Comparative Efficacy of Tongxinluo Capsule and Beta-Blockers in Treating Angina Pectoris: Meta-Analysis of Randomized Controlled Trials

Abstract

Objective:

There have been no systematic reviews, let alone meta-analyses, of randomized controlled trials (RCTs) comparing tongxinluo capsule (TXL) and beta-blockers in treating angina pectoris. This study aimed to evaluate the efficacy of TXL and beta-blockers in treating angina pectoris by a meta-analysis of eligible RCTs.

Methods:

The RCTs comparing TXL with beta-blockers (including metoprolol) in treating angina pectoris were searched and retrieved from databases including PubMed, Chinese National Knowledge Infrastructure, and WanFang Data. Eligible RCTs were selected according to prespecified criteria. Meta-analysis was performed on the odds ratios (OR) of symptomatic and electrocardiographic (ECG) improvements after treatment. Subgroup analysis, sensitivity analysis, meta-regression, and publication biases analysis were conducted to evaluate the robustness of the results.

Results:

Seventy-three RCTs published between 2000 and 2014 with 7424 participants were eligible. Overall ORs comparing TXL with beta-blockers were 3.40 (95% confidence interval [CI], 2.97–3.89; p<0.0001) for symptomatic improvement and 2.63 (95% CI, 2.29–3.02; p<0.0001) for ECG improvement. Subgroup analysis and sensitivity analysis found no statistically significant dependence of overall ORs on specific study characteristics except efficacy criteria. Meta-regression found no significant except sample sizes for data on symptomatic improvement. Publication biases were statistically significant.

Conclusion:

TXL seems to be more effective than beta-blockers in treating angina pectoris, on the basis of the eligible RCTs. Further RCTs are warranted to reduce publication bias and verify efficacy.

Introduction

Angina pectoris, a symptom of coronary heart disease (CHD), is pain or discomfort in the chest due to ischemia of the heart muscle during obstruction or spasm of the coronary arteries.¹Conventional anti-anginal drugs include four categories: beta-blockers (e.g., metoprolol), calcium channel blockers (e.g., verapamil), nitrates (e.g., isosorbide dinitrate), and potassium channel activators (e.g., nicorandil). Beta-blockers are the recommended first-line drug for relieving symptoms of stable angina.² Beta-blockers improve oxygen supply and demand balance through reduction of heart rates and blood pressures, decreases in systolic stress and contractility, prolongation of diastole, enhancement of coronary flows.² Chinese patent medicines, including danshen dripping pill, di'ao xinxuekang capsule, and tongxinluo capsule (TXL) were found to be more effective than starting doses of isosorbide dinitrate, as shown in a direct meta-analysis.^3
–5 It was interesting that indirect comparisons through meta-analysis found that TXL was even more effective than Danshen dripping pill.⁶

TXL was approved as a new drug (drug approval number Z19980015) by the Ministry of Health of China in 1996.⁷ According to the Chinese Pharmacopoeia 2010, the recommended dosages of TXL are two to four pills each time (three times daily) given a content of 0.26 g per pill.⁸ TXL comprises Radix ginseng, Hirudo species, scorpion, Radix paeoniae Rubra, Periostracum cicadae, Eupolyphaga species, Scolopendra species, sandalwood, Lignum dalbergiae odoriferae, frankincense, spina date seeds, and borneol.⁸ Ginseng and its active compound ginsenosides slow down the heart rate and reduce myocardial oxygen consumption.⁹ Hirudo species and its active compound hirudin reduce blood viscosity, improve blood circulation, and dilate blood vessels. Eupolyphaga species reduces left ventricular end-diastolic pressure and heart rate.⁹ As a result, TXL enhances myocardial contractility, dilates blood vessels, reduces cardiac afterload, and improves myocardial blood supply.¹⁰

Previous systematic reviews studied beta-blockers or TXL in treating angina pectoris but did not compare them head-to-head. Because hundreds of randomized controlled trials (RCTs) comparing TXL with beta-blockers have been published, a systematic review and meta-analysis would be in great demand to synthesize evidence from those RCTs. This study aims to conduct a meta-analysis to compare the efficacy of TXL with that of beta-blockers in treating angina pectoris.

Materials and Methods

The design, implementation, analysis, and reporting of this meta-analysis were in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹¹

Search strategies

Databases including PubMed, MEDLINE, Cochrane Library, ScienceDirect, China National Knowledge Infrastructure, WanFang Data, China Master Theses Full-text Database, and China Doctor Dissertations Full-text Database were searched for RCTs on the efficacy of TXL in treating angina pectoris between the inception dates of the databases and 2014 (last search was performed on May 27, 2013). The following search strategy with keywords was used in searching PubMed and other English-language databases:

1. “tongxinluo”

2. “tong-xin-luo”

3. “tong xin luo”

4. 1 OR 2 OR 3

The following search strategy was used in searching the Chinese National Knowledge Infrastructure and other Chinese databases:

1. “tongxinluo”

2. “guanxiabing” [coronary disease]

3. “xinjiaotong” [angina pectoris]

4. 1 IN abstract

5. 2 IN title

6. 3 IN title

7. 4 AND (5 OR 6)

where IN, AND, OR are logical operators for database search.

Study selection

Inclusion criteria for study selection were the following: (1) the participants had and were being treated for angina pectoris, (2) the study design was an RCT; (3) the RCT compared TXL with beta-blockers, and (4) the follow-up period was no less than 4 weeks. Exclusion criteria were the following: (1) duplicated or redundant reports on the same study, (2) studies did not include symptomatic improvement as a major outcome, and (3) the studies were inconsistent or there were discrepancies between methods and results. Figure 1 shows the flow for study selection according to the inclusion and exclusion criteria.

FIG. 1.

Results of the database search and study selection process. IHD, ischemic heart disease; RCT, randomized controlled trial.

Data extraction and quality assessment

For each of the included studies, the following data were extracted: (1) publication year, (2) sample characteristics, (3) follow-up periods, (4) baseline characteristics of participants between groups, (5) sample sizes, (6) outcome measures, including symptomatic and electrocardiography (ECG) improvement, (7) drug treatments in experimental and control groups, and (8) frequencies of adverse events. The quality of the included studies was assessed according to the Cochrane Collaboration's tool for assessing risk of bias,¹² the Jadad scale,¹³ and the refined version of the Jadad scale, the M scale.³ The Cochrane Collaboration's tool to assess the risk of bias comprises six domains assessed as low risk, high risk, and unclear risk: generation of the allocation sequence, concealment of the allocation sequence, blinding, incomplete outcome data, selective outcome reporting, and other biases.¹² The Jadad scale assesses the methodologic quality of a clinical trial in randomization, blinding, and withdrawals and dropouts.¹³ The M scale comprises the Jadad scale plus two additional items: the use of group baselines comparison and the adverse effects description.¹⁴ The quality of evidence was assessed by the grading of recommendation, assessment, development, and evaluation (GRADE) method¹⁴ and was classified into four categories: high, moderate, low, and very low.¹⁵

Efficacy criteria for symptomatic and ECG improvements

For efficacy evaluation, symptomatic improvements should achieve at least 50% (basic) or 80% (significant) reduction in frequency, duration, and severity of angina pain and palpitation. ECG improvements should achieve (1) at least 0.05 mV lowering at the ST segment on ECG (basic) or (2) nearly normal (significant) performance during an exercise test according to the American College of Cardiology/American Heart Association guidelines.¹⁶

Statistical analysis

Overall effect sizes were represented in odds ratios (OR)¹⁷ and 95% confidence intervals (CI).¹⁸ Meta-analysis used the random-effects model, with heterogeneity assessed by chi-square and I² tests.¹⁹ Subgroup and sensitivity analyses were conducted according to the publication years, follow-up periods, sample sizes, study quality scores, efficacy criteria, and treatments. Meta-regression²⁰ was performed to determine possible relationships between the overall effects and such factors as sample sizes, follow-up periods, M scores, and publication years. Funnel plot,²¹ the Egger test,²² and the Begg test²³ were used to assess publication bias. The trim-and-fill method²⁴ was used to correct funnel plot asymmetry arising from publication bias. Information about adverse events (AEs) of RCTs, including nonreported AEs and types and frequencies of AEs reported, was tabulated for evaluation. The Spearman rank correlation test was performed to determine possible correlation between ORs of symptomatic and ECG improvement. The Mann-Whitney-Wilcoxon test was used to compare two subgroups. The Kruskal-Wallis test was used to compare multiple subgroups at the same time. Bonferroni correction of p-values was performed for multiple comparisons. All statistical analyses were performed with statistical software R.²⁵ The “metafor”²⁶ package was used in R for meta-analysis. Any p-values below 0.05 were considered to represent statistically significant findings.

Results

Study selection and characteristics

The search of databases found 2328 records. According to the inclusion and exclusion criteria, 78 RCTs^{27

−104} were included in meta-analysis. Figure 1 shows the process of study selection. Table 1 summarizes the main characteristics of the included studies. All included studies with 7424 participants in total were published in Chinese language between 2000 and 2014. The mean sample size was 95.2 (median: 82; 95% CI, 84.6−105.7). The follow-up periods were between 28 and 180 days. Ten RCTs^{30

−33,42,49,50,75,81,95} reported participants with stable angina pectoris, and 25 RCTs^{28,29,34,35,37,41,46,51,54,55,57,60,64,78,79,82,83,86
–88,90,97,98,100,101} reported participants with unstable angina pectoris. One RCT⁸⁶ used single metoprolol as control daily dosage, 31 RCTs^{27,28,34,35,37,39,43,47,49,50
–52,54,58,61,64,68,69,71,73,74,79,81
–83,87,89,94,99,102,104} used metoprolol plus other conventional anti-anginal drugs as the control daily dosage, and other RCTs used beta-blockers plus other conventional anti-anginal drugs as the control daily dosage. One RCT⁵¹ selected 6 to 12 TXL pills. Four RCTs^48,86,87,91selected 6 TXL pills, 31 RCTs^{27,29
–31,33

–39,44
–46,56
–58,61,67,69,73,76,78,81,82,84,89,94,99,101,104} selected 9 TXL pills, and other RCTs selected 12 TXL pills as daily dosage for treatment. Dosage details were listed in Supplemental Table 1. (Supplementary materials are available online at http://www.liebertpub.com/acm). All 78 included studies reported symptomatic changes while only 47 studies reported ECG changes.

Table 1.

Summary of Included Studies

Study, Year	Authors (n)	Trial date	Sample size	Follow-up (d)	Comparable	AEs	Outcome measure	Jadad score	M score	Treatment group dosage
Cai HJ, 2006	1	1	108	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Cai ZL, 2010	2	0	120	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Chang SF, 2004	2	0	114	42	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Chen XH, 2004	1	1	60	90	1	0.5	SYM, ECG	2	3.5	TXL 9 pills/d + CG
Chen YJ, 2008	2	0	58	90	1	0.5	SYM	2	3.5	TXL 9 pills/d + CG
Fan LJ, 2007	1	1	58	28	0	1	SYM, ECG	3	4	TXL 12 pills/d + CG
Fang ML, 2009	1	0	60	56	1	0	SYM	2	3	TXL 9 pills/d + CG
Guo F, 2010	5	1	102	120	1	0.5	SYM, ECG	2	3.5	TXL 9 pills/d + CG
Guo RB, 2007	3	1	65	30	1	1	SYM	2	4	TXL 9 pills/d + CG
Guo XH, 2009	1	1	112	28	0	0	SYM, ECG	2	2	TXL 9 pills/d + CG
He FX, 2009	1	1	76	28	1	0	SYM	2	3	TXL 9 pills/d + CG
Hu MQ, 2008	3	1	68	28	0	0	SYM	2	2	TXL 9 pills/d + CG
Hu YM, 2005	1	1	108	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Lai JT, 2012	1	1	80	30	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Li DM, 2014	1	1	186	28	1	0	SYM	2	3	TXL 12/d + CG
Li H, 2010	1	1	122	90	1	0	SYM	2	3	TXL 12 pills/d + CG
Li KH, 2009	2	1	78	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Li YH, 2011	1	1	60	28	1	0	SYM	2	3	TXL 9 pills/d + CG
Li YP, 2003	1	1	308	30	1	0.5	SYM, ECG	3	4.5	TXL 9 pills/d + CG
Liao HH, 2013	1	1	60	28	1	1	SYM, ECG	2	4	TXL 9 pills/d + CG
Lin HY, 2004	3	1	65	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Lin SY, 2013	1	1	108	28	1	0	SYM, ECG	2	3	TXL 6 pills/d + CG
Liu HM, 2006	3	0	88	28	1	1	SYM	2	4	TXL 12 pills/d + CG
Liu J, 2002	1	1	97	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Luo H, 2013	1	1	120	90	0	0	SYM	2	2	TXL 6-12/d + CG
Luo XC, 2007	3	0	54	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Luo XM, 2010	1	1	68	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Luo Y, 2008	2	1	82	28	1	0	SYM	2	3	TXL 12 pills/d + CG
Ma YL, 2011	2	1	90	30	1	1	SYM	2	4	TXL 12 pills/d + CG
Qi W, 2010	2	1	124	120	1	0.5	SYM, ECG	2	3.5	TXL 9 pills/d + CG
Qu YX, 2005	2	1	90	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Re NGL, 2012	3	1	80	42	1	0	SYM	2	3	TXL 9 pills/d + CG
Ren CX, 2011	2	1	60	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Rui HM, 2010	2	1	74	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Shen GM, 2009	2	1	60	28	0	1	SYM, ECG	2	3	TXL 9 pills/d + CG
Shen JJ, 2006	5	1	120	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Shi CJ, 2013	3	1	268	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Shi HY, 2007	2	1	65	30	1	1	SYM	2	4	TXL 12 pills/d + CG
Sun GL, 2011	1	1	60	28	1	1	SYM	2	4	TXL 12 pills/d + CG
Sun L, 2005	1	0	68	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Sun L, 2012	3	1	52	28	1	1	SYM	3	5	TXL 9 pills/d + CG
Tao Y, 2007	5	1	60	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Wang B, 2009	3	0	108	28	1	0	SYM	2	3	TXL 9 pills/d + CG
Wang FL, 2011	2	1	120	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Wang G, 2012	2	1	64	28	1	0	SYM, ECG	3	4	TXL 12 pills/d + CG
Wang LY, 2007	1	0	66	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Wang ZL, 2006	3	0	120	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Wei MS, 2001	2	0	120	56	0	0	SYM, ECG	2	2	TXL 12 pills/d + CG
Wei ZH, 2009	3	1	98	84	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Wu SP, 2004	1	1	90	28	1	1	SYM	2	4	TXL 9 pills/d + CG
Xian LL, 2006	1	1	60	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Xiu YJ, 2008	1	1	70	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Xu S, 2011	1	1	263	28	1	0.5	SYM	2	3.5	TXL 12 pills/d + CG
Xu YM, 2006	2	1	56	28	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Yang L, 2005	1	1	86	42	0	0	SYM	2	2	TXL 9 pills/d + CG
Yao FN, 2003	1	1	30	28	1	1	SYM	2	4	TXL 9 pills/d + CG
Yao MC, 2012	2	1	68	28	1	1	SYM, ECG	3	5	TXL 12 pills/d + CG
Ye MF, 2008	1	0	60	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
You HZ, 2008	1	1	88	28	1	1	SYM	2	4	TXL 12 pills/d + CG
Yu SY, 2012	2	0	120	28	1	1	SYM	3	5	TXL 6 pills/d + CG
Zhan YM, 2011	3	1	60	180	1	1	SYM, ECG	2	4	TXL 6 pills/d + CG
Zhang J, 2009	2	1	166	90	1	1	SYM, ECG	2	4	TXL 12 pills/d + CG
Zhang NL, 2012	1	1	156	28	1	0	SYM	2	3	TXL 9 pills/d + CG
Zhang RZ, 2011	1	1	86	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhang SR, 2006	8	1	112	60	1	0	SYM, ECG	2	3	TXL 6 pills/d + CG
Zhang WL, 2005	2	0	120	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhang XQ, 2000	4	0	60	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhang YQ, 2005	2	0	120	28	1	0	SYM, ECG	2	3	TXL 9 pills/d + CG
Zhao JL, 2008	2	1	116	90	1	1	SYM	2	4	TXL 12 pills/d + CG
Zhao LX, 2012	1	0	144	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhao YW, 2010	2	1	82	90	1	1	SYM	2	4	TXL 12 pills/d + CG
Zheng HS, 2010	1	0	60	56	1	1	SYM	3	5	TXL 12 pills/d + CG
Zhou Q, 2013	5	1	132	84	1	1	SYM	3	5	TXL 9 pills/d + CG
Zhou Y, 2008	1	0	71	90	1	1	SYM	2	4	TXL 12 pills/d + CG
Zhou YB, 2009	2	1	80	28	1	0	SYM	2	3	TXL 9 pills/d + CG
Zhu CH, 2011	1	1	50	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhu HY, 2012	2	1	92	28	1	0	SYM, ECG	2	3	TXL 12 pills/d + CG
Zhu LC, 2006	1	1	74	28	1	0	SYM	2	3	TXL 9 pills/d + CG

Numbers 1 and 0 in the “Trial date” column mean that study reported or did not report the trial date, respectively. Numbers 1 and 0 in the “Comparable” column mean that the study reported the comparability between the experiment and control groups (1) or did not report that, respectively.

AE, adverse event; SYM, symptomatic improvement; ECG, electrocardiography improvement; TXL, tongxinluo capsule; CG, interventions in control group.

Quality assessment

Table 1 shows the results of quality assessment according to the Jadad and M scales. Eight RCTs^{32,45,67,71,83,86,98,99} had a score of 3 according to the Jadad scale, while the other 70 RCTs had a score of 2. According to the M scale, 5 RCTs^{36,38,51,74,81}had a score of 2, 5 RCTs^{30,31,34,56,79} had a score of 3.5, 24 RCTs^{32,35,40,46,49,52,55,59,62,64,65,71,72,75
−77,80,82,85,87,88,95,97,100} had a score of 4, 1 RCT⁴⁵ had a score of 4.5, 5 RCTs^{67,83,86,98,99} had a score of 5, and the other RCTs had a score of 3. Seventy RCTs^{32,36,38,51,61,74,81} did not report baseline comparison of participants in treatment and control groups while 71 included RCTs reported. Twenty-nine RCTs^{32,35,40,46,49,52,55,59,61,62,64,65,67,72,75,76,77,80,82,83,85,86,87,88,95,97,98,99,100} reported types and numbers of AEs and other RCTs did not report any AEs. Other six RCTs^{30,31,34,45,56,79} did not report complete information about types and numbers of AEs. The results of the quality assessment according to the Cochrane Collaboration's risk of bias tool are shown in Figure 2. The overall quality of the included studies were at low risk of bias.

FIG. 2.

Quality assessment of randomized controlled trials according to the Cochrane Collaboration's risk of bias tool.

Overall effect sizes

Overall OR of symptomatic improvement was 3.40 (95% CI, 2.97–3.89; Z=17.69; p<0.0001) with non-significant heterogeneity (I² =0%, p=0.9999) among the 78 studies with an outcome of symptomatic improvement (Fig. 3 and Table 2). Figure 4 and Table 3 show that the overall OR of ECG improvement was 2.63 (95% CI, 2.29–3.02; Z=13.85; p<0.0001) with non-significant heterogeneity (I² =0%; p=0.8602). Both ORs for symptomatic improvement and ECG improvement indicated that TXL was more effective than beta-blockers for treating angina pectoris. The Spearman correlation between symptomatic improvement and ECG improvement in ORs was statistically significant (rho=0.6193; p<0.0001), indicating that symptomatic improvement and ECG improvement corroborated with each other to provide positive evidence. According to GRADE in Table 4, the quality of evidence for overall effect sizes with data on symptomatic improvement was classified as high and the quality of evidence for overall effect sizes with ECG data was classified as moderate.

FIG. 3.

Forest plot of the symptomatic improvement outcome measure. CI, confidence interval; Neg, negative; OR, odds ratio; Pos, positive.

FIG. 4.

Forest plot of the electrocardiography improvement outcome measure.

Table 2.

Subgroup and Sensitivity Analyses Based on Odds Ratio of Symptomatic Improvement as Outcomes

Variable	RCTs (n)	Participants (n)	OR (95% CI)	Wilcoxon test	Z	p-Value (effect)	I² (%)	Chi-square	p-Value for heterogeneity
M score
≤3	43	4230	3.62 (3.02– 4.33)	W = 810	13.92	<0.0001	54	0	0.9993
>3	35	3194	3.13 (2.56– 3.85)	p = 0.4205	10.96	<0.0001	0	0	0.9865
Sample size
<95	48	3292	3.51 (2.89– 4.27)	W = 703	12.62	<0.0001	0	0	0.9990
≥95	30	4132	3.29 (2.72– 3.97)	p = 0.9875	12.40	<0.0001	0	0	0.9833
No. of authors
1	35	3373	3.01 (2.47– 3.66)	W = 592	10.97	<0.0001	0	0	0.8840
>1	43	4051	3.79 (3.14– 4.56)	p = 0.1553	13.97	<0.0001	0	0	1.0000
Publication year
≤2008	37	3255	3.03 (2.49– 3.69)	W = 867.5	11.04	<0.0001	0	0	0.9943
>2008	41	4169	3.76 (3.12– 4.54)	p = 0.1952	13.91	<0.0001	0	0	1.0000
Trial date
Reported	59	5693	3.37 (2.89– 3.93)	W = 525	15.51	<0.0001	0	0	1.0000
Not reported	19	1731	3.48 (2.61– 4.64)	p = 0.7631	8.50	<0.0001	0	0	0.9770
Baseline comparison
Reported	71	6800	3.45 (2.99– 3.97)	W = 318.5	17.09	<0.0001	0	0	0.9999
Not reported	7	624	2.90 (1.84– 4.56)	p = 0.1957	4.61	<0.0001	0	0	0.8087
AEs
Reported	35	3190	3.06 (2.49– 3.75)	W = 871	10.71	<0.0001	0	0	0.9918
Not reported	43	4234	3.68 (3.08– 4.41)	p = 0.1523	14.14	<0.0001	0	0	0.9992
Follow-up Period
28 d	53	4873	3.68 (3.10– 4.37)	p = 728	14.82	<0.0001	0	0	1.0000
>28 d	25	2551	2.98 (2.40– 3.72)	p = 0.3990	9.76	<0.0001	0	0	0.9267
Treatment
Beta-blocker + Chinese medicine	56	5129	3.33 (2.84– 3.91)	W = 420	14.84	<0.0001	0	0	0.9982
Metoprolol + Chinese medicine	20	1912	3.75 (2.82– 4.98)	p = 0.1207	9.10	<0.0001	0	0	0.9898
Improvement
Basic	78	7424	3.40 (2.97– 3.89)	W = 5021.5	17.69	<0.0001	0	0	0.9999
Significant	76	7186	1.90 (1.72– 2.10)	p < 0.00001	12.70	<0.0001	0	0	0.9577
Angina
Stable	10	843	3.18 (2.21– 4.56)	Chi-square = 2.6408	6.26	<0.0001	0	0	0.8552
Unstable	25	2400	3.21 (2.55– 4.04)	df = 2	9.92	<0.0001	0	0	0.9941
Angina	43	4181	3.56 (2.95– 4.16)	p = 0.2670	13.37	<0.0001	0	0	0.9900
Treatment
TXL, 6 pills/d	3	340	2.99 (1.39– 6.42)	Chi-square = 0.1475	2.81	0.0050	17	0.0788	0.2991
TXL, 9 pills/d	33	3097	3.20 (2.60– 3.94)	df = 2	10.97	<0.0001	0	0	0.9918
TXL, 12 pills/d	30	3987	3.60 (2.99– 4.33)	p = 0.9289	13.57	<0.0001	0	0	0.9989

Z and p-value (effect) evaluated the statistics of overall effect; I² , chi-square, and p-value for heterogeneity were computed to assess heterogeneity.

RCT, randomized controlled trial; OR, odds ratio; CI, confidence interval; CM, Chinese medicine; df, degrees of freedom.

Table 3.

Subgroup and Sensitivity Analyses Based on Odds Ratios for ECG Improvement as Outcomes

Variable	RCTs (n)	Participants (n)	OR (95% CI)	Wilcoxon test	Z	p-Value (effect)	I² (%)	Chi-square	p-Value for heterogeneity
M score
≤3	29	2872	2.67 (2.24–3.19)	W = 262.5	10.88	<0.0001	0	0	0.9874
>3	18	1664	2.70 (2.09–3.49	p = 0.9825	7.58	<0.0001	23	0.0677	0.1932
Sample size
<92	26	1727	2.60 (2.11–3.21)	W = 277	8.95	<0.0001	0	0	0.9931
≥92	21	2809	2.72 (2.22–3.33)	p = 0.9403	9.66	<0.0001	16	0.0348	0.2082
No. of authors
1	19	1771	2.20 (1.76–2.74)	W = 194.5	6.99	<0.0001	0	0	0.8901
>1	28	2765	2.94 (2.47–3.50)	p = 0.1237	12.12	<0.0001	0	0	0.8051
Publication year
≤2008	24	2274	2.20 (1.82–2.65)	W = 395.5	8.20	<0.0001	0	0	0.9770
>2008	23	2262	3.22 (2.64–3.93)	p = 0.0113	11.49	<0.0001	0	0	0.7726
Trial date
Reported	35	3370	2.66 (2.27–3.12)	W = 232	11.96	<0.0001	3	0.0065	0.7087
Not reported	12	1166	2.58 (1.95–3.41)	p = 0.5998	6.64	<0.0001	0	0	0.8203
Baseline comparison
Reported	43	4186	2.67 (2.32–3.08	W = 116.5	13.49	<0.0001	0	0	0.8411
Not reported	4	350	2.21 (1.37–3.57)	p = 0.2526	3.23	0.0012	0	0	0.5033
AEs
Reported	18	1600	2.63 (2.03–3.38)	W = 290	7.42	<0.0001	22	0.0624	0.2062
Not reported	29	2876	2.71 (2.27–3.24)	p = 0.5327	11.07	<0.0001	0	0	0.9869
Follow-up period
28 d	36	3192	2.61 (2.22–3.08)	W = 164.5	11.51	<0.0001	0	0	0.9943
>28 d	11	1344	3.01 (2.10–4.32)	p = 0.4069	6.02	<0.0001	44	0.1525	0.0492
Treatment
Beta-blocker + CM	34	3384	2.63 (2.24–3.08)	W = 164.5	12.01	<0.0001	0	0	0.8682
Metoprolol + CM	13	1152	2.64 (2.00–3.48)	p = 0.4069	6.90	<0.0001	0	0	0.4751
Improvement
Basic	47	4536	2.63 (2.29–3.02)	W = 1631	13.85	<0.0001	0	0	0.8602
Significant	47	4536	1.95 (1.71–2.22)	p = 0.0001	10.04	<0.0001	0	0	0.9993
Angina
Stable	4	313	2.71 (1.04–7.04)	Chi-square = 1.6214	2.05	0.0406	65	0.5979	0.0359
Unstable	11	1010	3.25 (2.41–4.36)	df = 2	7.70	<0.0001	0	0	0.6615
Angina	32	3213	2.47 (2.11–2.90)	p = 0.4445	11.06	<0.0001	0	0	0.9791
Treatment
TXL, 6 pills/d	2	220	3.29 (0.76–14.16)	Chi-square = 0.2030	1.60	0.1098	64	0.7392	0.0943
TXL, 9 pills/d	16	1702	2.30 (1.42–3.51)	df = 2	7.49	<0.0001	0	0	0.5830
TXL, 12 pills/d	29	2614	2.70 (2.26–3.21)	p = 0.9035	11.09	<0.0001	0	0	1.0000

Z and p-value (effect) evaluated the statistics of overall effect; I² , chi-square, and p-value for heterogeneity were computed to assess heterogeneity.

Table 4.

Summary of Evidence Quality with Different Improvement Criteria Based on GRADE

Outcomes	OR (95% CI)	No. of participants (no. of studies)	Quality of evidence (GRADE)
Symptomatic improvement: basic	3.40 (2.97–3.89)	7424 (78 studies)	High
ECG improvement: basic	2.63 (2.29–3.02)	4536 (47 studies)	Moderate
Symptomatic improvement: significant	1.90 (1.72–2.10)	7186 (76 studies)	Moderate
ECG improvement: significant	1.95 (1.71–2.22)	4536 (47 studies)	Moderate

GRADE, grading of recommendation, assessment, development, and evaluation.

Subgroup and sensitivity analyses

The ORs of the subgroups for both symptomatic improvement (Table 2) and ECG improvement (Table 3) were compared according to study characteristics, including M scores (≤3 or >3), sample sizes (<95 or ≥95), 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 AEs (yes or no), and follow-up periods (28 days or >28 days); different interventions in the control group (monotherapy with metoprolol, metoprolol with other Western medicines, or beta-blockers with other Western medicines); different improvement criteria (basic or significant); different type of angina pectoris (stable, unstable, or angina); and different daily dosage of TXL (6 pills, 9 pills, or 12 pills).

When the improvement criteria were raised to the significant level from the basic level, the overall results remained effective (i.e., OR>1.9) and statistically significant. The overall OR for symptomatic improvement decreased from 3.40 to 1.90 (95% CI, 1.72–2.10; Z=12.70; p<0.0001). The overall OR for ECG improvement decreased from 2.63 to 1.95 (95% CI, 1.71–2.22; Z=10.04; p<0.0001). This sensitivity test for symptomatic improvement and ECG improvement showed that the overall efficacy of TXL over beta-blockers was still significantly positive even when the improvement standards were raised. There was a statistically significant correlation between the significant improvement in ORs for symptomatic and ECG outcomes (rho=0.3083; p=0.0350). The quality of evidence for overall effect sizes with data on symptomatic improvement and ECG improvement was classified as moderate when the improvement criteria were raised to the significant level (Table 4).

There was no statistically significant difference between ORs of other subgroups. The agreement among the subgroup analysis results on different study characteristics indicated that the efficacies of TXL versus beta-blockers with all included studies were consistently stable.

Meta-regression

Meta-regression was performed between ORs and study characteristics. Table 5 shows no statistically significant or high correlation between efficacies of TXL over beta-blockers and study characteristics.

Table 5.

Meta-Regression of Basic Characteristics of RCTs and ORs of Symptomatic Improvement and ECG Improvement as Outcomes

Outcome	RCTs (n)	Participants (n)	Factor tested	β	p-Value
Symptomatic improvement	65	6064	M score	−0.0897	0.3546
			Sample size	−0.0017	0.0758
			No. of authors	0.0302	0.5700
			Publication year	0.0341	0.0951
			Trial date	−0.0320	0.8474
			Comparable	0.1732	0.4740
			AEs	−0.1312	0.3981
			Follow-up period	0.0001	0.9742
ECG	38	3704	M score	−0.1168	0.2741
			Sample size	−0.0011	0.2432
			No. of authors	0.0418	0.3964
			Publication year	0.0387	0.0572
			Trial date	0.0270	0.8687
			AEs	−0.0754	0.6422
			Follow-up period	0.0039	0.0996

Publication bias

Funnel plots (Fig. 5) show the presence of publication biases among the included studies. Both the Egger test (symptomatic improvement: t=0.2209, p=0.0044; ECG improvement: t=0.1626, p=0.1084) and the Begg test (symptomatic improvement: Z=2.8375, p=0.0045; ECG improvement: z=1.8697, p=0.0615) indicated statistically significant publication biases. Use of the trim-and-fill method found that on the left side of the funnel plots there should have been 23 missing studies for symptomatic improvement and 10 missing studies for ECG improvement. On the basis of data for symptomatic improvement, the OR was 2.95 (95% CI, 2.70–3.20; Z=17.14; p<0.0001) and heterogeneity was not statistically significant (Q=65.32; p=0.9971) after trim-and-fill adjustment. On the basis of ECG data, the OR was 2.34 (95% CI, 2.08–2.59; Z=13.01; p<0.0001) and heterogeneity was not statistically significant (Q=63.56; p=0.2275) after trim-and-fill adjustment.

FIG. 5.

Funnel plots for symptomatic (SYMPTOMS) and electrocardiography (ECG) improvement.

Adverse events

Table 6 listed the information about AEs. All AEs were minor or well tolerated; none caused dropouts except in one study,⁴⁵ in which two participants dropped out because of severe stomachache and abdominal distention. Nineteen studies reported that 56 participants in total had epigastric discomfort. Epigastric discomfort, flush, and headache were the top three AEs reported in the control groups. Thirty studies reported AEs and 42 studies did not report any AEs. The other five studies reported that 45 participants in total had epigastric discomfort. Overall, AEs of TXL were more frequent and severe than those of the control drugs.

Table 6.

Adverse Events of Included Studies

	Treatment group		Control group
AE	AEs (n)	Studies (n)	AEs (n)	Studies (n)
Epigastric discomfort	56	19	10	3
Nausea	9	3	NR	NR
Dry mouth	5	3	NR	NR
Flush	3	1	7	2
Headache	3	1	3	1
Melena	NR	NR	2	1
No AEs	0	11	0	26
Total AEs reports	75	30	22	30
No AE report	0	42	0	42

The other five RCTs reported 45 participants with epigastric discomfort.

NR, not reported.

Discussion

This analysis of 78 RCTs with 3812 participants in a treatment group and 3612 participants in a control group is the first PRISMA-compliant systematic review on the efficacy of TXL versus beta-blockers in treating angina pectoris. Overall ORs of symptomatic improvement and ECG improvement were 3.40 (95% CI, 2.97–3.89; Z=17.69; p<0.0001) and 2.63 (95% CI, 2.29–3.02; Z=13.85; p<0.0001), respectively. There was no significant heterogeneity among the 78 RCTs with data on symptomatic improvement (I² =0%; p=0.9999) and the 47 RCTs with data on ECG improvement (I² =0%; p=0.8526). Subgroup and sensitivity analyses on various features, such as study quality, sample sizes, follow-up periods, improvement criteria, and interventions, demonstrated that the efficacy findings were consistent. Meta-regression analysis showed no significant correlations between the selected features and overall efficacies. The Egger test, Begg test, and trim-and-fill method found significant publication biases. After trim-and-fill adjustment to cope with publication biases, the adjusted overall efficacy of TXL was still more effective than that of beta-blockers in treating angina pectoris.

Although the efficacy of TXL was improved as the daily dosages increase (6 pills, 9 pills, and 12 pills) for both symptomatic improvement (OR, 2.99, 3.20, and 3.60) and ECG improvement (OR, 3.29, 2.30, and 2.70) as outcome measures (Tables 2 and 3), there was no significant difference in subgroups between symptomatic improvement (chi-square=0.1475; p=0. 0.9289) and ECG improvement (chi-square=0.2030; p=0.9035).

Beta-blockers could not be analyzed individually because of sparse data. Further RCTs are warranted to compare the efficacies among beta-blockers. The overall ORs are higher than 1 no matter how categories RCTs are grouped and outcome measures used.

Low quality of the included RCTs is a major limitation in this meta-analysis, although the overall findings were consistent with those of previous studies.^105

–108 While all studies were described as RCTs, only 6 studies^{44,66,70,82,97,98} used randomization procedures. Two studies^31,85 were described as single blind. Only one RCT⁴⁴ clearly reported having dropouts. The mean Jadad score was 2.10 (median, 2.00; 95% CI, 2.04–2.17) and the mean M score was 3.42 (median, 3.00; 95% CI, 3.27–3.58). As such, high-quality RCTs would be necessary for this meta-analysis to draw a positive conclusion.

All included RCTs were conducted in China and reported in Chinese journals. The follow-up period of 53 RCTs was 28 days and the mean follow-up period of 78 RCTs was 42 days. Such short follow-up periods for patients with angina pectoris could not support the efficacy of longer treatment with TXL. The mean sample size of 95 was small. Thirty-eight RCTs did not report AEs at all, and others did not report AEs formally.

In conclusion, TXL seems to be more effective than beta-blockers in treating angina pectoris, according to the eligible RCTs. Further RCTs are warranted to reduce publication bias and verify efficacy.

Footnotes

Acknowledgments

The work of both authors was supported by research grants (MYRG190-Y3-L3-ICMS11-LSW and MYRG2014-00117-ICMS-QRCM) from the University of Macau.

Author Disclosure Statement

No competing financial interests exist.

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