Antiplatelet agents form a cornerstone of therapy for patients with acute coronary syndrome undergoing percutaneous coronary intervention, as well as in the secondary prevention of cardiovascular events
Currently available antiplatelet agents, including cyclooxygenase 1 inhibitors, P2Y purinoreceptor 12 (P2Y12) antagonists, protease-activated receptor 1 antagonists, and glycoprotein (GP) IIb/IIIa antagonists, inhibit processes important for both thrombosis and haemostasis
Bleeding remains a major limitation of current therapeutic approaches, with the most intensive antithrombotic regimens associated with an increased risk of bleeding
The adverse effects of bleeding on mortality and cardiovascular outcomes might offset the benefit of potent antiplatelet strategies
Experimental work has highlighted that thrombus formation in vivo is a dynamic process; new regulators of thrombus formation and, therefore, therapeutic targets that do not impair haemostasis have been identified
New antiplatelet strategies, including inhibitors of phosphatidylinositol 3-kinase-β (PI3Kβ), protein disulfide-isomerase (PDI), activated GPIIb/IIIa, GPIIb/IIIa outside-in signalling, protease-activated receptors, and platelet GPVI-mediated adhesion pathways, are in preclinical and early-phase clinical trials
Antiplatelet drugs, such as aspirin, P2Y12 antagonists, and glycoprotein (GP) IIb/IIIa inhibitors, have proved to be successful in reducing the morbidity and mortality associated with arterial thrombosis. These agents are, therefore, the cornerstone of therapy for patients with acute coronary syndromes. However, these drugs all carry an inherent risk of bleeding, which is associated with adverse cardiovascular outcomes and mortality. Thus, the potential benefits of more potent, conventional antiplatelet drugs are likely be offset by the increased risk of bleeding. Data from experiments in vivo have highlighted potentially important differences between haemostasis and thrombosis, raising the prospect of developing new antiplatelet drugs that are not associated with bleeding. Indeed, in preclinical studies, several novel antiplatelet therapies that seem to inhibit thrombosis while maintaining haemostasis have been identified. These agents include inhibitors of phosphatidylinositol 3-kinase-β (PI3Kβ), protein disulfide-isomerase, activated GPIIb/IIIa, GPIIb/IIIa outside-in signalling, protease-activated receptors, and platelet GPVI-mediated adhesion pathways. In this Review, we discuss how a therapeutic ceiling has been reached with existing antiplatelet drugs, whereby increased potency is offset by elevated bleeding risk. The latest advances in our understanding of thrombus formation have informed the development of new antiplatelet drugs that are potentially safer than currently available therapies.
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J.D.M. is supported by a Haematology Society of Australia and New Zealand New Investigator Scholarship. M.S. is supported by a fellowship from the French Foundation for Medical Research. K.P. is supported by a principal research fellowship from the National Health and Medical Research Council of Australia.
K.P. is an inventor on patents describing antiplatelet antibody compounds. The other authors declare no competing interests.
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McFadyen, J., Schaff, M. & Peter, K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol 15, 181–191 (2018). https://doi.org/10.1038/nrcardio.2017.206