The Effect and Safety of Xuefu Zhuoyue Prescription for Coronary Heart Disease: An Overview of Systematic Reviews and Meta-Analyses

Background In China, the traditional Chinese medicine compound Xuefu Zhuoyue prescription (XFZY) has been widely used in the therapy of coronary heart disease (CHD). Currently, several systematic reviews (SRs)/meta-analyses (MAs) of XFZY for the treatment of CHD have been published. This overview aims to evaluate the existing SRs/MAs and provide a scientific basis for evaluating the efficacy and safety of XFZY for the therapy of CHD. Methods The SRs/MAs of XFZY for the treatment of CHD were obtained from 7 electronic databases with the search date set at March 7, 2022. Two researchers independently assessed the methodological quality, reporting quality, and evidence quality of the included SRs/MAs using the following tools: the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results A total of 11 SRs/MAs were included in this overview. All SRs/MAs assessed by means of AMSTAR-2 had more than one critical defect, so all SRs/MAs were rated low. Regarding the assessment of reporting quality, the results of PRISMA 2020 showed that none of the SRs/MAs were fully reported. In addition, the results of the GRADE assessment of the quality of evidence indicated that only one outcome was rated as high quality across all SRs/MAs. Conclusion Current evidence suggests that XFZY is effective and safe for the management of patients with CHD. However, the high risk of bias of the original clinical studies and the low quality of the SRs/MAs reduced the reliability of the results.

metabolism, hypertension, hyperlipidemia, and obesity [6]. Although the use of antiplatelet agents and statins has signifcantly reduced the incidence of adverse cardiovascular events, drug dependence and residue as well as the long-term risk of coronary heart disease remain unresolved issues [7]. Terefore, it is urgent to search for a more efective treatment [8].
Over the past 10 years, there have been a number of systematic reviews (SRs)/meta-analyses (MAs) that focused on assessing the potential benefts of XFZY for the health management of patients with CHD. However, the methods and quality of the evidence for their work have not been assessed, which may mislead clinicians in actual decisionmaking [14]. Te overview is a new research methodology for assessing the quality of multiple SRs/MAs in an efort to resolve the inconsistencies in the evidence and identify key gaps in the use of the evidence [15]. We, therefore, conducted this study to evaluate the evidence of XFZY for CHD treatment in the real-world implementation arena. We assessed methodological quality, reporting quality, and evidence quality of relevant SRs/MAs by the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.

Methods
Tis research was conducted according to the Cochrane Handbook and some high quality articles with scientifc research methodologies [16][17][18]. Tis overview protocol has been registered with the INPLASY website (Registration number: INPLASY202260077).
Studies that met the following criteria were excluded: (1) network meta-analyses, SRs/MAs without meta-analysis, review articles, conference abstracts, editorials, case reports, and replication studies; (2) animal experiments; (3) the control group using any other traditional Chinese medical method.

Search Strategy.
Two researchers (HS-S and ZH-T) independently searched PubMed, Embase, Cochrane Library, CBM, CNKI, Wanfang database, and VIP database on March 7, 2022. A search strategy featuring the combination of keywords and free words was adopted, where the keywords include "Xuefu Zhuoyue," "coronary heart disease," "meta-analysis," and "systematic review." Te search strategy was adjusted to ft the diferent databases. In addition, we manually searched for relevant references to ensure the completeness of the search. Te search strategy for PubMed was shown in Table 1, and search strategies for other databases are shown in Supplementary File 2.
2.3. Literature Screening. Two independent researchers (WQ-C and RR-H) conducted the screening of the literature. Te retrieved publications were imported into a literature management system (EndNote X9), and the initial screening was performed by frstly removing the duplicates and subsequently reading the titles and abstracts. Finally, the full-text was read to identify the fnal literature for inclusion.

Data Extraction.
To ensure data integrity and consistency, the two researchers (ZH-T and HS-S) used a predesigned data extraction table to extract the data. Te extracts included the following: frst author and year of 2 Evidence-Based Complementary and Alternative Medicine publication (country), number of RCTs (number of subjects), interventions, risk of bias assessment methods, interventions, and main fndings.

Quality Evaluation for Inclusion in SRs/MAs.
Two independent researchers (HS-S and CD-D) assessed the methodological quality, report quality, and evidence quality of the included SRs/MAs. Any disagreements were referred to a third investigator (Y-L) for consultation.

Methodological Quality Evaluation.
Te methodological quality of the included SRs/MAs was assessed using the AMSTAR-2 [19]. Te tool contains seven key items (2, 4, 7, 9, 11, 13, and 15). Each item was categorized as "no," "partially yes," or "yes" depending on their adherence to the criteria. Te overall methodological quality was classifed into four levels: high, medium, low, or extremely low.

Report Quality Evaluation.
Te PRISMA 2020 [20] was used to assess the quality of the report and it covers 27 items. Each item can be assessed as "yes," "partially yes," or "no," with a ratio based on the assessment of each item.

Data Synthesis.
Narrative descriptions were given for the included SRs/MAs. Dichotomous variables are expressed as risk ratios (RR) or odds ratios (OR) with 95% confdence intervals (CI), while continuous variables are expressed as standardized mean diferences (SMD) or mean diferences (MD) with 95% CI. In addition, the results of the AMSTAR 2, PRISMA 2020, and GRADE assessments are shown in the table.

Characteristics of the SRs/MAs
. Te characteristics of the 11 SRs/MAs used for qualitative analysis in this overview were summarized in Table 2. All SRs/MAs were published between 2014 and 2022, with 6 (6/11, 54.5%) [30,31,34,35,37,38] of them being published within the last 5 years. All the included SRs/MAs were published by Chinese scholars, fve [29][30][31][32][33] of which were in English and six [34][35][36][37][38][39] in Chinese. Te number of RCTs included per SR/MA ranged from 8 to 30, and the participants in these RCTs ranged from 534 to 3,126. In terms of intervention modality, CT was used in the control group, while XFZY was used in the experimental group or added to the control group. Seven SRs/MAs [29][30][31][32][33][34] used the Cochrane criteria for risk of bias assessment of included RCTs, and the remaining 4 SRs/MAs [35,36,38,39] used the Jadad scale. All SRs/MAs were subjected to meta-analysis and all reported positive results.

Quality Assessment
3.3.1. Methodological Quality Assessment. AMSTAR-2 was used to assess the methodological quality of the SRs/MAs included in this research, the details of which are given in Table 3. Due to multiple defciencies in critical and noncritical items, the methodological quality of all SRs/ MAs was low.  (none of the SRs/MAs provided a list of excluded articles), and Item 10 (none of the SRs/MAs provided a list of funding for RCTs).

Report Quality Assessment.
Detailed information on the quality of the report was presented in Table 4. Although the titles, abstracts, introductions, and discussions of the SRs/MAs included in this overview were reported in their entirety, some reporting defciencies were found in other sections. In the method section, Item 7 (search strategy) and Item 13 e, f (synthesis methods) have less than 50% response rate. Less than half of the included SRs/MAs were reported on Item 20 d (results of syntheses) in the results section. In addition to this, only 2 (2/11, 18.2%) SRs/MAs provided information on the registration of study protocols, which makes the quality assessment of Item 24 (registration and protocol) reports also unsatisfactory. Evidence-Based Complementary and Alternative Medicine 3.5. Evidence Quality Assessment. Te 11 SRs/MAs included in this overview contain 51 outcomes. Te results of the quality of evidence assessment showed that 2 items were rated as high quality, 5 items were rated as moderate quality, 24 items were rated as low quality, and the remaining 20 items were rated as extremely low quality. Among the downgrading factors, publication bias (n � 46) was the most common downgrading factor, followed by risk of bias (n � 30), imprecision (n � 26), inconsistency (n � 18), and indirectness (n � 0). Detailed information on the quality of the evidence was presented in Table 5.

SRs/MAs Outcomes of Intervention.
In this overview, we provide a summary and narrative description of the outcome indicators quantitatively assessed by the SRs/MAs. Complete information was presented in Table 6.

Safety Assessment.
One SR/MA [31] quantifed the adverse events associated with XFZY for CHD treatment and showed no diference in the incidence of AEs (low-quality evidence) in XFZY compared to controls. In addition, nine SRs/MAs [29, 30, 32-36, 38, 39] gave a narrative description on the low incidence of adverse events in the XFZY group.

Discussion
TCM has been proven efective in the treatment of CHD, and XFZY is one of the representatives. As the highest level of evidence, SRs/MAs were becoming increasingly important for evidence-based clinical decision-making [40]. Although the number of published SRs/MAs on the XFZY for the treatment of CHD is on the rise, no published overview has thus far put them together and assessed their quality.

Key Findings of Tis Overview.
Tis overview is the frst evaluation of XFZY for CHD-related SRs/MAs using AMSTAR-2, PRISMA 2020, and GRADE. More than half (6/ 11, 54.5%) of these SRs/MAs were published in the last fve years, indicating the growing interest in XFZY for CHD. Te included SRs/MAs, on the other hand, were of poor quality. Based on the details of the AMSTAR-2 assessment, the major factors for the low methodological quality of the included SRs/MAs were as follows: Item 2 (protocol registration, 2/11, 18.2%), Item 7 (exclusion list, 0/11, 0%), and Item 10 (funding sources, 0/11, 0%). Study protocol registration is important when researchers identify topics for SRs/MAs, which helps improve processing transparency and minimize selective reporting bias [41]. A list of excluded literature was not provided for all included SRs/MAs, which may afect the reproducibility of results and undermine the transparency of the study, making it difcult to ensure the reliability of the results. None of the SRs/MAs provided funding resources, which may increase bias in the reporting Evidence-Based Complementary and Alternative Medicine Search strategy Study risk of bias assessment

Risk of bias in studies
Results of individual studies

Results of syntheses
Other information Availability of data, code, and other materials Evidence-Based Complementary and Alternative Medicine Table 5: Results of evidence quality. ① Te included studies have a large bias in methodology such as randomization, allocation concealment, and blinding. ② Te confdence interval overlaps less or the I2 value of the combined results was larger. ③ Te sample size from the included studies does not meet the optimal sample size or the 95% confdence interval crosses the invalid line. ④ Te funnel chart is asymmetry. Author Very Low Zhou Fang, 2016 [29] Clinical Efciency Rate Min Liu, 2016 [32] Clinical Efciency Rate  For reporting quality, the results of PRISMA 2020 suggest that, as with AMSTAR-2, neither the study protocol nor the source of funding for the RCT was reported in full. In addition, the lack of complete search strategy and sensitivity analysis is also an important reason for the low quality of the report. None of the SRs/MAs provided a complete search strategy for all electronic databases, which renders the studies nonreplicable and may also lead to publication bias. Only 2 (2/11, 18.8%) SRs/MAs had sensitivity analysis, and the absence of sensitivity analysis was detrimental to the stability of the judgmental assessment, which led to a decrease in the credibility of the results.
Regarding evidence quality, only 2 of the 51 outcomes assessed were rated as high quality. Further analysis revealed that publication bias (46/51, 90.2%), risk of bias (30/51, 58.8%), and imprecision (26/51, 51%) were the main factors contributing to the downgrading of the quality of the evidence. Te reasons for publication bias may be related to omissions during the literature search and the insufcient number of RCTs on relevant topics. Most of the original RCTs for XFZY treatment of CHD did not explicitly describe the methods of random sequence generation, allocation concealment, and blinding, which may have afected the potency of argumentation of SRs/MAs. Te implementation of blinding is difcult due to the particularity of TCM compounds, but scientifc methods should be attempted to blind patients, care providers, and outcome assessors. Te cause of imprecision is related to the insufcient number of subjects in the RCT, which may be associated with an irrational study design.
Trough a narrative overview of the outcome indicators of CHD treated with XFZY, we found that XFZY is efective and safe for CHD, and XFZY is benefcial in relieving angina pectoris, improving electrocardiogram, and reducing blood lipids. In addition, it has potential efects in improving vascular endothelial function and reducing oxidative stress. However, caution is still needed when recommending XFZY for CHD treatment because the low quality of the included SRs/MAs may hinder it from serving as a scientifc guidance for clinical practice.

Implications for Future Practice and Research.
XFZY exerts its unique advantages in the treatment of CHD through the multitargeted combined action of multiple herbal medicines.
Our fndings suggest that XFZY may be a promising complementary therapy for CHD, but due to the overall low quality of the included evidence, the following is strongly advised for future SRs/MAs and RCTs. For TCM-related SRs/ MAs, registration on international platforms (e.g., Cochrane Library, PROSPERO, etc.) and/or early publication of protocols is highly recommended. When conducting SRs/MAs, researchers should provide a complete list of search strategies for each electronic database, a list of excluded literature, and the source of funding for the RCT to increase the transparency and reduce the publication bias of the article. To improve the reliability of the results, a sensitivity analysis should be performed. With the development of evidence-based medicine in TCM, it is hoped that researchers will continue to promote the standardization of clinical trial procedures for TCM compounding in the future, including random assignment methods, blinding, and reasonable inclusion of subjects. Clinical researchers should enhance clinical trial top-level design through thorough assessment and sophisticated analysis. Te Consolidated Standards of Reporting Trials (CON-SORT) should be used to improve the quality of evidence from RCTs [42]. Careful design, rigorous implementation, and complete reporting of RCTs are considered the gold standard for avoiding the risk of bias [43]. In subsequent RCTs of XFZY for CHD, researchers should pay more attention to circulatoryrelated biochemical indicators or those related to oxidative stress to better investigate the underlying mechanism of XFZY's action. In addition, the dosage and preparation of each Chinese herbal medicine in the XFZY formula should be standardized to make clinical research more scientifc.

Strengths and Limitations.
Tis overview is the frst to evaluate the current evidence for XFZY in the treatment of CHD from the perspectives of methodological quality, report quality, and evidence quality in all aspects, which can ofer helpful advice for clinicians' decision-making as well as suggestions for the upcoming clinical trials. However, this overview also has some limitations, and we found that most of the included SRs/MAs were of poor quality, which may lead to low credibility of the fnal conclusions. Also, although the assessment has been conducted by two independent assessors, diferent assessors may have their own judgment on each factor, so the results may vary.

Conclusions
Te evidence suggests that XFZY appears to be an efective and safe method for treating CHD. However, issues with the methodology, quality of the supporting data, and reporting of SRs/MAs and original clinical trials decreased the results' dependability. In order to provide convincing evidence for researchers and clinicians in this feld, high-quality clinical studies of XFZY for CHD should be conducted so as to boost the methodological and reporting quality of SRs/MAs.

Data Availability
Te datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Disclosure
Hongsuo Shi, Zunhao Tang, and Ting Liu are the co-frst authors.

Conflicts of Interest
Te authors declare that the research was conducted in the absence of any commercial or fnancial relationships that could be construed as potential conficts of interest.