• 
  

  Drug summary:

  
  
  
  
  • 
    

    Warfarin (Coumadin) is a commonly prescribed vitamin K antagonist for the prevention of thromboembolism. However, the drug has a very narrow therapeutic index and a large interindividual variability in response, in part due to inherited genetic variability within genes involved in warfarin pharmacokinetics and pharmacodynamics.

    
    
  • 
    

    Clinical indications for anticoagulation therapy include atrial fibrillation, mechanical heart valves, deep venous thrombosis, and dilated cardiomyopathies.

    
    
  • 
    

    Interindividual and interethnic variability in therapeutic warfarin dose requirements is responsible for frequent adverse drug reactions and underutilization due to its toxicity.

    
    
  • 
    

    Several factors affect warfarin dosage, including age, body weight, concomitant medications, and DNA sequence variants in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit 1 (VKORC1).

    
    
  • 
    

    Common variant CYP2C9 and VKORC1 alleles are associated with impaired warfarin metabolism and sensitivity to warfarin, respectively, both resulting in lower therapeutic dose requirements.

    
    
  • 
    

    Individuals with impaired warfarin metabolism and/or increased sensitivity require decreased dosage to avoid their international normalized ratio (INR) increasing beyond the target range (typically 2-3). Increased INR values can be associated with morbidity and mortality due to major bleeding episodes.

    
    
  • 
    

    Although many variant CYP2C9 and VKORC1 alleles are found in several major racial and ethnic groups, some are specific to various subpopulations.

    
    
  • 
    

    Pharmacogenetic dosing algorithms including both clinical and genetic variables have been developed that predict the therapeutic warfarin dose.

    
    
  • 
    

    Clinical testing for variant CYP2C9 and VKORC1 alleles is available and generalized FDA-approved dosing recommendations are now noted on the warfarin package insert.

  
  

• 
  

  Monogenic forms:

  
  
  
  
  • 
    

    Rare heterozygous coding region VKORC1 mutations cause warfarin resistance (OMIM #122700). These mutations make VKORC1 less susceptible to warfarin inhibition, and generally result in doses in excess of 80 mg/wk to maintain appropriate anticoagulation. Homozygosity for these rare mutations results in combined deficiency of vitamin K-dependent clotting factors type 2 (OMIM #607473), which is responsive to oral administration of vitamin K.

  
  

• 
  

  Family history or heritability:

  
  
  
  
  • 
    

    The genetic determinants of warfarin dose variability are inherited germline variants, not acquired mutations.

  
  

• 
  

  Environmental factors:

  
  
  
  
  • 
    

    Age, diet, gender, body size, comorbidities, and concomitant medications are other factors that influence warfarin dosing.

  
  

• 
  

  Genome-wide associations:

  
  
  
  
  • 
    

    To date, three genome-wide association studies (GWAS) primarily using Caucasian patients have confirmed previous CYP2C9 and VKORC1 candidate gene studies, and have identified a small role for cytochrome P450 4F2 (CYP4F2) in warfarin dose variability.

  
  

• 
  

  Pharmacogenomics:

  
  
  
  
  • 
    

    CYP2C9, VKORC1, and CYP4F2 have been estimated to account for approximately 10%, 25%, and 2.5% of the variability in warfarin dosing among individuals. Although the variant alleles of these genes may be less common in certain racial or ethnic groups, their effect on warfarin dose variability remains constant.

  
  

Warfarin is the most commonly used oral anticoagulant worldwide. Indications for warfarin therapy include the treatment and prevention of venous and arterial thromboembolism, including deep venous thrombosis, pulmonary embolus, atrial fibrillation, and mechanical heart valves. Treatment is often prolonged and the use of anticoagulants is steadily increasing with an aging population. For example, in the United States, approximately 2 million new patients start warfarin therapy every year. Despite a long history of clinical use, warfarin treatment remains very challenging due to its narrow therapeutic index and large interindividual variability in patient response.

Narrow Therapeutic Index

Although warfarin is highly efficacious at the appropriate level of anticoagulation, it is less effective when anticoagulation levels are too low, and there is a significant risk of major bleeding complications when levels are too high. The rates of major bleeding in practice are approximately 7% to 8% per year; however, even minor bleeding can lead to withdrawal of therapy and repeat clinic and/or emergency room visits. The best predictors of bleeding complications are the INR and the variability in anticoagulation control. The risk of over-anticoagulation, and therefore of bleeding risk, is highest during the dose-titration period of warfarin use. Thus, genotype-guided warfarin dosing could reduce the risk of major bleeding and discontinuation of an efficacious therapy. In contrast, the effectiveness of warfarin is substantially reduced by insufficient levels of anticoagulation. Specifically, the risk of thromboembolism increases dramatically as the INR falls below 2. In addition to these serious clinical concerns, patients who have out-of-range INR values must be reassessed, often requiring dosage changes, generating additional clinic visits, blood tests, and costs.

Interindividual Dosing Variability

Although the average maintenance warfarin dose is 4 to 6 mg/d, there is a very wide range of doses required to achieve the same INR among individuals, varying by as much as 20-fold. Despite this, warfarin initiation remains largely empirical, with the majority of patients started on 5 mg/d during the initiation phase of treatment. Daily doses subsequently are titrated by INR until stable therapeutic warfarin doses are determined, which typically requires time (weeks), regular INR testing, frequent dose changes, and patient compliance. Even with careful follow-up, over- and under-anticoagulation are common during the initiation phase, reflected in high monthly bleeding rates during the first weeks of treatment. Reductions in the time that patients are over- or under-anticoagulated have been associated with reductions in bleeding, thromboembolism, and healthcare costs. Given INR values continue to fluctuate even after therapeutic INRs are attained on stable warfarin doses, patients typically require intermittent INR testing throughout their treatment.

Pharmacogenetics

The response to warfarin is multifactorial. Patient, clinical, and environmental factors that influence warfarin dose requirements include adherence, age, gender, body size, treatment indication, diabetes mellitus, liver disease, malignancy, comedications, alcohol, and diet, among others. Importantly, recent evidence has indicated that a significant proportion of the variation in warfarin dose requirements can be attributed to common pharmacogenetic variation among genes involved in warfarin pharmacokinetics and pharmacodynamics, most notably CYP2C9 and VKORC1, respectively. Together, common single-nucleotide polymorphisms (SNPs) within CYP2C9 and VKORC1 account for approximately 35% of warfarin dosing variability and notable variants are listed in Table 6-1. The identification of variant CYP2C9 and VKORC1 alleles in association with warfarin dosing prompted the FDA-approved warfarin product insert revision noting the availability of clinical genetic testing with dosing recommendations, and the recent inclusion of CYP2C9 and VKORC1 genotypes into pharmacogenetic-based dosing algorithms.