Improving Anticoagulant Therapy Through Warfarin Metabolite Profiling

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01964794
Recruitment Status : Completed
First Posted : October 17, 2013
Last Update Posted : October 7, 2016
Central Arkansas Veterans Healthcare System
Information provided by (Responsible Party):
University of Arkansas

Brief Summary:
Clinically relevant biomarkers for warfarin identified in this study will provide crucial leads for subsequent studies to assess their predictive value during anticoagulant therapy. This knowledge will aid stratifying risk among patients to improve therapeutic outcomes and decrease adverse drug events and associated health care costs. Collectively, these efforts will provide a critical foundation for future research using a metabolite biomarker strategy in a clinical setting to revolutionize warfarin therapy. Through its application, a real−time assessment of warfarin metabolism for each patient could lead to a truly personalized dosing strategy and improve patient safety for this life−saving drug.

Condition or disease
Stable Target INR

Detailed Description:

Coumadin (R/S-warfarin) is a commonly prescribed anticoagulant for over 20 million Americans for the treatment of atrial fibrillation, mechanical heart valves, venous thromboembolism and other coagulopathies. While highly efficacious, warfarin treatment is challenging due to a narrow therapeutic range and high inter-individual variations in response. Optimal warfarin dosage relies on a potentially lengthy trial-and-error process to optimize dosage for a desired anticoagulant response as measured by the international normalization ratio (INR), a prothrombin test. Even when a maintenance dose is achieved, patients are prone to testing out of the target INR range, and thus are at risk of hemorrhaging (over-dosing) or thromboembolism (under-dosing). In fact, warfarin is among the top ten drug-related causes of serious adverse drug events and increased health care costs. The progressive increase in warfarin use necessitates a better understanding of the mechanisms underlying inter-individual variability in responses to anticoagulant therapy. Our long-term goal is to identify metabolic biomarkers correlating with clinical responses to warfarin therapy and then utilize this knowledge to predict safe and effective dosing for patients based on a single blood draw.

Therapeutic outcomes for patients involve a balance between warfarin dosing and its metabolism to maintain a stable target INR. There is an initial lengthy titration stage in which dosing is increased to achieve but not surpass a target INR range. The potency of this effect depends on warfarin metabolism, which counters the dosing effect on patients by inactivating the drug. Warfarin undergoes extensive metabolism through distinct enantio- and regio-specific metabolic pathways to yield a complex array of essentially inactive isomeric metabolites. Warfarin is clinically available as an equal mixture of R and S enantiomers. S-Warfarin is about four times more potent than R-warfarin, and presumably dominates the anticoagulant response to therapy. During maintenance dosing, a longer metabolic half-life for R-warfarin leads to higher accumulation levels in plasma than those observed for S-warfarin. Variations in R-and S-warfarin plasma levels may potentiate the anticoagulant effect of both drug isomers and the corresponding responses to therapy. For our exploratory study, we will identify biomarkers within patient metabolic profiles for R-and S-warfarin that predict clinical outcomes for the patients.

Study Type : Observational
Actual Enrollment : 60 participants
Observational Model: Case-Only
Time Perspective: Cross-Sectional
Official Title: Improving Anticoagulant Therapy Through Warfarin Metabolite Profiling
Study Start Date : May 2012
Actual Primary Completion Date : October 2016
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners
U.S. FDA Resources

Primary Outcome Measures :
  1. Metabolite Profiling [ Time Frame: Up to 24 months ]
    Based on a single blood draw, identify metabolite biomarkers for achieving a stable target anticoagulant response among patients at a maintenance dose of warfarin.

Biospecimen Retention:   Samples With DNA
Blood specimens to identify coumadin genetic and metabolic biomarkers.

Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 69 Years   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Originally, for this pilot study, we chose a sample population size of 150 with a focus on veterans from the Korean War. Towards the end of recruitment the protocol was revised to remove the focus on veterans from just the Korean War.

Inclusion Criteria:

  1. Males aged 60 - 69 originally. Opened inclusion criteria age to include 18-79 years of age.
  2. Potential participant received a warfarin maintenance dose with a stable INR (defined as within target range over a two month (60 day) period that includes a minimum of two clinical visits).
  3. Potential participant has taken warfarin as prescribed over the past three days.

Exclusion Criteria:

  1. Female
  2. Potential participant receiving a warfarin while not achieving a stable INR (defined as within target range over a two month (60 day) period that includes a minimum of two clinical visits).
  3. Potential participant has not received any warfarin over the past three days.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01964794

United States, Arkansas
Central Arkansas Veterans Healthcare System
Little Rock, Arkansas, United States, 72205
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
Sponsors and Collaborators
University of Arkansas
Central Arkansas Veterans Healthcare System
Principal Investigator: Grover P Miller, PhD University of Arkansas
Principal Investigator: Eugene Smith, III, MD Dentral Arkansas Veterans Healthcare System

Responsible Party: University of Arkansas Identifier: NCT01964794     History of Changes
Other Study ID Numbers: 135288
First Posted: October 17, 2013    Key Record Dates
Last Update Posted: October 7, 2016
Last Verified: October 2016

Keywords provided by University of Arkansas:

Additional relevant MeSH terms: