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

• Published in: The American heart journal 2011, Vol.161 (1), p.1-4
• Main Author: Serebruany, Victor L., MD, PhD
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Adenosine - analogs & derivatives; Adenosine - blood; Adenosine - secretion; Adenosine - therapeutic use; Biological and medical sciences; Blood platelets; Cardiology. Vascular system; Cardiovascular; Drug therapy; Drug Therapy, Combination; Heart attacks; Heart failure; Humans; Hypotheses; Ischemia; Medical sciences; Myocardial Infarction - blood; Myocardial Infarction - drug therapy; Platelet Aggregation Inhibitors - therapeutic use; Proteins; Purinergic P2Y Receptor Antagonists - therapeutic use; Randomized Controlled Trials as Topic; Treatment Outcome
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/j.ahj.2010.09.017

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.