A Genomic Approach for Clopidogrel in Caribbean Hispanics

Early Phase 1

Active, not recruiting

• Conditions: Peripheral Arterial Disease; Stroke; Myocardial Infarction; Cardiovascular Disease (CVD); Acute Coronary Syndrome; Coronary Artery Disease
• Interventions: Genetic: CYP2C19 test; Diagnostic Test: P2RY12 assay

• Registration Number: NCT03419325
• Lead Sponsor: University of Puerto Rico

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.

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 Timeline

• Study First Submitted: 2018-01-20
• Study First Submitted QC: 2018-01-31
• Study First Posted: 2018-02-01
• Study Start: 2020-09-01
• Primary Completion: 2023-04-30
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-24
• Last Update Posted: 2024-06-26
• Study Completion: 2024-12-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 150

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
No-HTPR/No-LOF	CYP2C19 test	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.
HTPR/no-LOF	P2RY12 assay	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.
HTPR/no-LOF	CYP2C19 test	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.
No-HTPR/No-LOF	P2RY12 assay	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.
no-HTPR/LOF	CYP2C19 test	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.
HTPR/LOF	CYP2C19 test	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.
HTPR/LOF	P2RY12 assay	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.
no-HTPR/LOF	P2RY12 assay	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
Bleeding	six months after intervention	as defined by Bleeding Academic Research Consortium (BARC) criteria
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.

Trial Locations

Locations (2)

Cardiovascular Hospital of Puerto Rico and the Caribbean; 🇵🇷 San Juan, Puerto Rico

University Hospital at Carolina; 🇵🇷 Carolina, Puerto Rico