An observational study in Atrial Fibrillation, Deep Vein Thrombosis and Cardiac Valvular Insufficiency, sponsored by University of Puerto Rico. Completed at 3 sites in 2 countries. Open to participants aged 21 Years to 90 Years. Per ClinicalTrials.gov, last updated 2022-05-19.
Sponsored by University of Puerto Rico · Observational
Caribbean Hispanics are a population with a disproportionately high prevalence of cardio-metabolic disorders but with a limited expectation of benefits from current pharmacogenetic algorithms derived mainly in subjects of relatively pure ancestry. The investigators focus on warfarin responses to develop urgently-needed DNA-driven prescription guidelines for this population, who have arisen from European, West African and Amerindian genomic origins to produce a highly heterogeneous population. Our project combines admixture analysis and DNA-sequencing with development of more accurate rules for better predictability of warfarin dosing to immediately serve this medically underserved population.
Despite the substantial number of work published over the past years in different populations around the world, a fundamental gap remains in understanding whether and how genomic admixture and polymorphisms in warfarin-related pharmacogenes account for the high inter-individual dose variability observed in Caribbean Hispanic patients. In addition to being a medically underserved population, often marginally represented in clinical studies, Caribbean Hispanics are also a genomically heterogeneous population whose high level of admixture has produced a rich repertoire of combinatorial genotypes (e.g., CYP2C9*2/*5 + VKORC1-1639 A/A) that appear to challenge current pharmacogenetic-driven prescribing models. Our project takes a novel approach to definitively assess this admixture component and is also highly practical for its incorporation into a customized pharmacogenetic algorithm that will be implemented in "real-world" clinical settings through a web-based portal. Moreover, the project is also aimed at performing DNA-sequencing to identify those unknown variants on candidate pharmacogenes (i.e., CYP2C9 and VKORC1) that may contribute further to explain dose variability in Caribbean Hispanics. Shaped by strong preliminary data from a SC2 pilot project, the investigators will assess clinical validity and utility of an admixture-adjusted, pharmacogenetic-guided prescribing model for personalized prediction of effective warfarin dosing in Caribbean Hispanics, which also encompasses genetic (common and novel variants) and non-genetic clinical and demographic factors. The study will be conducted over 4 years in 300 patients with thromboembolic disorders receiving warfarin. Four collaborating/recruiting sites will be further connected through precise delivery of genotyping results and prescribing advice to clinicians via a web-based portal. Our novel assessment of genetic admixture will quantify the contribution of European, African and Amerindian ancestry, and the investigators will test whether this admixture component can explain the heritability that is currently missing in the response variability to this drug among Caribbean Hispanics. If successful in our target population, the same approach can ultimately render current pharmacogenomic models for clinical management of related thromboembolic conditions more accurate and predictive for other populations.
The proposed research will advance and expand our understanding of how these clinically relevant variants affect the response to warfarin in an admixed population. Advancing knowledge in the important and under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize oral anticoagulation therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.
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This study's enrollment of 200 is below the median of 392 across 324 observational studies indexed under Pulmonary Embolism.
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Caribbean Hispanics (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are Caribbean Hispanics as well.
Exclusion Criteria:
the standard clinical approach will be followed
Other: Standard-of-Care
algorithmically guided personalized therapy of warfarin, using a pharmacogenetic model developed in Caribbean Hispanics
Genetic: Genotype-guided
Individual warfarin dose adjustments by using a pharmacogenetically driven algorithm
Individual warfarin dose adjustments by using a clinically driven algorithm (standard care)
time spent within therapeutic range
percentage of time each patient spent within and out of the therapeutic range (TTR) during initiation, using the Rosendaal linear interpolation method.
Time frame: 6 months
number of warfarin dose adjustments
number of warfarin dose adjustments during the first 12 weeks of therapy
Time frame: 12 weeks
time to stable anticoagulation
time to get stabilization of warfarin doses based on achieving at least three consecutive INR measures within the range for the same average dose.
Time frame: 12 weeks
events-free time
the number of days elapsed between warfarin initiation (date of prescription) and the occurrence of the first event of interest. For the purpose of this analysis, we will use a composite of multiple events that includes hospitalization rates (the first hospitalization due to any cause or due to bleeding or thromboembolism), first overanticoagulation (INR\> 4) and first major or minor bleeding episode or ischemic stroke.
Time frame: 6 months
Plan to share: Yes — Data sharing plan is fully described in the corresponding section of the protocol. A thorough description of appropriate use of the data to be shared in this study is provided in informed consent documents. Limitations on data use are also described therein and in this Institutional Certification. Safeguards to protect the data according to Federal standards for information protection will be implemented. As stated by guidelines, data will be made available in the database of Genotype and Phenotype (dbGaP) http://www.ncbi.nlm.nih.gov/gap through controlled-access. This research involves individual-level human data. We expect to share both genotypes and phenotype data as well as additional information necessary to interpret such data, and we propose a data sharing plan that complies with NIH guidelines for NIH-funded studies (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html) and the new NIH Genomic Data Sharing (GDS) Policy's scope (http://gds.nih.gov/03policy2.html).
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University of Puerto Rico