Gene Testing Helps Get Warfarin [Coumadin] Dose Right

March 21, 2010 – Doctors are reporting an exciting win for gene testing and personalized medicine: Checking patients’ DNA before starting them on a popular blood thinner helps get the tricky dose right and keep them out of the hospital.

The drug is warfarin, sold as Coumadin and in generic form as Warfarin. About 2 million Americans start on it each year to prevent blood clots after surgery or for other medical conditions. However, the world’s most common blood thinner is also one of its most dangerous drugs. One person’s ideal dose can be 10 times that of another’s. Even certain foods can throw dosing seriously off. Too much warfarin can lead to bleeding, too little can lead to clots, and either one can kill. Up to 20 percent of patients wind up in the hospital in their first six months on the drug.

Several companies sell tests for the two genes, CYP2C9 and VKORC, respectively, that control how warfarin is metabolized and binds to its receptor. But doctors wonder: Is it worth a $250-to-$400 test to guide the dose of a drug that costs less than $6 a month? A new study, presented Tuesday at an American College of Cardiology conference, suggests it is. Patients given gene tests to set their initial warfarin dose had about a 30 percent lower risk of being hospitalized than similar patients whose doses were set by trial and error.

“If we reduce just two hospitalizations per 100 patients tested, that more than compensates for the cost,” said the study’s leader, Dr. Robert Epstein. He is chief medical officer of Medco Health Solutions Inc., a New Jersey-based pharmacy benefits manager for many big insurance companies. For the study, researchers at the Mayo Clinic in Rochester, Minn., did gene tests on cells from cheek swabs of 896 patients in Medco plans who were starting on warfarin. Each patient’s doctor was given the results and advice on how to interpret them to set a dose. For a comparison group, researchers selected 2,688 similar patients from the same insurance plans who also were starting on warfarin and whose initial dose was set by the doctor’s best guess.

After six months, 18 percent of the gene-tested patients and 26 percent of the others had been hospitalized. That worked out to about a 30 percent lower risk for those given gene testing. “This may help make this a safer drug to utilize,” said Dr. James McClurken, chief of the cardiology conference and a heart surgeon at Temple University in Philadelphia.

Study leader Epstein said, “We’ve demonstrated that you can make warfarin work better with genetics.” Newer drugs seeking to compete with warfarin should include gene testing for dose-setting to make a fairer comparison, he said.

Medco paid for the gene tests and other study costs. Researchers from the Mayo Clinic donated their time. Results also are published in the Journal of the American College of Cardiology. Medco is doing another study to see whether gene testing can predict if a patient will do better on the anti-clotting drug Plavix or a competitor. On Friday, the U.S. Food and Drug Administration added its strongest warning to the label for Plavix because some patients with a gene variation in CYP2D6 cannot metabolize the drug, putting them at increased risk for heart attack and stroke.

This article is totally copyrights© 2010 The Associated Press (AP). All rights remain with AP.

FDA Drug Safety Communication: Reduced effectiveness of Clopidogrel [Plavix] in patients who are poor metabolizers (i.e. carriers of selected CYP2C19 allelic variants) of the drug

March 17, 2010 – The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Clopidogrel [Plavix], the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. “poor metabolizers”, see below) and therefore may not receive the full benefits of the drug.

The Boxed Warning in the drug label will include information to:

• Warn about reduced effectiveness in patients who are poor metabolizers of Clopidogrel [Plavix]. Poor metabolizers do not effectively convert Clopidogrel [Plavix] to its active form in the body.
• Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
• Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients identified as poor metabolizers.

Clopidogrel [Plavix] is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Clopidogrel [Plavix] works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.

For Clopidogrel [Plavix] to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Clopidogrel [Plavix] to its active form. In these patients, Clopidogrel [Plavix] has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Clopidogrel [Plavix] effectively; this can result in reduced effectiveness of Clopidogrel [Plavix]. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in these patients.

Patients should not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix], or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Clopidogrel [Plavix] to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Clopidogrel [Plavix] in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients identified as poor metabolizers.

Additional Information for Patients and Health Care Providers Alike

Patients currently taking Plavix should:

• Be aware that some patients do not convert Clopidogrel [Plavix] to its active form as well as other patients. These patients may not get the same benefit from Clopidogrel [Plavix]and are known as poor metabolizers.
• Not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional.
• Talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix].
• Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

FDA recommends that healthcare professionals should:

• Be aware that some patients may be poor metabolizers of Clopidogrel [Plavix]. They do not effectively convert Clopidogrel [Plavix] to its active form because of low CYP 2C19 activity.The effectiveness of Plavix as a preventive therapy is reduced in these patients.
• Be aware that tests are available to determine patients’ CYP2C19 status.
• Consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients who have been identified as poor metabolizers.
• Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
• Review the newly approved Clopidogrel [Plavix] drug label for complete information on the use of Clopidogrel [Plavix].

Scientific Background and Data Summary

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Clopidogrel [Plavix]. Pharmacokinetic and antiplatelet tests of the active metabolite of Clopidogrel [Plavix] show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient’s genotype:

1. The CYP2C19*1 allele has fully functional metabolism of Clopidogrel [Plavix].

2. The CYP2C19*2 and *3 alleles have no functional metabolism of Clopidogrel [Plavix]. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.

3. The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Clopidogrel [Plavix], but are less frequent than the CYP2C19*2 and *3 alleles.

A patient who carries two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Clopidogrel [Plavix] were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.