OBJECTIVES: The 2002 AHA/ACC guideline recommends acute coronary syndrome patients who undergo percutaneous coronary intervention (ASC-PCI) be given 300mg loading dose (LD) of clopidogrel, but higher LD has emerged in practice. A recent trial involving 255 patients found 600 mg of clopidogrel had better outcomes than 300mg (Patti et al, 2005). The current study investigates whether patients treated with higher clopidogrel LD experience better outcomes in the usual care setting. METHODS: We followed 6,282 ACS-PCI patients in a national hospital database with time-stamp information (1/2003-9/2004) for 60 days upon discharge. Using the time-stamp, LD was measured as total dose within 24-hour window of peri-PCI procedure, and myocardial infarction (MI) was captured from post-procedure lab tests. Patients receiving >300mg are grouped into high LD (HLD) (nH=1,465) and ≤300 mg, the low LD group (LLD) (nL=4,152). Primary endpoints (i.e., death, stroke, repeat revascularization, and MI) plus bleeding and re-admission were monitored. Logistic regression tested effects of LD on events with controls for risk. RESULTS: LD ranged from 75mg to 1275mg. The HLD group did not experience better outcome. While 28.49% of LLD experienced an event, the rate was 44.23% for the HLD (p<0.0001). MI rate was higher for HLD at 42.18% compared to 25.91% of LLD (p<0.0001). Bleeding, readmission, and mortality were similar (p=NS). Risk-adjusted logistic regression also found no evidence for better outcome in patients given HLD of clopidogrel. CONCLUSIONS: Using time-stamp data, this large study retrospectively investigated effects of HLD clopidogrel in usual care setting. Patients receiving HLD did not experience better outcome. If providers tend to select HLD to treat high-risk patients in practice, an underlying dose-outcome bias would exist in the data. It is unclear how much of the bias is mitigated by higher dosing in the usual care setting. More research is needed.