Background
In the PLATO study, ticagrelor, a direct-acting and reversible P2Y 12 adenosine diphosphate receptor blocker, slightly but significantly reduced the incidence of cardiovascular and total mortality compared with clopidogrel . The accuracy of the PLATO mortality data has been questioned by some authors . In an adjusted indirect meta-analysis comparing prasugrel with ticagrelor for acute coronary syndromes (ACS), prasugrel and ticagrelor appeared similarly superior to clopidogrel, without any significant difference between them in terms of risk of death and overall major adverse events. Ticagrelor was associated with a significantly lower risk of any major bleeding, while prasugrel caused more bleeding . So, most of these allegations have been rebutted by the PLATO investigators .
Alternative interpretations may exist . In a review, Cattaneo et al. carried out a critical evaluation of recent publications that described an additional mode of action for 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. Most of the studies described were performed using in vitro models, healthy volunteers and animal models . In a recent study, Nanhwan et al. demonstrated that ticagrelor reduces myocardial infarct size; the protective effect of ticagrelor was dependent on adenosine receptor activation, with downstream upregulation of endothelial nitric oxide synthase and cyclooxygenase-2 activity.
In this editorial, we summarize our investigations into the effect of ticagrelor on adenosine plasma concentration (APC), and the consequential effect on endothelial function and endothelial cell migration, in the setting of ACS.
Effect of ticagrelor on APC during ACS
In a prospectively randomized trial, 60 patients with an ACS received ticagrelor or clopidogrel. Six hours after administration of the P2Y 12 -receptor antagonist loading dose, patients who received ticagrelor had a significantly higher APC than patients who received clopidogrel ( P < 0.01) ( Fig. 1 ) . The mechanism of action seems to be inhibition of adenosine uptake by red blood cells, as described in the review by Cattaneo et al. .
Is ticagrelor responsible for so-called “pleiotropic” properties, such as improvement of endothelial function, in ACS patients?
In a second study, we sought to determine whether the increase in APC achieved with ticagrelor improved endothelial dysfunction in patients with primary ACS . Sixty patients were prospectively randomized to receive ticagrelor or clopidogrel. Endothelial function was assessed by digital peripheral artery tonometry, and was evaluated using the reactive hyperaemia index (RHI). Endothelial dysfunction was suspected if the RHI was < 1.67 .
Treatment with ticagrelor improved peripheral arterial function compared with clopidogrel
Under basal conditions, all the patients had microvascular dysfunction (RHI < 1.67; mean, 1.37 ± 0.12). The APC and RHI did not differ between the two groups of patients. At day 30, the APC increased significantly only in the ticagrelor group. The APC was more than two-fold higher in patients taking ticagrelor than in patients taking clopidogrel. After 30 days, the mean RHI increased slightly (mean, + 15%) in the clopidogrel group and greatly (+100%) in the ticagrelor group. We found a correlation between the increase in the APC and the increase in RHI in the ticagrelor group ( Fig. 2 ). So, endothelial function responded more effectively to ticagrelor than to clopidogrel within 30 days. Ticagrelor induced an increase in APC that correlated with the increase in RHI; clopidogrel improved endothelial function, but this was not related to the increase in APC. Consequently, the underlying mechanism of action seems to be the increase in APC. Finally, our study demonstrated a correlation between the increase in APC and the improvement in RHI, but whether this increase in APC has a direct effect on endothelial function remains to be established.
