Ticagrelor Enhances Adenosine-Induced Coronary Vasodilatory Responses in Humans
What is the effect of ticagrelor on adenosine-induced coronary blood flow and the sensation of dyspnea in human subjects?
In this double-blind, placebo-controlled study, 40 healthy male subjects were randomized to receive a single dose of ticagrelor (180 mg) or placebo in a crossover fashion. Coronary blood flow velocity (CBFV) was measured by using transthoracic Doppler echocardiography at rest after multiple stepwise adenosine infusions given before and after study drug, and again after the infusion of theophylline. The effect of ticagrelor compared with placebo on the area under the curve (AUC) of CBFV versus the adenosine dose (primary endpoint) was estimated by using a mixed-model analysis of variance.
Ticagrelor significantly increased the area under the curve of CBFV versus the adenosine dose compared with placebo (p = 0.008). There was a significant correlation between ticagrelor plasma concentrations and increases in the AUC (p < 0.001). In both treatment groups, the adenosine-induced increase in CBFV was significantly attenuated by theophylline, with no significant differences between subjects receiving ticagrelor or placebo (p = 0.39). Furthermore, ticagrelor significantly enhanced the sensation of dyspnea during adenosine infusion, and the effects were diminished by theophylline.
The authors concluded that ticagrelor enhanced adenosine-induced CBFV and the sensation of dyspnea in these healthy male subjects via an adenosine-mediated mechanism.
This study suggests that ticagrelor augments adenosine-induced physiological responses in human subjects. This adenosine-mediated secondary mode of action of ticagrelor may provide a plausible mechanistic explanation for some of the cardioprotective effects, as well as the increased occurrence of dyspnea, observed in patients taking ticagrelor versus clopidogrel in the PLATO study.
Keywords: Theophylline, Cross-Over Studies, Area Under Curve, Ticlopidine, Pyrazoles, Dyspnea, Hemodynamics, Purinergic P2Y Receptor Antagonists, Blood Flow Velocity, Cardiovascular Diseases, Organoplatinum Compounds, Pyridones, Echocardiography
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