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Warfarin sensitivity - Considerations

Considerations based on your test result.

 Despite its widespread clinical use, warfarin (Coumadin®) dosing has remained problematic. It has a narrow therapeutic range, and dosing of warfarin needs to be carefully adjusted to be both safe and effective. Too much can cause adverse bleeding events while insufficient dosing leaves patients at risk of thrombosis, both of which may be fatal. 

 If you are taking or planning to take warfarin, your physician will have your blood clotting time checked. This involves drawing and testing a sample of blood for prothrombin clotting time, which is expressed as international normalized ratio (INR). Typically, an INR of 2.0-3.0 is desired, and your physician will adjust your warfarin dose up or down to keep the INR in this range. 
 
There is considerable variability in response to warfarin, and different people require different doses to achieve the desired INR. A number of factors affect variability in response to warfarin. These include age, height, weight, sex, ethnicity and other concomitant medications.  These factors are usually considered by the physician when starting a patient on warfarin. 
 
However, it is now known that about 40-50% of the variability in response to warfarin is genetic. This prompted the U.S. Food and Drug Administration (FDA) in 2007 to add a black box warning to the label alerting physicians to the genetic effects on warfarin response 1. In 2010, the FDA issued an additional label change to include the expected stable maintenance dose based on CYP2C9 and VKORC1genotype 2. The Genomic Express Warfarin Sensitivity genetic test will provide precisely this genotype information for you. Your physician can then utilize this information to more safely prescribe your warfarin treatment.
 
The AEI Brookings Institute concluded that if this patient genotype information was routinely utilized in warfarin dosing, it would prevent 85,000 serious bleeding events and 15,000 strokes per year 3. It was further estimated that the healthcare cost savings would be $1.1 billion.
 
Now, with genetic testing, you have a new tool to make warfarin dosing safer, less costly and provide more effective anti-thrombotic therapy. Ask your doctor today about genetic testing for warfarin sensitivity. Start your treatment utilizing all the information available in order to be both safe and effective.
  
3  Andrew McWilliam, Randall Lutter, Clark Nardinelli. Health care savings from personalized medicine using genetic testing: the case of warfarin. Working Paper 06-23, AEI-Brookings Joint Center for Regulatory Studies. 2006 [cited 2008 Nov 21].
 

 

Warfarin (Coumadin) Sensitivity - Information

Information this test provides.    

People at increased risk of forming blood clots may be prescribed warfarin, which is most commonly marketed under the tradename Coumadin® .  This can prevent serious health problems such as myocaridial infarction (heart attack) and stroke, both of which may be fatal.  While there are well established medical benefits for prescribing warfarin to certain patients, there are also potential adverse reaction to the drug, the most serious being hemorrhage (bleeding) which can be fatal.  It has historically been difficult for physicians to adjust warfarin dosages to maintain efficacy (anti-thrombotic effect) while minimizing side effects (hemorrhage).  Standard practice has been to periodically measure prothrombin clotting times (PT/INR) and adjust the dose of warfarin as needed. 

It is now known that genetic variants in each patient affect the dose of warfarin which will yield optimal medical benefit with reduced risk of side effects for that individual.  Approximately 40-50% of the variability in warfarin response is genetic.  In January, 2010, the U.S. Food and Drug Administration (FDA) updated the warfarin label to provide information on these genetic variants, and to recommend that physicians use a patient's genetic test results to select a starting dose of the drug.  The FDA also provided the expected stable maintenance dose of warfarin for patients, based on their genetic test results.  At this time, the FDA does not require that these genetic tests be performed prior to prescribing warfarin. 

 Warfarin sensitivity- basic panel                           

(not available at this time)

This genetic test determines whether the patients contain genetic variants that are known to increase sensitivity to warfarin.  These individuals may be prescribed lower doses of warfarin that will retain the desired therapeutic effects while minimizing the risk of hemorrhage.  The genetic variants tested for are:

  • CYP2C9  This gene encodes the cytochrome P-450 enzyme in the liver that is principally involved in elimination of warfarin.  The normally functioning gene product is referred to as *1.  Two genetic variants of CYP2C9, referrred to as *2 and *3, metabolize warfarin slower.  In individuals with one or both of these variants, warfarin is degraded slower and remains in their system longer.  Lower doses of warfarin are recommended for these patients. 
  • VKORC1  Warfarin inhibits blood clotting by interfering with the protein expressed by the VKORC1 gene.  Many people have a variation in this gene (-1639  G>A) that reduces the protein function even in the absence of warfarin.  Lower doses of warfarin are recommended for these patients. 

This genetic test will determine whether the patient has one or more of the above genetic variants.  Based on this genotype information, these individuals' physicians can prescribe doses of warfarin that retain clinical benefit while reducing the risk of adverse reactions.  The patient's expected stable maintenance dose, as reported by the FDA on the package insert, is included in the patient's test result report.  

 (not available at this time)

Additional warfarin sensitivity test information:

Additional pharmacogenetic information:

 

Pharmacogenetics: Tests by medication

The Clinical Pharmacogentics Implementation Consortium (CPIC) is an international, non-profit group of scientific and medical researchers. The CPIC creates, and periodically updates, standardized guidelines for prescribing medications based on the patient's genetics. The guidelines are based on peer reviewed research publications, evidence based, and are publically available (https://www.pharmgkb.org/cpic/pairs).

Genomic Express offers the following pharmacogentic tests.  This testing is recommended by current CPIC guidelines, and provides actionable results for medication choice and dosing based on germline genetic variations.

  • Clopidogrel  (Plavix®)
  • Tamoxifen     (Nolvadex®, Istubal® and Valodex®)
  • Warfarin       (Coumadin®, Jantoven®, Marevan®, Lawarin®, Waran®, and Warfant®)

 Clopidogrel (Plavix®) response                           

(not available at this time)

Clopidogrel is an antiplatelet agent sold under the tradnames Plavix®, Iscover®, Clopilet® and Ceruvin® .  It prevents the formation of platelets, and is prescribed to reduce the chance of blood clot formation in several clinical contexts.  Over 100 million prescriptions for clopidogrel have been written since its introduction in 2000.  It is now known that some individuals have diminished or no response to clopidogrel due to genetic variations.

This test determines whether the patient has a genetic variant that that causes them to be a poor metabolizer or non-matabolizer of clopidogrel.  Clopidogrel has diminished or no effect in these individuals.  Based on the results of this genetic test, their physician may adjust their dosage or choose other treatment regimes. 

Additional information on clopidogrel response test           

  Tamoxifen (Nolvadex®) response          

(not available at this time)

Tamoxifen is an antagonist of the estrogen receptor in breast tissue, and is marketed under the tradenames Nolvadex®, Istubal® and Valodex®.  .  It is prescribed as an adjuvant treatment for estrogen receptor (ER) positive breast cancer in pre-menopausal women.  Tamoxifen has been used for more than 30 years, and is also prescribed for other indications.  It is known that some individuals do not respond to tamoxifen due to genetic variations.  These individuals do not derive the intended benefit of tamoxifen, and are unnecessarily exposed to potential side effects.

This test determines whether the patient has a genetic variant that causes them to be a poor metabolizer or non-matabolizer of tamoxifen.  Tamoxifen is less effective or not effective in these individuals, and it is recommended that their physician choose other types of adjuvant treatment. 

Additional information on tamoxifen response test  

 Warfarin (Coumadin®) sensitivity                    

(not available at this time)

Warfarin is an anticoagulant which is prescribed to reduce the risk of blood clots in a variety clinical settings.  Warfarin is marketed under the tradenames Coumadin®, Jantoven®, Marevan®, Lawarin®, Waran®, and Warfant®.   Warfarin is sometimes referred to as a "blood thinner", and is the most widely prescribed anticoagulant drug in North America. Nearly 30 million people in the United States take warfarin daily, and there approximately 800,000 new prescriptions per year. 

Individuals metabolize and respond to warfarin differently.  This genetic test can be used by their physician to adjust their dose to achieve optimal efficacy with reduced risk of side effects.              

Additional information on warfarin sensitivity test:

 

Additional pharmacogenetics information:

 

Warfarin (Coumadin) sensitivity- Medical Indications

 Warfarin (Coumadin®) sensitivity        

(not available at this time)
  • Medical Indications:  Warfarin is indicated for the prevention and/or treatment of venous thrombosis and pulmonary embolism.  It is prescribed for the prevention of complications associated with atrial fibrillation and/or cardiac valve replacement.  Warfarin is prescribed to reduce the risk of death, recurrent myocaridial infarction and associated thromboembolic events such as stroke.
  • Mechanism of action:  Warfarin inhibits vitamin K epoxide reductase (encoded by the VKORC1 gene), thus reducing vitamin K recycling.  This inhibition leads to a reduction in blood clotting.
  • Adverse reactions:   The most serious side effect of warfarin is hemorrhage (bleeding), which may be fatal.  It is very important to properly adjust warfarin dose, since people metabolize the drug differently.  Individuals may be normal, intermediate or poor metabolizers of warfarin.  Patients should have routine blood draws to measure prothrombin (PT) clotting time, which is reported in International Units (INR).  Physicians use these periodic tests to adjust the individual's warfarin dosage.   
  • Pharmacogenetics:  Warfarin is the active drug, and the elimination of warfarin is almost entirely by metabolism.  It is metabolized by liver cytochrome P-450 enzymes and excreted in the urine and bile duct.  The hepatic P-450 enzyme principally involved in warfarin metabolism is encoded by the CYP2C9 gene.  As much as 50% of the general poplulation may have one or more genetic variants of CYP2C9 that reduce the efficiency of warfarin metabolism.  Warfarin efficacy can be achieved in these individuals at lower doses, which will also reduce the risk of adverse reactions.  There is also a genetic variant of the VKORC1 gene that reduces its function in the absence of warfarin.  These individuals may also be maintained on lower doses of warfarin to achieve efficacy with reduced side effects. 
(not available at this time)

Additional information on warfarin sensitivity test:

 

Additional pharmacogenetics information:

 

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