In May, Karen Schmale was rushed to Barnes-Jewish Hospital in St. Louis, gasping for air. Diagnosed with blood clots in her lungs, she was given a powerful blood thinner called warfarin.
The medicine probably helped save her life. Then it almost killed her. About a week later, Ms. Schmale, 49 years old, noticed blood in her urine and soon became so weak she could barely climb the stairs to her second-floor apartment. The warfarin was causing the bleeding, and she had to go back to the hospital for an emergency blood transfusion.
A genetic test revealed Ms. Schmale was unusually sensitive to the drug and needed a smaller dose. Before the test, "nobody knew I was going to react like that," says Ms. Schmale, a data-entry coordinator at a university in St. Louis.
The case shows the advances in personalized medicine, where treatment is tailored to an individual's genetic makeup. But, in a possible harbinger of battles to come, the warfarin tests have also led to a clash between the Food and Drug Administration and some doctors.
The FDA is set to announce today that warfarin's label will carry new information describing the role of genetics in dosing. The label will say that a lower initial warfarin dose "should be considered for patients with certain genetic variations."
Some specialists say testing hasn't been proved to reduce the risks of the drug. They fear patients who don't get the tests and run into trouble will sue doctors, citing the drug's label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don't. The insurers say they need more evidence about the benefits.
"It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label," said University of Washington professor Ann Wittkowsky in an interview before the FDA's decision. "It is fascinating science, but it is not yet ready for prime time."
Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has "substantial" evidence to support the new label and hopes it will improve safety by informing doctors.
Dr. Lesko is part of a larger initiative at the FDA to promote the use of genetic factors to predict how individuals will react to medicines. It's a shift for the agency, which traditionally has more of a reactive role as the regulator of the drug industry. "If the potential wasn't huge, we wouldn't be doing it," he says. "We felt we had to be more outspoken."
The agency has already included information about genetic testing on the labels of less-frequently used drugs for colon cancer and leukemia, among others. One drug, Genentech Inc.'s Herceptin for breast cancer, is designed especially for women whose tumor cells have a genetic abnormality.
But warfarin is the largest case study to date of what happens when the new science of genetics runs up against the everyday practice of medicine. Originally marketed as a rat poison, the drug was prescribed more than 30 million times last year in the U.S., according to IMS Health. It's available as an inexpensive generic pill.
Its main problem is the narrow window for safety. An excessive dose leads to bleeding. Warfarin is the second-most-likely drug, after insulin, to send Americans to the emergency room. By one estimate, it accounts for 43,000 ER visits a year in the U.S. (see a study on hospitalizations1).
If tests for warfarin-sensitivity genes become commonplace, it would encourage other efforts to develop genetic tests linked to popular drugs. Researchers are looking at how genes affect the action of such drugs as the antidepressant Prozac, the diabetes drug metformin and the asthma inhaler albuterol. A team of Harvard researchers has shown good results with a genetic test predicting who will fail to respond to albuterol and similar drugs, says Scott Weiss, a professor involved in the study.
"There's going to be a debate about every one of these tests," says Dr. Weiss.
Researchers began developing warfarin as a drug for people after an Army inductee during the Korean War tried to commit suicide by eating it. He survived, and doctors were struck by how effectively the poison had restricted his blood's clotting ability, or coagulation. President Eisenhower took it after a 1955 heart attack. The drug's generic name derives from the Wisconsin Alumni Research Foundation, or WARF, which originally held the patent on it. It is also known by the brand name Coumadin.
From the start, doctors struggled with how to give warfarin safely. In the 1990s, they began using a measure called International Normalized Ratio that compares the blood's clotting ability at a given moment to a standardized measure. Typically, doctors prescribe an initial warfarin dose based on factors including a patient's size, age and other medications. They check the patient's blood frequently -- every few days, at first -- and tweak the dose to bring the INR within the desired range.
Stephanie Davis, 58, a development director for a Johns Hopkins University cancer center in Baltimore, developed blood clots in both legs after a long flight home from California three years ago. As she was released from the hospital, she was prescribed warfarin to prevent new clots and told to visit a clinic two days later so her blood could be checked.
The test showed Ms. Davis's INR wasn't in the target range, so her dose was adjusted and she had to return two days later. In the end, she spent five months visiting the clinic every other morning before she went to work. Even after that, she still had to get checked twice a week. Eventually, she stopped taking warfarin. Her doctors felt she didn't need to be on a blood-thinner full-time. "It is so frustrating," says Ms. Davis, who is on the board of an organization for people with blood clots.
Without such scrutiny, warfarin can be deadly. Maria Tirado, a 79-year-old diabetic who suffered from an irregular heartbeat, was prescribed a high dose after a brief hospital visit. The doctor noted that if her INR went above a certain number, the drug should be halted. But staffers at the La Jolla Nursing and Rehabilitation Center in La Jolla, Calif., didn't check her INR, according to a state inspection report, and kept giving the high dose for at least three weeks.
Massive Bleeding
Ms. Tirado was eventually brought to an emergency room and died in January 2006 after "massive bleeding into the brain," the inspection report said. Ms. Tirado's family is suing the nursing center's owner and people involved in her care. Andrew Torok, the center's general counsel, declined to discuss specifics of the case but said the center is appealing the state's findings. He said the center is "dedicated to providing quality care" and is "committed to taking whatever corrective actions are warranted."
About a decade ago, research began to show that a gene known as CYP2C9 could affect how people's bodies process warfarin (see a study2). People with certain variants tended to break down the drug more slowly, meaning it stayed in the body longer in its potent form. A 2002 study in the Journal of the American Medical Association suggested these people were more likely to get too much warfarin and bleed.
A few years later, researchers discovered that a gene known as VKORC1 also plays a role. It affects how efficiently the body processes vitamin K. That is relevant because warfarin's anticlotting action comes from its ability to interfere with vitamin K. A 2005 study in the New England Journal of Medicine affirmed that patients with certain variants of VKORC1 appeared to need lower warfarin doses (see an abstract 3).
Doctors in the field say that traditional measurements such as size and age account for just 15% to 20% of the variability in responses to warfarin. Adding the genetic factors can raise that figure to 50% or higher, say advocates of genetic testing.
Ms. Schmale in St. Louis says she had a rare combination of both genes that made her highly sensitive to warfarin. Doctors had started her on a daily dose of 10 milligrams of the drug, but after the tests she ended up on a dose averaging less than one milligram a day.
For another patient, 60-year-old John D. Marlin, genetics pointed in the opposite direction. When he developed a clot in his lung this May, the retired biology teacher from Evansville, Ill., was told he would start with four milligrams of warfarin each day. But after the genetic test, doctors switched the dose to eight to nine milligrams daily. "I just don't absorb it very well, so it takes more of it to work," Mr. Marlin says.
Ms. Schmale and Mr. Martin were part of a study led by Brian Gage, an associate professor at Washington University in St. Louis. "There's clear agreement that variants of these genes affect the therapeutic dose of warfarin, so the product labeling ought to reflect that knowledge," says Dr. Gage.
| • | In milestone, FDA pushes genetic tests tied to drug
Agency Seeks to Tame Risks of Blood Thinner; Some Doctors Protest The Wall Street Journal, Thursday, Aug. 16, 2007 Byline: Anna Wilde Mathews |
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