The Usefulness of Xuefu Zhuyu Tang for Patients with Angina Pectoris: A Meta-Analysis and Systematic Review

Objective. To evaluate the efficacy of Xuefu Zhuyu Tang (XFZYT) for treating angina pectoris (AP). Methods. Six databases were searched (up to December, 2013). Eligible randomized controlled trials (RCTs) evaluating the efficiency of XFZYT plus traditional antianginal medications (TAMs) compared with TAMs alone in patients with AP were included. The outcomes were relief of anginal symptoms (RAS) and improvement of electrocardiogram (ECG) and blood high-density lipoprotein cholesterol (HDL-C) level. Result. Finally 14 RCTs were included. There were evidences that XFZYT combined with TAMs was more effective in improving RAS (RR = 1.29; 95% CI = [1.20, 1.38]), ECG (RR = 1.37; 95% CI = [1.22, 1.54]), and blood HDL-C level (MD = 0.29 mmol/L; 95% CI = [0.23, 0.35]) compared with TAMs alone. Our meta-analysis also showed the pooled number needed to treat (NNT) of the group with stable angina pectoris (SAP) was smaller in improving RAS (4.2 versus 5.7) and ECG (3.1 versus 5.5) compared with the group with both SAP and unstable angina pectoris (UAP). Conclusion. Combination therapy with XFZYT and TAMs is more effective in treating AP compared with TAMs alone. And XFZYT may be a more suitable choice for the treatment of SAP. However, the findings should be interpreted with caution due to the mediocre methodological quality of the included RCTs.


Introduction
Cardiovascular diseases are the number one cause of death globally [1]. According to the World Health Organization (WHO), an estimated 17.3 million people died from cardiovascular diseases in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million deaths were due to coronary heart disease. Angina pectoris is the most prevalent manifestation of coronary artery diseases and has a major negative impact on the general health status and quality of life [2].
Angina pectoris is clinically classified into stable angina pectoris (SAP) and unstable angina pectoris (UAP). Both SAP and UAP can use traditional antianginal medications (TAMs) such as organic nitrates, antiplatelet drugs, antithrombotic drugs, and blockers. Antiplatelet drugs include aspirin, platelet glycoprotein IIb/IIIa inhibitor, and clopidogrel, antithrombotic drugs include heparin and low-molecularweight heparin, and blockers included metoprolol tartrate [3,4]. Despite the effectiveness of TAMs, episodes of angina may still persist or become even worse, and many patients cannot tolerate a combination of TAMs due to their many serious adverse effects, such as antithrombotic complications, decreasing heart rate or blood pressure, and other hemodynamic changes [5,6]. Therefore, we need to research a new medication which is effective and tolerant in improving the symptoms of angina and will provide an alternative option for patients.
How about the efficacy of XFZYT in improving AP outcomes and the application of XFZYT in the treatment of different AP subtypes? We therefore conducted an updated systematic review and meta-analysis of published RCTs to answer these questions.

Eligibility Criteria.
We included RCTs met criteria as follows: (1) involving patients who were diagnosed with SAP or UAP according to the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for the Diagnosis and Management of Patients with Unstable Ischemic Heart Disease [11], the International Society and Federation of Cardiology/World Health Organization (ISFC/WHO) guideline [12], or the Chinese Society of Cardiology (CSC) guidelines [13,14]; (2) comparing XFZYT plus TAMs with TAMs alone for maintenance therapy for at least 4 weeks and the two groups were comparable on the basis of the characteristic of patients and studies, such as gender, age, and sample size; (3) using improvement of the relief of angina symptoms (RAS) and electrocardiogram (ECG) as the outcome measures [15] and quality of life (QL), blood lipid (HDL-C, LDL-C, TC, and TG) level, reduction of nitroglycerin use (RNU), and adverse events (AEs) were also included.

Data Extraction.
Two researchers (G. Z. Yi and Y. Q. Qiu) independently extracted from each article the authors information, year of publication, types of AP, sample size, the number of participants in each group, percent of male and average age, criteria for inclusion and exclusion, method of randomization, details of blinding, interventions of each group, duration of treatment, criteria for outcome assessments, and data reported. Disagreements were resolved after discussion with a third researcher (Y. Xiao).

Statistical Analysis.
Meta-analysis was carried out using Review Manager software (version 5.2), provided by the Cochrane Collaboration. Dichotomous data were presented as risk ratios (RRs) and continuous outcomes as mean difference (MD), both with 95% confidence interval (CI).
The chi-squared test and -squared statistic were performed to assess the heterogeneity, and heterogeneity was presented as significant when 2 was over 25%. In the absence of statistical heterogeneity, a fixed-effect model was used to pool the result; otherwise, a random-effect model was used [16]. In subgroup analysis, we used the number needed to treat (NNT) to evaluate the usefulness of XFZYT plus TAMs for each subgroup with different AP subtypes; the NNT was calculated as 1/(Therapeutic Gain). And we also performed a funnel plot of the improvement of RAS between XFZYT plus TAMs group and TAMs group to assess the publication bias.
All 14 studies included were RCTs, and all of them recruited participants for treatment with XFZYT combined with TAMs versus TAMs. Most of the studies used the improvement of RAS and ECG as the primary outcome measures; the reduction of nitroglycerin use (RNU) and blood lipid level were also reported in some studies. One study [23] used the Seattle Angina Questionnaire (SAQ) [31] and Short Form-36 (SF-36) [32] to evaluate the quality of life of patients after treatment. The characteristics of these original studies are presented in Table 1.

Methodological
Quality of Included Trials. The methodological quality of the RCTs included in our study was assessed by the criteria in the Cochrane Handbook for Systematic Review [16]. The quality of trials was evaluated as having low risk of bias, uncertain risk of bias, and high risk of bias according to the risk of trials, including sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of bias. All studies had described a correct randomization method, but only 2 [19,23] mentioned allocation concealment. 5 studies [19,20,23,25,30] described blinding of participants and 4 RCTs [19,23,25,28] mentioned withdrawal and dropout information. Among all these RCTs, the characteristics of participants in each study arm were similar at baseline (age, race, sex, and disease course). The details are shown in Table 2.

The Effect of XFZYT in Patients with AP. All the 14
RCTs tested XFZYT plus TAMs versus TAMs alone, and we analyzed the following outcomes: RAS (12 trials), ECG (9 trials), blood lipid (HDL-C, LDL-C, TC, and TG) level (3 trials), reduction of nitroglycerin use (2 trials), and quality of life (1 trial).

Publication Bias.
We performed a funnel plot of the improvement of RAS between XFZYT plus TAMs group and TAMs group (Figure 8). Visual inspection suggested that there was no publication bias.

Discussions
We performed a series of meta-analyses involving 14 RCTs with a total of 1116 participants, and what we can get from this review are as follows: (1) XFZYT combined with TAMs was more effective than TAMs alone for treating patients diagnosed with AP. It could significantly improve ECG and the relief of AP symptoms. The combination therapy of XFZYT and TAMs could also reduce the nitroglycerin use, improve blood HDL-C level which benefits patients with cardiovascular diseases [33], and decrease blood LDL-C, TG,  and TC level which seemed as risk factors of cardiovascular disease [34]. No significant differences were identified on the incidence of adverse effects between XFZYT plus TAMs and TAMs. (2) For patients with UAP, XFZYT combined with TAMs could improve ECG and quality of life in some aspects. The data of RAS was not reported, so we could not make a conclusion about the efficacy of XFZYT plus TAMs in improving RAS on patients with UAP. (3) The therapeutic gain and NNT showed that the SAP group could get more clinical benefits from the add-on effect of XFZYT than other groups. So XFZYT may be a more suitable choice for treating patients with SAP than those with UAP.
We are not able to make confident statements about the safety of XFZYT for reason of insufficient RCTs included and the short treatment duration, nor can we draw firm conclusion that XFZYT can benefit patients with UAP, for there was only one RCT [24] included into the meta-analysis and only the data of ECG improvement was reported; the NNT of the UAP group for ECG improvement (NNT = 7.5) was also larger compared with the other two groups. Although one RCT [23] with superior methodological quality showed that XFZYT can improve the quality of life of patients with UAP after PCI, more studies should be performed to confirm the efficacy of XFZYT for treating patients with UAP.
However, our meta-analysis showed that patients with SAP could get more clinical benefits such as RAS and ECG improvement from the add-on effect of XFZYT compared with the other two groups. We also found that the NNT varied from 3.7 to 32.3 for RAS improvement and from 3.6 to 23.8 for ECG improvement in the SAP and UAP group, which may be relevant to the variance in the percent of SAP of each study. But we failed to detect the correlation coefficient between the therapeutic gain and the percent of SAP, due to the fact that the number of patients with SAP in each included study was not reported. So the future studies should pay attention to the difference of the outcomes between SAP and UAP patients after the treatment with XFZYT, which may have important implication for clinical practice.
There are also limitations to this study. Visual inspection of the funnel plot revealed symmetry, so the publication bias may be minimized. But the methodological quality of the trials included was generally not high; only 3 [19,23,25] of these RCTs were scored as having superior quality. And only two RCTs [19,23] mentioned allocation concealment process, so the potential selection bias may exist. A few trials mentioned the blinding and withdrawal/dropout, and no multicenter, large sample, and cooperative RCTs were included. Apart from the limitations on the mediocre methodological quality of included studies, for outcome measures of patients with UAP, only the quality of life and ECG improvement were reported, and the estimates of some outcomes, such as the blood lipid level and reduction of nitroglycerin use, were limited by relatively small sample size, which may influence the precision of estimates.

Conclusion
In summary, these data suggest that XFZYT combined with TAMs is more effective than TAMs alone at improving the clinical symptoms of patients with AP, especially with SAP. And there is no significant difference in the incidence of adverse effects. XFZYT combined with TAM may be an alternative option for patients suffering from AP. However, most        of included RCTs were scored as having mediocre methodological quality; the findings should be interpreted with caution. Hence, future studies of XFZYT in the treatment of AP are warranted in rigorously designed, multicentre, and large-scale trials worldwide.