High-dose aspirin in dogs increases vascular resistance with limited additional anti-platelet effect when combined with potent P2Y12 inhibition

IntroductionWith the arrival of the potent P2Y12 antagonists, ticagrelor and prasugrel, the need for co-treatment with aspirin in acute coronary syndromes must be re-examined. This study assessed whether high-dose aspirin: a) provides additional anti-platelet efficacy, assessed in vivo and ex vivo, when combined with P2Y12 inhibition; and/or b) has a negative effect on vascular function.Materials and MethodsUsing an anaesthetized dog model of thrombosis, the effects of aspirin (50 mg/kg) in addition to clopidogrel and ticagrelor were evaluated at two levels of P2Y12 inhibition, maximal (≥ 96%) and sub-maximal (~ 80%), as assessed by ex vivo ADP-induced whole blood impedence aggregometry.ResultsIn the absence of aspirin, maximal and sub-maximal P2Y12 inhibition inhibited arachidonic acid-induced platelet aggregation by approximately 80% and 24%, respectively, without affecting platelet TXA2 formation. During maximal P2Y12 inhibition, aspirin provided less additional inhibition of ex vivo arachidonic acid- and collagen-induced platelet aggregation, as compared with sub-maximal P2Y12 inhibition, without additional anti-thrombotic effect in vivo. Aspirin significantly decreased in vivo PGI2 production (27%) and increased vascular resistance (16%), independently of P2Y12 antagonism.ConclusionIn the dog, P2Y12 antagonists inhibit TXA2-mediated platelet-aggregation independently of aspirin. Aspirin provides less additional anti-platelet effects during maximal compared with sub-maximal P2Y12 inhibition but increases vascular resistance.