Genetic Response to Warfarin in Healthy Subjects

Not Applicable

Completed

Conditions: Healthy

Interventions: Drug: Warfarin

Registration Number: NCT01520402

Lead Sponsor: Icahn School of Medicine at Mount Sinai

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Warfarin	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.

Primary Outcome Measures

Name	Time	Method
Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype	average of 2 - 13 days	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)	2-30 days	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

Name	Time	Method
Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status	average of 2 - 30 days	To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.
Explained Variation in Combined Therapeutic Warfarin Dose Models	average of 2 - 30 days	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.