Date of Award

2012

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Jean-Phillipe Collet

Funder/Sponsor

A. Menarini Pharmaceuticals, The Irish Heart Foundation, The European Society of Cardiology

Keywords

Theses, Coronary disease, Platelet Aggregation Inhibitors, Treatment Outcome

Abstract

SUMMARY

P2Y12 receptor antagonists including clopidogrel, prasugrel or ticagrelor in addition toaspirin are the standard of care for the treatment in acute coronary syndrome andpercutaneous coronary intervention. The benefit of this therapy is based on the balance between the reduction of ischaemic events and minimising bleeding risk. Therefore, it isimportant to have strategies to both ensure the optimal inhibition of the P2Y12 receptor andthe effective prevention and treatment of bleeding events. These form the basis for our three studies.

In the first study, we demonstrated in 241 patients after an acute coronary syndrome, thefeasibility of individualised P2Y12 receptor antagonist therapy based on rapid genotyping to identify common CYP2C19 polymorphisms associated with clopidogrel metabolism. Our findings show that this strategy, when combined with follow up point-of-care platelet function testing, almost eliminated high on-treatment platelet reactivity (2.9%) and allowed the more judicious use of prasugrel therapy, thereby minimising both thrombotic and bleeding risk.

In the latter two studies, we examined in an ex-vivo and in-vivo model the biological efficacy of platelet transfusion in the restoration of platelet function in patients on P2Y12 receptor antagonists. In 35 patients receiving loading doses of clopidogrel and prasugrel for acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) we demonstrated that increasing proportions of platelets are needed reverse stronger P2Y12 inhibition. In the ex-vivo model, we showed that in 33 cardiac surgery patients on P2Y12 receptor antagonists that were given platelet transfusion for perioperative bleeding, there was a 30% increase in platelet activation vasodilator stimulated phosphoprotein (VASP) phosphorylation platetet reactivity index (PRI), a sensitive marker of platelet activation. Platelet transfusion was also associated with changes in the rate and strength of clot formation as assessed by thromboelastograph (TEG).

In conclusion, we demonstrated strategies to best identify patients outside the therapeutic window of P2Y12 receptor antagonism using rapid genetic and point-of-care platelet function platforms, allowing the tailored selection of treatment with the potential to avoid future adverse clinical events. For those presenting with bleeding events, we showed the biological efficacy of the strategy of platelet transfusion for the rapid reversal of P2Y12 therapy in both the ACS/PCI and the cardiac surgery setting.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

6MB

Comments

A thesis submitted to the National University of Ireland in fulfillment of the requirements for Doctor of Medicine.

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