Ticagrelor

Ticagrelor

File:Ticagrelor structure.svg
Clinical data
Routes of administration	oral
ATC code	none
Identifiers
IUPAC name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
CAS Number	274693-27-5
PubChem CID	9871419
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C23H28F2N6O4S
Molar mass	522.567 g/mol
3D model (JSmol)	Interactive image
SMILES Fc2ccc(cc2F)C3CC3Nc5nc(SCCC)nc4c5nnn4C1CC(C(O)C1O)OCCO

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Overview

Ticagrelor (AZD6140) is a platelet aggregation inhibitor produced by AstraZeneca. As of February 2008, a clinical trial (PLATO: Platelet inhibition and patient outcomes) is comparing a combination of ticagrelor plus aspirin to clopidogrel plus aspirin for the prevention of thromboembolism.

Method of action

Like clopidogrel and ticlopidine, ticagrelor blocks ADP receptors of subtype P2Y₁₂. In contrast to the other antiplatelet drugs, the blockage is reversible. Moreover, it does not need hepatic activation, which could reduce the risk of drug interactions.

PLATO trial

This trial, recently published in New England Journal of Medicine, has confirmed the superiority of ticagrelor over clopidogel in patients with acute coronary syndromes.

FDA Panel Review of Ticagrelor on July 28th, 2010

While administration of Ticagrelor was associated with a reduction in adverse events in the PLATO trial as a whole, there was a lack of benefit, and in fact an excess risk of adverse events in patients treated with Ticagrelor in North America. There were few patients enrolled from Canada, and the hazard was apparent when the analysis was confined to those patients from the United States of America. Much of the panel discussion centered around the basis for the hazard associated with Ticagrelor administration observed in the United States. A key finding was that the aspirin dose in United States patients was higher than that in the rest of the world. The interaction term regarding the impact of aspirin dose on outcomes was highly statistically significant (p=0.00006, Chi2 of 16). Even if multiple exploratory comparisons were made, this p-value would remain statistically significant. Data from the rest of world was used to model the relationship between aspirin dose and clinical outcomes in the trial. The projected event rates from the rest of the world matched those observed in the Unites States. The interaction with clinical outcomes was explained almost exclusively by aspirin dose, and not the country the patient came from. The interaction with aspirin dose was observed for the dose chosen for chronic administration and not for teh loading dose chosen for acute administration. Some presenters argued that the higher aspirin dose explained 100% of the higher event rates in the United States. Other presenters argued that there were a variety of differences in practice patterns in the United States that may explain the hazard observed in the United States.

It should be noted that there are no randomized trials that evaluate the optimal dose of aspirin as part of chronic pharmacotherapy. Meta-analyses suggest that low-dose aspirin may be as if not more effective than full dose aspirin (325 mg daily). The CURRENT / OASIS 7 trial evaluated the relative efficacy of high and low dose aspirin over the course of the first 30 days in patients with acute coronary syndromes. High dose aspirin was not of benefit over the course of 30 days in this randomized study, but this study is not informative with respect to safety and efficacy of high vs low dose aspirin after 30 days. panel members as well as FDA officials also commented on the fact that aspirin monotherapy has not been compared with thienopyridine monotherapy. There has been a supposition that a thienopyridine can be substituted for aspirin in the patient with aspirin intolerance, but this has not been studied.

Several theories were offered regarding the underlying pathobiology of adverse outcomes associated with higher doses of aspirin in the context of ticagrelor therapy. At low doses, aspirin inhibits thromboxane A2 and thereby inhibits platelet aggregation. At high doses, aspirin begins to inhibit prostaglandins which are vasodilators, and may therefore cause vasoconstriction. These balance between platelet inhibition and vasoconstriction may be shifted to different degrees in the presence of a thienopyridine such as clopidogrel or a thienopyridine-like agent such as ticagrelor.

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