The Dogged Search for Cryptic Effects of Ticagrelor: Wishful Thinking or Real Benefits Beyond P2Y12 Inhibition?

Article, see p 1708 Greater protection against ischemic event occurrences has been associated with lower levels of platelet reactivity to adenosine diphosphate in patients with high-risk coronary artery disease.1–3 The latter observations serve as the basis of the platelet hypothesis, ie, greater inhibition of P2Y12 equals less thrombotic event occurrence.4 Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is indisputably a more potent P2Y12 inhibitor than clopidogrel5 and, when administered to patients with acute coronary syndrome in the PLATO trial (Platelet Inhibition and Patient Outcomes), it resulted in a reduction not only in myocardial infarction, but also vascular death in comparison with clopidogrel.6 The observed reduction in vascular death has provided a strong impetus to search for mechanisms of benefit beyond greater P2Y12 inhibition that are not shared by other P2Y12 inhibitors: the non–P2Y12-mediated hypothesis of ticagrelor. The latter hypothesis is largely based on the property of ticagrelor to inhibit adenosine reuptake, thereby increasing systemic and tissue adenosine levels.7 Most of the subsequent beneficial effects proceed downstream for this pivotal step, because adenosine has been proposed as an important molecule that attenuates ischemia-reperfusion injury. Indeed, there has already been significant exploration in the ticagrelor-adenosine area. 1. Ticagrelor has been shown to inhibit adenosine reuptake in erythrocytes by inhibition of the sodium-independent equilibrative nucleoside transporter-1. Dipyridamole has 16-fold greater affinity for equilibrative nucleoside transporter-1.7 2. No direct effect of ticagrelor on adenosine receptors has been reported, and ticagrelor is not metabolized to adenosine.7 3. In an in vitro study, the antiplatelet effect of ticagrelor was mediated in part by increased extracellular adenosine levels and adenosine-mediated platelet inhibition via the A2A receptor.7 4. In a canine coronary artery ligation model using 1 minute of left anterior descending coronary artery occlusion, ticagrelor and dipyridamole dose-dependently …