High on-treatment platelet reactivity (HPR): What does it mean, and does it matter?

Abstract

2013; 109: 347-355. In this issue of Thrombosis and Haemostasis, Saucedo et al. (1) demonstrate that the prevalence of high on-treatment platelet reactivity was decreased after changing clopidogrel to prasugrel. It is perhaps appealing that the patients with adverse “high on-treatment platelet reactivity (HPR)” with clopidogrel was reduced when switched to prasugrel. From a scientific point of view, the meaning of “HPR” is still unclear. This uncertainty is derived from an arguably confusing clinical development history of the thienopyridine-type antiplatelet agents (ticlopidine, clopidogrel, and prasugrel). Indeed, the use of these agents was greatly expanded based on the clinical experience, rather than on their mechanistic understanding. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)was published in 1996 (2). However, the precise mechanism of antiplatelet action exerted by clopidogrel was clarified only after cloning the target ADP receptor of P2Y12 in 2001 (3). Moreover, the extent of P2Y12 ADP receptor blockade by active metabolite of clopidogrel in an individual patient, which should be a real bio-marker for this drug, has been measured in a very limited number of studies only (4). Nonetheless, some uncertainty remains about how much percentage of P2Y12 receptor should be blocked to achieve appropriate antithrombotic effects in individual patients. Obviously, the goal is not to achieve 100% inhibition of P2Y12 because P2Y12 deficiency manifests as a bleeding disorder (5). Perhaps some focus should be on the drugs per se. Both clopidogrel and prasugrel are pro-drugs. The chemical structure of active metabolite(s) of clopidogrel was detected in 2002 (6). Since the active metabolite(s) of clopidogrel are very labile in character with a reactive thiol function, it is most likely that the majority of produced active metabolite(s) easily binds to P2Y12 receptors on platelets circulating in liver, where it is produced (▶ Figure 1A) Thus, plasma concentrations of active metabolite(s) per se would not necessarily be good pharmaco-dynamic marker(s) for the antiplatelet effects of clopidogrel (8). Thus, the extent of P2Y12 receptor blockage, once achieved in the liver circulation, would be the same in platelet circulating in peripheral blood.