Genetic Response to Warfarin in Healthy Subjects

NCT ID: NCT01520402

Last Updated: 2013-02-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2011-05-31

Brief Summary

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.

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.

Conditions

Healthy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Warfarin

Intervention Type: DRUG

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).

Interventions

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).

Intervention Type: DRUG

Other Intervention Names

anticoagulant; Coumadin

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: lead

Responsible Party

Jonathan L. Halperin

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jonathan L Halperin, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

Mount Sinai School of Medicine

New York, New York, United States

Countries

United States

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Other Identifiers

HSM # 11-00577

Identifier Type: -

Identifier Source: secondary_id

GCO 08-1442

Identifier Type: -

Identifier Source: org_study_id