Abstract 15019: Acetylsalicylic Acid (ASA) Adds Limited Additional Antiplatelet Effect When Given in Addition to High-Level P2y12 Receptor Inhibition and Can Increase Peripheral Vascular Resistance
Introduction: Dual antiplatelet therapy with acetylsalicylic acid (ASA) and P2Y12 receptor antagonists is well established. ASA mediates its protective effect through inhibition of platelet COX-1 and thromboxane A2 (TXA2) production. In other cell types, however, ASA will inhibit COX-1 and, depending on dose, COX-2, reduce the production of prostacyclin (PGI2). Since PGI2 has effects that oppose those of TXA2, its reduced production is potentially harmful to CV patients. Recent data suggest that high degree P2Y12 inhibition will potently inhibit TXA2-dependent pathways of platelet activation, questioning the need for ASA in this setting. We tested the hypothesis that high-dose ASA, when given in combination with high degree P2Y12 inhibition, would not further improve platelet inhibition, but that the reduction in PGI2 levels could induce thrombogenic and/or vasoconstrictive effects.
Methods: A modified Folts dog model was used to evaluate the P2Y12 receptor antagonists, ticagrelor and clopidogrel, alone and in combination with high-dose ASA (50 mg/kg). In vivo platelet-mediated thrombosis was visualized as cyclic blood flow reduction in the stenosed, damaged femoral artery. Ex vivo platelet aggregation and TXA2 formation were measured and vascular resistance was calculated.
Results: At maximal P2Y12 inhibition, each antagonist next to completely inhibited arachidonic acid (AA)-induced platelet aggregation in the absence of ASA. At sub-maximal P2Y12 inhibition for each antagonist, ASA contributed more additional antiplatelet (AA- and collagen-induced aggregation) and antithrombotic effects. High-dose ASA induced an increase in peripheral vascular resistance, but was not pro-thrombotic.
Conclusions: • High level P2Y12 inhibition inhibits AA-induced platelet activation independently of ASA. • ASA provides additional antiplatelet effect mainly when combined with sub-maximal P2Y12 inhibition. • The differences seen were related to the level of P2Y12 inhibition, not the antagonist used; thus, this appears to be a class effect. • High-dose ASA can increase peripheral vascular resistance. • No pro-thrombotic effect of high-dose ASA was evident.
- © 2010 by American Heart Association, Inc.