Click here to see the Web Seminar - Coumadin (warfarin) Genetics

News - FDA Approves Updated Warfarin (Coumadin) Prescribing Information

NPR story "Genetic Testing Can Help with Drug Dosages"

Every day millions of people take warfarin or Coumadin, powerful drugs used to control life threatening conditions. How much of these medicines people need is difficult to determine and often it takes several months of weekly clinic visits and blood tests.

According to the FDA, hemorrhage during warfarin therapy is a leading cause of death in Western countries and related adverse events account for 1 in 10 hospital admissions. Click here to see the FDA slides.

Thankfully, recent discoveries in DNA research make predicting the dose of warfarin a person needs much more accurate, and of equal importance, how long it takes them to eliminate the drug. More than half the population have variations in at least one of the two genes that are tested. These genetic variations are responsible for almost half of the individual variation seen in warfarin dose.

Order this pair of DNA tests, now available from Genelex, and help your doctor help you to reach your target dosage and INR (a measurement of your blood clotting levels) faster and safer.

Here's what a blue ribbon FDA advisory panel has to say about the genetics of warfarin/Coumadin:

• Use lower doses of warfarin for patients with genetic variations in CYP2C9 and or VKORC1 that lead to reduced activities.
  
  
• Genotyping patients at the begining of warfarin therapy would reduce adverse events and improve achievement of stable INR.
  
  
• Existing evidence of the influence of CYP2C9 and VKORC1 genotypes warrants re-labeling of warfarin to include genetic test information.

The FDA and others are sponsoring clinical trials to prove the extent to which using DNA testing will reduce adverse bleeding events and save money. Many scientists believe that the use of this testing will dramatically improve Warfarin efficacy and safety. In the meantime you can order these tests now, share the results with your doctor and know that you're taking advantage of the most recent scientific discoveries.

Genelex has available computer programs to help interpret the test results taking into account your size, age and other medicines that you may be taking. Call Genelex today at 800-523-3080 to order testing for yourself or someone you care for, order on-line, or download the order form and fax or mail in your order. Cost for the two genes with 4-day turnaround is only $550 and is typically reimbursed by insurance.

Frequently Asked Questions

Do I need a prescription to order this testing?
No, a prescription is not needed.

How are patients currently managed on warfarin therapy?
Coumadin (warfarin) is the most commonly prescribed anticoagulant for the treatment and prevention of thromboembolic events. The dose of warfarin required to maintain a safe degree of anticoagulation ranges from 2 mg/day or lower for some individuals to 10 mg per day or higher for others. Patients who are not taking the dose that is right for them are at an increased risk for severe toxicity or an inadequate response.

Currently, clinicians anticipate maintenance dose requirements based on the patients physical characteristics such as age, gender and weight and monitor the therapeutic effects closely by measuring the INR. However these physical characteristics do not account for the major sources of variation in dose requirement. Therefore the clinician must adjust the warfarin dosage when the INR is not within the safe range for anticoagulation. This can be a lengthy trial and error process where the patient is at increased risk until the most appropriate dosage for that patient is determined.

How does an individual’s genetic make-up effect how much warfarin should be administered?
In addition to the physical characteristics mentioned above, functional characteristics also influence the most appropriate dose of warfarin. The major functional characteristics which influence the warfarin dose are how rapidly the individual metabolizes warfarin and how much warfarin is required in the body to inhibit to formation of clotting factors. These characteristics can not be assessed without specific diagnostic testing.

The active component of warfarin is metabolized by cytochrome P450 2C9 (CYP2C9). Up to 35% of the population inherits a form of the CYP2C9 gene which results in a CYP2C9 enzyme deficiency. A deficiency in CYP2C9 causes slow metabolism and higher than expected concentrations of the active drug to accumulate. This increased warfarin concentration in the body increases the risk of bleeding.

Warfarin inhibits the formation of active clotting factors by inhibition of vitamin K epoxide reductase complex subunit 1 (VKORC1). Inherited differences in VKORC1 increase or decrease the amount of warfarin needed to inhibit the formation of the clotting factors. When the amount of warfarin exceeds what is needed, the risk of bleeding is increased.

How can this information be applied?
The difference in warfarin dose that is affected by the patient’s metabolism or the amount of drug needed for effect do not become apparent until the four to fifth day of therapy (Peyvandi F et al. Clin Pharm Ther 2004;75:198-203). Therefore, standard approaches to initiating treatment do not need to be postponed. A sample of blood can be collected for determination of CYP2C9 and VKORC1 status on the first day of therapy. Preferably the results of testing should be applied to dose selection on or shortly after the fifth day of therapy.

What is the scientific community saying about these services?
In November of 2005, the clinical pharmacology advisory committee reporting to the FDA reviewed the current literature surrounding the application of CYP2C9 and VKORC1 testing to treatment of patients with warfarin. At that meeting, the committee unanimously agreed that “…sufficient mechanistic and clinical evidence exists to support the recommendation: to use lower doses of warfarin for patients with genetic variations in CYP2C9 and or VKORC1 that lead to reduced activities”. And genotyping patients in the induction phase of warfarin therapy would reduce adverse events and improve achievement of stable INR? Eight out of ten committee members agreed “…that existing evidence of the influence of CYP2C9 and VKORC1 genotypes warrants re-labeling of warfarin to include genomic and test information."

Based on official meeting transcripts which can be found at: http://www.fda.gov/ohrms/dockets/ac/cder05.html#PharmScience

Is this testing likely to be cost effective?
There is a high likelihood that this testing will improve patient safety while providing significant savings to the healthcare system. Recent reports indicate that 70 to 100 severe bleeding events occur each year for every 1000 patients treated with warfarin (Higashi et al. JAMA 2002;287:1690-98; Margaglione M et al. Thromb Haemost 2000;84:775-8). Each of these events can result in an average hospital stay of 6 days and average healthcare costs of $16,000.00 for each event (Fanikos J et al Am J Cardiology 2005;96:595-8). PGXL charges $35.00 to process the sample, $ 266.00 for each CYP2C9 and VKORC1 test thus the total cost of testing is $ 567.00. If we apply this to a patient population of 1000 patients treated for a year, cost effectiveness will be achieved if 33 to 47% of the anticipated number of bleeding events are avoided. Any events avoided beyond this will have obvious positive benefits for the patient and directly reduce the financial burden on the healthcare system.

Are these laboratory services covered by health insurance?
This year, the American Medical Association (AMA) recommended to the Centers for Medicare & Medicaid Services (CMS) to establish CPT codes and reimbursement schedules which can be applied to pharmacogenetic diagnostics. The appropriate coding is dependent upon the technology used by the laboratory. The anticipated reimbursement is 70% of the total charge. Private insurance companies such as Anthem, Humana and others (By Lisa Barrett Mann, Special to The Washington Post, Tuesday, April 18, 2006; Page HE01) have covered costs for testing for the majority of our clients who submitted for coverage.

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