Last updated on February 2019

A Genomic Approach for Clopidogrel in Caribbean Hispanics

Brief description of study

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 with 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 population, it is known that patients with certain genetic variants have lower or magnified response 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 Study 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 propose to perform the first ever genome-wide association study (GWAS) of a pharmacogenetically actionable prescription drug in Caribbean Hispanics. 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 implement a treatment algorithm to guide DAPT in Caribbean Hispanics and will create a repository of genomic DNAs and fully annotated clinical and genomic dataset from Caribbean Hispanics with cardiovascular diseases. 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. This hypothesis will be tested with the following specific aims:

  1. To conduct a Genome-Wide Association Study (GWAS) of residual on-treatment platelet reactivity in Clopidogrel-treated Caribbean Hispanic patients of Puerto Rico. 2) To implement a treatment algorithm based on ex vivo PD and genetic test results to guide DAPT in Caribbean Hispanics. 3) To create a repository of biological specimens and fully annotated clinical and genomic dataset (relevant genotypes and phenotypes) from Caribbean Hispanics with cardiovascular diseases.

The study will be conducted over 5 years in 1,000 cardiovascular patients treated with Clopidogrel for secondary prevention of thromboembolic events. 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 in 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 current understanding on 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.

Clinical Study Identifier: NCT03419325

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