Adenosine release: A potential explanation for the benefits of ticagrelor in the PLATelet Inhibition and Clinical Outcomes trial?

Objective: The objective of the study was to hypothesize on the potential mechanism explaining the surprising mortality benefit of ticagrelor in the PLATO trial. Background: In PLATO, the mortality reduction (107 deaths) numerically exceeds the myocardial infarction prevention benefit (89 events), making it a hitherto unmatchable achievement of ticagrelor over active comparator. If confirmed, such an impressive mortality advantage will be critical for the further success of ticagrelor to compensate for its otherwise unfavorable safety profile. In fact, such an impressive survival represents an entirely unexpected benefit, which will serve as a key point in the drug approval process and subsequent use in clinical practice. Methods: The potential association of ticagrelor as a promoter of blood adenosine serving as adenosine agonist is assessed. Results: Multiple properties of adenosine, which can be closely matched with both clinical benefits and adverse events after ticagrelor, suggest that this novel pyrimidine is not a pure antiplatelet agent. Unquestionably, ticagrelor potently inhibits platelet activity via established mechanism of P2Y12 receptor blockade, probably chronically increasing blood adenosine levels and ultimately contributing to the vascular outcome benefit observed in PLATO. Conclusions: Future randomized trials of ticagrelor in acute heart failure, sudden death prevention, and treatment of atrial fibrillation are warranted and will expand our understanding of the potential role of adenosine in the outcome benefit after pyrimidines.