Coller24 to develop a monoclonal antibody. 25 The antibody was the first agent to enter clinical trials, later followed by a peptide and several small-molecule competitive inhibitors of this adhesion molecule receptor. Six large placebo-controlled, double-blind trials were undertaken to test IIb/IIIa antagonists in patients undergoing PTCA, as summarized in Table 2. 26–31 The Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial26 was the first “proof of concept” and demonstrated a marked, 36% reduction in the incidence of death or MI within 30 days of the procedure (Figure 1). This trial was conducted in high-risk patients, eligible because of an acute coronary syndrome or known angiographic liabilities for acute complications. 25 Either PTCA or directional atherectomy was the revascularization procedure. Of note, only the bolus and sustained infusion (12 hours) but not the bolus per se strategy was effective in reducing adverse outcomes. This strongly suggested that the duration of IIb/IIIa blockade would play out as an important modulator of therapeutic potential. The subsequent 5 trials confirmed and extended the EPIC findings in many ways. 27–31 First, each trial showed benefit of IIb/IIIa inhibition (Figure 1), with reduction of major adverse events. Second, the field of patients was expanded to include any routine percutaneous intervention rather than only a high-risk inclusion criterion. Third, the bleeding complications encountered in EPIC were related to excessive heparin and prolonged indwelling vascular sheath time. In the trials that followed, using lower doses of weight-adjusted heparin and reducing the time of vascular sheaths, the initial doubling of bleeding in the patients receiving IIb/IIIa was reduced to levels similar to those in the control group. 30