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  • Review Article
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The evolution of antiplatelet therapy in cardiovascular disease

Nature Reviews Cardiology volume 8, pages 547–559 (2011)Cite this article

Subjects

Abstract

The platelet—an anucleate cell—is the bedrock of thrombosis, both physiologically and pathologically. Antagonism of the P2Y12 receptor for ADP is one of several pathways inhibiting the activation and aggregation of platelets, thereby attenuating coronary thrombosis in response to spontaneous plaque rupture or percutaneous revascularization. The addition of clopidogrel to a background of aspirin therapy was a revolutionary change in the management of ischemic coronary syndromes. Despite this paradigm shift, clopidogrel has certain limitations, including variability in platelet inhibitory effect, which is associated with adverse thrombotic events. In the evolution of antiplatelet treatment strategies, two new P2Y12 receptor antagonists—prasugrel and ticagrelor—have been added to the armamentarium in the past few years. Both of these drugs confer greater platelet inhibition than clopidogrel. Nevertheless, more-potent platelet inhibition comes with an increased risk of hemorrhagic complications. Cangrelor and elinogrel are novel P2Y12 inhibitors that show potential in the periprocedural setting with their rapid onset and offset of activity. Successes in P2Y12 inhibitory therapies have reduced use of glycoprotein IIb/IIIa inhibitors, which block the final pathway leading to platelet aggregation and thrombosis. Newer therapies aimed at various molecular factors are under clinical investigation. Pharmacodynamic platelet function assays and pharmacogenetic testing to individualize and optimize antiplatelet therapy may find their way into clinical use, although much more study is needed.

Key Points

  • Addition of clopidogrel to aspirin is a cornerstone in the management of acute coronary syndromes and percutaneous coronary intervention (PCI), but has variable antiplatelet activity that can limit its efficacy

  • Novel P2Y12 receptor antagonists of ADP that have completed phase III clinical testing include the oral agents prasugrel and ticagrelor, and the parenteral agent cangrelor

  • Prasugrel and ticagrelor confer greater and faster platelet inhibition than clopidogrel and were shown to have superior efficacy in trials of patients with acute coronary syndromes

  • Increased platelet inhibition is invariably associated with increased bleeding; however, the reversibility of ticagrelor and cangrelor could potentially reduce hemorrhagic complications associated with CABG surgery or PCI

  • Clopidogrel, but not prasugrel or ticagrelor, appears susceptible to a reduced pharmacodynamic response in patients with CYP2C19*2 genetic polymorphisms

  • Ongoing investigations of tailored antiplatelet therapy in patients with high on-treatment platelet reactivity will determine whether routine platelet function testing and genetic testing will be useful to individualize therapy

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Figure 1: Sequelae of vascular injury.
Figure 2: Targeted antiplatelet therapies.
Figure 3: Metabolism of ADP antagonists.

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Omair Yousuf

  2. Veterans Affairs Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School, 1400 VFW Parkway, Boston, 02132, MA, USA

    Deepak L. Bhatt

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The authors contributed equally to researching data for the article and discussion of the content. O. Yousuf wrote the article and D. L. Bhatt reviewed/edited the manuscript before submission.

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Correspondence to Deepak L. Bhatt.

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Competing interests

D. L. Bhatt has received research support from Astra Zeneca, Bristol–Myers Squibb, Eisai, Sanofi Aventis, and The Medicines Company. O. Yousuf declares no competing interests.

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Selected ongoing trials of antiplatelet therapy in cardiovascular disease (DOC 112 kb)

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Yousuf, O., Bhatt, D. The evolution of antiplatelet therapy in cardiovascular disease. Nat Rev Cardiol 8, 547–559 (2011). https://doi.org/10.1038/nrcardio.2011.96

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