Impact of aspirin dose on adenosine diphosphate-mediated platelet activities

Abstract

Different aspirin dosing regimens have been suggested to impact outcomes when used in combination with adenosine diphosphate (ADP) P2Y12 receptor antagonists. Prior investigations have shown that not only aspirin, but also potent ADP P2Y12 receptor blockade can inhibit thromboxane A2-mediated platelet activation. The impact of aspirin dosing on ADP mediated platelet activities is unknown and represents the aim of this in vitro pilot pharmacodynamic (PD) investigation. Twenty-six patients with stable coronary artery disease on aspirin 81 mg/day and P2Y12 naïve were enrolled. PD assessments were performed at baseline, while patients were on 81 mg/day aspirin and after switching to 325 mg/day for 7 ± 2 days with and without escalating concentrations (vehicle, 1, 3, and 10 μM) of prasugrel's active metabolite (P-AM). PD assays included flow cytometric assessment of VASP to define the platelet reactivity index (PRI) and the Multiplate Analyzer (MEA) using multiple agonists [ADP, ADP + prostaglandin (PGE1), arachidonic acid (AA), and collagen]. Escalating P-AM concentrations showed incremental platelet P2Y12 inhibition measured by VASP-PRI (p<0.001). However, there were no differences according to aspirin dosing regimen at any P-AM concentration (vehicle: p=0.899; 1 μM: p=0.888; 3 μM: p=0.524; 10 μM: p=0.548). Similar findings were observed in purinergic markers assessed by MEA (ADP and ADP+PGE1). P-AM addition significantly reduced AA and collagen induced platelet aggregation (p<0.001 for all measures), irrespective of aspirin dose. In conclusion, aspirin dosing does not appear to affect PD measures of ADP-mediated platelet reactivity irrespective of the degree of P2Y12 receptor blockade. P2Y12 receptor blockade modulates platelet reactivity mediated by alternative activators.

Benefit and Risks of Aspirin in Addition to Ticagrelor in Acute Coronary Syndromes

“…The considered magnitude of aspirin benefit for patients with ACS and its very low cost has resulted in all other antiplatelet agents being tested on top of aspirin, with the assumption of additive effects of both medications. Nevertheless, in light of the central role of the P2Y12 signaling pathway on platelet activation and amplification processes, potent P2Y12 blockade can also lead to downregulation of other markers of platelet reactivity, including arachidonic acid-induced and collagen-induced aggregation …”

“…Yet aspirin still yields additive inhibition of arachidonic acid-induced and collagen-induced platelet aggregation, even in the presence of potent P2Y12 inhibition . Moreover, investigations have shown that high-dose aspirin does not interfere with the pharmacokinetic or pharmacodynamic effects of ticagrelor, and aspirin dosing does not modulate pharmacodynamic markers of P2Y12 signaling irrespective of the degree of P2Y12 receptor blockade . Therefore, the question remains as to whether the additive value of aspirin mediated through inhibition of TXA 2 -mediated platelet aggregation is offset by the inhibition of prostacyclin synthesis in vivo, which is generally not accurately assessed by laboratory studies .…”

“…Moreover, investigations have shown that high-dose aspirin does not interfere with the pharmacokinetic or pharmacodynamic effects of ticagrelor, and aspirin dosing does not modulate pharmacodynamic markers of P2Y12 signaling irrespective of the degree of P2Y12 receptor blockade . Therefore, the question remains as to whether the additive value of aspirin mediated through inhibition of TXA 2 -mediated platelet aggregation is offset by the inhibition of prostacyclin synthesis in vivo, which is generally not accurately assessed by laboratory studies . Consequently, the clinical data from prospective studies of aspirin in combination therapy have been eagerly awaited, underscoring the incremental value of this report from a large randomized study to the understanding of ticagrelor and aspirin interaction among patients with ACS.…”

Blood cells: an historical account of the roles of purinergic signalling

“…Clopidogrel has also been reported to enhance periodontal repair in rats through decreased inflammation [373]. P2Y 12 receptor antagonists are widely used in combination with aspirin for the treatment of thrombosis, especially for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention [374,375]. Clopidogrel has also been reported to prevent endothelial dysfunction and vascular remodelling in aortas from hypertensive rats [376].…”

Aspirin-free antiplatelet regimens after PCI: when is it best to stop aspirin and who could ultimately benefit?

“…Low cost and the benefit attributed to aspirin resulted in all other antiplatelet medications being tested on top of aspirin, with the assumption of additive and even synergistic effects of both agents. Nevertheless, in the context of the central role of the P2Y 12 signalling pathway on platelet activation and amplification processes, more potent P2Y 12 blockade was also shown to lead to downregulation of other markers of platelet reactivity, including arachidonic acid-and collagen-induced aggregation 2,20,21 . Aspirin was hypothesised to add little additional inhibition of platelet aggregation in the presence of potent P2Y 12 inhibitors 2,5,6 .…”