Improving Anticoagulant Therapy Through Warfarin Metabolite Profiling
Condition: Stable Target INR
Study type: Observational

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.
    

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.
    

Observational model: Case-Only
Time perspective: Cross-Sectional
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.
      
Biospecimen description: 
      Blood specimens to identify coumadin genetic and metabolic biomarkers.
    
Keywords: Warfarin