A comprehensive search strategy was formulated to identify all relevant studies. The PubMed, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), VIP and Wanfang databases were searched from their inception to August 3rd, 2024.

The keywords used for searching were “Tongxinluo” OR “Tong Xin Luo” OR “Tong-Xin-Luo” OR “TXL” combined with “Chronic Coronary Syndromes” OR “CCS” OR “Coronary Artery Disease” OR “CAD” OR “Myocardial Ischemia” OR “MI” OR “Angina Pectoris” OR “AP” OR “Myocardial Infarction”, adjusted for use in different databases. Supplementary Material S1 displays the search strategies for all the databases. No language restrictions were applied.

Three authors (SBL, YFW and JMH) develop a search strategy for each database. To avoid missing potentially relevant RCTs, we checked the reference lists of included publications.

One author (SBL) scanned the titles and abstracts of every record retrieved for eligibility assessment. Full texts were reviewed when necessary for clarification or potential eligibility. Two authors (SBL, ZCN) independently selected studies by reviewing full texts, cross-checking selections, and resolving disagreements through discussion with a third author (YLL).

Three authors (SBL, HMZ and YFL) were responsible for the data extraction on the basis of a predesigned form for this review, including study titles, author information, characteristics of participants (age, sex, disease duration, number of participants randomized, number of patients analysed, etc.), details of interventions and comparators (dosage, treatment duration, etc.), outcomes (primary and secondary outcomes specified and collected, time points reported), and information relevant to the study design (e.g., randomization, allocation concealment, blinding, random concealment, and blinding). In this process, one author (SBL) independently completed the data extraction for all included studies, which was then verified separately by the other two authors (HMZ, YFL). Disagreements were resolved through discussion.

The risk of bias for the primary outcome was assessed using the Cochrane risk of bias tool 2.0 (ROB 2.0) (14), covering five domains: (1) the randomization process, (2) deviations from the intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported result. Each domain was assessed as (a) low risk, (b) some concerns or (c) high risk. Finally, overall risk bias was developed on the basis of the results of the above five domains in each trial. When four or more domains were rated “some concerns” or when at least one domain was rated “high risk”, the risk of overall bias was considered “high risk”; when all domains were rated “low risk”, the overall bias was considered “low risk”; otherwise, it was considered “some concerns”. Two authors (SBL, YFL) conducted the assessments, resolving inconsistencies through discussion.

Data analysis was performed using Review Manager 5.4 (RevMan 5.4) software (15). The risk ratio (RR) with 95% confidence interval (CI) and the number needed to treat (NNT) (16) were used for dichotomous outcomes (cardiovascular endpoint events, adverse events). The NNT offers a measurement of the impact of a medicine or therapy by estimating the number of patients who need to be treated to have an impact on one person. For continuous outcomes {angina occurrence [frequency of angina occurrence, angina duration, Seattle angina questionnaire (SAQ) scores, nitroglycerin dosage], quality of life, and cost-effectiveness}, the mean difference (MD) with 95% CI was used when the outcome was measured by the same scale or with the same unit between different studies, and the standardized mean difference (SMD) with 95% CI was employed when different measurement scales or units were used. For outcome-related pretreatment continuous data, we performed a pooled analysis via the same methodology to confirm between-group comparability. Data that were unsuitable for meta-analysis, e.g., nonquantitative data, were presented descriptively.

We performed data synthesis (meta-analysis) when at least two studies were available. All meta-analyses were performed with a random effects model via the Mantel‒Haenszel (M-H) method, as potential sources of clinical heterogeneity exist between studies. We employed I² statistics to quantify heterogeneity among studies: the value ranges between 0% and 100%, with higher values indicating greater statistical heterogeneity (17). When I² > 50%, the data accuracy was checked first. If the data were accurate and appropriate, sensitivity analysis by excluding studies was conducted to explore the source of heterogeneity. Otherwise, the results would be carefully interpreted.

Sensitivity analysis was used to assess the robustness of the results between fixed effects and random effects analyses. Although we also planned to use sensitivity analyses to assess the impact of missing data on outcomes, the plan could not be implemented because most studies did not report whether data were missing.

Subgroup analysis was conducted according to the dose of TXL and the treatment duration to explore the effects of treatment duration and TXL dosage on the therapeutic effects.

A funnel plot was used to explore the possibility of publication bias if ten or more trials were included in a single meta-analysis (18).

The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation criteria) approach (19) via the GRADEpro Guideline Development Tool (GDT) online (https://gradepro.org/). Two authors (SBL, YFL) conducted the assessments, resolving inconsistencies through discussion.

As illustrated in the flow diagram (Figure 1), our initial search of electronic bibliographic databases identified 4,200 records. After preliminary screening, 457 records were classified as potentially relevant and subjected to full-text assessment. No additional eligible studies were identified from the reference lists of included publications. Ultimately, 437 reports were excluded for various reasons, as detailed in Supplementary Material S2. This process resulted in the inclusion of 20 studies, reported in 20 published articles (20–39), that met our predefined inclusion criteria.

For a detailed description of the studies, the characteristics of the included studies are presented in Table 1.

A funnel plot was utilized to assess potential publication bias for adverse event outcomes, given that more than ten studies were included in the meta-analysis. The asymmetrical funnel plot suggested a high risk of publication bias (Figure 8).

The certainty of evidence for outcomes was evaluated as low. They were downgraded mainly due to the high risk of performance bias (studies included failed to carry out blinding for participants and clinicians delivering the interventions), imprecision (small number (<300) of total events, RR with a relatively wide confidence interval), and large heterogeneity between the included studies and/or suspected publication bias. Table 2 presents details of the evaluation of the certainty of the evidence for the outcomes.

To our knowledge, this systematic review and meta-analysis is the first to compare patients with CCS treated with TXL and WM with those treated with only WM. Twenty RCTs involving 2,091 CCS participants that evaluated the therapeutic effects and safety of TXL as a supplement were included. The analysis results demonstrated that TXL in combination with WM was more effective for improving clinical outcomes in people with CCS. Two trials reported the occurrence of cardiovascular endpoint events (MI and sudden cardiac death), our primary outcome of interest, and suggested that the addition of TXL may reduce the risk of cardiovascular endpoint events, possibly resulting in a positive effect, although the estimates failed to achieve statistical significance. The results of the NNT analysis suggest that treating an average of 45 people with TXL would result in one person experiencing MI, and treating an average of 60 people with TXL would result in one person experiencing sudden cardiac death. There was also some evidence from this analysis that suggested that the addition of TXL to WM reduced the risk of angina occurrence, judging from the reduction in angina frequency, the shortening of angina duration, the increase in SAQ scores and the reduction in nitroglycerin dosage. Seventeen studies reported the occurrence of adverse events and demonstrated that the addition of TXL did not increase the risk of adverse events.

Notably, while these studies provide data on efficacy and safety, they do not specifically address potential pharmacodynamic interactions between TXL and WM. This means that the specific mechanisms by which these two treatments might interact remain unclear. However, the absence of increased adverse events suggests that TXL likely does not significantly interfere with the pharmacodynamics of WM; otherwise, it might have led to a higher incidence of side effects or adverse reactions.

However, our confidence in the effect estimate is limited, and the study findings should be interpreted with caution because all studies were at high risk of bias and all meta-analysis evidence had low-GRADE certainty.

Currently, in clinical practice in China, TXL is often used for the treatment of CCS together with WM. This review has important implications for future practice, as the strength of the evidence available has been systematically identified, appropriately analysed and appraised. These findings suggest that adding TXL to WM may further enhance therapeutic benefits for patients with CCS without increasing the risk of adverse events. Although there was no significant difference between add-on TXL and WM alone in reducing the risk of cardiovascular endpoint events, TXL as a supplement appeared to have greater potential for improving angina occurrence. In summary, TXL can potentially improve certain outcomes for patients with CCS treated with WM. On the basis of the characteristics of the included studies and the results of the subgroup analyses and safety profile, we suggest that clinicians use TXL (4 capsules tid) with a treatment duration of no less than 12 weeks (3 months), in addition to WM (antithrombotic therapy, lipid-lowering drugs, etc.) recommended by the 2019 ESC Guidelines (1)^, to treat CCS patients. However, it remains to be determined if extending treatment beyond 12 weeks offers additional benefits. During treatment, if adverse events such as abdominal discomfort and gastrointestinal symptoms occur in patients, an appropriate reduction in the TXL dosage to 2–3 capsules per time and/or twice daily can be attempted, but the therapeutic effects may be reduced. However, this needs to be further confirmed in future studies.

Our research also has important implications for future trials. First, due to the high risk of bias in the existing studies, further high-quality research is needed, particularly multicenter, placebo-controlled, and blinded RCTs. Improvements in methodological quality, including a valid method of randomization, allocation concealment, blinding, should be achieved. Second, the aims of the pharmacological management of CCS patients described in the 2019 ESC Guidelines (1) are to reduce angina symptoms and exercise-induced ischaemia and to prevent cardiovascular events. In future studies on TXL for CCS, more attention should therefore be given to the evaluation of these endpoints. Third, as an additional and complementary treatment to WM, TXL inevitably increases healthcare costs, necessitating a comparative evaluation of its cost-effectiveness. However, no included studies reported this information. Therefore, we recommend including cost-effectiveness outcomes in future studies to better inform medical decision-making. Furthermore, since quality of life improvements are critical for all patients, and none of the included studies reported on this outcome, we recommend that future studies also assess quality of life. Additionally, to ensure a more rigorous and comprehensive study design, as well as better dissemination and application of results, we recommend that future studies adhere to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (43). Study protocols should be developed and registered in advance on WHO-recognized platforms, such as ClinicalTrials.gov. Researchers should report their studies in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement (44).

Our findings may provide new insights and evidence for the use of TXL in the treatment of CCS, leading to more options for CCS patients in clinical practice. We strictly followed the process and specifications for producing systematic reviews as presented in the Cochrane Handbook (17). Efforts were made to minimize bias throughout the review process. The research protocol was developed by researchers in evidence-based medicine (SBL), along with clinicians (YLL, YFW, ZCN, JMH and JY) and cardiovascular disease researchers (YLL and YFW), ensuring that our research was conducted correctly and maximizing the value of the evidence for clinical practice. The review was conducted in strict accordance with the protocol registered on PROSPERO (CRD 42024499031). A comprehensive search without language restrictions was performed to identify all relevant studies on the topic. Study selection, risk of bias assessment, and data extraction were carried out independently or cross-checked by two review authors. Additionally, we assessed the certainty of evidence from all meta-analyses using the GRADE method. Thus, our research provides additional dimensions of reference that will add value to future clinical practice and research.

Potential limitations of this study should be acknowledged. Firstly, all the trials were conducted in China, which may limit the generalizability of the findings to patients from other countries or regions with different healthcare settings and patient populations. Secondly, the sample sizes of most included studies were relatively small, indicating that studies with larger sample sizes are necessary to provide stronger support for our findings. Moreover, despite standardizing the results to SMD, heterogeneity persisted in some meta-analyses of continuous outcomes. We attempted to explore possible sources of heterogeneity using various methods, including sensitivity analyses and subgroup analyses, but specific sources remained unidentified due to the limited number of included studies and the scarcity of detailed information available from these studies. However, qualitative comparative analyses of the study characteristics led us to conclude that clinical factors (such as variations in treatment duration, TXL dosages, control conditions, and outcome measures) were likely contributors to the observed heterogeneity.