Background:Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide, necessitating effective antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI). Prasugrel and Ticagrelor, both potent P2Y12 receptor inhibitors, have emerged as pivotal components of dual antiplatelet therapy in this setting. Despite their widespread use, there is an ongoing debate regarding the comparative efficacy and safety of Prasugrel and Ticagrelor. This systematic review and meta-analysis aim to compare the efficacy and safety of Prasugrel and Ticagrelor in patients undergoing percutaneous intervention (PCI) through an exhaustive examination of randomized controlled trials (RCTs). Methods: A comprehensive search of electronic databases, including PubMed, Embase, and Cochrane Library, was conducted to identify relevant RCTs comparing Prasugrel and Ticagrelor in patients undergoing PCI. Data extraction and quality assessment were performed independently by two reviewers. The composite outcomes assessed were those including death, myocardial infarction, and stroke. Secondary outcomes included bleeding events and dyspnea. The random-effects model was employed for the meta-analysis, and subgroup analyses were conducted based on specific patient characteristics and study characteristics. Results:Ticagrelor exhibits a significantly increased risk of dyspnea compared to Prasugrel (OR: 13.929, 95% CI: 3.495 to 55.514). The analysis reveals substantial heterogeneity (I2 = 3.734), indicating variability in the effect estimates across studies.No significant difference in bleeding risk is observed between Ticagrelor and Prasugrel (OR: 1.245, 95% CI: 0.996 to 1.555). The analysis suggests moderate heterogeneity (I2 = 1.926).The odds of death are comparable between Ticagrelor and Prasugrel (OR: 1.166, 95% CI: 0.919 to 1.479). Heterogeneity is low (I2 = 1.263).Ticagrelor is associated with a significantly higher risk of MI compared to Prasugrel (OR: 2.732, 95% CI: 2.155 to 3.465). The analysis indicates low heterogeneity (I2 = 8.294).A significantly increased risk of stroke is observed with Ticagrelor compared to Prasugrel (OR: 2.732, 95% CI: 2.155 to 3.465). Heterogeneity is low (I2 = 8.294).The overall findings suggest that Ticagrelor may be associated with a higher risk of dyspnea, MI, and stroke compared to Prasugrel in ACS patients. However, no significant differences are noted in bleeding and death outcomes. Conclusion: This systematic review and meta-analysis suggests that Prasugrel and Ticagrelor exhibit similar efficacy and safety profiles in patients undergoing PCI. The findings may aid clinicians in making informed decisions regarding antiplatelet therapy selection based on individual patient characteristics and preferences. Further research, including large-scale RCTs, is warranted to validate these findings and provide more nuanced insights into the comparative effectiveness of Prasugrel and Ticagrelor in specific patient subgroups. Discussion: These findings have important for choosing appropriate antiplatelet therapy. Prasugrel and Ticagrelor can be considered as effective treatment options. However, healthcare providers need to carefully consider the safety profiles and potential side effects of these medications when making treatment decisions. The study relied on aggregated data, which might introduce bias. High attrition rates and heterogeneity among studies limit the findings.