Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor: reply

Abstract

Introduction Ticagrelor is described as a reversible P2Y12 antagonist. However, residual platelet inhibition persists after discontinuation of ticagrelor when plasma levels are undetectable. We assessed the reversibility of platelet inhibition by ticagrelor and its active metabolite (T-AM) in comparison with cangrelor and prasugrel's active metabolite (P-AM). Methods Whole blood was treated in vitro with ~50% inhibitory concentrations of ticagrelor, T-AM, cangrelor, P-AM and assessed for ADP-stimulated activated GPIIb-IIIa and P-selectin and vasodilator stimulated phosphoprotein (VASP) platelet reactivity index (PRI) before and after 100-fold dilution. Results Platelets exposed for 30 minutes to ticagrelor, T-AM, or cangrelor showed full recovery of activated GPIIb-IIIa but only partial recovery of P-selectin. Longer exposure (24 hours) to drug decreased reversibility of activated GPIIb-IIIa by ticagrelor (65.1% [49.5 – 80.6], % of vehicle with 95% CI) and T-AM (88.8% [79.2 – 98.3]), but not by cangrelor (101.4% [96.4 – 106.4]). Compared to 30 minutes exposure, the reversibility of P-selectin further decreased after 24 hour exposure to ticagrelor (from 91.8% [82.1 – 101.5] to 51.8% [45.5 – 85.0]), but not T-AM (from 79.0% [67.8 – 90.3] to 77.4% [61.8 – 93.1]) or cangrelor (from 76.0% [67.6 – 84.4] to 76.2% [70.6 – 81.8]). In contrast, 24 hour exposure to ticagrelor, T-AM, and cangrelor resulted in full recovery of platelet reactivity as measured by PRI. Platelets exposed to P-AM showed no recovery of ADP reactivity. Conclusions Incomplete recovery after prolonged exposure to ticagrelor, observed by activated GPIIb-IIIa and P-selectin but not upstream VASP signaling, suggests that P2Y12 regains functionality and irreversible changes occur independent of VASP signaling. This article is protected by copyright. All rights reserved.