Dual antiplatelet therapy with aspirin and a thienopyridine is standard of care for preventing ischemic events in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI). The TRITON-TIMI 38 trial showed that prasugrel (60 mg loading dose [LD]/10 mg maintenance dose [MD]), a thienopyridine that provides greater, more rapid, and more consistent platelet inhibition compared with clopidogrel (300 mg LD/75 mg MD), produced a 19% reduction in the primary efficacy endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke in ACS patients with planned PCI, with higher non-coronary artery bypass grafting-related (non-CABG) TIMI major bleeding. Improved pharmacodynamic response to prasugrel relative to clopidogrel may account for the decrease in the risk of ischemic events, along with the increased risk of bleeding. Recent studies have linked the poor pharmacodynamic response to clopidogrel in some patients with pharmacogenomic variability in its metabolic conversion to an active metabolite. Landmark analyses of TRITON-TIMI 38 used a Day 3 cutoff point in order to separate events that could be attributed to the MD phase of the study. Compared with clopidogrel, prasugrel significantly reduced the risk for myocardial infarction (hazard ratio (HR) 0.69; P=0.001), stent thrombosis (HR 0.45; P<0.0001), and urgent target vessel revascularization (HR 0.65; P<0.0003) from 3 days until the end of the study (median follow-up of 14.5 months). (Prasugrel was also more effective in reducing thrombotic events than clopidogrel up to day 3.) A significant increase in the HR for non-CABG TIMI major bleeding was observed with prasugrel from 3 days until the end of the study (HR 1.39; P=0.036). Net clinical benefit favored prasugrel over clopidogrel (HR=0.87; P=0.28). In a separate analysis of late stent thrombosis (ie, after 30 days of treatment until end of study) in TRITON-TIMI 38, prasugrel significantly reduced definite/probable stent thrombosis (HR=0.60; P=0.03) compared with clopidogrel. These results provide evidence of a benefit of prasugrel for improving cardiovascular outcomes during the maintenance phase of antiplatelet therapy in ACS/PCI patients. Moreover, these findings support continuation of a treatment regimen with prasugrel to provide continued protection from ischemic events, particularly in those patients at high risk for such events or with a poor pharmacodynamic response to clopidogrel.