Genetic Response to Warfarin in Healthy Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jonathan L. Halperin, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01520402
First received: January 18, 2012
Last updated: February 6, 2013
Last verified: February 2013
  Purpose

The purpose of this study is to determine the importance of genetic differences on individuals' response to warfarin in a group of healthy subjects. Warfarin is also known by the "trade name" Coumadin and is in a class of medications called anticoagulants or "blood thinners." Warfarin works by reducing the blood's ability to make clots. It is used to stop blood clots from forming or growing larger in your blood and blood vessels. Warfarin is prescribed for many conditions, including for people with certain types of irregular heartbeat, people with replacement or mechanical heart valves, people who have suffered a heart attack, people who have had orthopedic surgery, or who have a history of having blood clots. Warfarin is used to prevent or treat deep vein thrombosis (swelling and blood clot in a vein), pulmonary embolism (a blood clot in the lung), and strokes (a blood clot in the brain). Researchers have found that certain genes may affect how a person's body will break down or react to warfarin. If genetic information can help doctors better determine the best dose of warfarin before it is first given, this may help the doctors get patients to the correct levels of blood thinning and thereby reduce the risk of bleeding or the risk of developing a blood clot. The expectation of this study is that this information will ultimately improve warfarin therapy while lessening the risks associated with dosing errors. This study is considered investigational because the subjects are healthy and not being prescribed warfarin for clinical care.


Condition Intervention
Healthy
Drug: Warfarin

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Quantitative Pharmacogenomics of the Anticoagulant Response to Warfarin in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype [ Time Frame: average of 2 - 13 days ] [ Designated as safety issue: No ]
    To assess the effect of genotype variants (CYP2C9 and VKORC1 -1639 G>A) on the anticoagulant response to warfarin, the primary outcome was the cumulative dose required to achieve an INR value in the usual clinical therapeutic range (>2.0) for two consecutive days.

  • Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) [ Time Frame: 2-30 days ] [ Designated as safety issue: No ]
    Subjects were also grouped into four categories based on CYP2C9 and VKORC1 genotype profile: Group 1 (CYP2C9 wild-type and VKORC1 wild-type), Group 2 (CYP2C9 wild-type and VKORC1 variant), Group 3 (CYP2C9 variant and VKORC1 wild-type), and Group 4 (CYP2C9 variant and VKORC1 variant). Median cumulative warfarin dose requirement was determined for each genotype category.


Secondary Outcome Measures:
  • Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status [ Time Frame: average of 2 - 30 days ] [ Designated as safety issue: No ]
    To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.

  • Explained Variation in Combined Therapeutic Warfarin Dose Models [ Time Frame: average of 2 - 30 days ] [ Designated as safety issue: No ]
    The proportion of variance (R^2) explained by each predictor was calculated using multivariate regression analysis and adjusted for age, gender and reported race, with outcome values logarithmically transformed. The study was powered to detect R^2 > 20%, and significance was accepted at p<0.05.


Enrollment: 35
Study Start Date: June 2009
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Warfarin
Healthy subjects age 18-74 with no medical indication for warfarin therapy, who are free of medications and co-morbid medical conditions with the potential to interfere with warfarin metabolism, and who are willing to follow a fixed vitamin K diet (men 120 micrograms/day, women 90 micrograms/day) are included.
Drug: Warfarin
Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin).
Other Names:
  • anticoagulant
  • Coumadin

Detailed Description:

Warfarin is a highly effective oral anticoagulant that is increasingly prescribed in the United States. It has a narrow therapeutic window, however, that represents an inherent limitation, such that insufficient and excessive levels of anticoagulation are associated with elevated risks of thrombosis and bleeding particularly frequent early in the initial dose-finding phase of therapy. Typically, anticoagulation is achieved through empiric dosing and titration with consideration of certain variables and frequent assessment of the international normalized ratio (INR). Despite these precautions, conventional dosing strategies are associated with therapeutic levels of anticoagulation only about half the time on treatment. Recently, genetic variants, specifically variations in the CYP2C9 and VKORC1 genes, have been identified that affect warfarin dose requirements, prompting the expectation that gene-based dosing strategies may maximize therapeutic efficacy while minimizing the risks associated with dosing errors. While the association between variation in these genes and differences in warfarin dose requirements has been identified, the specific contribution of allelic variation to the response to warfarin administration has not been thoroughly identified. The investigators therefore seek to assess the impact of allelic variation on warfarin dose-response relationships in a group of healthy subjects. The investigators hypothesize that genetic variation in the CYP2C9 and VKORC1 enzymes will result in differences in the warfarin dose-response relationships when accounting for non-genetic factors that can affect the pharmacokinetics of warfarin and its effect on coagulation.

  Eligibility

Ages Eligible for Study:   18 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy adult (> 18 years old.) subjects not taking warfarin
  • Willing and able to grant written informed consent
  • Available in proximity to the Medical Center for the anticipated duration of data collection (approximately 3 weeks).
  • Pre-menopausal women required negative pregnancy test at study onset and willingness to abstain from sexual activity or use barrier contraception; oral contraceptives interfere with coumadin.

Exclusion Criteria:

  • Daily prescribed medications including (1) a medication known to interact with warfarin, based on interactions listed in Micromedex as moderate or severe, and probable or definite (as of study start date, Appendix A) (2) aspirin or clopidogrel, which may increase bleeding risk in combination with warfarin.
  • Recent therapy (within two weeks) with a medication known to interact with warfarin based on medication interactions listed in Micromedex
  • History of thrombotic disorder requiring anticoagulant therapy
  • Thrombophilia or coagulopathy, by history or screening coagulation profile with INR or PTT level > 2x the upper limit of normal
  • Family history of thrombophilia or coagulopathy; prisoners or wards of the state; scheduled elective surgery within one month
  • Active liver disease based on clinical history or serum transaminase levels > 2x the upper limit of normal
  • Protein C or S Deficiency assessed on screening protein C and S activity profile
  • Age ≥ 75
  • Pre-menopausal women on oral contraception
  • Non-English speaking individuals
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01520402

Locations
United States, New York
Mount Sinai School of Medicine
New York, New York, United States, 10029
Sponsors and Collaborators
Mount Sinai School of Medicine
Investigators
Principal Investigator: Jonathan L Halperin, MD Mount Sinai School of Medicine
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jonathan L. Halperin, Principal Investigator, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01520402     History of Changes
Other Study ID Numbers: GCO 08-1442, HSM # 11-00577
Study First Received: January 18, 2012
Results First Received: October 24, 2012
Last Updated: February 6, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Mount Sinai School of Medicine:
Genetic Determinants of Warfarin Dose Variability

Additional relevant MeSH terms:
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 01, 2014