Efficacy of Ligustrazine Injection as Adjunctive Therapy for Angina Pectoris: A Systematic Review and Meta-Analysis

Background

Angina pectoris is triggered by decreased myocardial oxygen supply or increased myocardial oxygen demand [1]. An estimated 94.9 of every 100 000 urban residents die of coronary artery disease (CAD) in China and nearly 1 of every 6 deaths was due to CAD in the US in 2009 [2,3]. Chronic stable angina is the most prevalent manifestation of CAD, with an incidence of 500 000 new cases every year in the US [1]. Typical symptoms of angina pectoris are characterized by discomfort in various parts of the body, including the chest, jaw, shoulder, back, and arms. Angina pectoris elicited by exertion or emotional stress can be relieved by rest or nitroglycerin [4]. Conventional antianginal drugs (e.g., β-blockers, calcium antagonists, and nitrates) reduce angina attacks by lowering heart rate and blood pressure or enhancing coronary blood flow [5]. Despite the effectiveness of the antianginal drugs, episodes of angina pectoris may still persist or even worsen. In addition, most patients cannot tolerate the adverse effects of these antianginal drugs [6–8]. Therefore, a new treatment that has significant advantages in increasing the effects of conventional antianginal drugs is necessary. Recently, the benefits of traditional Chinese medicine (TCM) combined with the conventional antianginal drugs have attracted a growing and sustained interest from researchers and physicians.

Ligustrazine (2,3,5,6-tetramethylpyrazine, C8H12N2, Figure 1A) is an active ingredient from the plant Szechwan Lovage Rhizome. This plant has been widely used to treat cardiovascular disease, angina pectoris, and headache for hundreds of years in China as herbal medicine [9,10]. Owing to the impressive effects of ligustrazine in scavenging cytotoxic oxygen free radicals, promoting blood flow, and antiplatelet aggregation, various dosage forms based on ligustrazine are developed in China, such as injection, tablets, and capsule [11]. Ligustrazine injection is the most popular form among them and it is commercially available as ligustrazine hydrochloride (Figure 1B) (40 mg/10 mL) and ligustrazine phosphate (Figure 1C) (50 mg/10 mL). Ligustrazine injection ranges from 40 mg to 80 mg was usually used in the method of intravenous drip (diluted with 250–500 mL of isotonic normal saline or glucose solution; one time, once daily) [12]. In order to provide better efficacy in treating angina pectoris, ligustrazine injection is usually used in combination with conventional antianginal drugs in China.

The clinical studies on ligustrazine injection have been reported with potential positive results. However, neither systematic a review nor a meta-analysis on the therapeutic effect of ligustrazine injection as adjunctive therapy for angina pectoris has been reported so far. Therefore, this study offers a comprehensive and PRISMA-compliant systematic review with sensitivity and subgroup analysis for evaluating the efficacy of ligustrazine injection as adjunctive therapy in the treatment of angina pectoris [13].

Material and Methods

ELIGIBILITY CRITERIA:

The published RCTs were searched independently by 2 reviewers (HK, Shao and LG, Zhao). The participants with angina pectoris were examined according to the World Health Organization guideline [14]. Studies that met the following criteria were included: (a) Studies compared any antianginal drugs combined with or without ligustrazine injection (i.e., ligustrazine injection combined with antianginal drugs vs. antianginal drugs alone); (b) Duration of treatment was at least 2 weeks; (c) The sample size of studies was at least 50 patients; and (d) The primary outcome measures in RCTs were symptom improvement and ECG improvement.

Studies were excluded if they did not meet the criteria above and: (a) The RCTs involved animal, human cells or in vitro studies; (b) Studies did not include the symptom improvement and ECG improvement as the primary outcome measures; (c) Studies with same authors and similar content; and (d) The dosages of intervention in the treatment and control groups of included studies were not specifically stated.

INFORMATION SOURCES:

The databases PubMed, Medline, Cochrane Library, Embase, Sino-Med, Wanfang Databases, Chinese Scientific Journal Database, Google Scholar, Chinese Biomedical Literature Database, China National Knowledge Infrastructure and the Chinese Science Citation Database were independently searched and retrieved by 2 authors (HK, Shao and LG, Zhao). The latest search of databases was conducted on 29 May 2015.

SEARCH STRATEGIES:

The following terms were searched in separate or combined ways for English databases: ligustrazine injection, antianginal drugs, angina pectoris, cardiovascular diseases, coronary artery disease. The following terms were searched in separated or combined ways for Chinese databases: Chuanxiongqin zhusheye [ligustrazine injection], Chuanxiongqin [ligustrazine], guanxinbing [coronary artery disease], xinjiaotong [angina pectoris]. Moreover, the references listed in the selected articles were also searched to acquire additional papers related to this study.

STUDY SELECTION:

Two authors (HK. Shao and LG. Zhao) independently screened all titles and abstracts of clinical studies according to the eligibility criteria. Disagreement between the 2 authors was resolved by consensus.

DATA COLLECTION PROCESS:

One author (HK, Shao) extracted data from the included RCTs and then put them into Microsoft Excel. Another 2 authors (LG, Zhao and SQ, Liu) examined the accuracy of extracted data. Disagreements between authors were solved through discussion. The software Review Manager 5.0 was used to evaluate the extracted data.

DATA ITEMS:

Two authors (HK. Shao and LG. Zhao) independently extracted the following data items: (a) First author, publication year, and language of RCTs; (b) Characteristics of patients including age and sample size; (c) Intervention (dosages and duration); (d) Outcome measures; and (e) Incidence of adverse reactions.

RISK OF BIAS IN INDIVIDUAL STUDIES:

The methodological quality of included RCTs was independently evaluated by 2 authors (HK. Shao and LG. Zhao) in reporting baseline comparison of participants, randomization methods, concealment of treatment allocation, blinding, and adverse event report according to M score (Table 1) [15].

QUALITY ASSESSMENT:

Two authors (HK, Shao and LG, Zhao) independently assessed the quality of included RCTs based on M scale (Studies with M scale >3 were considered to be moderate-quality RCTs). Any disagreement among the 2 authors was resolved by consensus.

DEFINITIONS OF IMPROVEMENTS OF SYMPTOM AND ECG:

Improvement in symptom should reduce by at least 50% (i.e., basic improvement in angina symptoms) the frequency and duration of feeling angina chest pain. Improvement in ECG should achieve at least 0.05 mv at ST segment (i.e., basic improvements in ECG) in ECG during an exercise test, as mentioned in ACC/AHA guidelines [16].

SENSITIVITY AND SUBGROUP ANALYSIS:

Sensitivity analysis was conducted to verify whether the overall efficacy of ligustrazine injection combined with antianginal drugs over antianginal drugs alone would be affected by the low quality of included RCTs. Subgroup analysis was conducted to evaluate the overall effects in subgroups based on sample sizes and publication year of the study.

RISK OF BIAS ACROSS STUDIES:

The publication bias was assessed by funnel plots, Begg’s test, and Egger’s test with the software of STATA 12.0.

STATISTICAL ANALYSIS:

All analyses were performed with RevMan 5.0. For continuous outcome variables, standard mean difference was used with 95% confidence interval (CI). For dichotomous outcome variables, odds ratio (OR) was given with 95% CI. If OR <1, it indicated a lower risk for treatment group than control group. If OR >1, it showed that a greater risk for treatment group than control group. Statistical heterogeneity was measured by using the chi-squared test and I2 statistic. Significant difference for heterogeneity test was considered when P<0.05 or I2 statistic >50% [17–19]. The random-effects model was used to analyze the pooled effects when heterogeneity was significantly different, otherwise the fixed-effects model was used. The Z test was used to compare the overall effects of treatment group and control group, and differences were considered to be statistically significant when P<0.05. Results are expressed as pooled odds ratios (OR (95% confidence intervals, CIs)). The Mantel-Haenszel method with fixed-effects model was used to calculate the pooled OR and 95% CI considering the small trials, high event rates, and dichotomous outcome variable in this study.

Results

STUDY SELECTION:

The selection process is described in Figure 2. We initially identified 767 potential records, including 266 articles from CNKI, 176 articles from Wanfang data, 77 articles from VIP, 116 articles from PubMed, and 132 articles from Medline, Cochrane Library, Embase, Sino-Med, Google Scholar, Chinese Biomedical Literature Database, and Chinese Science Citation Database. After screening the titles and abstracts, 721 articles were excluded because a large number of records from 3 Chinese databases (CNKI, VIP, and Wanfang) were duplication and a large quantity of RCTs did not meet the inclusion criteria. Full texts of 46 articles were retrieved for further identification according to the pre-defined eligibility criteria; 11 studies were finally selected for quality assessment and meta-analysis.

STUDY CHARACTERISTICS:

The characteristics of 11 RCTs are summarized in the Supplementary Table 1. The included RCTs were all published in Chinese journals between the 2000 and 2015. The sample size of RCTs ranged from 50 to 120. Eleven RCTs with 870 patients (436 patients in treatment group) were included in this study [20–30]. The duration of treatment ranged from 14 to 28 days. Ten RCTs reported symptoms changes as the outcome measures and 7 studies reported ECG changes. The antianginal drugs used in the control groups included nitroglycerin, metoprolol, aspirin, isosorbide dinitrate, isosorbide-5-mononitrate, and simvastatin. Based on the drugs used in the control groups, the dosage of ligustrazine injection used in treatment group ranged from 80 to 240 mg daily.

RISK OF BIAS IN INDIVIDUAL STUDIES:

The M scale (between -1 and 7 points) was used to measure the methodological quality of the included studies. The results of quality assessment were provided in Table 2. Five RCTs scored 3 and 6 RCTs scored 4 according to M scale, indicating the poor methodological quality of most RCTs.

RESULTS OF INDIVIDUAL STUDIES AND THEIR SYNTHESIS:

As shown in Figure 3, the Pooled odds ratio of symptoms was 3.59 (95% CI, 2.39 to 5.40, Z=6.16, P<0.00001) with no heterogeneity (I2=0%; χ2=1.76; df=9, P=0.99) among the 10 studies with symptomatic improvements as outcome measure. Figure 4 showed that the Pooled odds ratio of ECG was 3.42 (95% CI, 2.33 to 5.01, Z=6.28, P<0.00001) with no heterogeneity (I2=0%; χ2=1.21; df=6, P=0.98) among the 7 studies with ECG as outcome measure. The Pooled odds ratios of symptoms and ECG indicated that ligustrazine injection as adjunctive therapy for angina pectoris was more effective than antianginal drugs alone.

RISK OF BIAS ACROSS STUDIES:

As shown in Figure 5, no obvious asymmetry was observed in the funnel plots for symptoms and ECG. Begg’s test (symptoms: Z=0.98, P=0.325; ECG: Z=0.15, P=0.881) and Egger’s test (symptoms: t=−1.45, P=0.185; ECG: t=0.23, P=0.827) also indicated that there was no statistically significant publication bias.

ADVERSE EVENTS:

One RCT reported ligustrazine injection as adjunctive therapy could cause discomfort in stomach for 1 patient. Respectively, 3 RCTs reported that there were 2 patients suffering from headache both in treatment group and control group. The rest of studies did not report the adverse events.

SUBGROUP AND SENSITIVITY ANALYSIS:

Based on the characteristics of RCTs including publication year (before or after 1 January 2008) and sample size (≤70 or >70), subgroup analysis was performed and the results were shown in Tables 3 and 4. No significant difference was found between the overall odds ratios of subgroups, indicating that the efficacies were consistently stable among all included studies.

Sensitivity analysis based on M scale was conducted in this study. When the lower quality studies (M score ≤3) were excluded, the odd ratio by symptom increased from 3.59 to 3.93 (95%, 2.15–7.19, Z=4.46, P<0.00001) with no heterogeneity (Chi2=0.85, P=0.97, I2=0%). The odd ratio by ECG decreased from 3.42 to 3.35 (95%, 1.88–5.96, Z=4.11, P<0.0001) with no heterogeneity (Chi2=0.25, P=0.97; I2=0%). However, the above results showed that no significant difference happened in odds ratios for symptoms (Table 3) and ECG (Table 4). It had statistical significance (the 95% CI did not contain the value 1) after all low quality studies were excluded during the process of sensitivity analysis. In addition, no obvious heterogeneity was found from the results of sensitivity analysis.

Discussion

ANALYSIS OF EFFECTIVENESS:

In recent years, Chinese medicine as adjunctive or alternative medicine for angina pectoris has attracted widely interests because conventional antianginal drugs might sometimes fail to treat angina pectoris. As one of the most popular medicine in China, ligustrazine injection had played a very important role in treating angina pectoris. Although there are many studies about ligustrazine injection, neither systematic review nor meta-analysis has been performed on ligustrazine injection as adjunctive therapy for angina pectoris so far. Therefore, in this study, we firstly provided a comprehensive and PRISMA-compliant systematic review with sensitivity and subgroup analysis for evaluating the efficacy of ligustrazine injection as adjunctive therapy in the treatment of angina pectoris. PRISMA Checklist was provided in Supplementary Table 2. The results from the 11 included RCTs suggested that ligustrazine injection as adjunctive therapy for angina pectoris was more effective than conventional antianginal drugs alone. Sensitivity and subgroup analysis conducted on M scale, sample size and year of publication also consistently proved that ligustrazine injection as adjunctive therapy has superior effects in the treatment of angina pectoris. Moreover, no publication bias was found in this study.

LIMITATIONS:

Some limitations existed in this study. The low quality of RCTs included in this study was the major limitation. Only half of RCTs scored 3 or above according to the M scale. Apart from this, the poor design of clinical trials in the RCTs was also an important limitation. The included RCTs were not strictly designed according to the golden standard. Allocation concealment and blinding were not clearly described in majority of the RCTs. Besides, this research had the following defects: (1) All included studies came from mainland China and were published in Chinese. Moreover, no multi-center/country clinical randomized controlled trial was found in this study. (2) The different dosage of ligustrazine injection used in the treatment group might lead to heterogeneity among the included RCTs. (3) Duration of treatment was relatively short as most duration of RCTs was 2 weeks. Therefore, further larger scale, higher quality and rigorously designed RCTs were still needed to confirm the efficacy of ligustrazine injection as an adjunctive therapy in the treatment of angina pectoris.

IMPLICATIONS FOR FURTHER RESEARCH:

At present, ligustrazine injection as adjunctive therapies are not well known to most Western physicians and its efficacy in treating angina pectoris has not been evaluated. This study could potentially help physicians manage the problem of drug tolerance and side effects occurred in their patients with angina pectoris.

This study found that a majority of the RCTs on ligustrazine injection had poor methodological quality. The description of randomization methods and concealment of allocation procedures was not provided in many RCTs. Problems existed in blinding of the patients and researchers were prevalent. In addition, placebo-controlled design was rarely adopted in their study. In some studies, the researchers were not blinded to treatment allocation when they assessed the treatment outcome. The low quality of RCTs included in this study indicated that many researchers might not be aware of the crucial components of RCTs. Therefore, future RCTs about ligustrazine injection should comply with the following recommendations: (1) Researchers should have received some formal educations about clinical trial design when they conducted RCTs; (2) Researchers should register clinical trials and publish their reports in a standard trial registration platforms; (3) The researchers should understand the rationale for selecting different types of control groups; (4) The CONSORT 2010 checklist should be adopted when the researchers reported the RCTs about ligustrazine injection. In general, further RCTs with good methodology were still required to accurately verify the efficacy of ligustrazine injection as adjunctive therapy in the treatment of angina pectoris.

This systematic review was more reliable than previous reviews on ligustrazine injection. The previous reviews had the following defects: (1) Non-randomized controlled trials were included in their search strategy; (2) The combination use of other medicines in both treatment and control groups was allowed in their study selection; (3) Sensitivity and subgroup analysis were not provided in their evidence evaluation; (4) Their performance did not follow the PRISMA requirements. On the contrary, this systematic review and meta-analysis included only the RCTs comparing the efficacy of ligustrazine injection combined with conventional antianginal drugs with antianginal drugs alone. Moreover, in order to avoid possible publication biases, subgroup and sensitivity analysis were performed in this study.

In summary, the overall result from the eleven RCTs indicated that the efficacy of ligustrazine injection as adjunctive therapy was more effective than conventional antianginal drugs alone for angina pectoris. Due to the low quality of the included RCTs, more rigorously designed RCTs were still needed to verify the efficacy of ligustrazine injection as adjunctive therapy for angina pectoris.

Conclusions

This study showed that ligustrazine injection combined with conventional antianginal drugs was more effective than conventional antianginal drugs alone in treating angina pectoris. Moreover, sensitivity and subgroup analysis conducted on M scale, sample size, and years of publication also consistently corroborated that ligustrazine injection as adjunctive therapy had superior effect in the treatment of angina pectoris. However, more rigorously designed RCTs were still needed to accurately verify the efficacy of ligustrazine injection as an adjunctive therapy for angina pectoris.