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

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Abstract

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.

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Acknowledgments

Dominick J. Angiolillo (corresponding author) reports receiving: honoraria for lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc; Astra Zeneca; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Astra Zeneca; Merck; Evolva; Abbott Vascular; research grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company; Portola; Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. José Luis Ferreiro reports honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; Astra Zeneca. Davide Capodanno reports honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca; consulting fees from Eli Lilly Co; Daiichi Sankyo. Luis A. Guzman reports honoraria for lectures from AstraZeneca. This investigator-initiated study was funded by Institutional funding with no external financial support. The Medicines Company provided cangrelor for in vitro investigational use.

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None of the other authors have conflict of interest to report.

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Authors and Affiliations

  1. University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA

    José L. Ferreiro, Masafumi Ueno, Antonio Tello-Montoliu, Salvatore D. Tomasello, Davide Capodanno, Piera Capranzano, Kodlipet Dharmashankar, Andrew Darlington, Bhaloo Desai, Fabiana Rollini, Luis A. Guzman, Theodore A. Bass & Dominick J. Angiolillo

  2. Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

    José L. Ferreiro

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  1. José L. Ferreiro
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Correspondence to Dominick J. Angiolillo.

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Ferreiro, J.L., Ueno, M., Tello-Montoliu, A. et al. Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation. J Thromb Thrombolysis 35, 155–164 (2013). https://doi.org/10.1007/s11239-012-0846-z

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  • DOI: https://doi.org/10.1007/s11239-012-0846-z

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