Abstract
Our knowledge of the mechanisms of platelet-mediated thrombosis has increased dramatically over the last 40 years. This increased understanding has identified treatment strategies for acute coronary syndromes (ACS) by targeting key mediators of platelet activation and aggregation processes. Aspirin (acetylsalicylic acid) monotherapy improves patient outcomes by irreversibly inhibiting the cyclooxygenase (COX)-1 enzyme in the arachidonic acid pathway. The later-developed thienopyridines, prodrugs that irreversibly inhibit the P2Y12 receptor, and therefore adenosine diphosphate (ADP) binding, further enhance platelet inhibition and patient outcomes. The thienopyridine clopidogrel has been the standard of care, but it is limited by variable response and treatment failure. A more potent thienopyridine, prasugrel, requires fewer hepatic metabolic steps for activation, and elicits significantly improved outcomes for patients with ACS. The increased potency of prasugrel is associated with an increase in Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding compared with clopidogrel. Ticagrelor represents a new chemical class of agents called the cyclopentyltriazolopyrimidines. It interacts reversibly with the platelet P2Y12 receptor, and does not require metabolic bioactivation for activity. Data show a significant improvement in ischaemic outcomes, including mortality, for ticagrelor compared with clopidogrel, without an increase in overall major bleeding, although non-coronary artery bypass graft bleeding is increased. Glycoprotein IIb/IIIa targeted agents (abciximab, tirofiban and eptifibatide) are also used in ACS patients undergoing percutaneous coronary interventions. These inhibitors utilize a different mechanism of action by preventing fibrinogen-mediated platelet aggregation. Other therapeutic strategies for platelet inhibition are being evaluated, including the investigative protease-activated receptor (PAR)-1 and thromboxane A2 antagonists. This review highlights the mechanisms of action of these agents, and the continuing evolution of ACS therapy.
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Acknowledgements
The author acknowledges editorial assistance provided by Josh Collis and Neil Fisher on behalf of Gardiner-Caldwell Communications in the preparation of this review article, funded by AstraZeneca. AstraZeneca is the manufacturer of ticagrelor. Views expressed in this review represent those of the author and the author did not receive financial compensation for authoring the manuscript.
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Angiolillo, D.J. The Evolution of Antiplatelet Therapy in the Treatment of Acute Coronary Syndromes. Drugs 72, 2087–2116 (2012). https://doi.org/10.2165/11640880-000000000-00000
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DOI: https://doi.org/10.2165/11640880-000000000-00000