Potential Benefits of Ticagrelor beyond Platelet Inhibition

Ticagrelor (AZD6140, Brilique/Brilinta) is a potent ADP P2Y12 receptor antagonist. In the Platelet Inhibition and Patient Outcomes (PLATO) trial it was found to be superior to clopidogrel with respect to cardiovascular outcomes and total mortality without increasing the risk of bleeding [1].Endothelial dysfunction has been recognized as an important early step in the development of atherosclerosis [2,3] and contributes to the development of an acute coronary syndrome (ACS) [2]. There is a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilation in the brachial artery [4]. Furthermore, microvascular dysfunction has been shown to increase the risk of future cardiovascular events [5].In the latest issue of Cardiology, Kristina Torngren and coworkers have evaluated the effect of ticagrelor as compared to clopidogrel, prasugrel and placebo, respectively, on the reactive hyperemia index in stable patients on maintenance therapy following an ACS [6]. This method has been shown to correlate with coronary endothelial dysfunction [7]. Patients were recruited from a real-world all-comer setting and were not randomized, but were well matched. The authors demonstrated a statistically significant improvement in peripheral arterial function favoring ticagrelor and there were fewer patients with endothelial dysfunction in the ticagrelor group. In the latter group, reactive hyperemia index was not correlated to age and glomerular filtration rate (GFR), which could be explained by a restoration of peripheral endothelial function in these patients. These findings are supported by those of the PLATO trial, in which patients with GFR <60 ml/min had a more pronounced reduction in the primary efficacy endpoint compared to patients with normal GFR [8].In contrast to clopidogrel and prasugrel, ticagrelor displays several pharmacological effects other than its antiplatelet action. It increases adenosine levels by inhibiting adenosine reuptake in red blood cells [9] and can also induce ATP release from human red blood cells [10]. Extracellular adenosine and ATP both stimulate vasodilation. Adenosine exerts a direct dilatory effect and ATP stimulates the endothelium to release vasodilatory factors such as nitric oxide, endothelial hyperpolarizing factor and prostacyclins [11].Adenosine is recycled recreating ATP in red blood cells, endothelial and myocyte cells which contain a rapid and efficient reuptake system of adenosine through equilibrative nucleoside transporter (ENT1/2). Adenosine administered intravenously causes dyspnea, transient atrioventricular block and vasodilation.Ticagrelor induces similar side effects as adenosine and may cause transient ventricular pauses [12] and dyspnea unrelated to lung function [13,14]. It has been shown to inhibit adenosine cell uptake in vitro and to augment endogenous and exogenous adenosine-induced increases in coronary blood flow in a dog model [9], recently confirmed in human subjects following a 180-mg loading dose of ticagrelor [15].In a canine model, ticagrelor improved coronary flow and myocardial tissue perfusion as well as decreasing infarct size [16]. Furthermore, ticagrelor induces ATP release from human red blood cells in a dose-dependent manner [10].Torngren et al. [6] suggest that the combined effects of ticagrelor on both ATP release and adenosine reuptake may result in circulating plasma levels of adenosine high enough to improve microcirculation. A contributing factor could be that vascular smooth muscle cells express P2Y12 receptors and contract in response to ADP [17]. Ticagrelor, but not clopidogrel, has been shown to inhibit this ADP-induced vasoconstriction [17,18].Platelet function testing was not performed in the present study, but it seems less likely that the improved circulation is mediated by the platelet inhibitory effects [19]. Assuming that peripheral endothelial dysfunction is improved by ticagrelor, this would imply a beneficial effect of this agent on coronary microcirculation, with a potential to reduce risk of secondary events following ACS. However, the results presented by Torngren et al. [6] are at present hypothesis-generating and need to be verified in future randomized studies.In patients with ACS initially intended for noninvasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results [20]. Furthermore, as the primary endpoint consisting of death from cardiovascular causes, myocardial infarction or stroke in TRILOGY [21] was not reduced by prasugrel as compared to clopidogrel in patients with unstable angina or myocardial infarction without ST segment elevation not undergoing revascularization, nonplatelet-related properties of an antiplatelet agent such as ticagrelor may play an important role in relation to clinical outcome. However, although these clinical observations may suggest a clinical impact of the physiological properties of ticagrelor not contained in its platelet inhibitory effect, this would have to be documented in a major randomized, placebo-controlled clinical trial comparing ticagrelor and prasugrel before it can serve as a basis for clinical management decisions.