Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2013 / Article

Review Article | Open Access

Volume 2013 |Article ID 282707 | 16 pages | https://doi.org/10.1155/2013/282707

The Efficacy of Guanxinning Injection in Treating Angina Pectoris: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Academic Editor: Myeong Soo Lee
Received22 Jul 2012
Revised20 Jan 2013
Accepted21 Jan 2013
Published24 Mar 2013

Abstract

Objective. The randomized controlled trials (RCTs) on Guanxinning injection (GXN) in treating angina pectoris were published only in Chinese and have not been systematically reviewed. This study aims to provide a PRISMA-compliant and internationally accessible systematic review to evaluate the efficacy of GXN in treating angina pectoris. Methods. The RCTs were included according to prespecified eligibility criteria. Meta-analysis was performed to evaluate the symptomatic (SYMPTOMS) and electrocardiographic (ECG) improvements after treatment. Odds ratios (ORs) were used to measure effect sizes. Subgroup analysis, sensitivity analysis, and metaregression were conducted to evaluate the robustness of the results. Results. Sixty-five RCTs published between 2002 and 2012 with 6064 participants were included. Overall ORs comparing GXN with other drugs were 3.32 (95% CI: [2.72, 4.04]) in SYMPTOMS and 2.59 (95% CI: [2.14, 3.15]) in ECG. Subgroup analysis, sensitivity analysis, and metaregression found no statistically significant dependence of overall ORs upon specific study characteristics. Conclusion. This meta-analysis of eligible RCTs provides evidence that GXN is effective in treating angina pectoris. This evidence warrants further RCTs of higher quality, longer follow-up periods, larger sample sizes, and multicentres/multicountries for more extensive subgroup, sensitivity, and metaregression analyses.

1. Introduction

Ischemic heart disease (IHD) is a major cause of death and global healthcare burden [1]. Angina pectoris, a symptom of IHD, is a severe chest pain due to ischemia of the heart muscle, during obstruction or spasm of the coronary arteries [2]. In the United States, IHD accounts for 26.6% of all deaths in 2005, with an age-adjusted male-to-female mortality ratio of 1.5 [3]. The morbidity and mortality of angina in middle-aged and elderly people were ranked the top among all common diseases in China [4]. Three categories of conventional Western medicine including nitrates (e.g., isosorbide mononitrate), beta-receptor blockers (e.g., atenolol), and calcium channel blockers (e.g., amlodipine) are commonly used in treating angina [3].

Guanxinning injection (GXN, also known as Danshen Chuanxiong Injection) comprises extracts from two well-known traditional Chinese medicines Danshen (Salvia miltiorrhiza) and Chuanxiong (Ligustrazine, Ligustium Wallichii Franch) [5]. Danshen and its active compounds tanshinones and isotanshinones have bioactivities against myocardial ischemia, inflammation, and angiotensin-converting enzyme [6]. Chuanxiong and its active compounds tetramethylpyrazine and ferulic acid can dilate coronary arteries, increase myocardial oxygen, and decrease platelet aggregation and thrombosis [7].

GXN was tested to be more effective than nitrates [8], beta-receptor blockers [9], and calcium channel blockers [10] in treating angina. Since the launch of GXN (2002) and prior to this study, there has been only one systematic review, which is not compliant with PRISMA [11] and includes only nine randomized controlled trials (RCTs) published in Chinese between 2002 and 2010 [12]. The methods and results of quality assessment of the included RCTs were not clearly reported in the systematic review. Sensitivity and subgroup analyses were missing. Hence, this study aims to provide an internationally accessible, comprehensive, and timely systematic review and meta-analysis in compliance with PRISMA to assess the efficacy of GXN as a monotherapy and combined therapy with conventional Western or Chinese medicines in treating angina pectoris.

2. Methods

The procedures of this systematic review and meta-analysis were conducted in accordance with the PRISMA guideline [11], including the search and selection of studies, data extraction from the studies, and meta-analysis (overall, subgroup, sensitivity, publication bias, and metaregression analysis).

2.1. Search Strategies

RCTs published on the efficacy of GXN in treating angina pectoris were retrieved from major bibliographical databases including Medline, PubMed, Cochrane Library, ScienceDirect, Embase, China National Knowledge Infrastructure (CNKI), WanFang Data, China Master Theses Full-text Database (CMTD), and China Doctor Dissertations Full-text Database (CDMD) between the inception dates of databases and 2012 (last search on 18 March 2012). A simple search strategy, that is, searching for the keywords “Guanxinning” or “danshen chuanxiong” or “danshenchuanxiong,” was used to search all fields. For instance, the search in WanFang Data using the keyword “Guanxinning” found 196 records and “danshen chuanxiong” found 17 records and “danshenchuanxiong” found none. Exact search strategies and query syntax for specific databases were customized according to the same strategy.

2.2. Study Selection

Inclusion criteria for each study were (a) the participants were suffering from and being treated for angina pectoris; (b) the study was claimed as an RCT; (c) the study compared the efficacy of GXN with conventional (Western and Chinese medicine) drugs. Exclusion criteria were (a) the study was a duplicated or redundant publication and (b) the study did not include symptomatic improvement as a major outcome.

Two reviewers (Y. Jia and F. Pan) independently searched the databases and selected studies according to the inclusion and exclusion criteria. Disagreements between reviewers were resolved by consensus after discussion. Figure 1 shows a flow diagram of study selection.

2.3. Data Extraction

Two reviewers (Y. Jia and F. Pan) independently extracted data items, including (a) years of publication; (b) numbers of authors; (c) follow-up periods; (d) baseline characteristics of participants between groups; (e) sample sizes; (f) outcome measures; (g) dosages and follow-up periods; (h) type of angina; (i) frequencies of adverse events (AE); and (j) the type of angina.

2.4. Quality Assessment of Included Studies

Two reviewers (Y. Jia and F. Pan) independently assessed the quality of the included studies according to the Jadad scale [13], its refined version the scale [14], and the Cochrane Collaboration’s tool for assessing risk of bias [15]. The Jadad scale focused on three criteria including “randomization,” “blinding,” and “dropouts” for assessing the quality of RCT. The scale added two criteria “baseline comparison of participants” and “adverse event report” on top of the Jadad scale. The Cochrane Collaboration’s tool for assessing risk of bias includes “random sequence generation,” “allocation concealment,” “blinding of participants and personnel,” “blinding of outcome assessment (patient-reported outcomes),” “blinding of outcome assessment (SYMPTOMS),” “incomplete outcome data addressed,” “reporting bias,” and “other sources of bias.”

2.5. Criteria for Symptomatic and ECG Improvements

Effective symptomatic improvements should achieve at least 50% (basic) or 80% (significant) reduction in frequency of feeling angina chest pain [16]. Effective ECG improvements should achieve (a) at least 0.05 mV lowering at ST segment in ECG (basic) or (b) nearly normal (significant) ECG during an exercise test according to the International Society and Federation of Cardiology/World Health Organization [16].

2.6. Meta-Analysis

Effect sizes were represented by odds ratios (ORs) [17] and their 95% confidence intervals (CI) [18]. Overall meta-analysis and subgroup analysis employed the random-effects model for conservative generalizability. Heterogeneity among studies was assessed by Chi-squared ( ) and I-squared ( ) tests [19].

2.7. Subgroup and Sensitivity Analyses

Subgroup analysis was conducted to evaluate the overall effects in the subgroups according to years of publication (≤2008 or >2008), numbers of authors (1 or >1), follow-up periods (≤14 days or >14 days), sample sizes (<mean sample size or ≥mean sample size), quality scores of the studies (<mean or ≥mean), different type of angina, and different daily dosage of GXN. The overall effects were also analyzed in subgroups of GXN for monotherapy and adjunctive therapy. Sensitivity analysis was carried out according to different criteria outcomes (basic or significant) in SYMPTOMS and ECG and excluding studies with maximum GXN dosage to assess their influence on the overall effect sizes. The Mann-Whitney-Wilcoxon test was used to compare two subgroups. The Kruskal-Wallis test and the Bonferroni correction were used to compare multiple subgroups. Kendall correlation between ORs of symptoms and ECG was performed.

2.8. Metaregression and Risk of Bias across Studies

Funnel plots [20], Begg’s test [21], and Egger’s test [22] were employed to assess publication bias. Trim-and-fill method [23] was conducted to identify and correct the funnel plot asymmetry arising from publication bias. Metaregression [24] was conducted to find the possible relationship between the overall effects and the factors such as sample sizes, follow-up periods, scores, and years of publication.

2.9. Adverse Events

Information about adverse events (AEs) of RCTs, including nonreported adverse events and types and frequency of adverse events reported, was tabulated and analyzed by basic statistics.

2.10. Statistical Analysis

All data analyses, including meta-analysis, forest plot generation, funnel plot generation, metaregression, Kendall correlation, Mann-Whitney-Wilcoxon test, Kruskal-Wallis test, Begg’s test, and Egger’s test, were performed using statistical software R [25] and its “metafor” package for meta-analysis. values lower than 0.05 were considered statistically significant.

3. Results

3.1. Study Selection

Figure 1 depicts the process of study selection. The search of bibliographical databases found 401 records, including 196 records from WanFang Data, 162 records from CNKI, 19 records from CMTD, 11 records from ScienceDirect, 6 records from Medline, 5 records from PubMed, and 2 records from CDMD. According to prespecified selection criteria as described in Methods, 65 studies [2690] were included for further quality assessment and meta-analysis.

3.2. Study Characteristics

Table 1 lists the main characteristics of the included studies. All included studies were published in the Chinese language between 2004 and 2011 with a total of 6064 participants. The mean sample size was 93.3 (median: 88.0; 95% CI: [56.5, 130.1]). The follow-up periods were between 1 and 30 days. GXN was compared with the conventional treatments in the included RCTs. Drugs in control group mainly included nitrates, beta-receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and some conventional Chinese medicinal products for treating heart disease. Fifty-nine out of 65 RCTs employed GXN plus the conventional treatments in the treatment group while the conventional treatments were employed in control group. Dosage details were listed in Supplementary Table  1 in the Supplementary Material available online at http://dx.doi.org/10.1155/2013/282707. For outcome measures, all 65 included studies reported symptomatic (SYMPTOMS) changes while 38 studies also reported ECG changes.


StudyNumber of authorsTrial date reportSample
size
Followup
(day)
Baseline comparisonAEOutcomes
measure
Treatment group dosageAngina

Chen 2009111001510SYM, ECGGXN 20 mL/d + CGAngina
Chen et al. 2011311001000SYMGXN 20 mL/d + CGAngina
Chen 200611621411SYM, ECGGXN 20 mL/d + CGAngina
Cheng and Zang 201021431410SYMGXN 30 mL/d + CGUnstable
Cheng et al. 201131761411SYM, ECGGXN 30 mL/d + CGAngina
Dong XP 200910100100.5SYMGXN 20 mL/dAngina
Fu and Meng 201120471010SYM, ECGGXN 20 mL/d + CGAngina
Fu et al. 201041561410SYM, ECGGXN 200 ml + CG + shenmaiyin 40 mlAngina
Gao et al. 200531601411SYM, ECGGXN 20 mL/dAngina
Gong et al. 200931851411SYM, ECGGXN 20 mL/d + xueshuantong 20 mlStable
He and Meng 200711491510SYMGXN 20 mL/d + CGUnstable
He 2009111202811SYM, ECGGXN 30 mL/d + atorvastatin 10 mgUnstable
Hou and Gao 2009211281411SYM, ECGGXN 20 mL/d + CGStable
Huang et al. 201140120711SYMGXN 20 mL/d + CG + xueshuantong 400 mgAngina
Jiang et al. 2010311161010SYM, ECGGXN 20 mL/d + CGUnstable
Jiang 200911682011SYM, ECGGXN 20 mL/dAngina
Jiang et al. 20105056701SYMGXN 30 mL/dAngina
Kong 2009101001411SYMGXN 30 mL/d + CGUnstable
Lan et al. 200631641411SYMGXN 20 mL/dAngina
Li and Jia 2011212001410SYM, ECGGXN 30 mL/d + CGAngina
Li and Lei 2005211561401SYM, ECGGXN 20 mL/d + CGAngina
Li et al. 2009511681410SYMGXN 20 mL/d + CGAngina
Li and Ran 2009211601011SYMGXN 20 mL/d + CGAngina
Li 20041083710SYM, ECGGXN 20 mL/d + CGUnstable
Liang and Feng 2010201201410SYM, ECGGXN 20 mL/d + CGUnstable
Liu 2004111041011SYMGXN 20 mL/d + CGUnstable
Liu and Li 200721881201SYMGXN 20 mL/d + CGUnstable
Liu 200511803010SYM, ECGGXN 20 mL/d + CGUnstable
Liu 2011111522810SYM, ECGGXN 20 mL/d + CGAngina
Lu et al. 200631683010SYMGXN 30 mL/d + CGAngina
Ma and Peng 2008211201410SYMGXN 30 mL/d + CGUnstable
Nie and Chen 200721601410SYM, ECGGXN 20 mL/d + CGAngina
Qiao and Wu 200420812811SYM, ECGGXN 20 mL/d + CGStable
Song 20101182700.5SYMGXN 20 mL/d + CG + diltiazem 90 mg/dUnstable
Su 200911901501SYM, ECGGXN 6 mL/d + CGAngina
Sun 201011901410SYM, ECGGXN 30 mL/d + CGUnstable
Sun et al. 200651981500SYMGXN 20 mL/d + CGAngina
Tian and Wu 200621621411SYMGXN 30 mL/d + CGUnstable
Wan and Xu 2009201201411SYM, ECGGXN 30 mL/d + CGUnstable
Wang 2007111001411SYM, ECGGXN 30 mL/d + CGAngina
Wang 201111851411SYM, ECGGXN 20 mL/d + CGUnstable
Wang 2011211121411SYM, ECGGXN 20 mL/d + CGUnstable
Wang and Ji 200821601400SYM, ECGGXN 20 mL/d + CGUnstable
Wang and Sun 200721921000SYMGXN 20 mL/d + CGUnstable
Wang 200521601510SYMGXN 20 mL/d + CGUnstable
Wang 201010801411SYM, ECGGXN 20 mL/d + CGStable
Wang 200510761500SYMGXN 20 mL/d + CG + shenmai 30 mL/d + tongxinluo 9 pills/dUnstable
Wang 200511601411SYMGXN 20 mL/d + CGUnstable
Wang et al. 201141601411SYMGXN 20 mL/d + CGUnstable
Wu et al. 2008301081410SYMGXN 20 mL/d + CGAngina
Wu et al. 201141144710SYMGXN 20 mL/d + CG + shenmai 50 mL/dUnstable
Xia 201111901410SYM, ECGGXN 30 mL/d + CGUnstable
Yang and Ma 200821901410SYM, ECGGXN 30 mL/d + CGUnstable
Ye et al. 200830761501SYMGXN 20 mL/d + CGUnstable
Yu and Wang 200921751510SYM, ECGGXN 20 mL/d + CGAngina
Yuan 2005101041410SYM, ECGGXN 20 mL/d + CGAngina
Zhang 200511601410SYM, ECGGXN 10 mL/dAngina
Zhang 2010112401511SYM, ECGGXN 20 mL/d + CGUnstable
Zhang 2004111021411SYM, ECGGXN 10 mL/d + CG + ginkgo leaf injection 10 mL/dAngina
Zhang 20041142701SYMGXN 20 mL/d + CGAngina
Zhao et al. 2010611001411SYM, ECGGXN 10 mL/d + CG + xueshuangtong 120 mgUnstable
Zhao and An 200821902811SYM, ECGGXN 20 mL/d + CG + simvastatin 10–20 mg/dUnstable
Zhao 201011861410SYM, ECGGXN 30 mL/d + CGAngina
Zhong et al. 200781601000SYMGXN 20 mL/d + CGAngina
Zhu 200511801500.5SYM, ECGGXN 20 mL/d + CGUnstable

GXN is Guanxinning injection; LMWH is low molecular weight heparin; and shenmai is Shenmai injection. CG is interventions of control group; SYM is SYMPTOMS; ECG is electrocardiogram; and AE is adverse event. The column of “Trial date report” shows that study did (1) or did not (0) report the trial date. The column of “Baseline comparison” shows that the study did (1) or did not (0) report the baseline comparison between the treatment and control groups.
3.3. Quality Assessment of Included Studies

Table 2 shows the results of quality assessment according to the Jadad scales, scales, and the Cochrane Collaboration’s tool. According to the Jadad scale (with a possible range between 0 and 5 points), 63 studies of all included studies scored 2 with two items “randomization” and “dropouts,” one study [34] scored 3, and one study [47] scored 4. According to the scale, six studies scored 2, three studies scored 2.5, 30 studies scored 3, 24 studies scored 4, and 2 studies scored 5. Fifty included studies reported baseline comparison of participants in experiment and control groups. Thirty-one studies did not report adverse events. Three studies reported types of adverse events. Thirty-one studies reported types and numbers of adverse events. The assessment results of the Cochrane Collaboration’s tool showed (1) low risk of bias in random sequence generation for selection bias, blinding of outcome assessment (SYMPTOMS) for detection bias, and incomplete outcome data addressed for attrition bias, (2) high risk of bias in allocation concealment for selection bias, blinding of participants and personnel for performance bias, blinding of outcome assessment (patient-reported outcomes) for detection bias, and reporting bias for selecting reporting, and (3) unclear risk of bias in other sources of bias for other bias.


StudyC1C2C3C4C5C6C7C8ComparableRandom Blind DropoutAEJadad M

Chen 2009LowHighHighHighLowLowHighHigh1101023
Chen et al. 2011LowUnclearHighHighLowLowHighHigh0101022
Chen 2006LowHighHighHighLowLowLowLow1101124
Cheng and Zeng 2010LowHighHighHighLowLowHighHigh1101023
Cheng et al. 2011LowHighHighHighLowLowLowLow1101124
Dong 2009LowHighHighHighLowLowUnclearHigh01010.522.5
Fu and Meng 2011LowHighHighHighLowLowHighHigh1101023
Fu et al. 2010LowHighHighHighLowLowHighHigh1101023
Gao et al. 2005LowLowHighHighLowLowLowLow1111135
Gong et al. 2009LowHighHighHighLowLowLowLow1101124
He 2007LowHighHighHighLowLowHighHigh1101023
He 2009LowHighHighHighLowLowLowLow1101124
Hou and Gao 2009LowHighHighHighLowLowLowLow1101124
Huang et al. 2011LowHighHighHighLowLowLowLow1101124
Jiang et al. 2010LowHighHighHighLowLowHighHigh1101023
Jiang 2009LowHighHighHighLowLowLowLow1101124
Jiang et al. 2010LowHighHighHighLowLowLowLow0101123
Kong 2009LowHighHighHighLowLowUnclearLow1101124
Lan et al. 2006LowHighHighHighLowLowLowLow1101124
Li and Jia 2011LowHighHighHighLowLowHighHigh1101023
Li and Lei 2005LowHighHighHighLowLowLowLow0101123
Li et al. 2009LowLowLowLowLowLowHighHigh1121045
Li and Ran 2009LowHighHighHighLowLowLowLow1101124
Li 2004LowHighHighHighLowLowHighLow1101023
Liang and Feng 2010LowHighHighHighLowLowHighHigh1101023
Liu 2004LowHighHighHighLowLowLowLow1101124
Liu and Li 2007LowHighHighHighLowLowHighHigh0101123
Liu 2005LowHighHighHighLowLowHighHigh1101023
Liu 2011LowHighHighHighLowLowHighHigh1101023
Lu et al. 2006LowHighHighHighLowLowHighHigh1101023
Ma and Peng 2008LowHighHighHighLowLowLowLow1101023
Nie and Chen 2007LowHighHighHighLowLowHighHigh1101023
Qiao and Wu 2004LowHighHighHighLowLowLowLow1101124
Song 2010LowHighHighHighLowLowLowUnclear01010.522.5
Su 2009LowUnclearHighHighLowLowLowLow0101123
Sun 2010LowHighHighHighLowLowHighHigh1101023
Sun et al. 2006LowHighHighHighLowLowHighUnclear0101022
Tian and Wu 2006LowHighHighHighLowLowLowLow1101124
Wan and Xu 2009LowHighHighHighLowLowLowLow1101124
Wang 2007LowHighHighHighLowLowLowHigh1101124
Wang 2011LowHighHighHighLowLowLowLow1101124
Wang 2011LowHighHighHighLowLowLowLow1101124
Wang and Ji 2008LowHighHighHighLowLowHighHigh0101022
Wang and Sun 2007LowHighHighHighLowLowHighUnclear0101022
Wang 2005LowHighHighHighLowLowHighHigh1101023
Wang 2010LowHighHighHighLowLowLowLow1101124
Wang 2005LowHighHighHighLowLowHighUnclear0101022
Wang 2005LowLowUnclearHighLowLowLowLow1101124
Wang et al. 2011LowHighHighHighLowLowLowLow1101124
Wu et al. 2008LowHighHighHighLowLowHighUnclear1101023
Wu et al. 2011LowHighHighHighLowLowHighHigh1101023
Xia 2011LowLowUnclearHighLowLowHighUnclear1101023
Yang and Ma 2008LowLowUnclearHighLowLowHighHigh1101023
Ye et al. 2008LowHighHighHighLowLowLowLow0101123
Yu and Wang 2009LowHighHighHighLowLowHighHigh1101023
Yuan 2005LowHighHighHighLowLowHighHigh1101023
Zhang 2005LowHighHighHighLowLowHighHigh1101023
Zhang 2010LowHighHighHighLowLowLowLow1101124
Zhang 2004LowHighHighHighLowLowLowLow1101124
Zhang 2004LowHighHighHighLowLowLowHigh0101123
Zhao et al. 2010LowHighHighHighLowLowLowLow1101124
Zhao and An 2008LowHighHighHighLowLowLowLow1101124
Zhao 2010LowHighHighHighLowLowHighUnclear1101023
Zhong et al. 2007LowHighHighHighLowLowHighHigh0101022
Zhu 2005LowHighHighHighLowLowUnclearUnclear01010.522.5

C1 is random sequence generation for selection bias; C2 is allocation concealment for selection bias; C3 is blinding of participants and personnel for performance bias; C4 is blinding of outcome assessment (patient-reported outcomes) for detection bias; C5 is blinding of outcome assessment (SYMPTOMS) for detection bias; C6 is incomplete outcome data addressed for attrition bias; C7 is reporting bias for selecting reporting; C8 is other sources of bias for other bias; Comparable is participants in treat group and control group comparable; Random is study described as randomized; Blind is study described as blinding; Dropout is withdrawals and dropouts of participants; AE is the adverse effects; Low is low risk of bias; High is high risk of bias; Unclear is unclear risk of bias.
3.4. Overall Effects of Included Studies

As shown in Figure 2 and Table 3, the overall OR of SYMPTOMS was 3.32 (95% CI: [2.72, 4.04], , ) with significant heterogeneity ( , , ) among the 65 studies with SYMPTOMS outcome. Figure 3 and Table 4 show that the overall OR of ECG was 2.59 (95% CI: [2.14, 3.15], , ) with nonsignificant heterogeneity ( , , ) among the 38 studies with ECG outcome. Both ORs (SYMPTOMS and ECG) indicated that GXN was more effective than the drugs in control group in treating angina pectoris. The Kendall correlation between SYMPTOMS and ECG in ORs was statistically significant ( ; ).


GroupNumber of
RCTs
Number of
participants
ORWilcoxon
test
95% CIZP (eff) P (het)

M score≤34036253.21W = 5462.36, 4.357.46<0.000154%0.50<0.0001
>32524393.51P = 0.53952.78, 4.4310.50<0.00010%00.9858
Sample size<933927723.22W = 445.52.59, 4.0110.51<0.00010%00.6150
≥932632923.37P = 0.41402.39, 4.766.89<0.000160%0.47<0.0001
Number of authors12724853.18W = 11892.39, 4.247.92<0.000128%0.160.1253
>13835793.40P = 0.75582.60, 4.468.87<0.000144%0.300.0031
Publication year≤20083124953.80W = 441.53.01, 4.8111.19<0.00011%0.010.2929
>20083435692.94P = 0.26422.20, 3.937.32<0.000148%0.340.0016
Trial date reportReported5147933.19W = 2112.52.57, 3.9510.52<0.000136%0.210.0189
Not reported1412713.84P = 12.33, 6.335.28<0.000147%0.400.0254
Baseline
comparison
Reported5048083.56W = 2112.52.84, 4.4511.10<0.000140%0.250.0057
Not reported1512562.53P = 11.75, 3.684.89<0.000114%0.080.1545
Adverse
events
Reported3129473.20W = 10062.58, 3.9710.59<0.00010%00.4304
Not reported3431173.48P = 0.46782.53, 4.787.68<0.000151%0.440.0003
Follow-up
period (day)
≤144844613.38W = 4402.75, 4.1611.51<0.000128%0.140.1321
>141716033.05P = 0.63821.81, 5.164.18<0.000161%0.710.0005
GXN daily6–200 mL6560643.32W = 20592.72, 4.0411.93<0.000137%0.230.0030
Dosage (mL)6–30 mL6460083.34P = 0.92312.73, 4.0711.83<0.000138%0.240.0025
GXN daily<2043523.42 = 0.42901.48, 7.912.880.004038%0.280.1717
Dosage (mL)204542353.16df = 22.45, 4.078.85<0.000146%0.330.0004
>201614773.87P = 0.80692.84, 5.298.51<0.00010%00.8315
Types of anginaStable43743.42 = 0.99001.89, 6.214.05<0.00010%00.7151
Unstable3128923.07df = 22.26, 4.167.18<0.000147%0.340.0013
Angina3027983.61P = 0.60962.72, 4.818.81<0.000132%0.190.1179
Improvement>50%6560643.32W = 02.52.72, 4.0411.93<0.000137%0.230.0030
>80%6358561.75P < 0.00011.54, 1.988.65<0.000125%0.060.0557
GXN164083.19 = 0.48911.86, 5.494.21<0.00010%00.8454
GXN + CG24946813.43df = 22.81, 4.1912.07<0.000121%0.110.1177
GXN + CG + additional3109753.07P = 0.78301.47, 6.412.990.0022872%0.98<0.0001

CI is confidence interval; Z and P (eff) are statistical terms for evaluating overall effect; , , and P (het) are statistical terms for assessing heterogeneity among studies.

GroupNumber of
RCTs
Number of
participants
ORWilcoxon
test
95% CIZ P (eff) P (het)

M score≤32119952.47W = 1491.79, 3.415.53<0.000152%0.280.0025
>31717092.71P = 0.39452.17, 3.398.77<0.00010%00.9136
Sample size<932317342.42W = 1271.93, 3.027.72<0.00010%00.9776
≥931519702.86P = 0.17891.94, 4.215.33<0.000167%0.370.0002
Number of authors11918722.30W = 1401.72, 3.085.65<0.000141%0.160.0358
>11918322.98P = 0.24282.34, 3.808.81<0.000113%0.040.4435
Publication year≤20081512682.49W = 2001.94, 3.207.17<0.00010%00.9538
>20082324362.68P = 0.42001.99, 3.616.47<0.000152%0.260.0025
Trial date reportReported3130692.43W = 571.97, 3.008.29<0.000134%0.120.0511
Not reported76353.67P = 0.05482.36, 5.705.79<0.00018%0.030.5363
Baseline
comparison
Reported3433182.64W = 852.14, 3.249.20<0.000135%0.120.0513
Not reported43862.29P = 0.43251.25, 4.192.680.007423%0.090.2200
Adverse
events
Reported1919552.67W = 1922.16, 3.309.14<0.00010%00.8792
Not reported1917492.54P = 0.74801.80, 3.595.28<0.000154%0.310.0020
Follow-up
period (day)
≤142725282.83W = 1292.34, 3.4210.67<0.00012%00.7120
>141111762.21P = 0.54071.37, 3.573.27<0.000165%0.390.0024
GXN daily6–200 mL3837042.59W = 707.52.14, 3.159.68<0.000132%0.110.0539
dosage (mL)6–30 mL3736482.58P = 0.96622.12, 3.149.45<0.000133%0.11750.0448
GXN daily<2043521.89 = 3.4288,1.00, 3.551.960.049727%0.11480.2425
dosage (mL)202423242.80df = 22.14, 3.667.51<0.000143%0.18200.0246
>201010282.53P = 0.18011.85, 3.465.81<0.000114%0.03650.5413
Types of anginaStable43743.03 = 0.70101.80, 5.094.18<0.00010%00.6688
Unstable1616762.48df = 21.95, 3.157.42<0.000110%0.020.2332
Angina1816542.60P = 0.70431.87, 3.615.68<0.000146%0.220.0191
Improvement>50%3837042.59W = 10502.14, 3.159.68<0.000132%0.110.0539
>80%3837041.84P < 0.00011.59, 2.148.06<0.00010%00.8367
GXN131883.15 = 1.66041.71, 5.813.680.00020%00.9202
GXN + CG22929632.68df = 22.10, 3.417.98<0.000142%0.170.0157
GXN + CG + additional365532.09P = 0.43601.45, 3.013.94<0.00010%00.6382

CI is confidence interval; Z and P (eff) are statistical terms for evaluating overall effect; , , and P (het) are statistical terms for assessing heterogeneity among studies.
3.5. Subgroup Analysis

ORs of the subgroups in both SYMPTOMS (Table 3) and ECG (Table 4) were compared based on the study characteristics including scores (≤3 or >3), sample sizes (<93 or ≥93), number of authors (1 or >1), years of publication (before or after January 1, 2008), reports of trial dates (yes or no), baseline comparison of participants (yes or no), reports of adverse events (yes or no), follow-up periods (≤14 days or >14 days), GXN daily dosages (<20 mL, 20 mL, >20 mL), different angina types, and different treatments including GXN monotherapy versus control treatment, GXN + control versus control, and GXN mixed treatment + control versus control. There was no statistically significant difference between ORs of these subgroups.

3.6. Sensitivity Analysis

When the improvement criteria were raised to the significant level from the basic level, the overall results remained effective (i.e., OR > 1) and statistically significant. The OR of overall SYMPTOMS decreased from 3.32 to 1.75 (95% CI: [1.54, 1.98], , ). The OR of overall ECG decreased from 2.59 to 1.84 (95% CI: [1.59, 2.14], , ). There was a statistically significant correlation between the changes in ORs of SYMPTOMS and ECG outcomes ( , ). When study [33] with maximum GXN dosage was excluded, there was no statistically significant difference between ORs of groups in both SYMPTOMS and ECG data.

3.7. Metaregression

Table 5 shows the results of metaregression between log OR and study characteristics. There seemed to be no statistically significant relationship between GXN’s efficacy and study characteristics, except that follow-up periods made a significant difference ( ) on the log OR with ECG data.


log ORNumber of RCTsNumber of participantsFactorCoefficientz P

SYMPTOMS656064M score0.06630.4378 0.6615
Sample size−0.0013−0.49550.6203
Number of authors−0.0466−0.62830.5298
Publication year−0.0838−1.91580.0554
Trial date report−0.1931−0.76340.4453
Baseline comparison0.32991.33760.1810
Adverse events−0.0965−0.46460.6422
Follow-up period0.01160.6126 0.5401

ECG383704M score0.11910.7160 0.4740
Sample size0.00060.2938 0.7689
Number of authors−0.0100−0.10710.9147
Publication year−0.0180−0.42960.6675
Trial date report−0.4255−1.56060.1186
Baseline comparison0.15200.44580.6558
Adverse events0.10660.53000.5961
Follow-up period−0.0423−2.60000.0093

3.8. Risk of Bias Across Studies

Visual assessment of funnel plots (Figure 4) found obvious asymmetry, indicating that there were publication biases in the results of both SYMPTOMS and ECG. Egger’s test (SYMPTOMS: , ; ECG: , ) and Begg’s test (SYMPTOMS: , ; ECG: , ) detected statistically significant publication biases. Trim-and-fill method found that there were 24 missing studies for SYMPTOMS and 13 missing studies for ECG on the left side of the corresponding funnel plots.

3.9. Adverse Events

As shown in Table 6, the most frequently reported adverse event of GXN was headache. All adverse effects were minor or well tolerated as they did not cause dropouts except in one study [31] where six participants dropped out because of the adverse effects. Headache, epigastria discomfort, and palpitation were noted as the top three adverse effects of drugs in control group. Adverse effects of GXN were less than those of control drugs in the number of types, severity, and frequency.


Treatment groupControl group
Number of AEsNumber of studiesNumber of AEsNumber of studies

Headache10493
Dizziness1111
Palpitation4273
Skin ecchymosis8261
Serum transaminase elevated11NRNR
Nausea1131
Epigastria discomfort4283
Abnormal liver function11NRNR
Skin allergyNRNR11
General weaknessNRNR11
Cold sweatNRNR51
HypotensionNRNR11
Skin mucosal bleedingNRNR11
No AEs027024
Total AEs reports3094311
No AE report028029

NR: not reported; AEs: adverse events.

4. Discussion

This study provides the first comprehensive, up-to-date, and PRISMA-compliant systematic review on the efficacy of GXN in treating angina pectoris. Among 65 included RCTs with 6064 participants, overall ORs of SYMPTOMS and ECG were 3.32 (95% CI: [2.72, 4.04]) ( ) and 2.59 (95% CI: [2.14, 3.15]) ( ), respectively. Subgroup analysis also found statistical significance in the differences between GXN treatment group and control group in testing GXN monotherapy and adjunctive therapy. These results indicated that GXN treatment is effective in treating angina pectoris.

The results of this meta-analysis were robust as shown in subgroup analysis, sensitivity analysis, and metaregression on various parameters including sample sizes, follow-up periods, daily dosages of GXN, types of angina pectoris, and the quality scores of RCTs. Although funnel plots, Begg’s test, Egger’s test, and trim-and-fill method found publication biases, the overall effects would still favor GXN treatment after enough number of less favorable studies were published to restore the symmetry of funnel plots.

The efficacy of GXN in both monotherapy and adjunctive therapy of angina pectoris exemplifies potential uses of chemical components of GXN as one of the herbal products that have offered great potentials in developing multitarget agents to treat complex diseases [91]. Experimental studies also showed that the aqueous extracts from both Danshen and Chuanxiong significantly reduced the myocardial infarct size in rat myocardial ischemia/reperfusion injury [92]. As seen from the clinical and experimental findings, GXN seems to be a promising resource for identifying new therapeutic agents or new drug targets [93] in treating angina pectoris. Although subgroup analysis and sensitivity analysis did not suggest any significant factors which would influence the efficacy of GXN, clinical heterogeneity may contribute to heterogeneity of this meta-analysis.

The limitations of this study include small sample sizes and short follow-up periods. The mean sample size was 93, which was lower than 124 as required by an alpha of 0.05, the proportions of 0.899 for GXN and 0.742 for control group, and a power of 0.8 [94]. The patients of angina pectoris would need long-term treatment [95], but most available RCTs have short follow-up periods.

Another major limitation of this systematic review is the low quality of included studies although most of included RCT reports achieved the average quality of Chinese RCTs [96, 97], which is still inadequate. Almost all (63 out of 65) studies scored 2 at the Jadad scale, which ranges between 0 and 5. One study [34] reported single blinding and another study [47] reported double blinding. Twenty-four RCTs scored 4 at the scale and 40 RCTs scored less than 4 at the scale. There is evidence of the Cochrane Library’s tool to show high risks of bias with the aspects of selection bias, performance bias, and detection bias. More than that, less than but almost half of included RCTs (28/65) did not report adverse events, one possible reason of which is high reporting bias for selecting reporting. Safety of GXN intervention cannot be assessed because of incomplete reporting data. Despite the fact that subgroup analysis found no statistically significant differences in ORs of SYMPTOMS and ECG between the RCTs of low and medium scores, high-quality RCTs would be necessary to further support the efficacy of GXN-based medicines over conventional Western drugs in treating angina pectoris.

Seventy-three out of 6064 participants had AE. The main AEs included headache (19), skin ecchymosis (14), epigastria discomfort (12), and palpitation (11). Headache was the most frequent AE in this paper. The AE mechanisms of GXN are not clear and definite. The functions of dilated blood vessels and coronary artery blood circulation activating are possible reasons that lead to adverse events.

According to this meta-analysis, GXN seems to be effective in treating angina pectoris. As GXN contains the herbal extracts from Salvia miltiorrhiza and Ligustrazine, hence DSS, PAC, PAL, CAA, and SAB as the main active ingredients with potential effects on coronary heart disease, angina pectoris, and cardiovascular diseases [98] by enhancing coronary blood flow, improving the myocardial systolic functions, and protecting myocardial cells [99], further clinical, herbal formulation and pharmacological studies are warranted for further research and development.

5. Conclusion

This meta-analysis of eligible RCTs provides evidence that GXN is effective in treating angina pectoris. This evidence warrants further RCTs of higher quality, longer follow-up periods, larger sample sizes, and multicentres/multicountries for more extensive subgroup, sensitivity, and metaregression analyses.

Conflict of Interests

The authors have no conflict of interests.

Authors’ Contributions

S. Leung and M. Lee conceived the meta-analytic assessment of GXN’s efficacy. S. Leung, M. Lee, and Y. Jia conducted the study design. G. Cui, X. Huang and M. Lee reviewed the pharmacology and potential clinical applications of GXN. Y. Jia and F. Pan searched the databases for RCTs, retrieved the studies, evaluated the quality of the studies, and extracted the data. Y. Jia and S. Leung analyzed the data and wrote the paper. All authors revised, read, and approved the paper.

Acknowledgments

The work of Y. Jia, F. Pan, and S. Leung was supported by a research Grant from the University of Macau for a study on “Open systematic reviewing of clinical trials” (MYRG190 (Y2-L3)-ICMS11-LSW). The work of G. Cui, X. Huang, M. Lee was supported by a Research Grant from the Science and Technology Development Fund, Macao, for a study on “Mechanistic studies of active compounds from Chinese medicine and their combinations for minimising and treating cardio-cerebrovascular complications” (ref. no. 014/2011/A1).

Supplementary Materials

Supplementary Table 1 provides the treatment (drugs and dosages for control and treatment groups) details about the RCTs included in this study.

  1. Supplementary Material

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Copyright © 2013 Yongliang Jia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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