Ticagrelor Compared with Clopidogrel Increased Adenosine and Cyclic Adenosine Monophosphate Plasma Concentration in Acute Coronary Syndrome Patients

Abstract

Ticagrelor produces a more potent antiplatelet effect than clopidogrel and inhibits cellular uptake of adenosine, which is associated with several cardiovascular consequences. We aimed to explore the correlation between adenosine and cyclic adenosine monophosphate (cAMP) plasma concentration and antiplatelet effect by clopidogrel or ticagrelor in patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (DAPT). We conducted a prospective, observational and single-centre cohort study enrolling 68 patients with non-ST-segment elevation ACS from January 2016 to May 2016. We monitored the inhibition of platelet aggregation (IPA) and assessed adenosine, adenosine deaminase (ADA) and cAMP plasma concentrations by immunoassay on admission and 48 hr after coronary angiography. The demographic and clinical data were collected by reviewing their medical records. The two groups exhibited similar baseline characteristics including adenosine, ADA and cAMP. The mean IPA in patients receiving ticagrelor was significantly higher than that in patients receiving clopidogrel (93.5% versus 67.2%; p = 0.000). Also, we observed that patients treated with ticagrelor had a significantly higher increase in levels of adenosine and cAMP compared with those treated with clopidogrel (1.04 (0.86; 1.41) versus 0.04 (À0.25; 0.26); p = 0.029 and 0.78 (À1.67; 1.81) versus 0.60 (À1.91; 4.60); p = 0.037, respectively). And there was a weak correlation between IPA and adenosine as well as cAMP plasma concentration (r = 0.390, p = 0.001 and r = 0.335, p = 0.005, respectively). Ticagrelor increased adenosine and cAMP plasma concentration compared with clopidogrel in patients with ACS.The P2Y 12 receptor antagonists play an important role in the inhibition of platelet aggregation and prevention of atherothrombotic events for the patients with acute coronary syndromes (ACSs) [1]. Ticagrelor, a new kind of P2Y 12 receptor antagonist, produced a faster, greater and more consistent antiplatelet effect than clopidogrel [2]. In the PLATO study, ticagrelor reduced the major adverse cardiac and cerebrovascular events (MACCE) compared with the standard treatment with clopidogrel [3]. However, ventricular pauses and dyspnoea were observed in patients treated with ticagrelor. These findings led to the hypothesis that the new P2Y 12 receptor antagonist ticagrelor may have a pleiotropic property.Many studies have concluded that ticagrelor could increase the plasma concentration of adenosine (APC), which might inhibit the cellular uptake of adenosine by the equilibrative nucleoside transporter-1 (ENT-1), leading to an increase in APC [3][4][5]. As a result of such critical role, studies have suggested that ticagrelor could augment adenosine-induced coronary blood flow velocity and the sensation of dyspnoea [6]. Adenosine is a purine nucleoside produced primarily through the metabolism of adenosine diphosphate (ADP) or adenosine triphosphate by the nucleotidases CD39 and CD73 [7]. Adenosine exerts biological effects on inflammatory re...

The Impact of Clinical and Genetic Factors on Ticagrelor and Clopidogrel Antiplatelet Therapy

“…Besides its antiplatelet effect, ticagrelor has a pleiotropic action and it increases plasma adenosine concentration by reducing recapturing of adenosine by red blood cells [32]. Plasma adenosine facilitates arterial vasodilatation and may decrease injury caused by reperfusion [33,34]. It has been reported that ticagrelor prescription before reper fusion, after 4 weeks of antiplatelet treatment, improved animal (a rat) heart function [34].…”

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

“…To date, the molecular mechanisms underlying these pleiotropic effects of ticagrelor have not been elucidated, but there is evidence suggesting that they are related to inhibition of the equilibrative nucleoside transporter-1 (ENT1) leading to increased circulating levels of adenosine and cyclic adenosine monophosphate (cAMP) [9,10]. Adenosine, by binding adenosine receptors (ARs), regulates biological processes involved in CAD and COPD progression including oxidative stress and inflammatory responses [11], and functions of monocytes, neutrophils, CD4 T-helper cells, and CD8 cytotoxic T-cells, all implicated in CAD [12,13].…”

“…The Notch pathway is regulated by cross-talks with a plethora of pathways [34,35] including the NAD + -dependent protein deacetylase, sirtuin1 (SIRT1), an oxidative stress sensor [36] and a repressor of inflammatory response [37], whose expression and activity is reduced in peripheral blood mononuclear cells (PBMCs) of stable CAD, ACS [38], and COPD [39] patients. Many studies have investigated the possible molecular mechanisms underlying the pleiotropic activity of ticagrelor in ACS [40][41][42][43] and SCAD [7] providing evidence of a ticagrelor-mediated increase in circulating levels of adenosine and cAMP [10,[44][45][46][47]. Additionally, several studies have also focused on the effects of ticagrelor on circulating inflammation markers [48][49][50][51].…”

Επίδραση Της Χορήγησης Αντιαιμοπεταλιακών Φαρμάκων Στη Θρόμβωση Και Τη Φλεγμονή Σε Ασθενείς Με Οξύ Στεφανιαίο Σύνδρομο

“…Τα ανωτέρω ευρήματα προκλινικών μελετών σε σχέση με την επίδραση της τικαγκρελόρης στα επίπεδα αδενοσίνης πλάσματος, έχουν επιβεβαιωθεί και σε κλινικές μελέτες [198,199]. Ο Bonello και συν [198] [196].…”

“…Επιλέγοντας στατιστική ισχύ 85% και αμφίπλευρο έλεγχο στατιστικής σημαντικότητας με α=0,05, συνολικά ≥48 ασθενείς απαιτούνταν για να επιτευχθεί στατιστική σημαντικότητα με βάση τις παραπάνω υποθέσεις. Η τικαγκρελόρη είναι ένα μόριο που, όπως έχει δειχθεί από αρκετές μελέτες, αυξάνει τα επίπεδα αδενοσίνης πλάσματος [198,199] και προάγει τη δράση της ενδογενούς και της εξωγενούς αδενοσίνης [192,196,200]…”