, Volume 35, Issue 2, pp 155-164
Date: 25 Nov 2012

Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation

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Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y12 receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y12 reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y12 receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.