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A paradigm shift in anti-platelet therapy?

Clopidogrel is a second generation thienopyridines which acts by a selective and irreversible blockade of the P2Y12 ADP receptor inhibiting platelet aggregation [1]. It is currently the most commonly used thienopyridine in addition to aspirin to prevent thrombotic events in coronary artery disease patients. Clopidogrel therapy was revealed to be critical in percutaneous coronary interventions (PCI) to reduce the occurrence of post-procedural thrombotic events and in particular early stent thrombosis [2]. The currently recommended loading and maintenance dose of clopidogrel are based on dose-effect studies performed on healthy volunteers. However, several trials have demostrated that in coronary artery disease patients, the response to the drug, as measured by ADP-induced aggregometry, varies greatly with some patients showing no or little response to clopidogrel [3]. Because aggregometry has methodological limitations and is technically demanding, other platelet assays have been developed including the VASP index and the VerifyNow P2Y12 which are standardized, reproducible and more specific to the P2Y12 ADP receptor pathway. In 2003, a study performed by Barragan et al. renewed the interest in this field by suggesting an association between platelet reactivity (PR) inhibition as measured by the VASP index and early stent thrombosis [4]. Since then, this link between biological clopidogrel resistance and thrombotic events has been confirmed by several studies. However, most of these studies focused on shortterm clinical outcome and in particular on early stent thrombosis [5–8]. In this issue of the journal, Gurbel et al. report the result of a large prospective study investigating the prognostic value of PR for ischemic events during an extensive follow-up of 2 years in 297 patients undergoing PCI after clopidogrel pre-treatment. The authors observed a link between PR, measured by light transmission aggregometry with two different doses of ADP, and thrombotic events during the 2 years follow-up. Interestingly, a threshold of PR predicted thrombotic events with a high sensitivity and specificity as illustrated by the ROC curves. Cutoff values of 459% aggregation using 20mM-ADPinduced platelet aggregation and 446% aggregation using a 5 mmol-ADP-induced platelet aggregation were powerful independent predictor of long-term thrombotic events with an Odds Ratio of respectively 3.9 and 3.8 [9]. The first evidence of a potential threshold of PR inhibition to prevent early thrombotic events after PCI had been suggested by the study of Barragan et al. In this case control-study, all patients with stent thrombosis had a PR inhibition as measured by VASP index above 50%. Consistently, prospective studies using various platelet assays have observed a threshold of PR for short-term post-PCI thrombotic events [4–8] (Table I). The study by Gurbel et al. significantly adds to those previous findings demonstrating that the predictive value of PR is not confined to the short-term but persists for long-term thrombotic events. The TRITON TIMI 38 trial was designed to compare the effectiveness of prasugrel, a new P2Y12 ADP receptor antagonist and clopidogrel in patients admitted for an acute coronary syndrome. In this study improved PR inhibition, as achieved by prasugrel compared to clopidogrel standard therapy, resulted in a decrease in the rate of thrombotic events post-PCI. Moreover, consistently with the findings by Gurbel et al. of a link between PR inhibition and late events, prasugrel maintenance dose was associated with a significant decrease in MACE