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Objectives: As current clinical practice guidelines, ticagrelor is the suggested therapeutic scheme to prevent adverse cardiovascular events in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI) treatment. However, this therapeutic strategy still fails, and around 30% patients display inadequate antiplatelet responses. Musk Tongxin Dripping Pill (MTDP) in Chinese hospital was usually considered as the combination with ticagrelor to improve the treatment effect. Unfortunately, the mechanism has not been elucidated. Methods: The untargeted metabolomic method was introduced based on liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) coupled with STI for the research of the drug combination mechanism between ticagrelor and MTDP. 28 patients with a confirmed diagnosis of AMI were selectively collected, who were then divided into two different dosage regimen groups, and the serum samples were collected for the untargeted metabolomics assay. Then the differential metabolites were associated with blood biochemical indicators. Results: The GLS values in both groups increased after treatment and those in the ticagrelor and MTDP combination group after treatment were higher than those in the ticagrelor group ( p < 0.05), suggesting that the combination medication has better therapeutic effect on patients with myocardial infarction. From metabolomics analysis, the species of metabolites changed in two groups before and after treatment. Moreover, 93 differential metabolites changed in the drug combination group compared with the ticagrelor group after treatment ( p < 0.05), which mainly related to changes in fatty acid metabolism pathways. Then the differential metabolites were found to be related with blood biochemical indicators, such as lipid, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Conclusion: This work will provide a possible mechanism of the drug combination interaction between ticagrelor and MTDP from two angles of echocardiography and metabonomics. Several potential metabolic pathways were also found to have a relationship with MTDP, which will provide a new perspective in clinical medication., Competing Interests: 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., (Copyright © 2021 Nan, Peng, Jinxia, Mengzhe, Jun, Haibo and Houfa.)