We read with great interest the study by Feldman et al in the February issue of the Journal regarding 600-mg clopidogrel loading <2 hours before percutaneous coronary intervention (PCI), in clopidogrel-naive patients with non–ST-segment elevation-acute coronary syndromes (NSTE-ACS). Current guidelines suggest that when a strategy of standard dose loading cannot be adopted for clopidogrel-naive patients, a 600-mg loading dose of clopidogrel should be administered ≥2 hours before PCI. However, it is a “common secret” that the timing of any loading dose is limited by reality to a few minutes before PCI, because most interventionists perform the latter on an ad hoc basis for both logistical and clinical reasons (e.g., unstable patients). A small randomized study of 203 stable patients had shown no short- or medium-term beneficial effect of clopidogrel pretreatment (300-mg loading dose and 75 mg once daily for 3 days) compared to post-PCI administration of a 300-mg loading dose. However, until recently, a paucity of additional data was available regarding this issue. The recent PRAGUE-8 study showed, in patients with stable angina, that nonselective loading with 600 mg of clopidogrel >6 hours before coronary angiography (CAG) could increase the risk of minor bleeding and did not reduce the risk of periprocedural myocardial infarction compared to selectively loading only those patients undergoing PCI. These results discouraged the strategy of nonselective loading, which had been silently adopted by an increasing number of cardiologists and leading to a reduction of the proportion of clopidogrel-naive patients treated at the catheterization laboratory. It also provided indirect evidence (subgroup analysis), that ad hoc PCI might be safe. The still unpublished Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-5) trial reached the same conclusion. That study compared in-laboratory 600-mg clopidogrel loading with loading 4 to 8 hours before CAG. In a single-center prospective randomized study of clopidogrel-naive patients with stable or unstable angina, we compared ad hoc PCI using with a guidelines adherent strategy (ie, PCI performed after a delay of 2 hours), after high-dose clopidogrel loading after CAG. Although prematurely terminated owing to the decreasing proportion of clopidogrel-naive patients referred for CAG, our study showed that the guidelines adherent strategy was not associated with fewer periprocedural and 30-day events (i.e., death, periprocedural myocardial in farction, stroke, reintervention) compared to ad hoc PCI. Our results have been confirmed by Feldman et al, who also found that the in-laboratory strategy of high-clopidogrel loading can be safely applied to the NSTE-ACS population. Their study was retrospective, and 44% of patients (n = 206) in the pretreatment arm had received a periprocedural repeat reloading dose of clopidogrel; however, this does not change the conclusion, because these patients could be considered more than adequately pretreated with clopidogrel. A separate analysis of this subgroup against the in-laboratory group would be interesting. Nevertheless, their findings add strength to the suggestion that high-dose clopidogrel loading “on the table” and performance of ad hoc PCI is safe and, with our study, extends the conclusion across-the-board for patients with NSTE-ACS. The accumulating evidence from these randomized and retrospective studies, including >1,000 clopidogrel-naive patients who underwent ad hoc PCI, might initiate a discussion regarding a change in the PCI guidelines.

However, one point in the study by Feldman et al needs further clarification. The authors found that within the subset of patients who received bivalirudin during PCI, those patients who received the in-laboratory clopidogrel loading dose had a greater incidence of myocardial infarction (8.1% vs 3.7%, p = 0.035) and major adverse cardiac events (8.5% vs 4.8%, p = 0.096) that was mostly driven by small creatine kinase-MB elevations after PCI. They concluded that the bivalirudin-treated NSTE-ACS population might benefit from “adequate” clopidogrel preloading, with a 600-mg dose given >2 hours before angiography. In contrast, 3 patients from the in-laboratory loading group (0.5%) developed post-PCI stent thrombosis compared to none in the pretreatment group. All 3 patients had been treated with bivalirudin periprocedurally. In our study, no patient experienced stent thrombosis after PCI, and we did not use bivalirudin. Although in discordance with the subgroup analysis of the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial in which the bivalirudin-treated patients had a similar rate of 30-day composite ischemic events when preloaded with clopidogrel before CAG (8.1%) compared to those receiving the in-laboratory treatment strategy (8.6%), the finding by Feldman et al raises serious concerns regarding the safety of ad hoc PCI with in-laboratory clopidogrel loading in patients treated with bivalirudin and needs additional study.