Pharmacogenomics in Prediction of Cardiovascular Drugs Adverse Reaction

Study Overview
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Brief Summary
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The research is planned as a prospective nested case-control study. The plan is to recruit about 1,200 consecutive subjects whose pharmacotherapy involves the drug(s) of interest within 4.5 years. The basic cohort - the subjects with the newly indicated indication for use: NOAC; platelet aggregation inhibitors from the P2Y12 receptor antagonist group; and HMG-CoA reductase inhibitors (statins); as monotherapy or without restriction with respect to any other concomitant pharmacotherapy. The ADRs will be analysed by CR by: age, gender, expectancy, severity, association, type (mechanism of event), and outcome, according to the classification of organ systems as well as association with the phenotype. Criteria for bleeding associated with the use of anticoagulant and antiplatelet therapy have been defined; as well as the myotoxicity and hepatotoxicity associated with statin therapy. Samples will be tested for biochemical, haematological, coagulation standard parameters and pharmacogenetic analyses of relevant genes depending on the used therapy. Pharmacogenetic analysis will be performed to genotype the polymorphisms of relevant pharmacogenes: Biological samples and clinical data will be anonymized plus all records of ADRs and other clinical variables will be protected. Possible drug-drug and drug-drug-gene interactions will be evaluated using the Clinical Decision Support System (CDSS) of Lexicomp, PharmGKB, the Flockhart Table, and other systems including panel consensus methods to determine the likelihood of an ADR being associated with drug interactions, and determine whether drug interactions contributed to the occurrence of ADRs to administered CV pharmacotherapy in subjects with variant pharmacogenes of interest (drug-drug-gene interaction). The overall project objective is to determine which pharmacogenes variants, together with clinical parameters, can be used as predictors of CV drug ADRs and are good candidates for inclusion in the clinical diagnostic panel for pre-emptive PGx testing.

Official Title
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Pharmacogenomics in Prediction of Cardiovascular Drugs Adverse Reaction

Conditions
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Pharmacogenetics, Drug-Related Side Effects and Adverse Reactions, Cardiovascular Drugs

Intervention / Treatment
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* Drug: Oral Anticoagulant, Direct-Acting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a) age 18 years or older; b) a new indication for the administration of any of the medicinal products of primary interest (NOAC, clopidogrel, prasugrel, ticagrelor, statins) for which at least a 3-month administration is predicted; c) signed informed consent (for repeated evaluations and donation of blood samples for genetic and eventual pharmacokinetic analysis). Exclusion Criteria: the existence of contraindications to the medicines of primary interest.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| The basic cohort<br>The subjects with the newly indicated indication for use: NOAC; platelet aggregation inhibitors from the P2Y12 receptor antagonist group; and HMG-CoA reductase inhibitors (statins | Drug: Oral Anticoagulant, Direct-Acting<br>* Newly indicated indication for use: DOAC; platelet aggregation inhibitors from the P2Y12 receptor antagonist group; and HMG-CoA reductase inhibitors (statins); as monotherapy or without restriction with respect to any other concomitant pharmacotherapy. Subjects will be followed up during regular visits.<br>* Other names: platelet aggregation inhibitors from the P2Y12 receptor antagonist group;|
| Cases<br>Cases will be subjects who have observed ADRs during follow-up: bleeding that meets the criteria of major or non-major, clinically relevant bleeding (for anticoagulants and platelet aggregation inhibitors); muscle or liver lesions (for statins); any other serious ADR. | Drug: Oral Anticoagulant, Direct-Acting<br>* Newly indicated indication for use: DOAC; platelet aggregation inhibitors from the P2Y12 receptor antagonist group; and HMG-CoA reductase inhibitors (statins); as monotherapy or without restriction with respect to any other concomitant pharmacotherapy. Subjects will be followed up during regular visits.<br>* Other names: platelet aggregation inhibitors from the P2Y12 receptor antagonist group;|
| Controls<br>Controls will be subjects in whom no ADRs were observed during the study | Drug: Oral Anticoagulant, Direct-Acting<br>* Newly indicated indication for use: DOAC; platelet aggregation inhibitors from the P2Y12 receptor antagonist group; and HMG-CoA reductase inhibitors (statins); as monotherapy or without restriction with respect to any other concomitant pharmacotherapy. Subjects will be followed up during regular visits.<br>* Other names: platelet aggregation inhibitors from the P2Y12 receptor antagonist group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The overall project objective is to determine which pharmacogenes variants, together with clinical parameters, can be used as predictors of CV drug ADRs |  | 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetics; adverse drug reactions; statins; DOAK; platelet aggregation inhibitors