A Genomic Approach for Clopidogrel in Caribbean Hispanics

Sponsor

University of Puerto Rico (Other)

Overall Status

Recruiting

CT.gov ID

NCT03419325

Collaborator

National Institute on Minority Health and Health Disparities (NIMHD) (NIH), Icahn School of Medicine at Mount Sinai (Other)

250

Enrollment

Locations

Arms

24.9

Anticipated Duration (Months)

125

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Clopidogrel is a prescription medicine used to minimize blood clot formation in patients with cardiovascular disease, particularly those undergoing heart catheterization and stroke. A substantial amount of medical evidence has proven that patients with stroke or heart diseases can benefit from this medicine. However, significant variability in such expected benefits has been found among individuals receiving clopidogrel, with some patients not having the benefit of reduced complications and adverse cardiovascular events. Prior studies have demonstrated a significant association between certain variants on patient's genes (e.g., CYP2C19) and poor response to clopidogrel and, therefore, major adverse cardiovascular events. Variation in other genes and other factors such as platelet activation, weight, diabetes mellitus (a medical condition that produces high blood sugar), concomitant use of other drugs, and smoking status have also been proposed to be related to the same adverse outcomes. In this study, the investigators would like to determine a possible association between these genes and the response to the medication among Caribbean Hispanic cardiovascular patients on clopidogrel. In other populations, it is known that patients with certain genetic variants have lower or magnified responses to this medication when compared to those individuals taking the same dose and not carrying the genetic variations. However, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for the observed high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease (CVD) Stroke Acute Coronary Syndrome Peripheral Arterial Disease Coronary Artery Disease Myocardial Infarction	Genetic: CYP2C19 test Diagnostic Test: P2RY12 assay	N/A

Detailed Description

Despite the substantial work in cardiovascular pharmacogenomics published over the past decade, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel. Caribbean Hispanics are disproportionately affected by cardio-metabolic disorders, but with a limited expectation of benefits from existing genomic-based algorithms. The investigators will focus on clopidogrel to develop urgently-needed genomic-driven prescription guidelines for this population. To this purpose, the investigators will implement a treatment algorithm to guide DAPT in Caribbean Hispanics and will create a repository of genomic DNAs and fully annotated clinical and genomic datasets from Caribbean Hispanics with cardiovascular diseases. This proposal will also take a novel approach to definitively assess the admixture component and is also highly practical for the development of a clinical decision support (CDS) tool. The investigators will test the following hypothesis: There are unknown genetic variants that uniquely contribute to clopidogrel responsiveness in Caribbean Hispanics to such extent that a developed CDS tool that incorporates personal ethno-specific genotypes and ex vivo pharmacodynamics (PD) testing will help enable more precise recommendations for optimizing medical outcomes to antiplatelet therapy in this population. To test this hypothesis we will work with the following aim: To implement a treatment algorithm based on ex vivo PD and genetic test results to guide DAPT in Caribbean Hispanics.

This clinical study will be conducted over 2-3 years in 250 naive cardiovascular patients to be treated with DAPT for secondary prevention of thromboembolic events (i.e., to be compared to another set of 250 clopidogrel-treated patients from a matched non-concurrent standard-of-care cohort). It is expected that this study advances the adoption of a Precision Medicine (PM) paradigm for the benefit of Hispanic patients. The richer genetic variance in Latinos is likely to contribute substantially to variability in response to drug treatments, a component that will be missed by traditional studies within homogeneous populations. This addressable oversight is of great concern since it will tend to exacerbate the healthcare disparity already experienced by Hispanic populations in the US. Hispanics have been largely excluded from Precision Medicine initiatives, which increase dramatically the disparities in translating benefits from new findings in pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare services. Accordingly, the proposed research will expand the current understanding of the pharmacogenomics of Clopidogrel. Advancing knowledge in the under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize DAPT in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

250 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

After being consented, patients will undergo rapid ex vivo platelet functional testing (i.e., residual platelet reactivity units, PRU, measured using the VerifyNow P2R12 assay for Clopidogrel response) and CYP2C19 genotyping. Patients will then be categorized into 4 groups based on tests results: 1) high on-treatment platelet reactivity (HTPR)/ CYP2C19 loss-of-function (LOF) alleles (i.e., presence of both HTPR and CYP2C19 LOF alleles); 2) HTPR/No-LOF (presence of HTPR, but no CYP2C19 LOF allele); 3) No-HTPR/LOF (presence of a CYP2C19 LOF allele, but no HTPR); 4) No-HTPR/No-LOF (absence of both HTPR and CYP2C19 LOF alleles).After being consented, patients will undergo rapid ex vivo platelet functional testing (i.e., residual platelet reactivity units, PRU, measured using the VerifyNow P2R12 assay for Clopidogrel response) and CYP2C19 genotyping. Patients will then be categorized into 4 groups based on tests results: 1) high on-treatment platelet reactivity (HTPR)/ CYP2C19 loss-of-function (LOF) alleles (i.e., presence of both HTPR and CYP2C19 LOF alleles); 2) HTPR/No-LOF (presence of HTPR, but no CYP2C19 LOF allele); 3) No-HTPR/LOF (presence of a CYP2C19 LOF allele, but no HTPR); 4) No-HTPR/No-LOF (absence of both HTPR and CYP2C19 LOF alleles).

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Adopting a Precision Medicine Paradigm in Puerto Rico: Leveraging Ancestral Diversity to Identify Predictors of Clopidogrel Response in Caribbean Hispanics

Actual Study Start Date :

Sep 1, 2020

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HTPR/LOF Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of both high on-treatment platelet reactivity (HTPR) and CYP2C19 loss-of-function (LOF) alleles: An alternative therapy with either prasugrel or ticagrelor (in line with specific contraindications and precautions for each agent) will be strongly recommended for HPR/LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.	Genetic: CYP2C19 test Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result). Diagnostic Test: P2RY12 assay Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).
Experimental: HTPR/no-LOF Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of HTPR, but no CYP2C19 LOF allele found: An alternative therapy should be considered for HTPR/no-LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.	Genetic: CYP2C19 test Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result). Diagnostic Test: P2RY12 assay Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).
Experimental: no-HTPR/LOF Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of a CYP2C19 LOF allele, but no HTPR: An alternative therapy should be considered for no-HTPR/LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.	Genetic: CYP2C19 test Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result). Diagnostic Test: P2RY12 assay Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).
Experimental: No-HTPR/No-LOF Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Absence of both HTPR and CYP2C19 LOF alleles: Maintaining clopidogrel for no-HPR/no-LOF patients. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.	Genetic: CYP2C19 test Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result). Diagnostic Test: P2RY12 assay Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).

Outcome Measures

Primary Outcome Measures

Major adverse cardiovascular events (MACE) reductions [six months after intervention]
MACE reductions will be the composite of all-cause death, MI (according to the universal definition), stroke or coronary revascularization.

Secondary Outcome Measures

number of patients with treatment-related cardiovascular (CV) death [six months after intervention]
death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, stroke, CV procedures, CV hemorrhage and other CV causes.
number of patients with treatment-related stent thrombosis [six months after intervention]
definite or confirmed stent thrombosis as proposed by the Academic Research Consortium (ARC): i.e., symptoms suggestive of an acute coronary syndrome and angiographic or pathologic confirmation of stent thrombosis.
Bleeding [six months after intervention]
as defined by Bleeding Academic Research Consortium (BARC) criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Caribbean Hispanics (Puerto Ricans, Dominicans or Cubans) residing in Puerto Rico, whose parents are also of Hispanic origin
Both genders (Males/Females)
Age ≥21
Receiving Clopidogrel for therapeutic indications.
No clinically active hepatic abnormality
The ability to understand the requirements of the study
The ability to comply with study procedures and protocol
A female patient is eligible to enter the study if she is of child-bearing potential and not pregnant or nursing, or not of child-bearing potential

Exclusion Criteria:

Non-Hispanic patients (race/ethnicity is self-reported by the patients)
Currently enrolled in another active research protocols at the participating institutions
BUN >30
Creatinine >2.0 mg/dL
Platelet count <100,000/mm3
Nasogastric or enteral feedings
Acute illness (e.g., sepsis, infection, anemia)
HIV/AIDS, Hepatitis B patients
Alcoholism and drug abuse
Patients with any cognitive and mental health impairment
Sickle cell patients
Active malignancy
Patients taking another antiplatelet