Focus turns to how genetics impacts warfarin therapy

A label change is coming, but some advise waiting until a large clinical trial is completed before genetic testing becomes widely used to determine dosing.

By Susan J. Landers — Posted Sept. 10, 2007

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Warfarin's label now includes information noting that some people's genetic makeup may influence how they respond to the popular blood thinner, which can be notoriously difficult to dose correctly. But how this new information should be used is raising more questions.

The Food and Drug Administration's Aug. 16 announcement of the label change was made after an analysis of recent studies found that people respond to the drug differently, based, in part, on whether they have variations of certain genes.

Most physicians who prescribe warfarin already are aware that as many as 30% to 40% of their patients miss targeted prothrombin times by wide margins, either scoring too low or too high. Genetics is likely the reason.

A large National Heart, Lung and Blood Institute study, scheduled to begin next year, is intended to make it clear once and for all whether widespread use of genetic tests would be helpful in terms of determining the drug's correct dose for individual patients. Results are expected by late 2011.

Already, though, these genetic tests have been marketed for more than a decade. Medicare will cover the cost, which ranges from $150 to $500, and other major insurers say they will consider coverage on a case-by-case basis.

Each year, an estimated 2 million people start taking warfarin, a drug available since the 1950s. The drug is used to prevent blood clots, heart attacks and strokes. Because its dose is affected by so many variables -- a patient's age, weight, diet, use of other medications and now genetic makeup -- gauging the proper dose always has been problematic, requiring frequent checks of how quickly a patient's blood clots. This need is especially acute when initiating treatment.

Often, despite careful monitoring, problems can ensue. Warfarin is the second most common drug, after insulin, implicated in emergency department visits for adverse drug events such as bleeding, according to the FDA. Help in determining the proper dosage via genetic tests, heralded by many as the way of the future, would be welcome news.

But while it is common knowledge that the presence of variants of CYP2C9 and VKORC1 genes plays a role in how a patient responds to treatment, until more data are available from the NHLBI study, the role the tests can play in proper dosing is unclear.

"I think, for right now, it is business as usual," said Rick Kellerman, MD, president of the American Academy of Family Physicians. It is relatively new information, so it will take some time to filter through the medical community, he noted.

Plus, any experienced physician who has prescribed warfarin already is aware of the genetic influence, he said. Sometimes physicians start patients on the blood thinner and wonder if the patient is even taking his or her medication because the results are so small. Other times, even a low dose will trigger an elevated internationalized normalized ratio. Patients' prothrombin time, or PT, which evaluates the blood's ability to clot, is compared with the expected value in healthy people or the INR.

Genetic tests not required

"The [genetic] test has tremendous theoretical value," said Samuel Goldhaber, MD, professor of medicine at Harvard Medical School. "I run an anticoagulation service for more than 2,000 patients, and we are constantly worrying about excessive dosing and underdosing of warfarin."

But in terms of the practical application of the test, "The jury is still out," he said.

Controversy surrounds the usefulness of routine, rapid-turnaround genetic testing done for patients starting warfarin therapy, Dr. Goldhaber added. Although he would rather wait for the NHLBI trial results before taking any action, the FDA does have responsibility for educating the medical community about the availability of the tests, he said. "FDA is not telling doctors to get the test, although the question does arise whether doctors will start ordering this test routinely and interpret this guideline as a mandate."

But physicians shouldn't interpret the labeling change as even a recommendation from the FDA, cautioned Raymond Woosley, MD, PhD, president of the Critical Path Institute, a nonprofit group based in Tucson, Ariz., and Rockville, Md., that collaborates with the FDA on drug development issues.

The institute is currently working with the AMA on a brochure about warfarin and genetic testing that is scheduled to be released by the end of next month.

"The FDA clearly states that we don't know yet how to use the tests to pick a dose. I think that is a quandary for the agency. How do you let people know that this is coming without them overreacting, and overinterpreting?" Dr. Woosley asked.

Test nuances also must be understood, he noted. For one thing, once a patient is titrated to the correct dose, the test won't be of any use. "It will probably be only the initial dose where these genetic tests will be found valuable."

In addition, rapid turnaround for the results is important. If it takes two weeks, as it does in some parts of the country, its use probably would be negligible, Dr. Woosley said.

Meanwhile, Brian F. Gage, MD, associate professor of medicine at Washington University in St. Louis, has devised an algorithm to help physicians determine proper warfarin dosage. Available for free online (link), the test was developed from data collected on more than 1,000 patients, Dr. Gage said.

He and his colleagues also published a study in the Sept. 1 Blood, the journal of the American Society of Hematology, describing how they developed their algorithm.

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Warfarin labeling

The Food and Drug Administration announced changes to warfarin's label and accompanied the Aug. 16 announcement with other advice. Among the highlights:

  • Genetic variations of CYP2C9 and VKORC1 were added to factors such as age, other medications taken, weight and height, that should be considered when prescribing warfarin. Lower doses may be required in patients with these variations to achieve the proper results.
  • Physicians are not required to obtain the tests before initiating warfarin therapy and should not delay therapy to obtain the tests.
  • Studies suggest that patients with CYP2C9*2 and CYP2C9*3 genetic variations are at an increased risk for bleeding from warfarin therapy because they metabolize the drug at a slower rate than do those without the variations. Patients with these variations generally required lower doses to achieve desired results and decrease their risk of bleeding.
  • More limited information is available for VKORC1 genetic variations, but one study found that the variation seemed to predict the need for a wide range in dose among the 201 white patients tested.
  • The presence of either aVKORC1 or CYP2C9 variation was thought to be responsible for up to 40% of the warfarin dose range. Other non-genetic factors, such as age and weight, were responsible for 10% to 15% of dose range.

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External links

AMA on genetics and molecular medicine (link)

Food and Drug Administration prescribing information for warfarin (link)

An algorithm for determining warfarin dose, developed by researchers at Washington University in St. Louis (link)

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