The clinical response to clopidogrel based on CYP2C19 gene polymorphisms in coronary patients after drug-eluting stent implantation: Summary of doctoral thesis in medical sciences: 321.03 – Cardiology

Abstract

The thesis is exposed on 110 pages and includes annotation (in Romanian, Russian, English), introduction, 4 chapters, 23 tables, 33 figures, synthesis of obtained results, general conclusions and practical recommendations, bibliography from 165 sources, three certificates of innovator, 6 implementing acts, information on capitalization of research results and declaration on assumption of responsibility. The study materials were reflected 16 scientific publications. Keywords: Double antiplatelet therapy (DAPT) with clopidogrel, gene polymorphisms CYP2C19. Field of study: cardiology. The aim of the stady is to evaluate the clinical-paraclinical and instrumental aspects, the ischemic and hemorrhagic risk of coronary patients, who have benefited from percutaneous coronary intervention with pharmacological stent implantation and the impact of the clinical response to clopidogrel within the DAPT. Objectives: To determine the frequency of CYP2C19 polymorphism in coronary patients, who have benefited from percutaneous coronary intervention (PCI) with pharmacological stent implantation (DES) and in healthy subjects in the Republic of Moldova; Study of clinicalparaclinical and instrumental aspects, cardiovascular risk factors in coronary patients who have benefited from PCI with DES implantation depending on the frequency of CYP2C19 polymorphism; Assessment of bleeding risk (PRECISEDAPT score) and ischemic risk (DAPT score); Estimation of the impact of CYP2C19 polymorphism on patients' metaboliser status: slow/intermediate, normal and fast/ultrafast, in association with major bleeding and cardiovascular events during 6 -12 months; Analysis of correlation of potential predictors of myocardial infarction in patients with DAPT (aspirin + clopidogrel) after PCI and development of prognostic models to determine the probability of occurrence of ischemic and hemorrhagic events.The importance and relevance of the theme. The study allowed the evaluation of clinical-paraclinical and instrumental aspects, ischemic and hemorrhagic risk of coronary patients, who benefited from PCI with DES implantation within DAPT. It was established the role of genetic factors - CYP2C19 polymorphism, which determines ischemic and bleeding risk, serum and instrumental markers in predicting fatal and non-fatal complications in coronary patients, who benefited from PCI with DES implantation. Scientific problem solved. There were determined the frequencies of CYP2C19 polymorphism, which determines the hepatic metabolism of clopidogrel in coronary patients, who benefited from PCI with DES implantation and in healthy subjects from the Republic of Moldova. The impact of CYP2C19 polymorphism on patients' metaboliser status of clopidogrel was assessed: poor/intermediate, normal and rapid/ultrarapid, in association with major bleeding and cardiovascular events during 6-12 months. The results of the evaluation allowed the elaboration of strategies for prediction of acute ischemic and hemorrhagic major events of genomepersonalized DAPT, based on genetic polymorphism of CYP2C19. Scientific novelty and originality. For the first time, the following were achieved: identification of allelic frequencies of CYP2C19 and phenotypes of healthy subjects according to CYP2C19 polymorphism; estimation of allelic frequencies of CYP2C19 and phenotypes of post-PCI coronary patients, administering DAPT (aspirin-clopidogrel) according to CYP2C19 polymorphism; evaluation of cardiovascular risk factors, clinical, paraclinical parameters, that can influence the management of DAPT (aspirinclopidogrel) using DAPT and PRECISE-DAPT scores in a period of 6-12 months; addressing major acute ischemic and bleeding events over 6-12 months of post-PCI patients administering DAPT (aspirin-clopidogrel) depending on CYP2C19 polymorphism; development of the Prediction model of acute ischemic major events in post-PCI coronary patients, administering DAPT (aspirin-clopidogrel), elaboration of the Predictive model for the probability of occurrence of bleeding events in a period of 6-12 months in post-PCI coronary patients, administering DAPT (aspirin-clopidogrel). Theoretical significance of research. The conducted study once again highlighted the literature data regarding the presence of interindividual variability in the response to clopidogrel and recurrent thrombotic events after PCI. Genetic variation in CYP2C19 is identified as one of the factors responsible for hyporesponsiveness to this antiplatelet agent. The obtained results support the theoretical concept data. Once again, the advantage of personalized medicine has been demonstrated, emphasizing its key role in preventing antiplatelet treatment failure in patients who have undergone PCI with drug-eluting stent implantation. The applicative value. The applicative value lies in the development of predictive models for recurrent ischemic events and bleeding in coronary patients post-PCI who are on DAPT with aspirinclopidogrel. The study results form the basis for the concept of strengthening the prediction of recurrent ischemic events and bleeding, contributing to: 1). recommending CYP2C12 genotyping with the inclusion of the individual's phenotype in the electronic medical record, this would enable clinicians to guide decision-making when the individual undergoes revascularization through PCI with DES. 2). recommending CYP2C19 genotyping for patients with a high risk of acute coronary syndrome, prone to ischemic and bleeding events, requiring personalized dual antiplatelet therapy before initiating clopidogrel treatment. Implementation of results. The scientific results were implemented in the Department of Interventional Cardiology and Endovascular Surgery IMSP SCM "Sf. Treime", cardiosurgery and cardiac rehabilitation department IMSP Institute of Cardiology.