Laurent Bonello1, Marc Laine2, Nathalie Kipson3, Julien Mancini4, Olfa Helal2, Julien Fromonot3, Vlad Gariboldi3, Jocelyne Condo3, Franck Thuny2, Corinne Frere5, Laurence Camoin-Jau5, Franck Paganelli2, Françoise Dignat-George6, Regis Guieu7. 1. Département de Cardiologie, Hôpital Universitaire Nord de Marseille, Assistance-Publique Hôpitaux de Marseille, Marseille, France; INSERM UMRS 1076, Aix-Marseille University, Marseille, France. Electronic address: laurentbonello@yahoo.fr. 2. Département de Cardiologie, Hôpital Universitaire Nord de Marseille, Assistance-Publique Hôpitaux de Marseille, Marseille, France. 3. Research Unit of Physiology and Dysoxia and suractivity, UMR MD2 and Institute of Biological Research, French Defense Ministry (IRBA), Marseille, France. 4. Assistance Publique, Hôpitaux de Marseille, Hôpital de la Timone, SSPIM, France; Aix-Marseille Université, Faculté de Médecine de Marseille, LERTIM (EA 3283), Marseille, France. 5. INSERM UMRS 1076, Aix-Marseille University, Marseille, France. 6. INSERM UMRS 1076, Aix-Marseille University, Marseille, France; Laboratoire d'Hématologie et de Biologie Vasculaire, Assistance-Publique Hôpitaux de Marseille, Centre Universitaire de la Conception, Marseille, France. 7. Research Unit of Physiology and Dysoxia and suractivity, UMR MD2 and Institute of Biological Research, French Defense Ministry (IRBA), Marseille, France; Laboratoire de Biochimie, Hôpital Universitaire Nord de Marseille, Assistance-Publique Hôpitaux de Marseille, Marseille, France.
Abstract
OBJECTIVES: This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. BACKGROUND:Ticagrelor is a direct-acting P2Y12-adenosine diphosphate receptor blocker. The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non-platelet-directed properties. Animal and in vitro models suggested that the "pleiotropic" properties of ticagrelor may be related to an interaction with adenosine metabolism. METHODS: We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel. The APC was measured by liquid chromatography. To assess the mechanism of APC variation, we measured adenosine deaminase concentration, adenosine uptake by red blood cells, and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors. The P2Y12-adenosine diphosphate receptor blockade was assessed by the vasodilator-stimulated phosphoprotein index. RESULTS: Patients receiving ticagrelor had significantly higher APC than patients receiving clopidogrel (1.5 μM [interquartile range: 0.98 to 1.7 μM] vs. 0.68 μM [interquartile range: 0.49 to 0.78 μM]; p < 0.01). The APC was not correlated with vasodilator-stimulated phosphoprotein (p = 0.16). Serum-containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls (p < 0.01 for both comparisons). Adenosine deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor (p = 0.1). Ticagrelor and clopidogrel had no direct impact on adenosine receptors (p = not significant). CONCLUSIONS:Ticagrelor increases APC in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells.
RCT Entities:
OBJECTIVES: This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. BACKGROUND:Ticagrelor is a direct-acting P2Y12-adenosine diphosphate receptor blocker. The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non-platelet-directed properties. Animal and in vitro models suggested that the "pleiotropic" properties of ticagrelor may be related to an interaction with adenosine metabolism. METHODS: We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel. The APC was measured by liquid chromatography. To assess the mechanism of APC variation, we measured adenosine deaminase concentration, adenosine uptake by red blood cells, and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors. The P2Y12-adenosine diphosphate receptor blockade was assessed by the vasodilator-stimulated phosphoprotein index. RESULTS:Patients receiving ticagrelor had significantly higher APC than patients receiving clopidogrel (1.5 μM [interquartile range: 0.98 to 1.7 μM] vs. 0.68 μM [interquartile range: 0.49 to 0.78 μM]; p < 0.01). The APC was not correlated with vasodilator-stimulated phosphoprotein (p = 0.16). Serum-containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls (p < 0.01 for both comparisons). Adenosine deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor (p = 0.1). Ticagrelor and clopidogrel had no direct impact on adenosine receptors (p = not significant). CONCLUSIONS:Ticagrelor increases APC in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells.