Advances in Antiplatelet Therapy: Agents in Clinical Development
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)
- et al.
Identification and biological activity of the active metabolite of clopidogrel
Thromb Haemost
(2000) - et al.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
(2001) - et al.
Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting
Thromb Res
(2005) - et al.
Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives
J Am Coll Cardiol
(2007) - et al.
Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity
Circulation
(2003) - et al.
Durability of platelet inhibition by clopidogrel
Am J Cardiol
(2003) - et al.
Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement
Thromb Haemost
(2003) - et al.
The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties
Br J Pharmacol
(2000) - 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) - 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)
Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450
Drug Metab Dispos
The disposition of prasugrel, a novel thienopyridine, in humans
Drug Metab Dispos
Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity
Semin Thromb Hemost
A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation
Am Heart J
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
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
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
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
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
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Statement of author disclosure: Please see the Author Disclosures section at the end of this article.