Abstract 16092: Dual Inhibition of Platelet ADP P2Y12 and P2Y1 Receptors Evokes a Rapid and Robust Attenuation of Recurrent Thrombosis: First In Vivo Evidence
Background:Current ADP receptor antagonists used clinically to attenuate recurrent platelet mediated-thrombosis: (i) act solely on the P2Y12 receptor subtype; and (ii) are either irreversible or require 8 h-5 days to restore platelet function after discontinuation of treatment. Recent development of the first antiplatelet agent that: (i) targets both the P2Y12 and P2Y1 receptors; and (ii) has a rapid onset of action and a short (7-8 min) plasma half-life (GLS-AP4A9: GLSynthesis Inc, Worcester MA) may yield significant therapeutic benefits. Accordingly, our aim was to provide the first in vivo characterization of this novel agent in a canine model mimicking unstable angina.
Methods: Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h post-injury + stenosis, dogs were randomized to receive: (i) vehicle (saline) or (ii) GLS-AP4A9: (54 µg/kg IV bolus + 108 µg/kg/h infusion: dose shown to inhibit ex vivo ADP-stimulated platelet aggregation by 90%). Coronary blood flow and hemodynamics were monitored throughout the 3 h protocol. Primary endpoints were: (i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); (ii) % duration of total thrombotic occlusion (flow=0); and (iii) assessment of template bleeding time.
Results: Both groups displayed poor coronary patency during the 1 h pretreat period: flow-time area averaged 28+4% vs 30+5%, and duration of total thrombotic occlusion was 21±6% vs 22+6% (p=ns). Patency remained unchanged following saline treatment (flow-time area = 24+5%; zero flow duration = 20+9%; p=ns vs pretreat). In contrast, GLS-AP4A9 evoked an immediate attenuation of recurrent thrombosis, with flow-time area increased to 60+10% (p<0.05 vs pretreat; p<0.05 vs vehicle) and duration of total thrombotic occlusion reduced to 1+1% (p=0.1). This robust improvement in patency was accompanied by a non-significant (p=0.21) increase in bleeding time, and had no effect on hemodynamics.
Conclusion: These data provide the first in vivo evidence that rapid and reversible, dual ADP P2Y12 and P2Y1 receptor inhibition provides a novel and effective therapy to attenuate recurrent platelet-mediated thrombosis.
- © 2012 by American Heart Association, Inc.