Pharmacogenetics of Warfarin in Puerto Ricans.

NCT01318057 | Completed DMC

• 2 other identifiers: 1SC2HL110393-01A2SC2HL110393
• Study Type: observational
• Target: 350
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Pharmacogenetics; Warfarin; Personalized Medicine; Puerto Ricans; Physiogenomics; Hispanics; Anticoagulants; Cardiovascular; Deep Vein Thrombosis with or without Pulmonary Embolism; Cardiac Valvular Replacement

Outcome Measures

Primary Outcomes (1)

• time to achieve stable warfarin dose

  time to get a stable warfarin dose is defined by the time span (days) from the initial dose until achieving three consecutive INR measurements within therapeutic range (2-3 or 2.5-3.5, according to indication.

  6 months

Secondary Outcomes (2)

• time to first bleeding

  6 months

• time to first INR>4

  6 months

Study Arms (2)

Wild-Type

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

Carriers

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

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Hispanic Puerto Rican patients from all geographic regions of the Island of Puerto Rico who are currently receiving a standard stable dose of warfarin at the anticoagulation clinic of the Veteran Affair Caribbean Healthcare System (VACHS)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Puerto Rico: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Hartford Hospital: collaborator
• VA Caribbean Healthcare System: collaborator

Study Sites (1)

Veteran Affair Caribbean Healthcare System

San Juan, 00921, Puerto Rico

Location

Related Publications (13)

• 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.

  PMID: 20488169 BACKGROUND

• 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.

  PMID: 20462345 BACKGROUND

• 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.

  PMID: 20077595 BACKGROUND

• 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.

  PMID: 20073138 BACKGROUND

• 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.

  PMID: 19374515 BACKGROUND

• 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.

  PMID: 21261182 BACKGROUND

• 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.

  PMID: 23227441 BACKGROUND

• 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.

  PMID: 24266824 BACKGROUND

• 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.

  PMID: 23215886 RESULT

• 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.

  PMID: 22274142 RESULT

• 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.

  PMID: 24040574 RESULT

• 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.

  PMID: 25244877 RESULT

• 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.

  PMID: 26745506 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Whole fresh blood and Genomic DNA samples fom enrolled patients

MeSH Terms

Conditions

Atrial Fibrillation; Venous Thrombosis; Antiphospholipid Syndrome; Hemostatic Disorders

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Thrombosis; Embolism and Thrombosis; Vascular Diseases; Autoimmune Diseases; Immune System Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Giselle T Rivera-Miranda, PharmD

  VACHS at San Juan

  PRINCIPAL INVESTIGATOR

• Jorge Duconge, PhD

  University of Puerto Rico

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD, MSc, BSc Pharm, Professor

Study Record Dates

• First Submitted: March 17, 2011
• First Posted: March 18, 2011
• Study Start: February 1, 2011
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: January 21, 2015

Record last verified: 2015-01

Locations

PR (1)