Pharmacogenetics of Warfarin in Puerto Ricans.

NCT ID: NCT01318057

Last Updated: 2015-01-21

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 350 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2011-02-28
• Study Completion Date: 2014-07-31

Brief Summary

Warfarin (Coumadin) is a prescribed "blood thinner" medication used to make the blood less thick in people with high risk of forming blood clots. Despite the various methods to monitor this drug, life-threatening bleeding is a common undesired effect and might result in patient death. Patients starting warfarin therapy may require several weeks or even months to reach the appropriate blood level of warfarin. This blind practice could place the patient at high risk. There are several demographic and clinical factors that significantly influence how much warfarin the patient needs to attain the desired response. Genes, which control hereditary traits, are also important. Now, the investigators know that by using the information encoded in patient's genes the investigators are able to individualize the therapy. Two genes are considered to be involved in warfarin response (CYP2C9 and VKORC1). This study proposes to ascertain what CYP2C9 and VKORC1 variants are present in warfarin-treated Puerto Rican patients. To this purpose, a novel physiogenomic array comprising 384 variants in 222 genes of cardio-metabolic relevance will be used so the investigators are able to determine the structure of the Puerto Rican population in terms of ancestral contributions and how the admixture may impact the prevalence of CYP2C9 and VKORC1 variants. Secondly, the investigators will assess the association of these variants to clinical responses in order to develop a better method of dose estimation. The expected result is the improvement of warfarin therapy in Puerto Ricans. The proposed study will fill a gap in the knowledge of warfarin pharmacogenetics, providing new information on the prevalence of CYP2C9 (metabolism) and VKORC1 (sensitivity) polymorphisms in Puerto Ricans as well as their role in the warfarin response variability observed in this admixed population.

Detailed Description

Warfarin is a frequently prescribed drug for both the treatment and prevention of thromboembolic complications. Although many reports have been published over the past years in different populations worldwide, there is a fundamental gap in understanding whether variations in CYP2C9 and VKORC1 genes account for the inter-individual variability in response to warfarin that is observed in Puerto Rican patients. This study is a first step toward the development of DNA-driven personalized guidelines for warfarin dose optimization in Puerto Rican patients with thromboembolic complications. Guided by strong preliminary data, this application will pursuit two specific aims: 1) Develop a physiogenomic (PG)-driven admixture analysis of 350 samples from a population of warfarin-treated Puerto Rican patients using the PG array in order to study the pharmacogenetics of warfarin in Puerto Ricans and 2) Determine whether combinatorial CYP2C9 and VKORC1 genotypes are associated with clinical phenotypes during warfarin therapy in Puerto Rican patients. Under the first aim, 350 DNA specimens from warfarin-treated Puerto Rican patients who consent to participate in this study will be genotyped at large-scale using a novel Illumina-based PG-array of 222 candidate genes from relevant cardio-metabolic and neuro-endocrine pathways in order to examine the population structure of Puerto Ricans and create a reference database of individual admixture, allele frequencies, linkage disequilibrium (LD) and haplotypes for pharmacogenetics studies. Noteworthy, this information remains to be determined in Puerto Ricans. Under the second aim, demographic and clinically relevant non-genetic data will be retrospectively collected from medical records of these patients in order to perform an association analysis between their previously obtained CYP2C9 and VKORC1 genotypes and the corresponding time to achieve stable warfarin dosing following survival analysis techniques and Cox proportional hazards model. Accomplishment of this specific aim will also give the basis for developing a DNA-guided warfarin dosing algorithm in Puerto Rican by using these patients as a learning sample. The long-term goal is to generate valuable information from the genetic background of Puerto Ricans in order to further validate the pharmacogenetic-driven warfarin dosing algorithm for this admixed population. The proposed research is significant because it is expected to advance and expand understanding of how these clinically relevant variants affect the way people from an admixed, under-served population respond to warfarin. This is an important and under-investigated area of pharmacogenetics in minority populations that will have potential applicability to personalize warfarin therapy.

Conditions

Atrial Fibrillation; Deep Vein Thrombosis; Cardiac Valvular Insufficiency; Antiphospholipid Syndrome; Coagulopathy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Study Groups

Wild-Type

Wild-Type are those individuals who were non-carriers of any functional (loss-of-function)variant in CYP2C9 and/or VKORC1 genes

No interventions assigned to this group

Carriers

Those patients who were identified as having any functional CYP2C9 and/or VKORC1 polymorphism

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patients whose parents are both Puerto Ricans; male and female aged > 18 years old
• Scheduled to receive the standard 5 mg/day oral dose of warfarin for therapeutic anti-coagulation in indications such as deep vein thrombosis (DVT) with or without Pulmonary Embolism (PE)
• Atrial fibrillation (AF) or other arrhythmias, cardiac valvular replacement, and previously diagnosed coagulopathy
• Hematocrit (Hct) > 40%
• Blood Urea Nitrogen (BUN)/creatinine < 30/1.5 mg/dL
• Patients having the ability to understand the requirements of the study and to comply with study procedures and protocol
• Female patient is eligible to enter the study if she is of child-bearing potential but not pregnant or nursing, or not of child-bearing potential

Exclusion Criteria

• Patients currently enrolled in another active research protocol at the Veteran Affairs Caribbean Healthcare System (VACHS) Hospital
• Blood Urea Nitrogen (BUN)/creatinine > 30/2.0 mg/dL
• Active hepatic disease (defined by a Child-Pugh score above 10 points)
• Ascites
• Total bilirubin above 2.0 mg/dl
• Serum albumin below 3.5 g/dl
• Prothrombin time in seconds prolonged over control > 4
• Hepatic encephalopathy
• Prolonged diarrhea (three or more days)
• Nasogastric or enteral feedings
• Acute illness (e.g., sepsis, infection, anemia)
• Lymphocyte function test (LFT)> 3x upper limit of normal (ULN)
• Active malignancy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Hartford Hospital

OTHER

Sponsor Role: collaborator

VA Caribbean Healthcare System

FED

Sponsor Role: collaborator

University of Puerto Rico

OTHER

Sponsor Role: lead

Responsible Party

Jorge Duconge

PhD, MSc, BSc Pharm, Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Giselle T Rivera-Miranda, PharmD

Role: PRINCIPAL_INVESTIGATOR

VACHS at San Juan

Jorge Duconge, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Puerto Rico

Locations

Veteran Affair Caribbean Healthcare System

San Juan, , Puerto Rico

Countries

Puerto Rico

References

Villagra D, Duconge J, Windemuth A, Cadilla CL, Kocherla M, Gorowski K, Bogaard K, Renta JY, Cruz IA, Mirabal S, Seip RL, Ruano G. CYP2C9 and VKORC1 genotypes in Puerto Ricans: A case for admixture-matching in clinical pharmacogenetic studies. Clin Chim Acta. 2010 Sep 6;411(17-18):1306-11. doi: 10.1016/j.cca.2010.05.021. Epub 2010 May 19.

Reference Type: BACKGROUND

PMID: 20488169 (View on PubMed)

Seip RL, Duconge J, Ruano G. Implementing genotype-guided antithrombotic therapy. Future Cardiol. 2010 May;6(3):409-24. doi: 10.2217/fca.10.6.

Reference Type: BACKGROUND

PMID: 20462345 (View on PubMed)

Duconge J, Cadilla CL, Windemuth A, Kocherla M, Gorowski K, Seip RL, Bogaard K, Renta JY, Piovanetti P, D'Agostino D, Santiago-Borrero PJ, Ruano G. For the patient. DNA makeup of Hispanic persons should be determined before warfarin prescription. Ethn Dis. 2009 Autumn;19(4):479-80. No abstract available.

Reference Type: BACKGROUND

PMID: 20077595 (View on PubMed)

Duconge J, Cadilla CL, Windemuth A, Kocherla M, Gorowski K, Seip RL, Bogaard K, Renta JY, Piovanetti P, D'Agostino D, Santiago-Borrero PJ, Ruano G. Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics. Ethn Dis. 2009 Autumn;19(4):390-5.

Reference Type: BACKGROUND

PMID: 20073138 (View on PubMed)

Ruano G, Duconge J, Windemuth A, Cadilla CL, Kocherla M, Villagra D, Renta J, Holford T, Santiago-Borrero PJ. Physiogenomic analysis of the Puerto Rican population. Pharmacogenomics. 2009 Apr;10(4):565-77. doi: 10.2217/pgs.09.5.

Reference Type: BACKGROUND

PMID: 19374515 (View on PubMed)

Rodriguez-Velez R, Ortiz-Rivera OJ, Bower B, Gorowski K, Windemuth A, Villagra D, Kocherla M, Seip RL, D'Agostino D, Vergara C, Ruano G, Duconge J. Exposure to non-therapeutic INR in a high risk cardiovascular patient: potential hazard reduction with genotype-guided warfarin (Coumadin) dosing. P R Health Sci J. 2010 Dec;29(4):402-8.

Reference Type: BACKGROUND

PMID: 21261182 (View on PubMed)

Duconge J, Ruano G. The Emerging Role of Admixture in the Pharmacogenetics of Puerto Rican Hispanics. J Pharmacogenomics Pharmacoproteomics. 2010 Oct 4;1(101):1000101. doi: 10.4172/2153-0645.1000101.

Reference Type: BACKGROUND

PMID: 23227441 (View on PubMed)

Duconge J, Cadilla CL. CYP2D6's functional status associated with the length of hospitalization stay in psychiatric patients: a twist in the tale or evidence that matters? Biomark Med. 2013 Dec;7(6):913-4. doi: 10.2217/bmm.13.109. No abstract available.

Reference Type: BACKGROUND

PMID: 24266824 (View on PubMed)

Ramos AS, Seip RL, Rivera-Miranda G, Felici-Giovanini ME, Garcia-Berdecia R, Alejandro-Cowan Y, Kocherla M, Cruz I, Feliu JF, Cadilla CL, Renta JY, Gorowski K, Vergara C, Ruano G, Duconge J. Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients. Pharmacogenomics. 2012 Dec;13(16):1937-50. doi: 10.2217/pgs.12.171.

Reference Type: RESULT

PMID: 23215886 (View on PubMed)

Valentin II, Vazquez J, Rivera-Miranda G, Seip RL, Velez M, Kocherla M, Bogaard K, Cruz-Gonzalez I, Cadilla CL, Renta JY, Feliu JF, Ramos AS, Alejandro-Cowan Y, Gorowski K, Ruano G, Duconge J. Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. Ann Pharmacother. 2012 Feb;46(2):208-18. doi: 10.1345/aph.1Q190. Epub 2012 Jan 24.

Reference Type: RESULT

PMID: 22274142 (View on PubMed)

Orengo-Mercado C, Nieves B, Lopez L, Valles-Ortiz N, Renta JY, Santiago-Borrero PJ, Cadilla CL, Duconge J. Frequencies of Functional Polymorphisms in Three Pharmacokinetic Genes of Clinical Interest within the Admixed Puerto Rican Population. J Pharmacogenomics Pharmacoproteomics. 2013 Mar 27;4(113):1000113. doi: 10.4172/2153-0645.1000113.

Reference Type: RESULT

PMID: 24040574 (View on PubMed)

Valentin II, Rivera G, Nieves-Plaza M, Cruz I, Renta JY, Cadilla CL, Feliu JF, Seip RL, Ruano G, Duconge J. Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans. P R Health Sci J. 2014 Sep;33(3):97-104.

Reference Type: RESULT

PMID: 25244877 (View on PubMed)

Duconge J, Ramos AS, Claudio-Campos K, Rivera-Miranda G, Bermudez-Bosch L, Renta JY, Cadilla CL, Cruz I, Feliu JF, Vergara C, Ruano G. A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics. PLoS One. 2016 Jan 8;11(1):e0145480. doi: 10.1371/journal.pone.0145480. eCollection 2016.

Reference Type: DERIVED

PMID: 26745506 (View on PubMed)

Other Identifiers

SC2HL110393

Identifier Type: NIH

Identifier Source: secondary_id

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1SC2HL110393-01A2

Identifier Type: NIH

Identifier Source: org_study_id

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