Advances in Antiplatelet Therapy: Agents in Clinical Development

https://doi.org/10.1016/j.amjcard.2008.11.023Get rights and content

Antiplatelet agents are the cornerstone of treatment for patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention. The current “gold standard” consists of a combination of aspirin and clopidogrel administered orally shortly before invasive procedures and then continued in the form of maintenance doses. Not all patients respond optimally to standard therapy. Resistance to the antiplatelet activity of both drugs when used either singly or in combination has been observed and may lead to treatment failure, including further atherothrombotic events. Potential limitations associated with the combined use of aspirin and clopidogrel have inspired clinical investigation into several promising new antiplatelet agents as potential additions or alternatives to standard therapy. The candidates include prasugrel, which has a mechanism similar to that of clopidogrel but with superior pharmacokinetics; ticagrelor, a nonthienopyridine that binds reversibly to the platelet P2Y12 receptor; cangrelor, an intravenously administered analogue of ticagrelor; and various thrombin receptor antagonists.

Section snippets

Prasugrel

The thienopyridines are prodrugs that require biotransformation to their active metabolites. These metabolites bind covalently to cysteine residues of the P2Y12 platelet receptor, inhibiting an interaction with adenosine diphosphate (ADP) that would normally result in platelet activation and aggregation.1 Because the P2Y12 receptor is inhibited irreversibly by the thienopyridines, platelets are inactivated for the remainder of their 7- to 10-day lifespan.

The US Food and Drug Administration

What if a higher clopidogrel loading dose were used?

The TRITON-TIMI 38 trial compared prasugrel with a 300-mg clopidogrel loading dose and a 75–mg/day maintenance dose because that is what is currently approved. It is therefore logical to ask how prasugrel would fare in comparison with a clopidogrel loading dose higher than the conventional 300 mg as well as a higher maintenance dose. Some insight was gained from the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation (PRINCIPLE)-TIMI 44 trial, a

Cangrelor

The rationale for the use of cangrelor has to do with the fact that oral P2Y12 inhibitors have a delayed onset of action, prolonged time to effect, and somewhat unpredictable levels of platelet inhibition, at least with clopidogrel. It remains to be seen if these issues with prasugrel in terms of variability of response in maintenance dosing, which is present but less marked than with clopidogrel, become problematic. Intravenous glycoprotein IIb/IIIa inhibitors have the disadvantage of

Ticagrelor (AZD6140)

All thienopyridines share the same mechanism of action. Alternative agents that provide more consistent platelet inhibition and are associated with an acceptable risk of bleeding are under investigation. One approach focuses on the use of adenosine triphosphate, a direct antagonist of ADP-induced platelet aggregation. Unfortunately, adenosine triphosphate is readily inactivated in vivo and has low potency at P2 receptors. Investigations of structure–function relations led to the development of

SCH 530348

SCH 530348 is a thrombin-receptor antagonist with no measurable effect on platelet aggregation induced by ADP, thromboxane A2, or collagen. Relative to standard antiplatelet agents, SCH 530348 is associated with a minimal effect on bleeding time, which suggests that, beyond serving as an adjuvant therapy for PCI, it might be evaluated as a replacement for clopidogrel or other antiplatelet drugs if its efficacy and safety are validated in large clinical trials. The underlying mechanisms that

Author Disclosures

The authors who contributed to this article have disclosed the following industry relationships.

Dominick J. Angiolillo, MD, PhD, has served on the Advisory Board of Accumetrics, Arena Pharmaceuticals, Bristol-Myers Squibb Company/sanofi-aventis, Eli Lilly and Company/Daiichi Sankyo, Inc, Medicure, The Medicines Company, Novartis, and Portola Pharmaceuticals, Inc; has been an investigator for Accumetrics, AstraZeneca, Eisai, Eli Lilly and Company/Daiichi Sankyo, Inc, GlaxoSmithKline, The

References (38)

  • P. Savi et al.

    Identification and biological activity of the active metabolite of clopidogrel

    Thromb Haemost

    (2000)
  • S. Yusuf et al.

    Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

    N Engl J Med

    (2001)
  • D.J. Angiolillo et al.

    Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting

    Thromb Res

    (2005)
  • D.J. Angiolillo et al.

    Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives

    J Am Coll Cardiol

    (2007)
  • P.A. Gurbel et al.

    Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity

    Circulation

    (2003)
  • P.A. Gurbel et al.

    Durability of platelet inhibition by clopidogrel

    Am J Cardiol

    (2003)
  • I. Müller et al.

    Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement

    Thromb Haemost

    (2003)
  • A. Sugidachi et al.

    The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties

    Br J Pharmacol

    (2000)
  • L. Wallentin et al.

    Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease

    Eur Heart J

    (2008)
  • G.J. Weerakkody et al.

    Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status

    Am J Cardiol

    (2007)
  • J.L. Rehmel et al.

    Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450

    Drug Metab Dispos

    (2006)
  • N.A. Farid et al.

    The disposition of prasugrel, a novel thienopyridine, in humans

    Drug Metab Dispos

    (2007)
  • Y. Niitsu et al.

    Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity

    Semin Thromb Hemost

    (2005)
  • J.T. Brandt et al.

    A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation

    Am Heart J

    (2007)
  • A. Sugidachi et al.

    The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite

    J Thromb Haemost

    (2007)
  • T. Jernberg et al.

    Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease

    Eur Heart J

    (2006)
  • S.D. Wiviott et al.

    Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial

    Circulation

    (2007)
  • S.D. Wiviott et al.

    Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial

    Circulation

    (2005)
  • S.D. Wiviott et al.

    Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet Inhibition with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38)

    Am Heart J

    (2006)

    • Cited by (91)

    • Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

      2018, Advances in Protein Chemistry and Structural Biology

    • Recent advances in the development of P2Y<inf>12</inf> receptor antagonists as antiplatelet agents

      2014, Annual Reports in Medicinal Chemistry
      Citation Excerpt :

      The overall result is inhibition of platelet aggregation which prevents development of a thrombus at the site of vascular injury. Clopidogrel that is not rapidly converted to 7 is enzymatically hydrolyzed to the inactive carboxylic acid (~ 85% of a typical dose).16 The need for metabolic activation results in a delayed onset of action for this class of antiplatelet agents and increased inter-individual variability as a result of genetic polymorphism in the required CYP enzymes.

    • Recomendações da SBA para segurança na anestesia regional em uso de anticoagulantes

      2014, Revista Brasileira de Anestesiologia

    • Development of Some Antiplatelet Salts as Drug Active Ingredients and Investigation Biological Activities

      2023, Pharmaceutical Chemistry Journal

    • Antiplatelet and anticoagulant agents

      2021, Management of Bleeding Patients

    • The p48 Flow Modulation Device with Hydrophilic Polymer Coating (HPC) for the Treatment of Acutely Ruptured Aneurysms: Early Clinical Experience Using Single Antiplatelet Therapy

      2020, CardioVascular and Interventional Radiology
    View all citing articles on Scopus

    Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

    View full text
    Copyright © 2009 Elsevier Inc. All rights reserved.