zhang et al.

Quality assessment of the included studies

All 11 RCTs mentioned the term randomization, but onlythree described it in detail. None mentioned allocationconcealment or intention-to-treat analysis. Because not allthe trial protocols were accessible, the extent of selectivereporting was generally unclear (Figs. 2 and 3).

Fig. 2 Risk of bias graph: review authors’ judgments about eachstudies.

Effects of interventions

RASRAS was evaluated in eight studies including 529 patients,with 274 in the experimental group and 255 in the controlgroup. A random-effects model was used to analyze thedata according to heterogeneity testing (I2 Z 78%,

risk of bias item presented as percentages across all included

Fig. 3 Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. þ: Low risk of bias;�: High risk of bias; ?: Unclear risk of bias.

Traditional Chinese medicine in unstable angina pectoris 75

P < .0001). Overall, the outcomes showed a statisticallysignificant difference in favor of the experimental group(RR, 1.23; 95% CI, 1.05e1.44; P Z .001; Fig. 4). This indi-cated that ABCD Chinese medicine exhibited superioreffectiveness in relieving angina symptoms.

ECG improvementSix studies including 377 patients, with 196 in the experi-mental group and 181 in the control group, analyzed ECGimprovement. Data were analyzed using a random-effectsmodel according to heterogeneity testing (I2 Z 87%,P < .00001). Overall, the results showed that ABCD Chinesemedicine produced no significant ECG improvementcompared with control interventions (RR, 1.21; 95% CI,0.91e1.62; P Z .19; Fig. 5).

Serum blood lipid levelsFour studies involving 247 patients, with 124 in the exper-imental group and 123 in the control group, reported serumblood lipid levels, including total cholesterol (TC), triglyc-eride (TG), high-density lipoprotein cholesterol (HDL-C),and low-density lipoprotein cholesterol (LDL-C). The resultsindicated that ABCD Chinese medicine significantly lowered

Fig. 4 Forest plots for reduc

TC, TG, and LDL-C levels and increased HDL-C levelscompared with control interventions. The details are shownin Table 2 and Fig. 6.

Anti-inflammatory effectsFive studies analyzed serum hs-CRP levels. After poolingthese trials, we observed that ABCD Chinese medicinesignificantly decreased hs-CRP levels (WMD, �0.86; 95% CI,�1.14w �0.57; P< .00001). Data concerning tumor necrosisfactor alpha (TNFa) andCRPwere extracted fromtwo trials; asummary of these indices is shown in Table 3 and Fig. 7.Overall, we noted that ABCD Chinese medicine exhibitedbetter anti-inflammatory effectswith regard to serumhs-CRPand TNFa levels compared with control interventions.

Anticoagulant effectsPlasma fibrinogen (FIB) levels were measured in two trials.ABCD Chinese medicine significantly decreased FIB levels(WMD, �0.58; 95% CI, �0.95w �0.21; P Z .002; Fig. 8).Furthermore, one trial claimed that CD62p (P-selectinprotein) decreased from 8.69 � 2.11% to 5.40 � 1.46% withABCD Chinese medicine, while vWF decreased from142.47 � 17.06% to 110.58 � 18.57%.

tion of angina symptoms.

Fig. 5 Forest plots for ECG improvement.

Table 2 Summary of the weighted mean differences (WMDs) for blood lipid levels.

Outcomes Included studies WMD and 95% CI P-value Heterogeneity P-value for heterogeneity

TC (mmol/L) 11,14,15,17 �0.20 [�0.38, �0.02] 0.03 7% 0.36TG (mmol/L) 11,14,15,17 �0.22 [�0.40, �0.04] 0.02 0% 1.00LDL-C (mmol/L) 11,14,15,17 �0.20 [�0.36, �0.04] 0.01 4% 0.37HDL-C (mmol/L) 11,14,15,17 0.07 [0.02, 0.11] 0.003 18% 0.30

CI: confidence interval; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipo-protein cholesterol.

76 Y. Zhang et al.

Other outcomes

One trial reported the frequency of angina attacks (FAA)and the total duration of angina attacks in 24 h (DAA) asoutcomes. Compared with control interventions, ABCDChinese medicine significantly decreased FAA (3.50 � 3.20times/week to 6.22 � 3.87 times/week; P < .05) and DAA(10.68 � 8.42 min/d to 27.91 � 14.70 min/d; P < .05).Another trial reported the stopping or reducing rate ofnitroglycerin (SRRN) as an outcome; this was 90.48% and68.42% in the experimental and control groups,respectively.

Publication bias

Because of the insufficient number of included trials, wedid not use a funnel plot to detect publication bias.

Adverse effects

Only one trial reported adverse events in the form of milddiarrhea in four patients in the experimental group thatdisappeared after dose reduction. No severe adverse eventswere reported.

Discussion

This systematic review analyzed evidence for 686 patientsincluded in 11 RCTs. The pooled results showed significantRAS and superior anti-inflammatory, anticoagulant, andlipid-lowering effects for ABCD Chinese medicine. To thebest of our knowledge, the present meta-analysis is the firstto evaluate the efficacy of ABCD Chinese medicine for UAP.

Systemic markers of inflammation have been found inpatients with UAP. Disruption of culprit coronary stenosismay cause a greater inflammatory response in patients withunstable angina than in those with stable angina. Our studyshowed that ABCD Chinese medicine decreased TNFa andhs-CRP more than did conventional therapy. Therefore,anti-inflammation might be one of the mechanisms bywhich ABCD Chinese medicine exerted its protective effecton UAP patients.

Recently, several meta-analyses on herbs, TCMformulae, or Chinese patent medicines for angina pectorishave been published. One study suggested that combina-tion therapy with Xuefu Zhuyu decoction and conventionaldrugs is more beneficial and effective in treating anginapectoris compared with conventional drugs alone, and thatXuefu Zhuyu decoction may be a better choice for thetreatment of stable angina pectoris (SAP),22 Another ofthese meta-analyses indicated that Chinese patent medi-cines could improve the survival of angina patients whoconsumed Western medicines.23 Yet another systematicreview showed that compound salvia pellet, a Chinesepatent medicine, could relieve angina symptoms andimprove ECG results with few adverse effects.24 However,neither these studies nor the present study can drawdefinitive conclusions from the results because of thefollowing limitations.

First, most of the included studies provided insufficientinformation about randomization procedures. Unsuccessfulrandomization can lead to selection bias while allocatinginterventions to participants.25 Second, none of the studieswere double-blind trials, even though blinding is veryimportant to ensure that patients have equivalent experi-ences and that each patient has an equal chance of beingallocated to one or other of the conditions during the

Fig. 6 Forest plots for blood lipid. A: triglyceride; B: total cholesterol; C: low-density lipoprotein cholesterol; D: high-densitylipoprotein cholesterol.

Traditional Chinese medicine in unstable angina pectoris 77

clinical trial procedure. Third, none of the included trialsmentioned allocation concealment, withdrawal, or dropoutevents. Fourth, although UAP is a lifelong disease, allincluded trials featured short-term outcomes because ofthe absence of follow-ups. This could also explain why theincidence of adverse events was too low for safety evalu-ations. Fifth, as described previously, we only searchedChinese and English databases. However, herbal medicinesare also used commonly in other Asian countries such as

Table 3 Summary of the weighted mean differences (WMDs) fo

Outcomes Included studies WMD and 95% CI

hs-CRP (mg/L) 10,11,13,14,15 �0.86 [�1.14, �0.57]TNFa (ng/mL) 9,17 �5.05 [�7.51, �2.59]CRP (mg/L) 9,10 �3.53 [�12.35, 5.30]

CI: confidence interval; hs-CRP: high-sensitivity C-reactive protein; T

Japan and Korea. This may have led to a potential selectionbias, thus limiting external generalization of evidence.

In addition to quality limitations, the estimates of someoutcomes were limited by small sample sizes. The samplesize in all trials was <100 and could have influenced theprecision of estimates. Even so, we believe this meta-analysis is of great importance because it at least providesmoderate evidence regarding the effectiveness of ABCDChinese medicine for UAP in clinical settings. Further

r inflammatory factors.

P-value Heterogeneity P-value for heterogeneity

<0.00001 2% 0.39<0.0001 99% <0.000010.43 99% <0.00001

NFa: tumor necrosis factor alpha; CRP: C-reactive protein.

Fig. 7 Forest plots for inflammatory factors. A: high-sensitivity C-reactive protein; B: tumor necrosis factor alpha; C: C-reactiveprotein.

Fig. 8 Forest plots for fibrinogen.

78 Y. Zhang et al.

studies should explore the mechanisms of action of ABCDChinese medicine in UAP patients.

Conclusions

The present study provides preliminary evidence that sup-ports the continued use of ABCD Chinese medicine as apotentially optimistic and reliable intervention for UAP.Further work is needed to improve understanding of thistreatment using rigorously designed, multicenter, large-scale clinical trials that investigate the effectiveness andsafety of ABCD Chinese medicine for UAP.

Author contributions

Study conception and design: Dazhuo Shi.Performance of experiments: Ying Zhang, Xiaojuan Ma,

Dazhuo Shi.Data analysis: Ying Zhang, Xiaojuan Ma.Contribution of reagents/materials/analysis tools: Ying

Zhang.

Manuscript writing: Ying Zhang.Manuscript revising: Hua Qu.

Conflicts of interests

The authors declare that they have no competing interests.

Acknowledgments

This work was supported by grants from the National Nat-ural Science Foundation of China (Grant Nos. 81030063 andno.81202837). The authors’ work was independent of thefunders and the funding source had no involvement in thedesign of the study.

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