We greatly appreciate the comments by Drs. Davlouros and Alexopoulos. The body of data, accumulated from both randomized and retrospective studies, support the strategy of in-laboratory high-dose clopidogrel loading for ad hoc percutaneous coronary intervention (PCI). Early trials have demonstrated the efficacy of glycoprotein (GP) IIb/IIIa inhibition with or without adequate pretreatment with thienopyridines. In contrast to GP IIb/IIIa inhibitors, direct thrombin inhibition with bivalirudin does not provide a direct inhibitory effect on platelet aggregation. Thus, timely thienopyridine pretreatment might be of particular importance in patients undergoing PCI who had been treated with bivalirudin monotherapy. In low-risk patients with acute coronary syndrome (ACS) undergoing PCI, the efficacy of bivalirudin is not affected by the timing of clopidogrel pretreatment. The examination of the specific timing of thienopyridine administration in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial to moderate- and high-risk patients with ACS also revealed reassuring results with respect to bivalirudin therapy. The bivalirudin-treated patients receiving thienopyridine therapy before angiography had 30-day composite ischemic outcomes similar to those of patients receiving “inadequate” clopidogrel loading only after angiography or within 30 minutes after PCI (8.1% vs 8.6%, respectively; p = NS). In our analysis of bivalirudin-treated patients, a small increase was found in the incidence of periprocedural myocardial infarction (8.1% vs 3.7%, p = 0.035) and major adverse cardiac events rates (8.5% vs 4.8%, p = 0.096) when patients were “inadequately” loaded (immediately before or after PCI). In the ACUITY trial, the bivalirudin-treated patients loaded “late” (after angiography or within 30 minutes after PCI) had a 30-day composite ischemic event rate (8.6%) very similar to that of the bivalirudin-treated patients in our study (8.5%). However, in our analysis, the bivalirudin-treated patients receiving clopidogrel loading before angiography had a lower major adverse cardiac events rate (4.8%) than those in the ACUITY trial (8.1%). Such a difference between the results of our analysis and the ACUITY trial might indicate that the difference in ischemic outcomes in our bivalirudin-treated patients could have resulted from a statistical chance, given the relatively small number of patients examined and the nature of a subgroup analysis in a nonrandomized retrospective study.

The 30-day stent thrombosis rates after PCI increase from those in patients with stable coronary artery disease (<1%) to those in patients with non–ST-segment elevation-ACS (∼1.1% to 1.5%), and are greatest in those presenting with ST-segment elevation myocardial infarction (1.9% to 2.5%). In the ACUITY analysis, perhaps a minor trend was detected in stent thrombosis between the patients treated with bivalirudin (1.5%) and those treated with heparin plus GP IIb/IIIa inhibitors (1.1%, p = 0.37). In our subgroup analysis of postangiographic administration of clopidogrel, the bivalirudin-treated patients also appeared to have a nonsignificantly greater risk of stent thrombosis (0.7%) compared to no events in the GP IIb/IIIa-treated patients (p = NS; unpublished data). However, these data need to be interpreted cautiously and should only be hypothesis generating, given the very small number of stent thrombosis events (3 vs 0). In contrast, in the patients with ACS at greatest risk and presenting with ST-segment elevation myocardial infarction, in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial comparing bivalirudin and heparin plus GP IIb/IIIa inhibition, patients receiving bivalirudin had a greater rate of acute stent thrombosis (<24 hours) than those receiving heparin plus GP IIb/IIIa inhibitor (1.3% vs 0.3%, p <0.001), whereas the total number of stent thromboses by 30 days was similar in the 2 groups (1.9% vs 2.5%, p = 0.30). Therefore, in high-risk patients with ACS receiving clopidogrel after angiography, unfractionated heparin plus GP IIb/IIIa inhibition might provide slightly better protection against stent thrombosis than bivalirudin monotherapy. Given that, in total, the ischemic events are similarly reduced with bivalirudin and unfractionated heparin plus GP IIb/IIIa therapy, but bleeding complications are decreased by ∼50% with bivalirudin monotherapy, the clinical relevance of a potential small increase in stent thrombosis needs to be investigated further. A randomized clinical trial is needed to evaluate the optimal timing of clopidogrel treatment in bivalirudin-treated patients. In the absence of such a trial, our findings suggest that thienopyridines can be safely administered either before or immediately after PCI in bivalirudin-treated patients during PCI for ACS, but that early thienopyridine administration might be favored.