A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics

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.

Inclusion Criteria:

- Caribbean Hispanic origin (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are
Caribbean Hispanics as well

- Age ≥ 21 years and ≤90 years.

- Willingness and ability to sign informed consent.

- Able to be followed up over 3 months.

- Expected duration of warfarin therapy of at least 3 months.

- Anticoagulation management for the patient will be performed in-hospital and/or as an
outpatient by clinicians (i.e., participating Physicians, PharmD) that will adhere to
the study dosing algorithms and dose-titration plans.

Exclusion Criteria:

- Non-Hispanic patients (race/ethnicity is self-reported by the patients)

- Age <21 years and >90 years.

- Currently taking warfarin or any other new oral anticoagulant (e.g., Xarelto, Pradaxa,
Eliquis, and Savaysa/Lixiana).

- Prior warfarin therapy with known required stable dose.

- Clinician opinion that warfarin dosing needs to be adjusted for reasons not accounted
for by dosing algorithm (i.e., other than age, gender, body size, co-meds,
comorbidities, diet, genetics, ancestry, INRs and target INR).

- Abnormal baseline INR (off warfarin), e.g., due to liver disease, antiphospholipid
antibody

- Contraindication to warfarin treatment for at least 3 months.

- Life expectancy of less than 1 year.

- Pregnant women or childbearing women not using medically approved method of birth
control.

- Inability to follow-up on a regular basis with anticoagulation practitioners
participating in trial.

- Any factors likely to limit adherence to warfarin, (e.g., dementia, alcohol or
substance abuse, plans to move in the next 3 months, history of unreliability in
medication taking or appointment keeping, significant concerns about participation in
the study from spouse, significant other, or family members, lack of support from
primary health care provider).

- Sickle cell, HIV-positive/ AIDS patients

- Cognitive or other causes of inability to provide informed consent or follow study
procedures.

- Participating in another trial that prohibits participation in the current trial or
planned enrollment in such a trial within the first 3 months of warfarin therapy.

- Anemia: a reduction in Hg ≥2g/dl within 48 hours before randomization and requiring
blood transfusions.

- Creatinine Clearance (CrCL) ≤ 15 mL/min.

- Genotype (CYP2C9 or VKORC1) known to participant from prior testing.