Choosing among clopidogrel, ticagrelor, and prasugrel after percutaneous coronary intervention (PCI) remains clinically important because each agent carries distinct ischemic and bleeding risks. A systematic review and mixed-treatment meta-analysis published in JAMA Cardiology evaluated the comparative efficacy and safety of oral P2Y12 inhibitors across randomized clinical trials involving patients undergoing PCI.

The analysis included randomized clinical trials identified through PubMed and Embase searches conducted through November 15, 2025. Trials directly comparing at least two of the three oral P2Y12 inhibitors were eligible for inclusion. Major adverse cardiovascular events (MACE) served as the primary efficacy endpoint, while major bleeding was the primary safety outcome.

Findings

• The analysis included 15 randomized clinical trials involving 48,904 patients undergoing PCI.
• Prasugrel reduced MACE risk versus clopidogrel (OR 0.80; 95% CI 0.69–0.93), with lower myocardial infarction (OR 0.71; 95% CI 0.62–0.82) and stent thrombosis risk (OR 0.48; 95% CI 0.37–0.62).
• Ticagrelor did not reduce MACE versus clopidogrel but lowered stent thrombosis risk (OR 0.73; 95% CI 0.59–0.91).
• Compared with ticagrelor, prasugrel lowered MACE risk (OR 0.83; 95% CI 0.70–0.98), myocardial infarction risk (OR 0.78; 95% CI 0.65–0.94), and stent thrombosis risk (OR 0.66; 95% CI 0.49–0.88).
• Ticagrelor increased major bleeding risk compared with clopidogrel (OR 1.24; 95% CI 1.01–1.52), including intracranial hemorrhage risk (OR 1.89; 95% CI 1.08–3.33).
• Prasugrel ranked highest for prevention of MACE, myocardial infarction, and stent thrombosis among the evaluated oral P2Y12 inhibitors.

The findings supported prasugrel as the highest-ranked oral P2Y12 inhibitor for ischemic outcomes after PCI, while ticagrelor showed higher bleeding risk compared with clopidogrel. The analysis may help inform antiplatelet selection in patients requiring dual antiplatelet therapy after PCI.