Acute coronary syndrome (ACS) is a continuum of disease that includes non-ST-segment elevation ACS and ST-segment elevation myocardial infarction. The purpose of this article is to define the developing role of ticagrelor in ACS and compare it to currently available P2Y12 receptor inhibitors. While clopidogrel remains the "workhorse" P2Y12 receptor inhibitor for many patients with ACS and prasugrel has an established role in select situations, clinicians must now assimilate the evolving role of ticagrelor. Although ticagrelor offers important advances in the management of ACS (eg, reversibility), there are also notable clinical considerations (eg, unique adverse effects such as dyspnea). Based on the current evidence, we propose an algorithm to aid clinicians in the selection of a P2Y12 receptor inhibitor for patients with ACS in various clinical situations.

Cette thèse est dédiée à l'approche pharmacogénétique des effets anti-inflammatoires de la thérapie par les thiénopyridines. Prenant en compte que les plaquettes activées jouent un rôle central dans les états inflammatoires et que des polymorphismes du cytochrome P450 (CYP) 2C19 ont été montré responsable de différences inter individuelle dans la réponse de l'effet antiplaquettaire de thiénopyridines, nous avons émis l'hypothèse que CYP2C19 *2 ou *17 sont également associés à la variabilité interindividuelle du potentiel antiinflammatoire des thiénopyridines. Les marqueurs d'inflammation utilisés pour suivre l'effet des thiénopyridines sont : la CRP, l'haptoglobines et l'orosomucoïde. Nous avons démontré que pour interpréter les valeurs de l'haptoglobine il était nécessaire de tenir compte du statut génétique et obtenir des valeurs de référence stratifiés. D'abord dans une population saine, nous n'avons pas trouvé d'association entre les valeurs de base des marqueurs inflammatoires et les polymorphismes fréquents de CYP époxygenases. Dans une population après intervention coronarienne percutanée qui était composée de 1128 sujets traités par clopidogrel ou prasugrel, le niveau de CRP observé a montré une interaction significative entre le tabac et le polymorphisme de CYP 2C19 ; cet effet est indépendant du niveau d'agrégation plaquettaire. Dans une 3ème population, sur plus de 1000 sujets hospitalisés à Coimbra, nous avons identifié une interaction entre le clopidogrel CYP2C19 et les médicaments bloqueurs des canaux calciques. En résumé, tous ces résultats obtenus sur plusieurs populations laissent envisager que les marqueurs d'inflammation pourraient être un moyen intéressant de suivi des patients lors de la thérapeutique par les thiénopyridines / The main part of the thesis is devoted to pharmacogenetic approach to the anti-inflammatory effects of thienopyridine therapy. Taking into the account that activated platelets play a central role in the inflammatory responses and that CYP2C19 gain- and loss-of-function polymorphisms (*2 and *17) are sources of inter-individual difference in response to the anti-platelet effects of thienopyridines, we hypothesized that *2 and/or *17 alleles are also associated with inter-individual variability in the potential inflammation-reducing effects of thienopyridines. The following markers were used to test the hypothesis: CRP, haptoglobin and orosomucoid acid. To be reliably interpretable in daily medical practice, genetic status should be considered for partitioning the reference values of haptoglobin. In a small healthy population, no significant association was observed between *2 allele and changes in levels of inflammatory markers from baseline to 7 days after administration of clopidogrel and our findings did not support the notion that the genetic variations of CYP epoxygenases are associated with the level of inflammatory markers. Also, in post-PCI population consisting of 1128 on-clopidogrel or on-prasugrel patients, CRP levels were observed to be regulated with a significant interaction between smoking and CYP2C19 polymorphisms; this effect was independent to the level of platelet aggregation. Additionally, in a large population of 1000 on-clopidogrel patients, whether there is a potential interaction between clopidogrel and calcium channel blockers. Collectively, we demonstrated in this thesis that inflammatory markers might be alternative tools for the prediction of response to thienopyridines

Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events. The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28). Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not. In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.