Study Shows Ticagrelor Enhances Adenosine-Induced Coronary Blood Flow Velocity

Ticagrelor enhances adenosine-induced coronary blood flow velocity (CBFV) and the sensation of dyspnea in healthy male subjects through an adenosine-medicated mechanism, according to a study published on Jan. 9 in the Journal of the American College of Cardiology.
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The double-blind, placebo-controlled study looked at 40 healthy male subjects who were randomized to receive ticagrelor (180 mg) or placebo. Results showed that ticagrelor significantly increased the area under the curve of CBFV vs. the adenosine dose compared with placebo (p = 0.008). There was a significant correlation between ticagrelor plasma concentrations and increases in the area under the curve (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.

As previous studies have shown ticagrelor significantly and dose dependently augmented adenosine-meditated coronary blood flow increases in a dog model, the study authors note that their study showed "that ticagrelor augments adenosine-induced physiological responses in human subjects" for the first time. They add that further clinical studies are warranted to determine if this "adenosine-mediated secondary mode of action of ticagrelor may provide a plausible mechanistic explanation for the cardioprotective effects."

Meanwhile, a separate article published on Dec. 31 in Circulation found that treatment with ticagrelor compared with clopidogrel resulted in a reduction in total events, including first and subsequent recurrent cardiovascular events.

The analysis of the PLATO study showed that patients randomized to ticagrelor had 1,057 total primary events vs. 1,225 for clopidogrel (rate ratio = 0.86, 95 percent CI 0.79-0.93, p = 0.003). The number of additional events was low for ticagrelor (189 vs. 205, p – 0.40), resulting in a hazard for time to second event/death of 0.80 (95 percent CI 0.70-0.90, p < 0.001) and a number needed to treat of 54. For cardiovascular disease, myocardial infarction, stroke, severe and recurrent ischemia, transient ischemic attacks, and arterial thrombotic events, total events were fewer with ticagrelor (2,030 vs. 2,290, rate ratio 0.88, 95 percent CI 0.82 – 0.95, p < 0.001), with fewer recurrent events with ticagrelor (740 vs. 834, p = 0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95 percent CI 0.75 – 0.91, p < 0.001).

The authors concluded that "when taking all events into account, the benefit of using ticagrelor in patients with ACS is even larger than previously reported with the protocol-based analyses focusing only on the first event." They add that "clinically, these results have important implications for guiding physicians to continue ticagrelor therapy, rather than changing therapy to alternative agents, even for patients who may experience an event while on treatment."

Keywords: Theophylline, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Blood Flow Velocity, Ticlopidine, Blood Platelets, Organoplatinum Compounds, Dyspnea, United States

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