Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 1400990 10.3389/fphar.2024.1400990 Pharmacology Systematic Review Comparative effectiveness and safety of four traditional Chinese medicine injections with invigorating blood circulation, equivalent effect of anticoagulation or antiplatelet in acute myocardial infarction: a Bayesian network meta-analysis Chen et al. 10.3389/fphar.2024.1400990 Chen Jiaping Shang Juju Liu Hongxu Li Xiang * Lai Xiaolei Lou Yan Zhou Huiwen Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

Edited by: Michael Heinrich, University College London, United Kingdom

Reviewed by: Songxiao Xu, University of Chinese Academy of Sciences, China

Marcellino Monda, University of Campania Luigi Vanvitelli, Italy

 *Correspondence: Xiang Li, lixiang11897@bjzhongyi.com 14 08 2024 2024 15 1400990 14 03 2024 01 08 2024 Copyright © 2024 Chen, Shang, Liu, Li, Lai, Lou and Zhou. 2024 Chen, Shang, Liu, Li, Lai, Lou and Zhou

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Background: Traditional Chinese medicine injections with invigorating blood circulation (TCMI-IBCs), which have been used as antithrombosis therapies, are widely employed by Chinese clinicians as adjuvant therapy for acute myocardial infarction (AMI).

Objective: A Bayesian network meta-analysis was conducted to contrast the effectiveness and safety of four TCMI-IBCs in AMI.

Methods: Eight Databases were thoroughly searched before 31 December 2023, for randomized controlled trials (RCTs) focusing on the application of TCMI-IBCs combined with conventional treatments (CT) to treat AMI. All-cause mortality (ACM) was the major endpoint. Secondary outcomes included bleeding events, malignant arrhythmia (MA), recurrent myocardial infarction (RMI), left ventricular ejection fraction (LVEF), and adverse events. Stata17.0 and GeMTC software were employed for Bayesian network meta-analysis.

Results: A total of 73 eligible RCTs involving 7,504 patients were enrolled. Puerarin injection (PI), Danhong injection (DI), sodium Tanshinone IIA Sulfonate injection (STSI), and Danshen Chuanxiongqin injection (DCI) combined with CT can significantly reduce the occurrence of ACM and improve LVEF in AMI (P < 0.05), while without significant impact on bleeding events or MA (P > 0.05). STSI + CT would be the optimal treatment strategy in lowering RMI and ACM. DI + CT was the most likely to be the optimal strategy in reducing MA occurrence and improving LVEF. CT was likely the most effective strategy in reducing bleeding events. However, DI + CT exhibited the least favorable safety.

Conclusion: TCMI-IBCs + CT had potential benefits in the treatment of AMI. STSI + CT showed the most favorable performance in treating AMI, followed by DI combined with CT.

Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384067, identifier CRD42022384067.

 Graphical Abstract

Chinese medicine injections acute myocardial infarction network meta-analysis traditional Chinese medicine invigorate blood circulation section-at-acceptance Ethnopharmacology 1 Introduction

According to the Global Burden of Disease Report 2020, ischemic heart disease claimed the lives of 8.95 million people globally (Tsao et al., 2022). Among them, acute myocardial infarction (AMI) is the ischemic heart disease with the highest mortality and disability rate worldwide (Roth et al., 2020), which also occurs in China. Over the past decade, the management of AMI in China has made some progress. However, the China Cardiovascular Disease and Health Report 2021 Summary indicates that the overall mortality of AMI patients in China is still increasing, imposing a significant burden on both the economy and healthcare system (The Writing Committee of the Report on Cardiovascular Health and Diseases in China, 2022). The treatment of AMI involves general treatment, reperfusion therapy, as well as pharmacotherapy (anti-myocardial ischemia, antiplatelet, anticoagulation, lipid-lowering, etc.) (Levine et al., 2016; Ibanez et al., 2018; Collet et al., 2021). Early reperfusion therapy can restore blood flow in the occluded vessel, reducing the mortality among AMI patients (Roger et al., 2010; Hall et al., 2016). Nonetheless, there are still several unresolved issues following reperfusion, including decreased myocardial contractility, ventricular arrhythmia, no-reflow phenomenon, and in-stent restenosis (Eeckhout and Kern, 2001; Thiele et al., 2017; de Waha et al., 2018; Pantea-Rosan et al., 2020). These complications have a significant impact on patients’ prognosis (Heusch and Gersh, 2017). Exploring alternative, effective treatment approaches is still necessary.

Classified as “True heartache,” AMI is thought to be a consequence of the obstruction of cardiac blood vessels, according to traditional Chinese medicine theory. Promoting blood circulation and removing blood stasis is the focus of the treatment principle (Doctor Society of Integrative Medicine, 2018). In China, traditional Chinese Medicine injections (TCMIs) have gradually emerged as an adjunctive therapy for AMI (Spatz et al., 2018). TCMIs with invigorating blood circulation (TCMI-IBCs), which have equivalent effects of anticoagulant and antiplatelet, have been demonstrated in several trials to reduce the mortality and the risk of in-stent restenosis in AMI patients (Liu et al., 2012; Liu et al., 2014). However, the evidence regarding the effectiveness and safety of these TCMI-IBCs in terms of methodology and evidence-based evaluation is limited (Liu et al., 2011; Shang et al., 2012).

Previous systematic reviews (Liao et al., 2015; Hua et al., 2021; Wang and Xie, 2021) have assessed the effectiveness of TCMI-IBCs in the management of AMI, but the comparative effectiveness and safety among different TCMI-IBCs remain uncertain. Network meta-analysis is an analytical approach derived from routine meta-analysis, enabling the comparison and ranking of the efficacy of various interventions for one disease (Wu et al., 2017). This study utilized the data platform of the “National Drug Standards of China State Food and Drug Administration” (https://www.nmpa.gov.cn/) to identify TCMI-IBCs indicated for AMI treatment. Four TCMI-IBCs were discovered through the search: Puerarin Injection (PI), Danhong Injection (DI), Sodium Tanshinone IIA Sulfonate Injection (STSI), and Danshen Chuanxiongqin Injection (DCI). Networks meta-analysis was employed to contrast the clinical effectiveness and safety of four TCMI-IBCs combined with conventional treatment (CT) for AMI, thus to provide more reference for clinical treatment.

 2 Methods

This study was conducted following the protocol registered with PROSPERO (Protocol number: CRD42022384067). The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Hutton et al., 2015) were employed to conduct our network meta-analysis, as seen in Supplementary Figure. To ensure accurate reporting of four TCMIs in this analysis, we adhered to the guidelines established in the consensus statement on the Phytochemical Characterization of Medicinal Plant extract (ConPhyMP) (Supplementary Tables 1–4).

2.1 Search strategy

We searched PubMed, Cochrane Library, Embase, the Web of Science, Chinese Biological Medicine Database (CBM), Wanfang Database, China National Knowledge Infrastructure (CNKI), and Chinese Scientific Journal Database (VIP) without language limitation published before 31 December 2023. Other online search resources included ClinicalTrials.gov and proceedings of major cardiovascular conferences. A subset of Chinese and English journals related to AMI was also manually searched. Search terms include acute myocardial infarction, puerarin injection, Danhong injection, Sodium Tanshinone IIA Sulfonate injection, Danshen Chuanxiongqin injection, and randomized controlled trial. The search strategy is shown in Supplementary Tables 5.

 2.2 Study selection

Study selection was independently performed by two researchers (JPC and HWZ) and disagreements were resolved by discussion with the third researcher (HXL).

The inclusion criteria are as follows: 1. Participants: All study participants need to meet the diagnostic criteria of AMI (Gao, 2001; Thygesen et al., 2018); 2. Interventions: The control group received CT or CT combined with a placebo. CT included general treatment (monitoring of vital signs, alleviating symptoms, etc.), medication (antiplatelet, lipid-lowering, anticoagulant, etc.), and reperfusion therapy (percutaneous coronary intervention (PCI), thrombolysis, and coronary artery bypass surgery). Based on the control group, the intervention group was combined with one of these four TCMI-IBCs (including PI, DI, STSI, and PI), and the treatment dose and duration of the above drugs need to conform to the drug instructions; 3. Outcome measures: At least one outcome was reported. 1) Primary outcome: all-cause mortality (ACM) (all-cause deaths during hospitalization); 2) Secondary outcomes: Any bleeding events, malignant arrhythmias (MA), recurrent myocardial infarction (RMI), left ventricular ejection fraction (LVEF), and adverse events; 4. Study design: randomized controlled trials (RCTs), blinded or not, were included.

Studies that meet the following criteria will be excluded: 1. Full text is unavailable, data cannot be extracted or is incomplete, and there are obvious problems with the data; 2. Case report, review, conference literature, theoretical discussion, and experience summary; 3. Patients’ baseline information was inconsistent; 4. Repeated publications (retain the most comprehensive one).

 2.3 Data extraction

Data extraction was completed by two researchers (XL and XLL) independently and cross-checked. When necessary data were missing in the literature, we attempted to contact the authors to complete the data. The extracted data include the first author, publication year, sample size, gender composition, age, treatment course, intervention measures, outcomes, and the information of quality assessment of RCTs. If the result index was measured at various times, the data measured at the last moment were included.

 2.4 Risk of bias and quality of evidence assessment

Two investigators (YL and JJS) independently evaluated the risk of bias and the quality of evidence. Through discourse with the third researcher (HXL), discrepancies were resolved. The Cochrane Risk of Bias Tool was employed to evaluate the risk of bias of included RCTs, based on the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The CINeMA online application (https://cinema.ispm.unibe.ch/#) was employed to evaluate the quality of the evidence. Different from the GRADE method, CINeMA comprehensively evaluates the results of network meta-analysis in six areas: intra-study bias, interstudy bias, indirectness, inaccuracy, heterogeneity, and inconsistency (Nikolakopoulou et al., 2020).

 2.5 Data synthesis and statistical analysis

In this study, the analysis results for LVEF are reported as mean differences (MD), while odds ratios (OR) are used to represent the analysis results for binary variables such as ACM, bleeding events, MA, RMI, and adverse events. Each effect size is accompanied by a 95% confidence interval (CI). A network meta-analysis was performed using Stata17.0 to visualize the network relationships among different intervention measures. If a closed loop appears in the evidence network plot, the consistency between indirect and direct comparisons is assessed using inconsistency testing. In this study, no closed loops were observed in any of the outcomes, indicating that a consistency model was selected for the network meta-analysis. A “calibration-comparison” funnel plot was created to determine the presence or absence of small sample effects and evaluate publication bias. GeMTC software was employed to conduct a Bayesian model network meta-analysis, beginning with four Markov chains. The initial value was set to 2.5, and a pre-iteration of 20,000 times was conducted for annealing. Iteration was then continued for 50,000 times to achieve model convergence. Model convergence was deemed satisfactory when the potential scale reduction factor (PSRF) approached 1. Otherwise, additional iterations were performed. Using the surface under the cumulative ranking curve (SUCRA) ranked the efficacy of different TCMI-IBCs on each outcome (Yi et al., 2015). Sensitivity analysis was conducted by setting the criterion of ≥80 participants to assess the robustness of the study results. Additionally, we performed conventional meta-analyses using the DerSimonian-Laird random-effects model and the Mantel-Haenszel fixed-effects model to provide direct estimates.

 3 Results 3.1 Study selection

The initial review yielded 837 articles, leaving 391 articles after removing duplicates. After selection based on title or abstract, 125 articles were subjected to full text review. Of these, 13 articles were combined with oral commercial Chinese polyherbal preparation (CCPP), 26 articles’ outcomes failed to meet criteria, two articles had duplicate publications, six articles had unquantifiable data, and five articles were case reports. At last, 73 articles were included, 70 of which were in Chinese and three in English, all of which had been conducted in mainland China. The literature screening process is shown in Figure 1.

Flow chart of the study selection. The initial review yielded 837 articles, leaving 391 articles after removing duplicates. After selection based on title or abstract, 125 articles were screened for full text review. Of these, 13 articles were combined with oral commercial Chinese polyherbal preparation, 26 articles’ outcomes missed criteria, two articles had duplicate publications, six articles had unextractable data, and five articles were case reports.

 3.2 Study characteristics

The 73 RCTs (Lu et al., 2001; Li et al., 2002; Gu and Wang, 2004; Xiao et al., 2004; Qi et al., 2006; Chen, 2007; Liu and Zhong, 2008; Qu, 2008; Yu et al., 2008; Gao, 2009; Gui et al., 2009; Chen et al., 2010; Han, 2010; Zhou et al., 2010; Du and Wang, 2011; Hao and Ren, 2011; Sun, 2011; Feng and He, 2012; Han et al., 2012; Huang, 2012; Zhang, 2012; Zhao, 2012; Chen and Liu, 2013; Kong et al., 2013; Ren and Jia, 2013; Liu and Mao, 2014; Qin et al., 2014; Zhou, 2014; Bin and Shaopeng, 2015; Fan and Yang, 2015; Liu, 2015; Wang and Jie, 2015; Xu et al., 2015; Yang et al., 2015; Huang, 2016; Ji et al., 2016; Liu et al., 2016; Sun et al., 2016; Ceng et al., 2017; Fan and Chen, 2017; Xu and Liu, 2017; Zhang, 2017; Zhou, 2017; Fu Z. G. et al., 2018; Luo R. X., 2018; Luo X. Y., 2018; Hu, 2018; Lin et al., 2018; Miao et al., 2018; Zhang et al., 2018; Cao and Di, 2019; Huo et al., 2019; Jin et al., 2019; Mao et al., 2019; Qi et al., 2019; Shen et al., 2019; You, 2019; Zhang et al., 2019; Lan et al., 2020; Li and Xu, 2020; Liu et al., 2020; Qin et al., 2020; Zhiyong et al., 2020; Chen L. F. et al., 2021; Chen Q. et al., 2021; Cui et al., 2021; Feng, 2021; Lu et al., 2021; Zhang, 2021; Dong and Fang, 2022; Song, 2022) included were two-arm trials with a total of 7,504 patients. All the included RCTs described the baseline information, ensuring comparability among the groups. In all studies, the follow-up duration spanned from 2 weeks to 12 months, respectively. The details of the study characteristics are depicted in Table 1; Supplementary Tables 6. Figure 2 presents the evidence network diagram for each outcome, and none of them formed a closed loop, therefore, the assumption of consistency was not tested.

Characteristics of the included studies.

Study ID N (E/C) Sex (M/F) Age(Y) (E/C) STEMI, Non-STEMI (E/C) I(E) I (C) Course Follow-up Outcomes
Cao and Di (2019) 63/63 72/54 55.7 ± 5.2/58.5 ± 5.8 NR STSI 40 mg Qd + Am Am 3M NR I
Chen et al. (2021a) 40/40 45/35 71.98 ± 2.86/72.31 ± 2.89 NR DI 30 mL Qd + TT TT 14d NR V
Chen, (2007) 33/31 49/15 54 ± 4/52 ± 6 NR STSI 40 mg Qd + P + Ac + B + N P + Ac + B + N 14d NR I
Chen et al. (2010) 29/30 43/16 62 ± 5/65 ± 4 All STEMI DI 20 mL Qd + P + Ac + PCI P + Ac + PCI 14d NR V
Chen and Liu (2013) 39/36 40/35 52.3 ± 3.6/53.1 ± 2.9 All Non-STEMI DI 30 mL Qd + P + Ac + S + B + N P + Ac + S + B + N 14d NR VI
Chen et al. (2021b) 46/47 56/37 62.9 ± 9.5/63.2 ± 8.5 All STEMI DI 40 mL Qd + P + Ac + S + B + N + PCI P + Ac + S + B + N + PCI 2 h 1M I; III; IV
Cui et al. (2021) 45/45 46/44 57.53 ± 3.35/56.35 ± 3.23 NR DI 30 mL Qd + A + S + TT A + S + TT 60d 6M IV
Dong and Fang (2022) 49/49 55/39 47.61 ± 1.94/47.82 ± 1.72 NR PI 200 mg Qd + P + N + Am + TT P + N + Am + TT 24d NR V; VI
Du and Wang (2011) 26/22 NR 59 ± 12 NR STSI 80 mg Qd + P + PCI P + PCI 14d NR I; III
Fan and Yang (2015) 47/42 49/38 59.7 ± 5.6/58.9 ± 4.4 NR STSI 60 mg Qd + P + Ac + TT P + Ac + TT 7d NR V
Fan and Chen (2017) 49/49 53/45 53.6 ± 3.9/57.6 ± 3.9 NR PI 300 mg Qd + P + Ac + TT P + Ac + TT+ 14d NR V; VI
Feng and He (2012) 50/50 56/44 61.5 ± 5.2/61.1 ± 5.3 NR STSI 60 mg Qd + P + Ac + N + TT P + Ac + N + TT 7d NR III
Feng and He (2012) 79/78 82/95 60.19 ± 1.38/60.25 ± 1.21 All STEMI DI 40 mL Qd + P + Ac + PCI P + Ac + PCI 7d 3M V; VI
Fu et al. (2018a) 48/48 60/36 58.9 ± 4.9/58.3 ± 5.2 All STEMI DI 30 mL Qd + P + Ac + TT P + Ac + TT 7d 12M I; II
Gao (2009) 60/60 82/44 57.9/56.6 NR DI 30 mL Qd + P + N + TT P + N + TT 14d NR I
Gao (2015) 40/40 62/18 59.1 ± 2.86/59.6 ± 3.2 NR STSI 80 mg Qd + P + Ac + S + B + A + TT + PCI P + Ac + S + B + A + TT + PCI 14d NR III; V;VI
Gu and Wang (2004) 34/31 49/16 61.5 NR PI 500 mg Qd + P + Ac + A + N + TT P + Ac + A + N + TT 21d NR V
Gui et al. (2009) 26/22 Sep-39 56.38 ± 8.86/55.86 ± 10.94 NR DI 20 mL Qd + P + Ac + S + N + TT P + Ac + S + N + TT 14d NR I; II; IV
Han (2010) 50/50 69/31 53.0 ± 16.2/52.5 ± 16.5 NR DI 20 mL Qd + P + Ac + TT P + Ac + TT 7d NR I; II
Han et al. (2012) 76/58 74/60 55.6 ± 12.5/51.8 ± 13.6 NR DI 20 mL Qd + P + Ac + TT P + Ac + TT 14d NR I; II
Hao and Ren (2011) 60/60 79/41 59.2 ± 11.2 NR DI 30 mL Qd + PAc + B + A + TT P + Ac + B + A + TT 7d NR I; II
Hu (2018) 44/43 48/39 60.71 ± 5.51/59.60 ± 5.62 NR DI 30 mL Qd + P + Ac + S + B + N + TT P + Ac + S + B + N + TT 15d NR II; VI
Huang (2012) 42/43 50/35 60.2 ± 6.7/61.5 ± 6.4 NR STSI 400 mg Qd + P + Ac + B + N P + Ac + B + N 7d NR I
Huang (2016) 50/50 63/37 52.13 ± 8.59/53.61 ± 9.47 NR DCI 10 mL Qd + P + Ac + S + N P + Ac + S + N 28d NR V
Huo et al. (2019) 40/40 54/26 62 ± 4/61 ± 6 NR DI Qd + P + Ac + S + B + A + N P + Ac + S + B + A + N 14d NR V
Ji et al. (2016) 54/54 74/34 62.3 ± 6.5/61.8 ± 6.7 All Non-STEMI DI 40 mL Qd + P + Ac + S + N P + Ac + S + N 28d NR II
Jia (2010) 48/50 56/42 66 ± 9/67 ± 8 NR STSI 60 mL Qd + P + Ac + B + A + N P + Ac + B + A + N 28d NR II
Jin et al. (2019) 57/60 77/40 57.7 ± 5.49/57.4 ± 6.37 NR DI 40 mL Qd + P + Ac + B + A + N P + Ac + B + A + N 14d NR V
Kong et al. (2013) 48/42 48/42 66.2 ± 12.0/65.8 ± 13.1 NR STSI 40 mg Qd + Am Am 14d NR I
Li et al. (2002) 30/30 41/19 52.8 ± 8.5/53.6 ± 7.8 NR PI 500 mg Qd + P + Ac + TT P + Ac + TT 15d NR I; II
Li et al. (2019) 45/45 43/47 60.14 ± 4.81/60.17 ± 2.85 All STEMI DI 30 mL Qd + P + PCI P + PCI 7d NR III; VI
Li and Xu (2020) 86/80 85/81 59.25 ± 6.69/58.75 ± 5.68 All STEMI DI 4 mL Qd + P + Ac + S + PCI P + Ac + S + PCI 14d NR V; VI
Bin and Shaopeng (2015) 30/30 44/16 55.6 ± 2.3/56.7 ± 3.4 NR DCI 10 mL Qd + P + S + B + A + N P + S + B + A + N 14d NR V
Liu and Zhong (2008) 23/23 28/18 53.11 ± 7.31/51.86 ± 7.38 NR PI 0.4 g Qd + P + Ac + N + TT P + Ac + N + TT 14d NR I; II
Liu et al. (2014) 80/80 112/48 62.8 ± 8.2/63.1 ± 8.6 NR STSI 60 mg Bid + P + Ac + TT P + Ac + TT 1d NR III
Liu (2015) 40/40 49/31 60 ± 5.5/61 ± 6.5 NR DI 20 mL Qd + Ac + TT Ac + TT 3d NR I
Liu et al. (2016) 49/49 56/42 56.9 ± 4.7/57.1 ± 4.8 NR STSI 40 mg Qd + Am Am 10d NR I
Liu et al. (2020) 61/61 70/52 58.97 ± 6.52/59.32 ± 5.87 All STEMI DCI 10 mL Qd + P + S + PCI P + S + PCI 14d 14d V; VI
Lu et al. (2021) 100/100 115/85 58.06 ± 4.84/58.13 ± 5.16 NR STSI 80 mg Qd + P + S + PCI P + S + PCI 7d 12M I; III; IV
Luo (2018a) 43/43 47/39 57.85 ± 4.61/58.01 ± 5.02 NR STSI 80 mg Qd + P + PCI P + PCI 7d NR IV; V
Luo (2018b) 54/54 55/53 57.12 ± 5.33/56.23 ± 5.48 NR STSI 40mgQd + Am Am 24d NR I
Lu et al. (2001) 32/28 42/18 61.6 ± 9.6/60.8 ± 8.8) NR PI 400 mg Qd + P + Ac + PCI P + Ac + PCI 21d NR V
Mao et al. (2019) 50/51 51/50 68.19 ± 9.67/68.63 ± 10.23 NR STSI 80 mg Qd + P + S + B + A P + S + B + A 7d 6M I; IV
Miao et al. (2018) 44/44 47/41 59.67 ± 8.14/60.01 ± 8.27 NR DCI 10 mL Qd + P + B + A + Am P + B + A + Am 14d 1M V
Qi et al. (2006) 48/46 65/29 65.22 ± 6.98/62.11 ± 10.25 NR STSI 80 mg Qd + P + Ac + N P + Ac + N 14d NR I
Qin et al. (2014) 56/56 61/51 52.31 ± 11.24/55.12 ± 10.52 All STEMI DI 40 mL Qd + P + Ac + S + B + A + PCI P + Ac + S + B + A + PCI 7d NR II; V
Qin et al. (2020) 53/53 63/43 71.43 ± 6.12/70.51 ± 6.09 NR STSI 40 mg Qd + P + S + TT P + S + TT 14d NR II; V;VI
Qu (2008) 26/26 37/15 60.2 ± 5.3/60.7 ± 5.2 NR PI 500 mg Qd + B + A + N + TT B + A + N + TT 28d NR I
Ren and Jia (2013) 20/20 27/13 63.1 ± 8.3 NR DI 40 mL Qd + P + Ac + S + B + A + N P + Ac + S + B + A + N 14d 14d I; IV
Shen et al. (2019) 100/100 117/83 59.65 ± 3.79/59.82 ± 3.70 All STEMI DI 40 mL Qd + P + PCI P + PCI 14d NR II; V
Song (2022) 99/99 108/90 62.19 ± 5.02/62.52 ± 4.78 NR STSI 80 mg Qd + P + T P + T 14d NR II; V;VI
Sun (2011) 72/64 76/60 56.34/57.82 All Non-STEMI STSI 80 mg + P + N P + N 14d NR III
Sun et al. (2016) 60/60 64/56 62.7 ± 11.9/62.7 ± 4.2 All STEMI DCI 15 mL Tid + P + PCI P + PCI 6d NR I; IV
Wang and Jie (2015) 30/30 36/25 64.7 ± 5.6/64.2 ± 5.1 NR DI 20 mL Qd + P + Ac + S + B + A + N + TT P + Ac + S + B + A + N + TT 14d NR I; III
Xiao et al. (2004) 31/30 43/18 61.3/60.2 NR PI 500 mg Qd + B + A + N + TT B + A + N + TT 14d NR I
Xu et al. (2015) 36/35 49/22 64 ± 12 NR DI 40 mL Qd + P + S + B + A + N P + S + B + A + N 14d NR I; VI
Xu and Liu (2017) 42/42 55/49 71.4 ± 5.8/72.3 ± 6.2 NR DCI 10 mL Qd + P + S + B + A + PCI P + S + B + A + PCI 7d NR V
Yang et al. (2015) 28/29 40/17 64 ± 12.3/65 ± 11.7 All STEMI DI 40 mL Qd + P + S + A + N P + S + A + N 10d NR I; VI
You (2019) 57/53 95/15 56.8 ± 8.9/55.4 ± 9.5 All STEMI DI 40 mL Qd + PCI PCI 4-6d 6M I
You (2019) 62/57 103/16 58.1 ± 9.9/58.0 ± 9.7 All STEMI DI 40mlQd + P + Ac + S + PCI P + Ac + S + PCI 7d 6M I; V;VI
Yu et al. (2008) 46/50 66/30 63 ± 6.96/62.11 ± 10.26 NR STSI 80 mg Qd + P + Ac + S + N + TT P + Ac + S + N + TT 14d NR I
Ceng et al. (2017) 60/60 74/46 65.13 ± 2.38/64.38 ± 2.12 All STEMI DI 40 mL Qd + P + Ac + B + N P + Ac + B + N 14d 6M I; IV; V
Zhang (2012) 30/30 39/21 56.9 ± 5.62/56.67 ± 6.41 NR DI 30 mL Qd + P + Ac + S + B + A + TT P + Ac + S + B + A + TT 7d NR II; III
Zhang (2017) 50/50 48/52 65.23 ± 2.14 NR STSI 40 mg Qd + Am Am 14d NR I
Zhang et al. (2018) 55/55 68/42 61.9 ± 4.9/62.5 ± 4.2 All Non-STEMI DI 20 mL Qd + P + Ac + S + N P + Ac + S + N 14d NR II
Zhang et al. (2019) 40/40 46/34 69.88 ± 3.16/68.92 ± 3.08 All STEMI DI 30 mL Qd + P + Ac + S P + Ac + S 7d NR I
Zhang (2021) 50/50 55/45 60.23 ± 6.54/60.45 ± 6.56 NR DI 30 mL Qd + P + Ac + S + N + TT P + Ac + S + N + TT 14d NR V
Zhao (2012) 30/26 32/24 60.0 ± 9.0/58.0 ± 9.0 NR DI 30 mL Qd + TT TT 14d NR I; IV
Zhou et al. (2010) 33/32 35/30 64.5 ± 6.3/62.5 ± 8.4 NR DI 30 mL Qd + P + Ac + S + B + A + N + PCI P + Ac + S + B + A + N + PCI 14d NR V
Zhou (2014) 100/100 146/54 55.9 ± 1.48/56.0 ± 1.51 All STEMI DCI 10 mL Qd + P + Ac + B + N P + Ac + B + N NR NR I; IV; VI
Zhou (2017) 42/42 54/30 67.3 ± 5.8/68.1 ± 5.9 All STEMI DCI 10 mL Tid + P + PCI P + PCI 6d NR I; IV
Lin et al. (2018) 70/60 NR 75 ± 9/74 ± 8 All STEMI DCI 10 mL Qd + P + PCI P + PCI 7d 6M II; IV
Zhiyong et al. (2020) 74/74 82/66 56.28 ± 7.43/56.73 ± 7.85 NR DCI 10 mg Qd + P + S + B + A + N + Am P + S + B + A + N + Am 14d 1M I; VI

Note: N, number; E, experimental group; C, control group; M, male; F, female; Y, years old; STEMI, ST segment elevation myocardial infarction; Non-STEMI, non-ST segment elevation myocardial infarction; I, intervention measures; d, day; M, month; NR, not report; PI, puerarin injection; DI, danhong injection; STSI, Sodium Tanshinone IIA sulfonate injection; DCI, danshen chuanxiongqin injection; Tid, 3 times a day; Bid, twice a day; Qd, once a day; A, angiotensin converting enzyme inhibitors or angiotensin receptor antagonists; B, beta-blockers; N, nitrate esters; P, antiplatelet aggregation drugs; S, statins; T, trimetazidine; TT, thrombolytic therapy; Am, amiodarone; PCI, percutaneous coronary intervention; Ac, anticoagulation; I, all-cause mortality. II, bleeding events; III, malignant arrhythmia; IV, recurrent myocardial infarction; V, LVEF; VI, adverse reactions.

Network graph of the outcomes. This figure presents the evidence network diagram for each outcome measure, and none of them formed a closed loop. (A), 38 RCTs involving four TCMI-IBCs (PI, DI, STSI, and DCI) reported the ACM; (B), 17 RCTs involving three TCMI-IBCs (PI, DI, and STSI) reported the incidence of bleeding events; (C), MA was reported in 10 RCTs involving two TCMI-IBCs (DI and STSI); (D), RMI was reported in 13 RCTs involving three TCMI-IBCs (DI, STSI, and DCI); (E), 27 RCTs involving four TCMI-IBCs (PI, DI, STSI, and DCI) reported LVEF; (F), 23 RCTs involving four TCMI-IBCs (PI, DI, STSI, and DCI) reported adverse events. Each node represents an intervention, and the line thickness between nodes represents the number of studies included between the two interventions. The Stata17.0 was used to visualize the network relationships among different intervention measures.

 3.3 Quality evaluation

For randomization, three studies (Lin et al., 2018; Qi et al., 2019; You, 2019) used stratified randomization, two studies (Zhou, 2017; Mao et al., 2019) used computer randomization, one study (Jin et al., 2019) used a coin toss, and 21 studies (Chen et al., 2010; Jia, 2010; Bin and Shaopeng, 2015; Fan and Yang, 2015; Yang et al., 2015; Huang, 2016; Liu et al., 2016; Ceng et al., 2017; Xu and Liu, 2017; Luo R. X., 2018; Hu, 2018; Zhang et al., 2018; Li and Xu, 2020; Liu et al., 2020; Zhiyong et al., 2020; Chen L. F. et al., 2021; Feng, 2021; Lu et al., 2021; Zhang, 2021; Dong and Fang, 2022; Song, 2022) used a random number table. The risk of the above studies was considered low, while the remaining studies did not describe specific random methods and were rated as unclear. None of the included studies reported allocation concealment, so selection bias was rated as unclear. Three studies (Gui et al., 2009; Liu et al., 2016; Qi et al., 2019) were double-blinded, the remaining studies did not mention the blinding method and were judged to be high-risk as it was difficult to apply blinding according to specific treatment measures. One study (Mao et al., 2019) blinded the outcome evaluators and was judged to be low-risk. The remaining studies did not mention the blinded outcome evaluation and were judged to be unclear. All included RCTs had complete data, so they were considered to be low-risk. Taking into account the inability to acquire a complete implementation scheme, the risk of reporting bias was considered unclear, except two RCTs (Mao et al., 2019; You, 2019). For other bias, no significant bias was observed in all studies, so it was considered to be low risk. The Cochrane bias risk results are shown in Figure 3; Supplementary Figure F1 .

Risk-of-bias graph. For randomization, three studies used stratified randomization, two studies used computer randomization, one study used a coin toss, and 21 studies used a random number table. The risk of the above studies was considered low, while the remaining studies did not describe specific random methods and were rated as unclear. None of the included studies reported allocation concealment, so selection bias was rated as unclear. Three studies were double-blinded, the remaining studies did not mention the blinding method and were judged to be high-risk as it was difficult to apply blinding according to specific treatment measures. One study blinded the outcome evaluators and was judged to be low-risk. The remaining studies did not mention the blinded outcome evaluation and were judged to be unclear. All included RCTs had complete data, so they were considered to be low-risk. Taking into account the inability to acquire a complete implementation scheme, the risk of reporting bias was considered unclear, except two RCTs. For other bias, no significant bias was observed in all studies, so it was considered to be low risk.

 3.4 Results of the network meta-analysis 3.4.1 ACM

Thirty-eight RCTs (Li et al., 2002; Xiao et al., 2004; Qi et al., 2006; Chen, 2007; Liu and Zhong, 2008; Qu, 2008; Yu et al., 2008; Gao, 2009; Gui et al., 2009; Han, 2010; Du and Wang, 2011; Hao and Ren, 2011; Han et al., 2012; Huang, 2012; Zhao, 2012; Kong et al., 2013; Ren and Jia, 2013; Zhou, 2014; Liu, 2015; Wang and Jie, 2015; Xu et al., 2015; Yang et al., 2015; Liu et al., 2016; Sun et al., 2016; Ceng et al., 2017; Zhang, 2017; Zhou, 2017; Fu Z. X. et al., 2018; Luo X. Y., 2018; Cao and Di, 2019; Mao et al., 2019; Qi et al., 2019; You, 2019; Zhang et al., 2019; Lan et al., 2020; Zhiyong et al., 2020; Chen L. F. et al., 2021; Lu et al., 2021) involving four TCMI-IBCs (PI, DI, STSI, and DCI) reported the ACM. Compared with CT alone, PI + CT [OR = 0.39, 95%CI (0.15, 0.96)], DI + CT [OR = 0.40, 95%CI (0.24, 0.63)], STSI + CT [OR = 0.31, 95%CI (0.18, 0.51)], and DCI + CT [OR = 0.42, 95%CI (0.17, 0.96)] could significantly reduce ACM in AMI patients (Table 2). According to the SUCRA results (Figure 4A; Table 5; Supplementary Tables 7), STSI + CT may be the optimal combination to reduce the occurrence of ACM among the four combinations.

Risk ratios (95%CIs) of the all-cause mortality and incidence of bleeding events.

ACM (Left lower part) Incidence of bleeding events (Right upper part)
PI + CT 0.87 (0.10, 6.04) 0.60 (0.05, 5.82) - 0.95 (0.13, 6.12)
0.97 (0.34, 2.78) DI + CT 0.72 (0.15, 2.78) - 1.10 (0.64, 1.88)
1.25 (0.43, 3.69) 1.30 (0.64, 2.55) STSI + CT - 1.55 (0.44, 6.32)
0.92 (0.27, 3.30) 0.96 (0.36, 2.56) 0.74 (0.27, 2.04) DCI + CT -
0.39 (0.15, 0.96) 0.40 (0.24, 0.63) 0.31 (0.18, 0.51) 0.42 (0.17, 0.96) CT

Note: Bold numbers in the table indicate a statistically significant difference between this group and the CT group (p < 0.05).

Plot of the surface under the cumulative ranking curves for outcomes. (A) In terms of rankings for reducing the incidence of all-cause mortality from the SUCRA analysis, STSI + CT plus ranked the first, followed by PI + CT, DI + CT, DCI + CT, and CT; (B) In terms of rankings for reducing the incidence of bleeding events from the SUCRA analysis, CT plus ranked the first, followed by PI + CT, DI + CT, and STSI + CT; (C) In terms of rankings for reducing the incidence of malignant arrhythmias from the SUCRA analysis, DI + CT plus ranked the first, followed by STSI + CT and CT; (D) In terms of rankings for reducing the incidence of recurrent myocardial infarction from the SUCRA analysis, STSI + CT plus ranked the first, followed by DI + CT, DCI + CT, and CT; (E) In terms of rankings for improving LVFE from the SUCRA analysis, DI + CT plus ranked the first, followed by PI + CT, STSI + CT, DCI + CT, and CT; (F) In terms of rankings for ruducing the occurrence of adverse reactions from the SUCRA analysis, DCI + CT plus ranked the first, followed by PI + CT, CT, STSI + CT, and DI + CT. Bayesian model network meta-analysis was performed using GeMTC software with four Markov chains as initial values. The initial value was set to 2.5, and a pre-iteration of 20,000 times was conducted for annealing. Iteration was then continued for 50,000 times to achieve model convergence. Model convergence was deemed satisfactory when the potential scale reduction factor (PSRF) approached 1. Otherwise, additional iterations were performed. The intervention effects of different TCMIs on each outcome indicator were ranked using the surface under the cumulative ranking curve (SUCRA).

 3.4.2 Incidence of bleeding events

Seventeen RCTs (Li et al., 2002; Liu and Zhong, 2008; Gui et al., 2009; Han, 2010; Jia, 2010; Hao and Ren, 2011; Han et al., 2012; Zhang, 2012; Qin et al., 2014; Ji et al., 2016; Fu Z. G. et al., 2018; Hu, 2018; Lin et al., 2018; Zhang et al., 2018; Shen et al., 2019; Qin et al., 2020; Song, 2022) involving three TCMI-IBCs (PI, DI, and STSI) reported the incidence of bleeding events. In comparison to CT alone, the combination of TCMI-IBCs had no significant effect on reducing the occurrence of bleeding events in AMI (Table 2). The results of SUCRA suggested that CT may be the best strategy to reduce the occurrence of bleeding events (Figure 4B; Table 5; Supplementary Tables 8).

 3.4.3 MA

MA was reported in 10 RCTs (Du and Wang, 2011; Sun, 2011; Feng and He, 2012; Zhang, 2012; Liu and Mao, 2014; Wang and Jie, 2015; Li et al., 2019; Lan et al., 2020; Chen L. F. et al., 2021; Lu et al., 2021) involving two TCMI-IBCs (DI and STSI). Compared with CT alone, the combination of TCMI-IBCs had no significant effect on MA in AMI patients (Table 3). According to SUCRA results (Figure 4C; Table 5; Supplementary Tables 9), DI + CT may be the optimal combination in reducing the incidence of MA.

Risk ratios (95%CIs) of the incidence of recurrent myocardial infarction and malignant arrhythmias.

RMI (Left lower part) MA (Right upper part)
DI + CT 0.56 (0.01, 22.01) - 0.15 (0.00, 2.71)
2.69 (0.42, 20.71) STSI + DCI - 0.27 (0.02, 1.98)
1.03 (0.17, 5.86) 0.38 (0.05, 2.33) DCI -
0.47 (0.12, 1.53) 0.18 (0.03, 0.65) 0.46 (0.13, 1.48) CT

Note: Bold numbers in the table indicate a statistically significant difference between this group and the CT group (p < 0.05).

 3.4.4 RMI

RMI was reported in 13 RCTs (Gui et al., 2009; Zhao, 2012; Ren and Jia, 2013; Zhou, 2014; Sun et al., 2016; Ceng et al., 2017; Zhou, 2017; Luo R. X., 2018; Lin et al., 2018; Mao et al., 2019; Chen Q. et al., 2021; Cui et al., 2021; Lu et al., 2021) involving three TCMI-IBCs (DI, STSI, and DCI). Compared with CT alone, STSI combined with CT significantly reduced RMI in AMI patients [OR = 0.18, 95%CI (0.03, 0.65)] (Table 3). According to the results of SUCRA (Figure 4D; Table 5; Supplementary Tables 10), STSI + CT may be the best combination in reducing the incidence of RMI.

 3.4.5 LVEF

Twenty-seven RCTs (Lu et al., 2001; Gu and Wang, 2004; Chen et al., 2010; Zhou et al., 2010; Qin et al., 2014; Bin and Shaopeng, 2015; Fan and Yang, 2015; Huang, 2016; Ceng et al., 2017; Fan and Chen, 2017; Xu and Liu, 2017; Luo R. X., 2018; Miao et al., 2018; Huo et al., 2019; Jin et al., 2019; Mao et al., 2019; Shen et al., 2019; You, 2019; Lan et al., 2020; Li and Xu, 2020; Liu et al., 2020; Qin et al., 2020; Chen L. F. et al., 2021; Feng, 2021; Zhang, 2021; Dong and Fang, 2022; Song, 2022) involving four TCMI-IBCs (PI, DI, STSI, and DCI) reported LVEF. Compared to CT alone, PI + CT [MD = 5.86, 95%CI (1.67, 10.07)], DI + CT [MD = 6.93, 95%CI (4.49, 10.07)], STSI + CT [MD = 5.14, 95%CI (1.72, 8.55)], and DCI + CT [MD = 4.44, 95%CI (0.70, 8.19)] could significantly enhance LVEF in AMI patients (Table 4). According to SUCRA results (Figure 4E; Table 5; Supplementary Tables 11), DI + CT may be the most effective combination in improving LVEF.

Mean difference (95%CIs) of the LVEF and adverse events.

RMI (Left lower part) MA (Right upper part)
PI + CT 0.40 (0.05, 2.69) 2.18 (0.28, 16.64) 1.09 (0.15, 13.20) 0.61 (0.12, 3.65)
−1.07 (−5.91, 3.79) DI + CT 0.85 (0.19, 3.82) 2.93 (0.57, 22.19) 1.57 (0.64, 4.71)
0.71 (−4.69, 6.12) 1.79 (−2.39, 5.97) STSI + CT 2.45 (0.45, 21.26) 1.32 (0.46, 5.20)
1.40 (−4.21, 7.04) 2.48 (−1.96, 6.93) 0.70 (−4.36, 5.78) DCI + CT 0.54 (0.11, 2.21)
5.86 (1.67, 10.07) 6.93 (4.49, 9.36) 5.14 (1.72, 8.55) 4.44 (0.70, 8.19) CT

Note: Bold numbers in the table indicate a statistically significant difference between this group and the CT group (p < 0.05).

Surface under the cumulative ranking curve results of the outcomes.

Intervention All-cause mortality(%) Bleeding events(%) Malignant arrhythmias(%) Recurrent myocardial infarction(%) LVEF(%) Adverse events(%)
PI + CT 59.8 59.0 - - 65.3 75.8
DI + CT 56.3 46.7 77.0 50.7 83.7 22.2
STSI + CT 79.3 32.3 64.5 91.0 54.8 35.7
DCI + CT 55.0 - - 51.7 45.2 77.1
CT 1.0 62.0 9.5 6.7 0.5 39.2
3.4.6 Adverse events

34 RCTs reported adverse events, of which 11 trials (Qu, 2008; Han et al., 2012; Zhang, 2012; Liu, 2015; Wang and Jie, 2015; Huang, 2016; Sun et al., 2016; Luo X. Y., 2018; Miao et al., 2018; Huo et al., 2019; Mao et al., 2019) indicated no adverse events. 23 studies (Gu and Wang, 2004; Qi et al., 2006; Yu et al., 2008; Jia, 2010; Hao and Ren, 2011; Huang, 2012; Zhang, 2012; Chen and Liu, 2013; Zhou, 2014; Xu et al., 2015; Yang et al., 2015; Fan and Chen, 2017; Hu, 2018; Li et al., 2019; Shen et al., 2019; You, 2019; Li and Xu, 2020; Liu et al., 2020; Qin et al., 2020; Feng, 2021; Dong and Fang, 2022; Song, 2022) involving four TCMI-IBCs (PI, DI, STSI, and DCI) described specific adverse events, such as gastrointestinal symptoms, ecchymosis, dizziness, headache, and so on (Table 6). Compared to CT alone, PI + CT [OR = 0.61, 95%CI (0.12, 3.65)], DI + CT [OR = 1.57, 95%CI (0.64, 4.71)], STSI + CT [OR = 1.32, 95%CI (0.46, 5.20)], and DCI + CT [OR = 0.54, 95%CI (0.11, 2.21)] could not increase the occurrence of adverse reactions in AMI patients (Table 4). According to SUCRA results (Figure 4F; Table 5; Supplementary Tables 12), DCI + CT exhibited the best favorable safety.

Occurrence of adverse events of TCMI-IBCs.

Intervention measures PI + CT DI + CT STSI + CT DCI + CT CT
Number of studies 3 11 6 3 23
Sample size 10 26 35 20 104
Digestive tract symptom 4 7 12 2 27
Ecchymosis 0 3 0 15 17
Dizziness 2 3 0 1 7
Headache 0 2 11 0 8
Hypotension 2 0 3 1 9
Bradycardia 2 2 1 1 19
Palpitation 0 0 2 0 2
Flush face 0 3 4 0 3
Elevated serum creatinine 0 4 0 0 3
Elevated blood uric acid 0 2 0 0 2
Other adverse reactions 0 0 2 0 7
3.5 Sensitivity analysis

Fifty-four RCTs (n = 6,092) with ≥80 cases were included in the sensitivity analysis, which revealed that the result of DCI + CT vs. CT was different from the original result of ACM, and the result of PI + CT vs. CT was different from the original result of LVEF, and no significant deviations were observed for the rest outcomes (Supplementary Tables 16–18). Given that the number of participants may affect the study’s outcomes, the number of patients participating in the trial should be adequately calculated to obtain more reliable results.

 3.6 Publication bias

Since more than 15 RCTs reported the ACM, incidence of bleeding events, LVEF, and adverse events, the publication bias of these four results was evaluated by using funnel plots (Figure 5). The dots in different colors represent the comparison between different interventions. All four results show that the studies are roughly asymmetrically distributed on both sides of the X = 0 vertical line, and there is a large angle between the fitting line and the vertical line, suggesting that there may be some publication bias. The lack of negative results and large-scale RCTs may be responsible for this bias.

Funnel plots of the all-cause mortality, bleeding events, LVEF, and adverse events. (A) A funnel plot of all-cause mortality, the blue dots represent the comparison between CT and DCI + CT, the red dots represent the comparison between CT and DI + CT, the green dots represent the comparison between CT and PI + CT, the yellow dots represent the comparison between CT and STSI + CT; (B) a funnel plot of the incidence of bleeding events, the blue dots represent the comparison between CT and DCI + CT, the red dots represent the comparison between CT and PI + CT, the yellow dots represent the comparison between CT and STSI + CT; (C) a funnel plot of LVEF, the blue dots represent the comparison between CT and DCI + CT, the red dots represent the comparison between CT and DI + CT, the green dots represent the comparison between CT and PI + CT, the yellow dots represent the comparison between CT and STSI + CT; (D) a funnel plot of adverse events, the blue dots represent the comparison between CT and DCI + CT, the red dots represent the comparison between CT and DI + CT, the green dots represent the comparison between CT and PI + CT, the black dots represent the comparison between CT and STSI + CT. All three results show that the studies are roughly asymmetrically distributed on both sides of the X = 0 vertical line, and there is a large angle between the fitting line and the vertical line, suggesting that there may be some publication bias. “Calibration-comparison” funnel plot was created to evaluate publication bias by using Stata17.0.

 3.7 Evidence quality evaluation

CINeMA rated the quality of evidence for each outcome as very low. Most included trials lack detailed descriptions of specific implementations of randomization and blindness in detail, so most of the within-study bias was illustrated as “some concerns.” The absence of negative results and large-scale RCTs raised “some concerns” regarding “reporting bias.” Inconsistency in baseline health conditions and reperfusion treatment measures among certain studies gives rise to “some concerns” regarding “indirectness.” The absence of a closed loop in the network limits the evaluation of inconsistency, leading to “major concerns” regarding “heterogeneity.” “Major concerns” regarding “imprecision” are present, possibly attributed to the limited number of trials available for comparison in certain outcome measures. See Supplementary Table 13 for details.

 3.8 General meta-analysis and heterogeneity assessment

Supplementary Figures F2–F7 display forest plots of six outcomes including heterogeneity assessment. The findings revealed low heterogeneity in ACM(I 2 = 0%), bleeding events (I 2 = 0%), RMI (I 2 = 0%), and adverse events (I 2 = 22.22%). Moderate to high heterogeneity is observed in the MA (I 2 = 60.31%) and LVEF (I 2 = 98.30%). Subgroup analysis was performed based on the mean age, treatment period, sample size, reperfusion therapy type, and so on (Supplementary Tables 14, 15). The results showed that the average age of patients may be the source of heterogeneity in MA of AMI patients treated with STSI. No major causes of heterogeneity were observed in LVEF, which was assumed to be attributable to the variable levels or standards of LVEF testing between studies due to the differences in the ultrasound equipment and technical standards used for LVEF assessment.

 4 Discussion

AMI is a deadly cardiac condition with the highest global death rates (Benjamin et al., 2019). In China, TCMI-IBCs combined with CT are commonly utilized as a therapy option for AMI intervention. TCMIs are the combination of Chinese medicine and modern technology, with characteristics such as the rapid onset of efficacy, high bioavailability, and complex composition (Jiang et al., 2016; Xiao et al., 2019; Chen et al., 2020). The flavonoid glycoside, which has been demonstrated in studies to relieve vasospasm and reduce heart rate and myocardial oxygen consumption, is the major metabolite of PI (Song et al., 1988; Zhang et al., 2013). DI is made up of Salvia miltiorrhiza (Salvia miltiorrhiza Bunge) and Safflower (Carthamus tinctorius L.), which reduces vascular resistance, acts as antioxidants, and preserves the vascular endothelium (Lyu et al., 2017; Fu Z. X. et al., 2018). Tanshinone IIA sodium sulfonate is the main metabolite of STSI, which has the efficacies of anti-lipid oxidative stress, anti-inflammation, reducing myocardial ischemia-reperfusion injury, and alleviating myocardial metabolic disorders (Li and Wang, 2011). DCI is a compound preparation of chuanxiongzine hydrochloride and danshenin that exhibits anti-atherosclerosis and blood viscosity-lowering properties (Gao et al., 2019). TCMI-IBCs mentioned above all have equivalent effects of anticoagulant and antiplatelet. (Jiang, 2011; Wang et al., 2011; Maione et al., 2014; Wei et al., 2014).

Given the Chinese society’s respect for traditional medicine and the support of medical policies, the utilization rate of TCM in general medicine hospitals throughout China had not decreased (Yu et al., 2019). However, biomedicine treatment guidelines for AMI in China have not yet recommended TCM as supplementary treatment (Gao, 2001; Cardiology and Diseases, 2010; Ren et al., 2015), and adverse events do occur on occasion as a result of clinical misuse of CCPP. As a result, it is critical to investigate the efficacy and safety of TCMI-IBCs (Practitioners, 2012; Spatz et al., 2018).

We conducted a comprehensive network meta-analysis, comparing and summarizing the effectiveness and safety of four TCMI-IBCs in treating AMI patients. The results showed that: 1) TCMI-IBCs plus CT can significantly reduce ACM and improve LVEF in AMI patients. Compared to using CT alone, there are no significant impacts on bleeding events or MA. STSI combined with CT can markedly reduce the occurrence of RMI. 2) STSI + CT had the highest probability of being the best treatment strategy to reduce ACM and RMI. DI + CT was the most likely to be the best treatment strategy to reduce MA occurrence and improve LVEF, and CT may be the most effective strategy in terms of bleeding events. 3) Among the four TCMI-IBCs, DI + CT exhibited the least favorable safety. Based on the results of all indexes, STSI can be preferred for the supplementary treatment of AMI. The quality of evidence for the above conclusions needs to be enhanced, as indicated by the findings of CINeMA. Therefore, it is recommended that clinicians make informed decisions regarding the selection of TCMI-IBCs based on individual patient conditions.

The effective metabolites of TCMIs directly enter the blood. Furthermore, because TCMIs are frequently used in conjunction with biomedicine in clinical practice, clinical safety is difficult to ensure. Fatal cases of DI and PI have reported in the past (Li, 2007; Cai et al., 2011). But retrospective studies didn’t find any correlation between the hospital mortality of AMI and the application of TCMI-IBCs (Spatz et al., 2018). Four TCMI-IBCs, when combined with CT, were demonstrated to significantly reduce ACM in AMI patients. However, most of the included studies discontinued follow-up after treatment, making long-term mortality analysis impossible to obtain. The efficacy of TCMI-IBCs on the cardiogenic mortality of AMI patients remains unknown because the included trials did not explain the cause of death. In the sensitivity analysis with the number of participants ≥80, the studies related to PI were excluded due to the small number of participants. And the result of DCI + CT vs. CT was different from the original result, suggesting that the number of cases could affect the accuracy of the results to some extent.

Antiplatelet and anticoagulation therapy can reduce the incidence of ischemic events in patients with AMI, but correspondingly increase the risk of bleeding (Udell et al., 2016). Balancing the risk of ischemia and bleeding is a difficult problem for clinicians. Previous studies have shown that Danshen-based TCMI can increase the risk of bleeding in AMI patients (Yu et al., 2019). In addition, when AMI patients receive routine antithrombotic therapy combined with TCMI-IBCs, more attention should be paid to lowering the bleeding risk. No significant distinction was observed between using CT alone and the combination of TCMI-IBCs with CT in terms of bleeding occurrences, according to this research. However, according to the results of SUCRA, CT was the optimal treatment strategy, suggesting that TCMI-IBCs combined with CT may increase the risk of bleeding to some extent. In clinical practice, AMI is a high-thrombosis risk event, and adequate antithrombotic therapy may be the best treatment strategy, especially for patients with relatively low risk of bleeding. Therefore, clinicians should carefully assess the thrombosis/bleeding risk of each AMI patient.

During AMI attacks, various arrhythmias, especially ventricular tachycardia and ventricular fibrillation, may occur due to myocardial ischemia and the formation of myocardial scar tissue (Zareba et al., 1994; Verma et al., 2005), which may lead to cardiac arrest in severe cases (Fang et al., 2022). Moreover, there is limited evidence of the benefit of antiarrhythmic drugs for AMI patients (Piccini et al., 2011), which poses a challenge for clinical treatment. The active metabolites of TCMIs enter the blood directly, which is complex and effecting quickly, and has the risk of arrhythmia (Wang et al., 2014). In this study, the combination of DI or STSI with CT had no effect on reducing occurrence of malignant arrhythmias in AMI patients. In view of the small number of included literatures, the improvement of MA caused by PI and DCI remains unclear and needs further study.

PCI is regarded as the therapeutic strategy to reduce the major cardiovascular adverse events and mortality after AMI (Ibanez et al., 2018), but some scholars believe that it is a risk factor for RMI (Arnold et al., 2015; Yudi et al., 2019; Song et al., 2020). PCI will damage and tear the intima of the vessel and destroy the endothelium, leading to platelet activation, and increasing the risk of acute and subacute thrombus re-occlusion and vessel restenosis after PCI (Claessen et al., 2014). Studies have shown that some patients can still develop RMI even after oral treatment with P2Y12 inhibitors (Fanaroff et al., 2018). Prevention of RMI after PCI is one of the most difficult problems in the PCI era (De Luca et al., 2021). This study found that STSI plus CT could reduce the occurrence of RMI in AMI patients, and we obtained the same conclusion in sensitivity analysis. However, given the limited number of studies included, the efficacy of PI needs further confirmation.

Myocardial ischemia and loss of functional cardiomyocytes due to coronary artery occlusion after AMI can lead to impaired pumping function of the heart (Komai et al., 2022), while reperfusion therapy can induce further myocardial injury (Hausenloy and Yellon, 2013). LVEF is an important index reflecting the contractility and number of cardiomyocytes (Park et al., 2018). In this study, it was found that TCMIs + CT had a certain efficacy in improving LVEF. In the sensitivity analysis of patients ≥80, the result of PI + CT vs. CT were different from the original result. At the same time, there is great heterogeneity in general meta-analysis, which still needs to be further explored by large-scale clinical research in the future.

In terms of adverse events, studies suggest that DI has a higher probability of adverse events, which are considered to be related to the complex composition, the great influence of solubility on the pH of the solution, and the instability of the active composition (Hu, 2019). The factors that lead to adverse events of TCMIs are complex, including excessive dose, improper compatibility, rapid drip rate, inappropriate concomitant administration and individual differences (Chen, 2013). Therefore, the supervision of the standardized use of TCMI-IBCs should be strengthened.

This study is the first systematic review using network meta-analysis to indirectly compare the efficacy and safety of four TCMI-IBCs in patients with AMI. The studies included in this meta-analysis still have the following shortcomings: 1) The methodological quality of the included studies is not high, and the generation of random sequence, allocation hiding method and blinding method are not reported in detail, which may lead to selection and implementation bias. 2) Few RCTs included in some outcomes and the existence of heterogeneity affected the reliability of results to a certain extent. 3) Baseline health status, categories of reperfusion therapy, duration of clinical application of TCMI-IBCs, definition of clinical endpoints, and duration of follow-up were inconsistent across trials, reducing the accuracy of results. 4) All the included studies were carried out in Chinese mainland, with a single ethnic group, which led to low generalization of the research conclusions. 5) There are only indirect comparisons between TCMI-IBCs, with wide confidence intervals, which may cause false negative results. 6) Treatment based on syndrome differentiation is one of the characteristics of TCM. Since most included studies did not classify participants by syndrome differentiation, the reliability of conclusions was affected. These deficiencies lead us to view the results with caution.

 5 Conclusion

This study found that TCMI-IBCs combined with CT had potential benefits in the treatment of AMI. STSI + CT showed the best performance in the treatment of AMI, followed by DI + CT. However, patients’ specific conditions should also be considered in clinical selection of TCMI-IBCs. Due to the low quality of the original studies, additional large-scale and high-quality RCTs are needed to verified the aforementioned conclusions.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

 Author contributions

JC: Conceptualization, Formal Analysis, Methodology, Validation, Visualization, Writing–original draft, Writing–review and editing. JS: Formal Analysis, Investigation, Writing–review and editing. HL: Funding acquisition, Methodology, Supervision, Writing–review and editing. XLi: Formal Analysis, Funding acquisition, Investigation, Methodology, Writing–review and editing. XLa: Investigation, Writing–review and editing. YL: Formal Analysis, Investigation, Writing–review and editing. HZ: Investigation, Writing–review and editing.

 Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by Grants from the National Natural Science Foundation of China (No. 82104767; No. 82174315); Beijing major and difficult diseases collaborative research project of traditional Chinese and Western medicine (2023BJSZDYNJBXTGG-011); Beijing “The Fourteenth Five-Year” key specialty of Traditional Chinese Medicine cardiovascular Department (demonstration class) (BJZKLC0011); and Research and Translational Application of Clinical Specialized Diagnosis and Treatment Techniques in the Capital (No. Z221100007422127).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

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References Arnold S. V. Smolderen K. G. Kennedy K. F. Li Y. Shore S. Stolker J. M. (2015). Risk factors for rehospitalization for acute coronary syndromes and unplanned revascularization following acute myocardial infarction. J. Am. Heart Assoc. 4, e001352. 10.1161/JAHA.114.001352 Benjamin E. J. Muntner P. Alonso A. Bittencourt M. S. Callaway C. W. Carson A. P. (2019). Heart disease and stroke statistics-2019 update: a report from the American heart association. Circulation 139, e56–e528. 10.1161/CIR.0000000000000659 Bin L. Shaopeng W. (2015). The effect of Danshen Chuanxiongqin on LVEDD and LVEF of acute myocardial infarction. Chin. Med. Pharm. Chin., 72–74. Cai W. Ding Z. P. Du H. Q. (2011). A case of death of thrombocytopenic purpura caused by Chinese medicine injection combined with aspirin. Chin. Mod. Appl. Pharm. Chin. 28, 972. Cao S. Di X. (2019). Clinical study on the combination therapy for acute myocardial infarction complicated with atrial fibrillation. Chin. Contin. Med. Educ. Chin. 11, 112–114. Cardiology C. S. O. Diseases E. B. O. T. (2010). Guidelines for diagnosis and treatment of acute ST-segment elevation myocardial infarction. Chin. J. Cardiovasc. Dis. 38, 675–690. 10.3760/cma.j.issn.0253-3758.2010.08.002 Ceng G. W. Wang C. Y. Xue Y. G. Qin C. S. Kang X. J. (2017). The effect of Danhong injection on serum IL-6 and IL-17 levels in patients with acute myocardial infarction after percutaneous coronary intervention therapy. J. Clin. Pathol. Sci. Chin. 37, 1887–1893. 10.3978/j.issn.2095-6959.2017.09.020 Chen H. Zhao L. X. Chu R. P. Feng Y. P. Wang S. C. (2010). Study on the myocardial protective effect of Danhong injection on patients with acute myocardial infarction after interventional surgery. Hebei Med. J. Chin. 32, 1391–1392. 10.3969/j.issn.1002-7386.2010.11.022 Chen J. (2007). Interventional effect of sodium tanshinone IIA sulfonate injection on thrombolysis in acute myocardial infarction. Tianjin Pharm. Chin., 35–36. 10.3969/j.issn.1006-5687.2007.04.019 Chen L. Zhao F. Li W. Chen Z. Pan J. Xiong D. (2020). Evaluation of a multiple and global analytical indicator of batch consistency: traditional Chinese medicine injection as a case study. Rsc. Adv. Chin. 10, 10338–10351. 10.1039/c9ra10065b Chen L. F. Li Y. J. Zhang L. Q. (2021a). Effect of Danhong injection combined with intravenous thrombolysis on cardiac function, myocardial enzymes, and lipoprotein related phospholipase A2 levels in elderly patients with acute myocardial infarction. Chin. J. Prim. Med. Pharm. Chin. 28, 1323–1327. 10.3760/cma.issn1008-6706.2021.09.009 Chen L. Y. (2013). Clinical application and safety analysis of Chinese medicine injection for promoting blood circulation and removing stasis. Tradit. Chin. Med. Inf. Chin. 30, 107–109. 10.3969/j.issn.1002-2406.2013.01.044 Chen Q. Lin Z. S. Ma T. Y. Liu Z. (2021b). The efficacy of combined use of tigrel and Danhong injection in the prevention and treatment of reperfusion arrhythmia after PCI in patients with acute anterior wall STEMI and its impact on myocardial injury indicators. Mod. J. Integr. Tradit. Chin. West. Med. Chin. 30, 2555–2560. 10.3969/j.issn.1008-8849.2021.23.010 Chen X. L. Liu X. R. (2013). The effect of Danhong on serum MCP-1 and H-FABP in non ST segment elevation myocardial infarction. Chin. J. Gen. Pract. Chin. 11, 1378–1379. Claessen B. E. Henriques J. P. Jaffer F. A. Mehran R. Piek J. J. Dangas G. D. (2014). Stent thrombosis: a clinical perspective. JACC Cardiovasc. Interv. 7, 1081–1092. 10.1016/j.jcin.2014.05.016 Collet J. P. Thiele H. Barbato E. Barthelemy O. Bauersachs J. Bhatt D. L. (2021). 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Heart J. 42, 1289–1367. 10.1093/eurheartj/ehaa575 Cui X. P. Yan W. He J. H. (2021). Clinical efficacy analysis of tigrel combined with Danhong injection in the treatment of patients with acute myocardial infarction after PCI surgery. J. Guangxi Med. Univ. Chin. 38, 1609–1614. 10.16190/j.cnki.45-1211/r.2021.08.026 De Luca L. Paolucci L. Nusca A. Putini R. L. Mangiacapra F. Natale E. (2021). Current management and prognosis of patients with recurrent myocardial infarction. Rev. Cardiovasc. Med. 22, 731–740. 10.31083/j.rcm2203080 de Waha S. Jobs A. Eitel I. Poss J. Stiermaier T. Meyer-Saraei R. (2018). Multivessel versus culprit lesion only percutaneous coronary intervention in cardiogenic shock complicating acute myocardial infarction: a systematic review and meta-analysis. Eur. Heart J. Acute Cardiovasc. Care 7, 28–37. 10.1177/2048872617719640 Doctor Society Of Integrative Medicine C.M.D.A. (2018). Diagnosis and treatment guide of integrated Chinese and Western medicine for acute myocardial infarction. Chin. J. Integr. Med. Chin. 38, 272–284. 10.7661/j.cjim.20180119.038 Dong S. J. Fang X. Y. (2022). Clinical efficacy of puerarin injection in treating arrhythmia after acute myocardial infarction and its impact on related indicators. J. Pract. Tradit. Chin. Intern. Med. Chin. 36, 83–85. Du Q. M. Wang C. X. (2011). Protective effect of sodium tanshinone IIA sulfonate on myocardial ischemia-reperfusion arrhythmias. Chin. J. Elder. Cardiovasc. Cerebrovasc. Dis. Chin. 13, 349–351. 10.3969/j.issn.1009-0126.2011.04.019 Eeckhout E. Kern M. J. (2001). The coronary no-reflow phenomenon: a review of mechanisms and therapies. Eur. Heart J. 22, 729–739. 10.1053/euhj.2000.2172 Fan L. Y. Yang J. (2015). Study on the effects of sodium tanshinone IIA sulfonate on blood lipid metabolism, serum inflammatory factors, and cardiac function in patients with acute myocardial infarction. Pract. J. Card. Cereb. Pneum. Vasc. Dis. Chin. 23, 14–17. 10.3969/j.issn.1008-5971.2015.09.005 Fan Q. X. Chen K. (2017). Clinical study of puerarin injection combined with atenolol in the treatment of acute myocardial infarction. Mod. Med. Clin. Pract. Chin. 32, 2354–2357. Fanaroff A. C. Kaltenbach L. A. Peterson E. D. Akhter M. W. Effron M. B. Henry T. D. (2018). Antiplatelet therapy changes for patients with myocardial infarction with recurrent ischemic events: insights into contemporary practice from the TRANSLATE-ACS (treatment with ADP receptor inhibitors: longitudinal assessment of treatment patterns and events after acute coronary syndrome) study. J. Am. Heart Assoc. 7, e007982. 10.1161/JAHA.117.007982 Fang C. Chen Z. Zhang J. Jin X. Yang M. (2022). Construction and evaluation of nomogram model for individualized prediction of risk of major adverse cardiovascular events during hospitalization after percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction. Front. Cardiovasc. Med. 9, 1050785. 10.3389/fcvm.2022.1050785 Feng H. (2021). Exploring the clinical efficacy of Danhong injection combined with conventional therapy in patients with ST segment elevation acute myocardial infarction undergoing percutaneous coronary intervention (PCI). World Latest Med. Inf. Chin., 72–74. 10.3969/j.issn.1671-3141.2021.66.032 Feng X. X. He Y. (2012). Protective effect of sodium tanshinone IIA sulfonate on ischemia-reperfusion injury after thrombolysis in acute myocardial infarction. Chin. J. Biochem. Drug. (Chin). 33, 460–462. Fu Z. G. Liu L. T. Wang Y. F. Li C. (2018a). Danhong injection clinical application Chinese expert consensus. Chin. J. Integr. Med. Chin. 38, 389–397. 10.7661/j.cjim.20180312.064 Fu Z. X. Li H. J. Guo X. C. Gao J. (2018b). Clinical study of Danhong injection combined with enoxaparin sodium in the treatment of acute ST segment elevation myocardial infarction. Mod. Med. Clin. Pract. Chin. 33, 492–495. 10.7501/j.issn.1674-5515.2018.03.010 Gao R. L. (2001). Guidelines for diagnosis and treatment of acute myocardial infarction. Chin. J. Cardiovasc. Dis. Chin. 1, 9–24. 10.14164/j.cnki.cn11-5581/r.2015.23.211 Gao L. (2015). Effect and mechanism of sodium tanshinone IIA sulfonate on ventricular arrhythmias in acute myocardial infarction patients with reperfusion therap. Shandong, China: Taishan Medical University. Gao Y. Wang G. Q. Wang J. Zhang M. X. Xie Y. M. Liu H. (2019). Expert consensus statement on Danshen Chuanxiongqin Injection in clinical practice. Chin. J. Tradit. Chin. Med. Chin. 44, 2937–2942. 10.19540/j.cnki.cjcmm.20190509.503 Gao Z. Q. (2009). Clinical observation on the effect of Danhong injection on the complications of acute myocardial infarction. Chin. J. Med. Guid. Chin. 11, 532–582. 10.3969/j.issn.1009-0959.2009.04.029 Gu S. Z. Wang Z. M. (2004). The effect of puerarin on infarct size and cardiac function in patients with acute anterior myocardial infarction. Youjiang Med. Chin., 140–141. 10.3969/j.issn.1003-1383.2004.02.028 Gui X. Shi Z. S. Dong G. P. (2009). A study on the treatment of acute myocardial infarction with Danhong injection and intravenous thrombolysis. J. Med. Forum(Chin). 30, 73–74. Hall M. Dondo T. B. Yan A. T. Goodman S. G. Bueno H. Chew D. P. (2016). Association of clinical factors and therapeutic strategies with improvements in survival following non-ST-elevation myocardial infarction, 2003-2013. JAMA 316, 1073–1082. 10.1001/jama.2016.10766 Han G. J. Liu W. H. Yang D. W. Gao Z. Y. Cao J. W. Zhang L. Y. (2012). Observation on the effect of Danhong injection on myocardial reperfusion injury in acute myocardial infarction. People Mil. Med. Chin. 55, 514–515. Han J. X. (2010). The effect of Danhong injection combined with thrombolytic therapy on vascular reattachment rate in early acute myocardial infarction. Chin. J. Misdiagn. Chin. 10, 3556. Hao X. Y. Ren L. (2011). Danhong injection combined with urokinase intravenous thrombolysis in the treatment of 60 cases of early acute myocardial infarction. Shaanxi tradit. Chin. Med. Chin. 32, 1284–1285. 10.3969/j.issn.1000-7369.2011.10.008 Hausenloy D. J. Yellon D. M. (2013). Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J. Clin. Invest. (Chin). 123, 92–100. 10.1172/JCI62874 Heusch G. Gersh B. J. (2017). The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur. Heart J. 38, 774–784. 10.1093/eurheartj/ehw224 Hu B. G. (2019). Analysis on the characteristics of adverse reactions caused by TCM injection for promoting blood circulation and removing blood stasis. Collect. Contemp. Med. Essay(Chin). 17, 181–182. Hu Y. N. (2018). The effect of intravenous urokinase thrombolysis combined with compound Danhong injection on changes in serum MPO and cTnI levels in patients with acute myocardial infarction. J. North Pharm. Chin. 15, 122–123. Hua Y. Shao M. Wang Y. Du J. Tian J. Wei K. (2021). Xuesaitong injection treating acute myocardial infarction: a systematic review and meta-analysis. Medicine 100, e27027. 10.1097/MD.0000000000027027 Huang L. (2016). Clinical observation on the treatment of acute myocardial infarction with danshen ligustrazine combined with atorvastatin calcium. J. Hubei Univ. Tradit. Chin. Med. Chin. 18, 18–20. 10.3969/j.issn.1008-987x.2016.03.06 Huang P. H. (2012). Analysis of the protective effect of sodium tanshinone IIA sulfonate on ischemia-reperfusion injury after thrombolysis in acute myocardial infarction. Med. Front. Chin. 350. Huo Y. J. Chen S. P. Han X. C. (2019). Observation on the therapeutic effect of Danhong injection on patients with acute myocardial infarction. J. Liaoning Univ. Tradit. Chin. Med. Chin. 21, 194–197. 10.13194/j.issn.1673-842x.2019.10.052 Hutton B. Salanti G. Caldwell D. M. Chaimani A. Schmid C. H. Cameron C. (2015). The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann. Intern. Med. 162, 777–784. 10.7326/M14-2385 Ibanez B. James S. Agewall S. Antunes M. J. Bucciarelli-Ducci C. Bueno H. (2018). 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 39, 119–177. 10.1093/eurheartj/ehx393 Ji C. F. Li P. Lu W. R. (2016). Clinical efficacy analysis of Danhong injection in the treatment of acute non ST segment elevation myocardial infarction. Label. Immunoass. Clin. Med. Chin. 23, 680–682. 10.11748/bjmy.issn.1006-1703.2016.06.024 Jia S. J. (2010). Clinical observation of tanshinone II-A sulfonate sodium combined with low molecular weight heparin in the treatment of non ST segment elevation myocardial infarction. Guid. Chin. Med. Chin. 8, 132–133. 10.3969/j.issn.1671-8194.2010.18.085 Jiang Y. Liu L. S. Shen L. P. Han Z. F. Jian H. Liu J. X. (2016). Traditional Chinese Medicine treatment as maintenance therapy in advanced non-small-cell lung cancer: a randomized controlled trial. Complement. Ther. Med. Chin. 24, 55–62. 10.1016/j.ctim.2015.12.006 Jiang Y. Q. (2011). The effect of Danhong injection on platelet activation and coagulation function in patients with coronary heart disease. Chin. Mod. Dr. Chin. 49, 68–70. 10.3969/j.issn.1673-9701.2011.14.035 Jin D. D. Wang H. W. Tang G. M. (2019). Effect of Danhong injection on serum retinol binding protein 4 and cardiac function in patients with acute myocardial infarction. Chin. J. Tradit. Med. Sci. Technol. Chin. 26, 220–222. Komai K. Kawasaki N. K. Higa J. K. Matsui T. (2022). The role of ferroptosis in adverse left ventricular remodeling following acute myocardial infarction. Cells 11, 1399. 10.3390/cells11091399 Kong L. J. Gu S. X. Xi S. Y. An G. H. Liu L. X. Cao Q. Y. (2013). Observation on the therapeutic effect of tanshinone IIA sodium sulfonate injection combined with amiodarone hydrochloride injection in the treatment of 48 cases of acute myocardial infarction complicated with atrial fibrillation. Hebei J. Tradit. Chin. Med. Chin. 35, 96–97. Lan G. Hai-Yan S. Zhen W. Xiao-Wu M. Fang J. Du Z.-lan. (2020). Effect and mechanism of sodium tanshinone ⅡA sulfonate on ventricular arrhythmias in acute myocardial infarction patients with reperfusion therapy. J. Taishan Med. Coll. Chin. 41, 667–670. 10.3969/j.issn.1004-7115.2020.09.007 Levine G. N. Bates E. R. Blankenship J. C. Bailey S. R. Bittl J. A. Cercek B. (2016). 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines and the society for cardiovascular angiography and interventions. Circulation 133, 1135–1147. 10.1161/CIR.0000000000000336 Li C. Xu L. C. (2020). Clinical efficacy of Danhong injection combined with conventional therapy in patients with ST segment elevation acute myocardial infarction undergoing PCI. Chin. Pat. Drug(Chin). 42, 1769–1773. 10.3969/j.issn.1001-1528.2020.07.017 Li G. S. Pan M. X. Zhu D. J. (2019). Effect of Danhong injection on cardiac function and reperfusion index in patients with acute ST segment elevated myocardial infarction after PCI. Clin. Res. Tradit. Chin. Med. Chin. 11, 34–36. 10.3969/j.issn.1674-7860.2019.08.012 Li L. H. Yang X. F. Zhang G. H. Guo Y. S. (2002). The effect of Pulelin on reperfusion injury after thrombolysis in acute myocardial infarction. J. Cardiovasc. Rehabil. Med. Chin., 176–177. 10.3969/j.issn.1008-0074.2002.02.039 Li S. Wang L. (2011). Progress in pharmacology and clinical application of tanshinone ⅱA-sodium sulfonate injection. Chin. Med. Clin. Chin. 2, 61–63. Li X. (2007). Study on the microcirculatory effect of shenyuan yiqi huoxue capsule on unstable angina pectoris patients during selective PCI perioperative period. Chin. Foreign Med. Treat. Chin. 19, 26–27. Liao P. Wang L. Guo L. Zeng R. Huang J. Zhang M. (2015). Danhong injection (a traditional Chinese patent medicine) for acute myocardial infarction: a systematic review and meta-analysis. Evid. Based Complement. Altern. Med. Chin. 2015, 646530. 10.1155/2015/646530 Lin Z. Jiajun L. Jigang R. Jian W. Jin Y. Xueyan L. (2018). The Effficacy to retinol binding protein of salvia-chuanxiong combined with tirofiban in patients with acute ST-eleva-tion myocardial infarction receiving percutaneous coronary intervention. Chin. J. Clin. Healthc. Chin. 21, 51–54. 10.3969/J.issn.1672-6790.2018.01.015 Liu D. P. Mao J. (2014). Protective effect of sodium tanshinone IIA sulfonate on myocardial oxidative stress injury in patients with myocardial infarction after thrombolytic therapy. Chin. J. Mod. Med. Chin. 24, 96–99. Liu H. X. Wang S. R. Lei Y. Shang J. J. (2011). Characteristics and advantages of traditional Chinese medicine in the treatment of acute myocardial infarction. J. Tradit. Chin. Med. Chin. 31, 269–272. 10.1016/s0254-6272(12)60002-8 Liu L. J. Yuan Q. R. Zhao M. Z. Dong S. J. (2016). The effect of amiodarone combined with sodium tanshinone IIA sulfonate in the treatment of acute myocardial infarction complicated with atrial fibrillation. Chin. J. Clin. Pharm. Chin. 32, 781–782. 10.13699/j.cnki.1001-6821.2016.09.004 Liu X. H. (2015). Clinical observation on the treatment of 40 cases of acute myocardial infarction with Danhong injection combined with urokinase thrombolysis. Chin. J. Ethnopham. Chin. 24, 85–86. Liu X. Y. Zhong F. P. (2008). Observation on the therapeutic effect of puerarin injection combined with urokinase in the treatment of acute myocardial infarction. Shanxi Tradit. Chin. Med. Chin. 24, 11–12. Liu Y. Cao Q. X. Gao L. (2020). Mechanism of myocardial protective effect of Danshen Chuanxiong injection on patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention. Southeast Natl. Def. Med. Chin. 22, 468–472. Liu Y. Yin H. J. Shi D. Z. Chen K. J. (2012). Chinese herb and formulas for promoting blood circulation and removing blood stasis and antiplatelet therapies. Evid. Based Complement. Altern. Med. 2012, 184503. 10.1155/2012/184503 Liu Y. Yin H. J. Shi D. Z. Chen K. J. (2014). The use of Chinese medicinal herbs and formulas that activate blood circulation and antiplatelet therapies. Sci. Bull. Chin. 59, 647–655. 10.1360/972013-669 Lu H. M. Lu J. M. Lu A. M. (2001). The effect of puerarin on myocardial infarction area and left ventricular function. Chin. J. Misdiagn. Chin., 1811–1812. 10.3969/j.issn.1009-6647.2001.12.025 Lu Y. Yan Y. Liu X. (2021). Effects of alprostadil combined with tanshinone IIa injection on microcirculation disorder, outcomes, and cardiac function in AMI patients after PCI. Ann. Palliat. Med. Chin. 10, 97–103. 10.21037/apm-20-2147 Luo R. X. (2018a). The effect of tanshinone IIA sodium sulfonate injection combined with tigregolol on postoperative patients with acute myocardial infarction undergoing PCI. Henan Med. Res. Chin. 27, 2987–2988. 10.3969/j.issn.1004-437X.2018.16.054 Luo X. Y. (2018b). Observation on the therapeutic effect of amiodarone combined with sodium tanshinone IIA sulfonate in the treatment of acute myocardial infarction with atrial fibrillation. Strait Pharm. Chin. 30, 106–107. Lyu M. Yan C. L. Liu H. X. Wang T. Y. Shi X. H. Liu J. P. (2017). Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection. Sci. Rep. 7, 15427. 10.1038/s41598-017-14692-3 Maione F. De Feo V. Caiazzo E. De Martino L. Cicala C. Mascolo N. (2014). Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. J. Ethnopharmacol. 155, 1236–1242. 10.1016/j.jep.2014.07.010 Mao S. Taylor S. Chen Q. Zhang M. Hinek A. (2019). Sodium tanshinone IIA sulfonate prevents the adverse left ventricular remodelling: focus on polymorphonuclear neutrophil-derived granule components. J. Cell Mol. Med. Chin. 23, 4592–4600. 10.1111/jcmm.14306 Miao C. Lei M. M. Hu W. N. Wang Y. Wang G. F. Yao F. C. (2018). Study on the effect of danshen ligustrazine injection on serum carcinoembryonic antigen CA199 level in patients with acute myocardial infarction complicated with atrial fibrillation. J. Liaoning Univ. Tradit. Chin. Med. Chin. 20, 198–201. Nikolakopoulou A. Higgins J. Papakonstantinou T. Chaimani A. Del G. C. Egger M. (2020). CINeMA: an approach for assessing confidence in the results of a network meta-analysis. Plos Med. 17, e1003082. 10.1371/journal.pmed.1003082 Pantea-Rosan L. R. Pantea V. A. Bungau S. Tit D. M. Behl T. Vesa C. M. (2020). No-reflow after PPCI-A predictor of short-term outcomes in STEMI patients. J. Clin. Med. Chin. 9, 2956. 10.3390/jcm9092956 Park J. J. Park J. B. Park J. H. Cho G. Y. (2018). Global longitudinal strain to predict mortality in patients with acute heart failure. J. Am. Coll. Cardiol. 71, 1947–1957. 10.1016/j.jacc.2018.02.064 Piccini J. P. Schulte P. J. Pieper K. S. Mehta R. H. White H. D. Van de Werf F. (2011). Antiarrhythmic drug therapy for sustained ventricular arrhythmias complicating acute myocardial infarction. Crit. Care Med. 39, 78–83. 10.1097/CCM.0b013e3181fd6ad7 Practitioners C. J. O. G. (2012). 70% of proprietary Chinese medicines are prescribed by Western doctors: experts call for the development of guidelines for the clinical use of Western proprietary Chinese medicines. Chin. J. Gen. Pract. Chin. 11, 1. Qi H. Zhao X. Li Y. F. (2006). Application of tanshinone IIA sulfonate sodium injection in acute myocardial infarction. Chin. Med. Her. Chin., 22–24. 10.3969/j.issn.1673-7210.2006.23.009 Qi Y. Jing W. Wei D. Feng T. Hong-Xu L. Jing J. (2019). Protective effect of Danhong injection in patients with acute myocardial infarction at a high risk of no-reflow during primary percutaneous coronary intervention. J. Geriatr. Cardiol. Chin. 16, 406–413. 10.11909/j.issn.1671-5411.2019.05.001 Qin H. L. Ma H. Liang S. L. Ma H. L. (2020). Urokinase combined with tanshinone II_ Clinical evaluation of sodium A sulfonate in the treatment of elderly acute myocardial infarction. Chin. Pharm. Chin. 29, 145–147. 10.3969/j.issn.1006-4931.2020.06.044 Qin L. M. Zuo H. Wang A. L. Sun X. X. (2014). Observation on the therapeutic effect of Danhong injection on interventional treatment of ST segment elevation acute myocardial infarction. Shaanxi Tradit. Chin. Med. Chin. 35, 648–650. Qu C. (2008). The effect of puerarin on infarct size in patients with acute myocardial infarction. Chin. J. Misdiagn. Chin., 5091–5092. 10.3969/j.issn.1009-6647.2008.21.037 Ren J. Li X. Sun J. Han M. Yang G. Y. Li W. Y. (2015). Is traditional Chinese medicine recommended in Western medicine clinical practice guidelines in China? A systematic analysis. BMJ Open 5, e006572. 10.1136/bmjopen-2014-006572 Ren Q. Jia G. J. (2013). Effect of Danhong injection on high sensitivity C-reactive protein in patients with acute myocardial infarction. Shaanxi Tradit. Chin. Med. Chin. 34, 651–652. 10.3969/j.issn.1000-7369.2013.06.007 Roger V. L. Weston S. A. Gerber Y. Killian J. M. Dunlay S. M. Jaffe A. S. (2010). Trends in incidence, severity, and outcome of hospitalized myocardial infarction. Circulation 121, 863–869. 10.1161/CIRCULATIONAHA.109.897249 Roth G. A. Mensah G. A. Johnson C. O. Addolorato G. Ammirati E. Baddour L. M. (2020). Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J. Am. Coll. Cardiol. 76, 2982–3021. 10.1016/j.jacc.2020.11.010 Shang J. J. Shi H. Zhou Q. Gao W. Liu H. X. (2012). A study of prognosis, outcome, and changing tendency of hospitalized AMI patients in Beijing third-grade A-level traditional Chinese medicine hospitals from 1999 to 2008. Evid. Based Complement. Altern. Med. 2012, 837194. 10.1155/2012/837194 Shen S. R. Wang X. D. Zhou L. Chen Z. Cheng P. Jiang L. M. (2019). Clinical study of Danhong injection combined with tegrelol in the treatment of acute ST segment elevated myocardial infarction. Mod. Med. Clin. Pract. Chin. 34, 1313–1317. Song D. G. (2022). Analysis of the efficacy of recombinant human brain natriuretic peptide for injection combined with tanshinone IIA sulfonate sodium in the treatment of acute myocardial infarction. Healthy Vis. Chin., 109–112. Song J. Murugiah K. Hu S. Gao Y. Li X. Krumholz H. M. (2020). Incidence, predictors, and prognostic impact of recurrent acute myocardial infarction in China. Heart (Chin). 107, 313–318. 10.1136/heartjnl-2020-317165 Song X. P. Chen P. P. Chai X. S. (1988). Effects of puerarin on blood pressure and plasma renin activity in spontaneously hypertensive rats. Chin. J. Pharm. Chin. 9, 55–58. Spatz E. S. Wang Y. Beckman A. L. Wu X. Lu Y. Du X. (2018). Traditional Chinese medicine for acute myocardial infarction in western medicine hospitals in China. Circ. Cardiovasc. Qual. Outcomes 11, e004190. 10.1161/CIRCOUTCOMES.117.004190 Sun H.-Y. (2011). The effect of Sulfotanshinone sodium injection to plasminogen activator inhibitor-1 in patient with non-ST-segment elevatinon myocardial infarction. Clin. Ration. Drug Use Chin. 4, 15–16. 10.3969/j.issn.1674-3296.2011.28.008 Sun Y. H. Zhang Z. H. Zhang H. B. Zhang L. X. Gan S. J. (2016). Clinical study on the combination of danshen ligustrazine injection and tirofiban in the treatment of acute ST segment elevated myocardial infarction. Mod. Med. Clin. Pract. Chin. 31, 776–779. 10.7501/j.issn.1674-5515.2016.06.010 The Writing Committee of the Report on Cardiovascular Health and Diseases in China (2022). Summary of the 2021 report on cardiovascular health and disease in China. Chin. Recycl. Mag. Chin. 37, 553–578. 10.3969/j.issn.1000-3614.2022.06.001 Thiele H. Akin I. Sandri M. Fuernau G. de Waha S. Meyer-Saraei R. (2017). PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N. Engl. J. Med. 377, 2419–2432. 10.1056/NEJMoa1710261 Thygesen K. Alpert J. S. Jaffe A. S. Chaitman B. R. Bax J. J. Morrow D. A. (2018). Fourth universal definition of myocardial infarction (2018). Glob. Heart 13, 305–338. 10.1016/j.gheart.2018.08.004 Tsao C. W. Aday A. W. Almarzooq Z. I. Alonso A. Beaton A. Z. Bittencourt M. S. (2022). Heart disease and stroke statistics-2022 update: a report from the American heart association. Circulation 145, e153–e639. 10.1161/CIR.0000000000001052 Udell J. A. Bonaca M. P. Collet J. P. Lincoff A. M. Kereiakes D. J. Costa F. (2016). Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur. Heart J. 37, 390–399. 10.1093/eurheartj/ehv443 Verma A. Marrouche N. F. Schweikert R. A. Saliba W. Wazni O. Cummings J. (2005). Relationship between successful ablation sites and the scar border zone defined by substrate mapping for ventricular tachycardia post-myocardial infarction. J. Cardiovasc. Electrophysiol. 16, 465–471. 10.1046/j.1540-8167.2005.40443.x Wang G. H. Shi Z. Sun X. M. Wang Y. H. Sun H. Du G. H. (2014). Effects of Guanxin, puerarin and breviscapine injection on cardiac electrical activity in rats. Chin. J. Gerontol. Chin. 34, 5156–5160. 10.3969/j.issn.1005-9202.2014.18.064 Wang R. Han Q. H. Jia Y. P. Lu J. Y. (2011). Effect of danshen Chuanxiongqin injection on the myocardial damage of unstable angina patients undergoing percutaneous coronary intervention. Chin. J. Integr. Med. Chin. 31, 899–902. Wang S. K. Jie Q. G. (2015). Clinical efficacy of edaravone combined with Danhong injection in the treatment of ischemia/reperfusion injury after acute myocardial infarction. Chin. Mod. Med. Chin. 22, 138–141. Wang Y. Y. Xie G. X. (2021). Meta-analysis of tanshinone IIA sodium sulfonate combined with amiodarone in the treatment of acute myocardial infarction with atrial fibrillation. World Tradit. Chin. Med. Chin. 16, 779–783. 10.3969/j.issn.1673-7202.2021.05.018 Wei S. Y. Chen Y. Xu X. Y. (2014). Progress on the pharmacological research of puerarin: a review. Chin. J. Nat. Med. Chin. 12, 407–414. 10.1016/S1875-5364(14)60064-9 Wu J. L. Ge L. Zhang J. H. Zhou J. G. Gao Y. Ma X. N. (2017). Comparison of the accuracy of multiple diagnostic tests: introduction to mesh meta-analysis methods. Chin. J. Evid. Based Med. Chin. 17, 987–992. Xiao L. Z. Huang Z. Ma S. C. Ceng Z. Y. Luo B. R. Lin X. Y. (2004). Study on the effect and mechanism of puerarin on the size of infarction in patients with acute myocardial infarction. Chin. J. Integr. Med. Chin. 24, 790–792. 10.7661/CJIM.2004.9.790 Xiao Z. Wang C. Zhou M. Hu S. Jiang Y. Huang X. (2019). Clinical efficacy and safety of Aidi injection plus paclitaxel-based chemotherapy for advanced non-small cell lung cancer: a meta-analysis of 31 randomized controlled trials following the PRISMA guidelines. J. Ethnopharmacol. 228, 110–122. 10.1016/j.jep.2018.09.024 Xu J. Liu D. S. (2017). Effect of danshen chuanxiong injection on oxidative stress and cardiac function in patients with acute myocardial infarction after PCI. Chin. J. Biochem. Drug. (Chin). 37 (4). 10.3969/j.issn.1005-1678.2017.08.052 Xu X. M. Cui H. M. Yang J. Gui Y. P. Wang J. M. Ren Y. S. (2015). Protective effect of Danhong injection on ischemic myocardium after direct percutaneous coronary intervention in acute myocardial infarction. Southeast Natl. Def. Med. Chin. 17, 451–454. 10.3969/j.issn.1672-271X.2015.05.001 Yang J. Cui H. M. Ren Y. S. Wu Z. G. (2015). Study on Danhong injection in the treatment of ST segment elevated myocardial infarction without reflow/slow flow after direct percutaneous coronary intervention. World J. Integr. Tradit. Chin. West. Med. Chin. 10, 210–213. 10.13935/j.cnki.sjzx.150220 Yi Y. X. Zhang Y. Liu X. Y. Zhang J. Zhu D. J. Lu Q. Y. (2015). Interpretation of graph results of mesh meta-analysis. Chin. J. Evid. Based Med. Chin. 15, 103–109. You Q. (2019). Clinical study on predicting the risk of no reflow and perioperative myocardial protection in emergency PCI patients with acute myocardial infarction. [Beijing, China] Chin. People Lib. Army Med. Coll. Chin. Yu Y. Spatz E. S. Tan Q. Liu S. Lu Y. Masoudi F. A. (2019). Traditional Chinese medicine use in the treatment of acute heart failure in western medicine hospitals in China: analysis from the China PEACE retrospective heart failure study. J. Am. Heart Assoc. 8, e12776. 10.1161/jaha.119.012776 Yu Z. H. Chen F. D. Sun D. X. (2008). Clinical study of sodium tanshinone ⅡA sulfonate injection in treatment acute myocardial infarction. Mod. Healthc. Med. Innov. Res. Chin. 5, 7–8. Yudi M. B. Clark D. J. Farouque O. Andrianopoulos N. Ajani A. E. Brennan A. (2019). Trends and predictors of recurrent acute coronary syndrome hospitalizations and unplanned revascularization after index acute myocardial infarction treated with percutaneous coronary intervention. Am. Heart J. 212, 134–143. 10.1016/j.ahj.2019.02.013 Zareba W. Moss A. J. le Cessie S. (1994). Dispersion of ventricular repolarization and arrhythmic cardiac death in coronary artery disease. Am. J. Cardiol. 74, 550–553. 10.1016/0002-9149(94)90742-0 Zhang G. S. (2012). Clinical study of Danhong injection on reperfusion injury after thrombolysis in acute myocardial infarction of Qi deficiency and blood stasis type. [Fujian, China]: fujian univ. Tradit. Chin. Med. Chin. Zhang H. (2021). Clinical efficacy of auxiliary application of Danhong injection in patients with acute myocardial infarction. Mod. Med. Health Res. Chin. 5, 65–68. Zhang H. B. Ai J. X. Gao R. Li Y. L. Zhu H. Zheng X. J. (2018). Clinical efficacy analysis of Danhong injection in the treatment of acute non ST segment elevation myocardial infarction. Chin. Minkang Med. Chin. 30, 62–64. 10.3969/j.issn.1672-0369.2018.16.030 Zhang Q. Y. (2017). Clinical observation of amiodarone combined with tanshinone IIA sulfonate sodium in the treatment of acute myocardial infarction with atrial fibrillation. Henan Med. Res. Chin. 26, 2987–2988. 10.3969/j.issn.1004-437X.2017.16.062 Zhang Y. Fu J. P. Xu B. (2019). Effect of Danhong injection on ischemic modified albumin and homocysteine levels and prognosis in acute myocardial infarction patients without reperfusion therapy. J. Integr. Tradit. Chin. West. Med. Cardiovasc. Cerebrovasc. Dis. Chin. 17, 2974–2976. 10.12102/j.issn.1672-1349.2019.19.025 Zhang Z. Lam T. N. Zuo Z. (2013). Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J. Clin. Pharm. Chin. 53, 787–811. 10.1002/jcph.96 Zhao S. R. (2012). Study on the short-term and long-term myocardial protective effects of Danhong injection on thrombolysis patients with acute myocardial infarction. Hebei Med. J. Chin. 34, 1528–1530. 10.3969/j.issn.1002-2619.2012.10.052 Zhiyong Z. Jun X. Zhonghua F. Weiqing W. (2020). Study on effect of salviae miltiorrhizae and ligustrazine hydrochloride injection combined with amiodarone on serum carcinoembryonic antigen CA-125 level of patients with acute myocardial infarction complicated with atrial fibrillation. Liaoning J. Tradit. Chin. Med. Chin. 47, 112–115. Zhou A. Q. Huang Q. Yang Y. H. (2010). Analysis of the therapeutic effect of Danhong injection on acute myocardial infarction with left ventricular dysfunction. Jiangxi Pharm. Chin. 45, 34–35. 10.3969/j.issn.1006-2238.2010.01.021 Zhou T. J. (2017). Clinical evaluation of the combination therapy of Danshen Ligustrazine Injection and Tirofiban in the treatment of acute ST segment elevation myocardial infarction. Guid. Chin. Med. Chin. 15, 192–193. Zhou X. (2014). The effect of Danshen Chuanxiong Injection on myocardial perfusion in patients with acute ST segment elevation myocardial infarction. [Liao Ning, China]: liaoning Univ. Tradit. Chin. Med. Chin.