Pharmacogenomics in Prediction of Cardiovascular Drugs Adverse Reaction

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.

Study Overview

• Status: Recruiting
• Conditions: Drug-Related Side Effects and Adverse Reactions; Pharmacogenetics; Cardiovascular Drugs
• Intervention / Treatment: Drug: Oral Anticoagulant, Direct-Acting

• Study Type: Observational
• Enrollment (Anticipated): 1200

Contacts and Locations

• Study Contact: Name: Tamara Bozina, PhD; Phone Number: +385 1 45 66 777; Email: tamara.bozina@mef.hr
• Study Contact Backup: Name: Livija Šimičević, PhD; Phone Number: +385 1 2388 888; Email: lsimicev@kbc-zagreb.hr

Study Locations

• Croatia
  • Zagreb, Croatia, 10000
    • Recruiting
    • UHC Zagreb
    • Contact: Livija Šimičević, PhD; Phone Number: +385 1 2388 888; Email: lsimicev@kbc-zagreb.hr
    • Contact: Tamara Bozina, PhD; Phone Number: +385 1 4566 777; Email: tamara.bozina@mef.hr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The primary cohort is represented by subjects who have a new indication for the administration of a) new oral anticoagulants (NOAC); b) platelet aggregation inhibitors from the P2Y12 receptor antagonist group (clopidogrel, prasugrel, ticagrelor); c) an HMG-CoA reductase inhibitor (statins); for the purpose of treatment or prophylaxis for at least 3 months; as monotherapy or without restriction with respect to any other concomitant pharmacological therapy.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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	Drug: Oral Anticoagulant, Direct-Acting; 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.; Other Names: HMG-CoA reductase inhibitors; platelet aggregation inhibitors from the P2Y12 receptor antagonist group
Cases; 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; 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.; Other Names: HMG-CoA reductase inhibitors; platelet aggregation inhibitors from the P2Y12 receptor antagonist group
Controls; Controls will be subjects in whom no ADRs were observed during the study	Drug: Oral Anticoagulant, Direct-Acting; 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.; Other Names: HMG-CoA reductase inhibitors; platelet aggregation inhibitors from the P2Y12 receptor antagonist group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Clinical Hospital Centre Zagreb
• Collaborators: Croatian Science Foundation; University of Zagreb School of Medicine
• Investigators: Principal Investigator: Tamara Bozina, PhD, University of Zagreb, Schooll of Medicine

Publications and helpful links

Helpful Links

• Project web site

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2020
• Primary Completion (Anticipated): December 14, 2025
• Study Completion (Anticipated): December 14, 2025

Study Registration Dates

• First Submitted: March 23, 2022
• First Submitted That Met QC Criteria: March 23, 2022
• First Posted (Actual): April 1, 2022

Study Record Updates

• Last Update Posted (Actual): April 1, 2022
• Last Update Submitted That Met QC Criteria: March 23, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacogenetics; adverse drug reactions; statins; DOAK; platelet aggregation inhibitors
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Purinergic P2Y Receptor Antagonists; Platelet Aggregation Inhibitors; Factor Xa Inhibitors
• Other Study ID Numbers: UIP-2020-02-8189

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No