Efficacy and Safety of Prasugrel, Ticagrelor, or Clopidogrel After Percutaneous Coronary Intervention

Importance: The relative efficacy and safety of oral P2Y purinergic receptor 12 (P2Y12) inhibitors (clopidogrel, ticagrelor, or prasugrel) after percutaneous coronary intervention (PCI) are not well defined. Objective: To assess the efficacy and safety of oral P2Y12 inhibitors in patients who underwent PCI. Data Sources and Study Selection: PubMed and Embase were searched until November 15, 2025, for randomized clinical trials comparing at least 2 of the 3 agents. Data Extraction and Synthesis: Data were abstracted by 2 independent authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Random-effects odds ratios (ORs) and 95% confidence intervals were calculated. Data were analyzed in December 2025. Main Outcomes and Measures: The primary efficacy outcome was major adverse cardiovascular events (MACE), while the primary safety outcome was major bleeding. The primary analysis compared prasugrel and ticagrelor in reference to clopidogrel using a mixed treatment comparison meta-analysis. Results: Data were analyzed from 15 randomized clinical trials that included 48 904 patients (mean [SD] age, 63.2 [4.21] years; 13 330 female patients [27.3%]). Compared with clopidogrel, there was a lower risk of MACE (OR, 0.80; 95% CI, 0.69-0.93) driven by lower myocardial infarction (OR, 0.71; 95% CI, 0.62-0.82) and stent thrombosis (OR, 0.48; 95% CI, 0.37-0.62) with prasugrel. MACE was not reduced with ticagrelor compared with clopidogrel, although there was lower stent thrombosis (OR, 0.73; 95% CI, 0.59-0.91). Furthermore, there was lower risk of MACE with prasugrel compared to ticagrelor (OR, 0.83; 95% CI, 0.70-0.98) driven by lower myocardial infarction (OR, 0.78; 95% CI, 0.65-0.94) and stent thrombosis (OR, 0.66; 95% CI, 0.49-0.88). There was a higher risk of major bleeding with ticagrelor vs clopidogrel (OR, 1.24; 95% CI, 1.01-1.52) driven by higher intracranial hemorrhage (OR, 1.89; 95% CI, 1.08-3.33). Prasugrel ranked first, followed by ticagrelor and clopidogrel, for MACE, myocardial infarction, and stent thrombosis. Conclusions and Relevance: In this systematic review and meta-analysis of 15 randomized clinical trials in patients who underwent PCI, prasugrel provided the optimal balance between efficacy and safety compared with ticagrelor and clopidogrel.