View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 63, No. 23, 2014 Ó 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.03.031 Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance Marco Cattaneo, MD,* Rainer Schulz, MD, PHD,y Sven Nylander, PHDz Milan, Italy; Giessen, Germany; and Mölndal, Sweden This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists. (J Am Coll Cardiol 2014;63:2503–9) ª 2014 by the American College of Cardiology Foundation Ticagrelor is a direct-acting, reversibly binding P2Y12 Outcomes) study, ticagrelor was superior to clopidogrel in antagonist that provides rapid onset of antiplatelet effects preventing cardiovascular death, myocardial infarction, or after oral administration. P2Y12, 1 of the 2 purinergic stroke (9.8% vs. 11.7%, a 16% reduction) in patients with receptors for adenosine diphosphate (ADP) expressed by acute coronary syndrome (ACS); two-thirds of these pa- platelets, is essential for normal ADP-induced platelet tients had undergone percutaneous coronary intervention fi aggregation. P2Y12 signaling ampli es platelet responses (PCI) (3). Prasugrel was also superior to clopidogrel in to agonists that cause ADP release from delta granules, preventing the same composite endpoint in patients with stabilizes platelet aggregates, and opposes the anti- ACS who underwent PCI in the TRITON (Therapeutic platelet effects of natural platelet inhibitors such as pro- Outcomes by Optimizing Platelet Inhibition With Pra- stacyclin that induce production of the inhibitory cyclic sugrel) trial (4). Although the 2 trials had quite different adenosine monophosphate (cAMP) by activating adenylyl designs, they showed that more rapid, higher, and more cyclase (1). consistent P2Y12 inhibition than afforded by clopidogrel The essential role of P2Y12 in hemostasis and thrombosis was associated with better clinical outcome. PLATO and is demonstrated by observations that patients with inherited TRITON did display some differences. In PLATO, tica- fi P2Y12 defects have a bleeding diathesis and that the grelor slightly but signi cantly reduced the incidence of administration of antagonists reduces the incidence of major cardiovascular (4.0% vs. 5.1%) and total (4.5% vs. 5.9%) adverse cardiovascular events in patients at risk (1). The mortality compared with clopidogrel, whereas no significant most widely used P2Y12 antagonist is the thienopyridine reduction in cardiovascular (2.1% vs. 2.4%) or total (3.0% prodrug clopidogrel, which, through hepatic conversion to vs. 3.2%) mortality was observed with prasugrel versus its active metabolite, irreversibly inhibits P2Y12. Compared clopidogrel in TRITON (3,4). In addition, a greater inci- with clopidogrel, ticagrelor provides higher and much less dence of dyspnea and ventricular pauses was observed with variable P2Y12 inhibition. This is also true for the third- ticagrelor (3). Although the accuracy of the PLATO generation thienopyridine prasugrel (1), albeit ticagrelor mortality data has been questioned by some authors (5), has been shown to provide slightly greater platelet inhibi- their allegations have been rebutted by the PLATO in- tion (2). In the PLATO (Platelet Inhibition and Patient vestigators (6). Thus, although alternative interpretations exist (7), the PLATO data on mortality suggest that ticagrelor may have unique and clinically relevant effects, From the *Unità di Medicina 3, Ospedale San Paolo, Dipartimento di Scienze as also demonstrated by the observed increased incidence of della Salute, Università degli Studi di Milano, Milan, Italy; yInstitute of Physiology, Justus-Liebig University Giessen, Giessen, Germany; and zAstraZeneca Research and dyspnea and ventricular pauses (3). These effects of tica- Development, Mölndal, Sweden. Dr. Cattaneo has received research grants from grelor may be accounted for by its reversible binding to AstraZeneca, Eli Lilly, Daiichi Sankyo, and Evolva; and has received honoraria P2Y12, its systemic presence at pharmacologically active for lectures or for service on advisory boards from AstraZeneca, Eli Lilly, Daiichi Sankyo, Evolva, Sanofi-Aventis, and Merck Sharp & Dohme. Dr. Schulz has received concentrations over 24 h of the day (8),and/orbyaddi- research grants from Zealand Pharma and honoraria for lectures and membership tional P2Y12-independent effects (9). on advisory boards from AstraZeneca, Recordati, Sanofi-Aventis, and Servier. Here, we will review the experimental and clinical evi- Dr. Nylander is an employee of AstraZeneca. Manuscript received February 4, 2014; revised manuscript received March 21, 2014, dence that ticagrelor increases the half-life and plasma accepted March 24, 2014. concentration of adenosine, and critically evaluate whether 2504 Cattaneo et al. JACC Vol. 63, No. 23, 2014 Ticagrelor and Adenosine Mode of Action June 17, 2014:2503–9 Abbreviations this additional effect of tica- relevance. Importantly, it has been demonstrated that tica- and Acronyms grelor may explain the drug’s grelor does not display relevant direct activity on adenosine clinical profile. receptors (11,18) and is not metabolized to adenosine (19). ACS = acute coronary syndrome(s) ADP = adenosine Ticagrelor Inhibits Cellular Biological Effects of Adenosine diphosphate Uptake of Adenosine Adenosine exerts its biological effects by interacting with 4 cAMP = cyclic adenosine – monophosphate Adenosine is a purine nucleoside G-protein coupled receptors: A1R and A3R are coupled to CNT = concentrative produced primarily through the Gi, the inhibitory G protein, which inhibits adenylyl cyclase nucleoside transporter metabolism of ADP or adenosine and thus decreases intracellular cAMP, whereas A2AR and ENT1 = equilibrative triphosphate by the nucleotidases A2BR are coupled to the stimulatory G protein, Gs, which nucleoside transporter CD39 and CD73; its plasma levels stimulates adenylyl cyclase, increasing intracellular cAMP. PCI = percutaneous coronary increase after cellular stresses such Of the 2 A2R subtypes, A2A is the high- and A2B the low- intervention as injury, ischemia/reperfusion, or affinity receptor (12,20). fl in ammation (10). Adenosine is Effects of adenosine on blood vessels. A2AR is the main rapidly taken up by cells through adenosine receptor responsible for coronary vasodilation, sodium-independent equilibrative nucleoside transporters (ENT which is mediated by both nitric oxide-dependent and 1/2) and sodium-dependent concentrative nucleoside -independent pathways (21).A2BR also mediates coronary transporters (CNT 2/3) (11). Intracellular adenosine is vasodilation, whereas both A1R and A3R negatively metabolized to inosine by adenosine deaminase or modulate coronary vasodilation induced by A2AR and/or – transformed into adenine nucleotides by adenosine kinase A2BR activation (22 24). Adenosine also induces endothe- (10,12). Because of its rapid cellular uptake and metabolism, lial progenitor cell migration via A2A and A3 (25). extracellular adenosine has a half-life of a few seconds (13), Effects of adenosine on platelets. Adenosine is a potent which can be prolonged by inhibition of its transport into inhibitor of platelet aggregation in platelet-rich plasma but cells (Fig. 1). not in whole blood as a consequence of its rapid uptake by Several studies provide evidence that ticagrelor inhibits erythrocytes. This discrepancy is abolished by the addition of cellular uptake of adenosine (11,14,15). Ticagrelor inhibited dipyridamole to whole blood samples (26). Adenosine in- adenosine uptake by washed human erythrocytes and by hu- hibits platelet activation mainly via A2AR but also via A2BR man, dog, and rat cell lines. Considering that the experiments (27). The gene that encodes for A2B is up-regulated after were performed under sodium-free conditions and with cell injury and systemic inflammation in vivo; as a consequence, lines that express ENT1 but not ENT2, it was assumed that the contribution of A2B to adenosine-mediated platelet in- ticagrelor inhibits sodium-independent ENT1 (14).The hibition appears to increase under stress conditions (28). identity of the target transporter was recently confirmed with Effects of adenosine on inflammatory responses. Ade- cells transfected with human transporters (ENT1, ENT2, nosine modulates the inflammatory responses to a variety of CNT2, and CNT3). In these experiments, ticagrelor signif- stressful conditions. Low concentrations of adenosine, icantly inhibited adenosine uptake only in cells that expressed which activate A1R and A3R, promote neutrophil chemo- ENT1 (11). Compared with dipyridamole, an established taxis and phagocytosis, whereas high concentrations of fi ENT1 inhibitor (16), ticagrelor displayed a lower af nity adenosine,