Genetic Response to Warfarin in Healthy Subjects
Condition: Healthy
Study type: Interventional

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.
    

Intervention name(s): Warfarin
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): anticoagulant; Coumadin
Intervention MeSH terms: Warfarin; Anticoagulants
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Genetic Determinants of Warfarin Dose Variability