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Current and future antiplatelet therapies: emphasis on preserving haemostasis

Nature Reviews Cardiology volume 15, pages 181–191 (2018)Cite this article

Subjects

This article has been updated

Key Points

  • 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

Abstract

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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Figure 1: Mechanisms of platelet adhesion and aggregation.
Figure 2: The heterogeneous nature of thrombus formation in vivo.
Figure 3: Current targets of antiplatelet therapies.
Figure 4: Novel therapeutic targets to differentiate thrombosis from haemostasis.

Change history

  • 16 January 2018

    In the version of this article initially published online, joint first authorship was not attributed to James D. McFadyen and Mathieu Schaff. This error has been corrected for the HTML, print and PDF versions of the article.

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Acknowledgements

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.

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Author notes

  1. James D. McFadyen and Mathieu Schaff: These authors contributed equally to this work.

Authors and Affiliations

  1. Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, 75 Commercial Road, PO Box 6492, Melbourne, 3004, Victoria, Australia

    James D. McFadyen, Mathieu Schaff & Karlheinz Peter

  2. Department of Medicine, Monash University, Melbourne, 3800, Victoria, Australia

    James D. McFadyen & Karlheinz Peter

  3. Department of Clinical Haematology, Alfred Hospital, 55 Commercial Road, Melbourne, 3004, Victoria, Australia

    James D. McFadyen

  4. Department of Immunology, Monash University, Melbourne, 3800, Victoria, Australia

    Karlheinz Peter

  5. Heart Centre, Alfred Hospital, 55 Commercial Road, Melbourne, 3004, Victoria, Australia

    Karlheinz Peter

Authors
  1. James D. McFadyen
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  2. Mathieu Schaff
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  3. Karlheinz Peter
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Contributions

All the authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

Corresponding author

Correspondence to Karlheinz Peter.

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Competing interests

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

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