| Summary: | Platelets are key mediators in the pathogenesis of atherothrombosis. Antiplatelet therapy (APT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with cardiovascular disease (CVD) and following percutaneous coronary intervention with stent implantation. Clinical studies have consistently demonstrated heterogeneity in responses to APT determined using ex vivo platelet function tests and reduced responsiveness is overwhelmingly associated with increased risk of adverse events including stent thrombosis (ST) and cardiovascular death. Nonetheless, assessment of responses to APT with a view to providing tailored treatment is currently not undertaken in routine clinical practice largely due to the lack consensus regarding the most appropriate platelet function test as well as controversy surrounding the optimal definition of APT hyporesponsiveness. The objectives of the studies in this thesis are: Firstly, to determine the reproducibility and reliability of a well validated point-of-care platelet function test known as Short thrombelastography (TEG) in the assessment of responses to APT. Secondly, to employ Short TEG as a clinical tool to provide tailored APT in a consecutive series of patients admitted acutely with ST. Thirdly, to use Short TEG to conduct a series of clinically relevant experiments in patients with CVD as well as in healthy volunteers. Specifically, I investigated: (i) the effect of clopidogrel cessation one year after drugeluting stent implantation on platelet reactivity and vascular inflammation, (ii) whether the pharmacological response to aspirin in patients with acute ischaemic stroke can be reliably determined from a functional test of AA-induced whole blood clotting, and (iii) whether there are any significant inter- or intra-individual differences in the antiplatelet effect ofPlavix® (clopidogrel hydrogen sulphate) versus the cheaper generic clopidogrel salts that are in widespread clinical use in patients with CVD despite limited data to support their efficacy. The results generated from these studies not only lend support to the concept of routine testing of responses to APT using a standardised and reliable test with a view to providing tailored therapy for all, but also provide insights into potential mechanisms by which P2Y12 receptor antagonists elicit their antiplatelet effects and, specifically, their interactions with aspirin. Our study findings could form the basis of large scale clinical trials that may have a significant impact on the future of APT prescribing in CVD.
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