Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment

Abstract

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is the current mainstay of pharmacological treatment in both patients with stable coronary artery disease and acute coronary syndrome managed invasively by percutaneous coronary intervention (PCI). 1 The primary goal of DAPT is to reduce the risk of ischemic events including (re)-infarction and stent thrombosis. Contrary, this well-recognized ischemic benefit of DAPT is cut down by an increased on-treatment bleeding risk including major and fatal bleeding in both a nonoperative and operative setting like coronary artery bypass grafting (CABG).2,3 Bleeding risks differ for the currently available oral P2Y 12 receptor inhibitors. On the basis of the results of large-scale clinical trials and the clinical experience in recent years, we considered that the risk of bleeding to be modest for the second-generation thienopyridine clopidogrel, whereas more potent platelet inhibition, such as it is delivered by the third-generation thienopyridine prasugrel or the cyclo-pentyl-triazolo-pyrimidine ticagrelor, comes along with a substantially higher risk of bleeding. 2-4Immediate and sustained restoration of platelet function in patients on DAPT may become mandatory in a nonoperative setting with acute bleeding (eg, intracranial bleeding) or during cardiac and noncardiac surgery. From a pharmacological point of view, the ability to restore platelet function may differ for the irreversibly acting P2Y 12 receptor inhibitors clopidogrel and prasugrel when compared with the directacting reversibly binding antiplatelet agent ticagrelor. This is because of the circumstance that active metabolites of both clopidogrel and prasugrel exhibit a short plasma half-life and their binding to the P2Y 12 receptor is irreversible. Hence, transfused allogeneic platelet concentrates remain uninhibited in patients on thienopyridine maintenance treatment. In contrast and because of its pharmacological properties, ticagrelor and its active metabolite may inhibit fresh platelets after allogeneic platelet transfusion. ) and in an in vivo setting with allogeneic platelet transfusion in cardiac surgery patients on DAPT who had excessive bleeding during surgery (APTITUDE-CABG). As a key result of the APTITUDE-ACS study (n=59 patients), the authors were able to show that the level of restoration of platelet function by ex vivo administration of autologous platelet-rich plasma significantly decreased with increasing potency of the antiplatelet agent. In clopidogrel-treated patients, platelet function restoration was highest, whereas restoration was lower in prasugreltreated subjects and by comparison lowest in the subgroup of ticagrelor-treated patients. In APTITUDE-CABG (n=52 patients), platelet transfusion resulted in a significant 23% relative increase (42.2±23.6% platelet reactivity index [PRI] before transfusion versus 56.6±23.6% PRI after transfusion; P=0.008) of the VASP PRI and the primary study end point was met. Of note, for the merged subgroup of patients (n=9) treat...

Bleeding associated with the management of acute coronary syndromes

“…Adenosine diphosphate (ADP) and thrombin activate platelets through P2Y 12 receptor and protease-activated receptor-initiated pathways, respectively, even in the presence of aspirin 22 23. The adjunctive use of a second antiplatelet agent to inhibit ADP-mediated platelet aggregation is especially critical in patients with ACS undergoing PCI, and has been shown to provide more effective platelet inhibition and to reduce ischaemic events in NSTE-ACS24 25 and STEMI 26–28.…”

Oral antiplatelet therapy: impact for transfusion medicine

“…The increased risk of untreatable bleeding in patients on ticagrelor demands very stringent therapeutic indication, at least until a specific antidote finds its way into clinical application . Moreover, due to the impending bleeding risk the duration of dual antiplatelet therapy should be kept as short as possible .…”