VARIABILITY IN THE RESPONSE TO COUMARIN DRUGS AND CLOPIDOGREL: PHARMACOGENETIC EVALUATION AND CLINICAL IMPLICATIONS

Highly effective treatment protocols have been designed for the management of cardiovascular diseases. However, large variability in clinical outcomes and frequent occurrence of adverse events have been observed, both attributed to the characteristics of some antithrombotic drug. Warfarin and clopidogrel are the most prescribed cardiovascular medications, highly effective in the treatment and prevention of arterial thromboembolism. However, both drugs show high variability as for efficacy, safety or dose requirement. Because of this variability, patients may be exposed to increased risk of bleeding and thrombosis. To minimize the risk, new strategies have been proposed, useful to design tailored anticoagulation and antiplatelet therapies. The most promising approach for predicting the maintenance dose of coumarins is the VKORC1 and CYP2C19 genotype-guided dosing protocol. Currently available algorithms can at most explain 80%, approximately, of the variablilby in the response to coumarins. Thus, efforts have been made to identify new candidate genes that could explain some of the missing variation and better inform coumarin dosing decisions. The CYP4F2 pV433M polymorphism has recently emerged as the most promising predictor of dose requirements. Its role in determining the mean daily dose has been evaluated through a meta-analysis involving more than 9000 treated subjects from thirty studies. Results are presented in the first chapter of this thesis. The second part of the thesis concerns achievements in the personalization of clopidogrel therapy. To date, treatment regimen is based on predefined doses, although the results of laboratory tests of platelet function represent the most promising way to predict the activity of clopidogrel in treated patients and to guide medical decision. Among different, commercially available tests, frequently used in clinical research, the VASP assay might represent the candidate “biochemical” gold standard for assessing the effectiveness of P2Y12-receptor blockade. Data presented here provides new steps towards the identification of the best predictor of the in vivo antiplatelet activity of clopidogrel. Evidence is given that the VASP assay (which measures the P2Y12-dependent inhibition by ADP of vasodilator-stimulated phosphoprotein, VASP) closely reflects the levels of clopidogrel active metabolite achieved in vivo. VASP phosphorylation can thus be considered for the treatment with P2Y12 antiplatelet agents as the equivalent of the prothrombin time used in the monitoring of anticoagulation therapy with coumarins.