Evidence-Based Complementary and Alternative Medicine

Volume 2013 (2013), Article ID 282707, 16 pages

http://dx.doi.org/10.1155/2013/282707

Review Article

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

Yongliang Jia,¹ Siu-wai Leung,1,2 Ming-Yuen Lee,¹ Guozhen Cui,¹ Xiaohui Huang,¹ and Fongha Pan¹

¹State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China

²School of Informatics, University of Edinburgh, Edinburgh EH8 9AB, UK

Received 22 July 2012; Revised 20 January 2013; Accepted 21 January 2013

Academic Editor: Myeong Soo Lee

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.

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.

Figure 1: Process of searching and screening studies.

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 [26–90] 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.

Table 1: Characteristics of the included studies.

Study
Number of authors
Trial date report
Sample

size
Followup

(day)
Baseline comparison
AE
Outcomes

measure
Treatment group dosage
Angina

Chen 2009
1
1
100
15
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Chen et al. 2011
3
1
100
10
0
0
SYM
GXN 20 mL/d + CG
Angina

Chen 2006
1
1
62
14
1
1
SYM, ECG
GXN 20 mL/d + CG
Angina

Cheng and Zang 2010
2
1
43
14
1
0
SYM
GXN 30 mL/d + CG
Unstable

Cheng et al. 2011
3
1
76
14
1
1
SYM, ECG
GXN 30 mL/d + CG
Angina

Dong XP 2009
1
0
100
1
0
0.5
SYM
GXN 20 mL/d
Angina

Fu and Meng 2011
2
0
47
10
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Fu et al. 2010
4
1
56
14
1
0
SYM, ECG
GXN 200 ml + CG + shenmaiyin 40 ml
Angina

Gao et al. 2005
3
1
60
14
1
1
SYM, ECG
GXN 20 mL/d
Angina

Gong et al. 2009
3
1
85
14
1
1
SYM, ECG
GXN 20 mL/d + xueshuantong 20 ml
Stable

He and Meng 2007
1
1
49
15
1
0
SYM
GXN 20 mL/d + CG
Unstable

He 2009
1
1
120
28
1
1
SYM, ECG
GXN 30 mL/d + atorvastatin 10 mg
Unstable

Hou and Gao 2009
2
1
128
14
1
1
SYM, ECG
GXN 20 mL/d + CG
Stable

Huang et al. 2011
4
0
120
7
1
1
SYM
GXN 20 mL/d + CG + xueshuantong 400 mg
Angina

Jiang et al. 2010
3
1
116
10
1
0
SYM, ECG
GXN 20 mL/d + CG
Unstable

Jiang 2009
1
1
68
20
1
1
SYM, ECG
GXN 20 mL/d
Angina

Jiang et al. 2010
5
0
56
7
0
1
SYM
GXN 30 mL/d
Angina

Kong 2009
1
0
100
14
1
1
SYM
GXN 30 mL/d + CG
Unstable

Lan et al. 2006
3
1
64
14
1
1
SYM
GXN 20 mL/d
Angina

Li and Jia 2011
2
1
200
14
1
0
SYM, ECG
GXN 30 mL/d + CG
Angina

Li and Lei 2005
2
1
156
14
0
1
SYM, ECG
GXN 20 mL/d + CG
Angina

Li et al. 2009
5
1
168
14
1
0
SYM
GXN 20 mL/d + CG
Angina

Li and Ran 2009
2
1
160
10
1
1
SYM
GXN 20 mL/d + CG
Angina

Li 2004
1
0
83
7
1
0
SYM, ECG
GXN 20 mL/d + CG
Unstable

Liang and Feng 2010
2
0
120
14
1
0
SYM, ECG
GXN 20 mL/d + CG
Unstable

Liu 2004
1
1
104
10
1
1
SYM
GXN 20 mL/d + CG
Unstable

Liu and Li 2007
2
1
88
12
0
1
SYM
GXN 20 mL/d + CG
Unstable

Liu 2005
1
1
80
30
1
0
SYM, ECG
GXN 20 mL/d + CG
Unstable

Liu 2011
1
1
152
28
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Lu et al. 2006
3
1
68
30
1
0
SYM
GXN 30 mL/d + CG
Angina

Ma and Peng 2008
2
1
120
14
1
0
SYM
GXN 30 mL/d + CG
Unstable

Nie and Chen 2007
2
1
60
14
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Qiao and Wu 2004
2
0
81
28
1
1
SYM, ECG
GXN 20 mL/d + CG
Stable

Song 2010
1
1
82
7
0
0.5
SYM
GXN 20 mL/d + CG + diltiazem 90 mg/d
Unstable

Su 2009
1
1
90
15
0
1
SYM, ECG
GXN 6 mL/d + CG
Angina

Sun 2010
1
1
90
14
1
0
SYM, ECG
GXN 30 mL/d + CG
Unstable

Sun et al. 2006
5
1
98
15
0
0
SYM
GXN 20 mL/d + CG
Angina

Tian and Wu 2006
2
1
62
14
1
1
SYM
GXN 30 mL/d + CG
Unstable

Wan and Xu 2009
2
0
120
14
1
1
SYM, ECG
GXN 30 mL/d + CG
Unstable

Wang 2007
1
1
100
14
1
1
SYM, ECG
GXN 30 mL/d + CG
Angina

Wang 2011
1
1
85
14
1
1
SYM, ECG
GXN 20 mL/d + CG
Unstable

Wang 2011
2
1
112
14
1
1
SYM, ECG
GXN 20 mL/d + CG
Unstable

Wang and Ji 2008
2
1
60
14
0
0
SYM, ECG
GXN 20 mL/d + CG
Unstable

Wang and Sun 2007
2
1
92
10
0
0
SYM
GXN 20 mL/d + CG
Unstable

Wang 2005
2
1
60
15
1
0
SYM
GXN 20 mL/d + CG
Unstable

Wang 2010
1
0
80
14
1
1
SYM, ECG
GXN 20 mL/d + CG
Stable

Wang 2005
1
0
76
15
0
0
SYM
GXN 20 mL/d + CG + shenmai 30 mL/d + tongxinluo 9 pills/d
Unstable

Wang 2005
1
1
60
14
1
1
SYM
GXN 20 mL/d + CG
Unstable

Wang et al. 2011
4
1
60
14
1
1
SYM
GXN 20 mL/d + CG
Unstable

Wu et al. 2008
3
0
108
14
1
0
SYM
GXN 20 mL/d + CG
Angina

Wu et al. 2011
4
1
144
7
1
0
SYM
GXN 20 mL/d + CG + shenmai 50 mL/d
Unstable

Xia 2011
1
1
90
14
1
0
SYM, ECG
GXN 30 mL/d + CG
Unstable

Yang and Ma 2008
2
1
90
14
1
0
SYM, ECG
GXN 30 mL/d + CG
Unstable

Ye et al. 2008
3
0
76
15
0
1
SYM
GXN 20 mL/d + CG
Unstable

Yu and Wang 2009
2
1
75
15
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Yuan 2005
1
0
104
14
1
0
SYM, ECG
GXN 20 mL/d + CG
Angina

Zhang 2005
1
1
60
14
1
0
SYM, ECG
GXN 10 mL/d
Angina

Zhang 2010
1
1
240
15
1
1
SYM, ECG
GXN 20 mL/d + CG
Unstable

Zhang 2004
1
1
102
14
1
1
SYM, ECG
GXN 10 mL/d + CG + ginkgo leaf injection 10 mL/d
Angina

Zhang 2004
1
1
42
7
0
1
SYM
GXN 20 mL/d + CG
Angina

Zhao et al. 2010
6
1
100
14
1
1
SYM, ECG
GXN 10 mL/d + CG + xueshuangtong 120 mg
Unstable

Zhao and An 2008
2
1
90
28
1
1
SYM, ECG
GXN 20 mL/d + CG + simvastatin 10–20 mg/d
Unstable

Zhao 2010
1
1
86
14
1
0
SYM, ECG
GXN 30 mL/d + CG
Angina

Zhong et al. 2007
8
1
60
10
0
0
SYM
GXN 20 mL/d + CG
Angina

Zhu 2005
1
1
80
15
0
0.5
SYM, ECG
GXN 20 mL/d + CG
Unstable

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.

Table 2: Quality assessment of included studies.

Study
C1
C2
C3
C4
C5
C6
C7
C8
Comparable
Random　
Blind　
Dropout
AE
Jadad　
M

Chen 2009
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Chen et al. 2011
Low
Unclear
High
High
Low
Low
High
High
0
1
0
1
0
2
2

Chen 2006
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Cheng and Zeng 2010
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Cheng et al. 2011
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Dong 2009
Low
High
High
High
Low
Low
Unclear
High
0
1
0
1
0.5
2
2.5

Fu and Meng 2011
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Fu et al. 2010
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Gao et al. 2005
Low
Low
High
High
Low
Low
Low
Low
1
1
1
1
1
3
5

Gong et al. 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

He 2007
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

He 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Hou and Gao 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Huang et al. 2011
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Jiang et al. 2010
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Jiang 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Jiang et al. 2010
Low
High
High
High
Low
Low
Low
Low
0
1
0
1
1
2
3

Kong 2009
Low
High
High
High
Low
Low
Unclear
Low
1
1
0
1
1
2
4

Lan et al. 2006
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Li and Jia 2011
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Li and Lei 2005
Low
High
High
High
Low
Low
Low
Low
0
1
0
1
1
2
3

Li et al. 2009
Low
Low
Low
Low
Low
Low
High
High
1
1
2
1
0
4
5

Li and Ran 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Li 2004
Low
High
High
High
Low
Low
High
Low
1
1
0
1
0
2
3

Liang and Feng 2010
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Liu 2004
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Liu and Li 2007
Low
High
High
High
Low
Low
High
High
0
1
0
1
1
2
3

Liu 2005
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Liu 2011
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Lu et al. 2006
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Ma and Peng 2008
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
0
2
3

Nie and Chen 2007
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Qiao and Wu 2004
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Song 2010
Low
High
High
High
Low
Low
Low
Unclear
0
1
0
1
0.5
2
2.5

Su 2009
Low
Unclear
High
High
Low
Low
Low
Low
0
1
0
1
1
2
3

Sun 2010
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Sun et al. 2006
Low
High
High
High
Low
Low
High
Unclear
0
1
0
1
0
2
2

Tian and Wu 2006
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wan and Xu 2009
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wang 2007
Low
High
High
High
Low
Low
Low
High
1
1
0
1
1
2
4

Wang 2011
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wang 2011
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wang and Ji 2008
Low
High
High
High
Low
Low
High
High
0
1
0
1
0
2
2

Wang and Sun 2007
Low
High
High
High
Low
Low
High
Unclear
0
1
0
1
0
2
2

Wang 2005
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Wang 2010
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wang 2005
Low
High
High
High
Low
Low
High
Unclear
0
1
0
1
0
2
2

Wang 2005
Low
Low
Unclear
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wang et al. 2011
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Wu et al. 2008
Low
High
High
High
Low
Low
High
Unclear
1
1
0
1
0
2
3

Wu et al. 2011
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Xia 2011
Low
Low
Unclear
High
Low
Low
High
Unclear
1
1
0
1
0
2
3

Yang and Ma 2008
Low
Low
Unclear
High
Low
Low
High
High
1
1
0
1
0
2
3

Ye et al. 2008
Low
High
High
High
Low
Low
Low
Low
0
1
0
1
1
2
3

Yu and Wang 2009
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Yuan 2005
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Zhang 2005
Low
High
High
High
Low
Low
High
High
1
1
0
1
0
2
3

Zhang 2010
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Zhang 2004
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Zhang 2004
Low
High
High
High
Low
Low
Low
High
0
1
0
1
1
2
3

Zhao et al. 2010
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Zhao and An 2008
Low
High
High
High
Low
Low
Low
Low
1
1
0
1
1
2
4

Zhao 2010
Low
High
High
High
Low
Low
High
Unclear
1
1
0
1
0
2
3

Zhong et al. 2007
Low
High
High
High
Low
Low
High
High
0
1
0
1
0
2
2

Zhu 2005
Low
High
High
High
Low
Low
Unclear
Unclear
0
1
0
1
0.5
2
2.5

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 (; ).

Table 3: Subgroups and sensitivity analysis on SYMPTOMS outcomes.

Group
Number of

RCTs
Number of

participants
OR
Wilcoxon

test
95% CI
Z
P (eff)

P (het)

M score
≤3
40
3625
3.21
W = 546
2.36, 4.35
7.46
<0.0001
54%
0.50
<0.0001

>3
25
2439
3.51
P = 0.5395
2.78, 4.43
10.50
<0.0001
0%
0
0.9858

Sample size
<93
39
2772
3.22
W = 445.5
2.59, 4.01
10.51
<0.0001
0%
0
0.6150

≥93
26
3292
3.37
P = 0.4140
2.39, 4.76
6.89
<0.0001
60%
0.47
<0.0001

Number of authors
1
27
2485
3.18
W = 1189
2.39, 4.24
7.92
<0.0001
28%
0.16
0.1253

>1
38
3579
3.40
P = 0.7558
2.60, 4.46
8.87
<0.0001
44%
0.30
0.0031

Publication year
≤2008
31
2495
3.80
W = 441.5
3.01, 4.81
11.19
<0.0001
1%
0.01
0.2929

>2008
34
3569
2.94
P = 0.2642
2.20, 3.93
7.32
<0.0001
48%
0.34
0.0016

Trial date report
Reported
51
4793
3.19
W = 2112.5
2.57, 3.95
10.52
<0.0001
36%
0.21
0.0189

Not reported
14
1271
3.84
P = 1
2.33, 6.33
5.28
<0.0001
47%
0.40
0.0254

Baseline

comparison
Reported
50
4808
3.56
W = 2112.5
2.84, 4.45
11.10
<0.0001
40%
0.25
0.0057

Not reported
15
1256
2.53
P = 1
1.75, 3.68
4.89
<0.0001
14%
0.08
0.1545

Adverse

events
Reported
31
2947
3.20
W = 1006
2.58, 3.97
10.59
<0.0001
0%
0
0.4304

Not reported
34
3117
3.48
P = 0.4678
2.53, 4.78
7.68
<0.0001
51%
0.44
0.0003

Follow-up

period (day)
≤14
48
4461
3.38
W = 440
2.75, 4.16
11.51
<0.0001
28%
0.14
0.1321

>14
17
1603
3.05
P = 0.6382
1.81, 5.16
4.18
<0.0001
61%
0.71
0.0005

GXN daily
6–200 mL
65
6064
3.32
W = 2059
2.72, 4.04
11.93
<0.0001
37%
0.23
0.0030

Dosage (mL)
6–30 mL
64
6008
3.34
P = 0.9231
2.73, 4.07
11.83
<0.0001
38%
0.24
0.0025

GXN daily
<20
4
352
3.42
= 0.4290
1.48, 7.91
2.88
0.0040
38%
0.28
0.1717

Dosage (mL)
20
45
4235
3.16
df = 2
2.45, 4.07
8.85
<0.0001
46%
0.33
0.0004

>20
16
1477
3.87
P = 0.8069
2.84, 5.29
8.51
<0.0001
0%
0
0.8315

Types of angina
Stable
4
374
3.42
= 0.9900
1.89, 6.21
4.05
<0.0001
0%
0
0.7151

Unstable
31
2892
3.07
df = 2
2.26, 4.16
7.18
<0.0001
47%
0.34
0.0013

Angina
30
2798
3.61
P = 0.6096
2.72, 4.81
8.81
<0.0001
32%
0.19
0.1179

Improvement
>50%
65
6064
3.32
W = 02.5
2.72, 4.04
11.93
<0.0001
37%
0.23
0.0030

>80%
63
5856
1.75
P < 0.0001
1.54, 1.98
8.65
<0.0001
25%
0.06
0.0557

GXN
1
6
408
3.19
= 0.4891
1.86, 5.49
4.21
<0.0001
0%
0
0.8454

GXN + CG
2
49
4681
3.43
df = 2
2.81, 4.19
12.07
<0.0001
21%
0.11
0.1177

GXN + CG + additional
3
10
975
3.07
P = 0.7830
1.47, 6.41
2.99
0.00228
72%
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.

Table 4: Subgroups and sensitivity analysis on ECG outcomes.

Group
Number of

RCTs
Number of

participants
OR
Wilcoxon

test
95% CI
Z
P (eff)

P (het)

M score
≤3
21
1995
2.47
W = 149
1.79, 3.41
5.53
<0.0001
52%
0.28
0.0025

>3
17
1709
2.71
P = 0.3945
2.17, 3.39
8.77
<0.0001
0%
0
0.9136

Sample size
<93
23
1734
2.42
W = 127
1.93, 3.02
7.72
<0.0001
0%
0
0.9776

≥93
15
1970
2.86
P = 0.1789
1.94, 4.21
5.33
<0.0001
67%
0.37
0.0002

Number of authors
1
19
1872
2.30
W = 140
1.72, 3.08
5.65
<0.0001
41%
0.16
0.0358

>1
19
1832
2.98
P = 0.2428
2.34, 3.80
8.81
<0.0001
13%
0.04
0.4435

Publication year
≤2008
15
1268
2.49
W = 200
1.94, 3.20
7.17
<0.0001
0%
0
0.9538

>2008
23
2436
2.68
P = 0.4200
1.99, 3.61
6.47
<0.0001
52%
0.26
0.0025

Trial date report
Reported
31
3069
2.43
W = 57
1.97, 3.00
8.29
<0.0001
34%
0.12
0.0511

Not reported
7
635
3.67
P = 0.0548
2.36, 5.70
5.79
<0.0001
8%
0.03
0.5363

Baseline

comparison
Reported
34
3318
2.64
W = 85
2.14, 3.24
9.20
<0.0001
35%
0.12
0.0513

Not reported
4
386
2.29
P = 0.4325
1.25, 4.19
2.68
0.0074
23%
0.09
0.2200

Adverse

events
Reported
19
1955
2.67
W = 192
2.16, 3.30
9.14
<0.0001
0%
0
0.8792

Not reported
19
1749
2.54
P = 0.7480
1.80, 3.59
5.28
<0.0001
54%
0.31
0.0020

Follow-up

period (day)
≤14
27
2528
2.83
W = 129
2.34, 3.42
10.67
<0.0001
2%
0
0.7120

>14
11
1176
2.21
P = 0.5407
1.37, 3.57
3.27
<0.0001
65%
0.39
0.0024

GXN daily
6–200 mL
38
3704
2.59
W = 707.5
2.14, 3.15
9.68
<0.0001
32%
0.11
0.0539

dosage (mL)
6–30 mL
37
3648
2.58
P = 0.9662
2.12, 3.14
9.45
<0.0001
33%
0.1175
0.0448

GXN daily
<20
4
352
1.89
= 3.4288,
1.00, 3.55
1.96
0.0497
27%
0.1148
0.2425

dosage (mL)
20
24
2324
2.80
df = 2
2.14, 3.66
7.51
<0.0001
43%
0.1820
0.0246

>20
10
1028
2.53
P = 0.1801
1.85, 3.46
5.81
<0.0001
14%
0.0365
0.5413

Types of angina
Stable
4
374
3.03
= 0.7010
1.80, 5.09
4.18
<0.0001
0%
0
0.6688

Unstable
16
1676
2.48
df = 2
1.95, 3.15
7.42
<0.0001
10%
0.02
0.2332

Angina
18
1654
2.60
P = 0.7043
1.87, 3.61
5.68
<0.0001
46%
0.22
0.0191

Improvement
>50%
38
3704
2.59
W = 1050
2.14, 3.15
9.68
<0.0001
32%
0.11
0.0539

>80%
38
3704
1.84
P < 0.0001
1.59, 2.14
8.06
<0.0001
0%
0
0.8367

GXN
1
3
188
3.15
= 1.6604
1.71, 5.81
3.68
0.0002
0%
0
0.9202

GXN + CG
2
29
2963
2.68
df = 2
2.10, 3.41
7.98
<0.0001
42%
0.17
0.0157

GXN + CG + additional
3
6
553
2.09
P = 0.4360
1.45, 3.01
3.94
<0.0001
0%
0
0.6382

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.

Figure 2: Forest plot of outcome measure SYMPTOMS.

Figure 3: Forest plot of outcome measure ECG.

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.

Table 5: Metaregression analysis of the relationship between outcomes and the study characteristics.

log OR
Number of RCTs
Number of participants
Factor
Coefficient
z
P

SYMPTOMS
65
6064
M score
0.0663
0.4378
0.6615

Sample size
−0.0013
−0.4955
0.6203

Number of authors
−0.0466
−0.6283
0.5298

Publication year
−0.0838
−1.9158
0.0554

Trial date report
−0.1931
−0.7634
0.4453

Baseline comparison
0.3299
1.3376
0.1810

Adverse events
−0.0965
−0.4646
0.6422

Follow-up period
0.0116
0.6126
0.5401

ECG
38
3704
M score
0.1191
0.7160
0.4740

Sample size
0.0006
0.2938
0.7689

Number of authors
−0.0100
−0.1071
0.9147

Publication year
−0.0180
−0.4296
0.6675

Trial date report
−0.4255
−1.5606
0.1186

Baseline comparison
0.1520
0.4458
0.6558

Adverse events
0.1066
0.5300
0.5961

Follow-up period
−0.0423
−2.6000
0.0093

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.

(a)

(b)

Figure 4: Funnel plots of (a) the included studies with SYMPTOMS data and (b) the included studies with ECG data.

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.

Table 6: Adverse events reported in the included studies.

Treatment group
Control group

Number of AEs
Number of studies
Number of AEs
Number of studies

Headache
10
4
9
3

Dizziness
1
1
1
1

Palpitation
4
2
7
3

Skin ecchymosis
8
2
6
1

Serum transaminase elevated
1
1
NR
NR

Nausea
1
1
3
1

Epigastria discomfort
4
2
8
3

Abnormal liver function
1
1
NR
NR

Skin allergy
NR
NR
1
1

General weakness
NR
NR
1
1

Cold sweat
NR
NR
5
1

Hypotension
NR
NR
1
1

Skin mucosal bleeding
NR
NR
1
1

No AEs
0
27
0
24

Total AEs reports
30
9
43
11

No AE report
0
28
0
29

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).

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