By Lisa Ellis
InteliHealth News Service
November 12, 2003
ORLANDO, Fla. — A new drug, ximelagatran, works just as well as warfarin in preventing strokes for high-risk patients with a major heart-rhythm disorder, a study of nearly 4,000 patients has found.
Warfarin (Coumadin) and ximelagatran (Exanta) both are anti-coagulants — popularly known as blood-thinners. They help to prevent the blood clots that can cause strokes.
Old and highly effective, warfarin is taken by millions of people worldwide. In generic form, it also is inexpensive. But researchers have been searching for an alternative because warfarin has drawbacks as well.
"Warfarin is a very difficult drug for patients and physicians to manage," said Jonathan L. Halperin, M.D., of Mount Sinai School of Medicine in New York, who presented the study results at the annual American Heart Association Scientific Sessions.
As a result, he said, more than half of the people who begin taking it eventually "cannot sustain this type of therapy."
Warfarin requires careful monitoring and frequent blood tests and interacts with alcohol, certain foods and many drugs, including common ones such as aspirin and ibuprofen.
The dose varies widely and may change even for an individual patient. Proper dosing is important because too much can lead to excessive bleeding and too little may be ineffective in preventing strokes. Warfarin must be discontinued several days before surgery to prevent excessive bleeding.
Ximelagatran, in contrast, is delivered at a fixed dose and has no known interactions with other medicines, Dr. Halperin said. Its effects on the blood fade quickly, so it can be stopped right before surgery, he said.
Warfarin currently is recommended for people with atrial fibrillation, the group of patients in the ximelagatran study, because their irregular heart rhythm can cause clots to form. This disorder affects more than 2 million Americans, Dr. Halperin said.
Nearly 4,000 patients were enrolled in the study at 400 medical centers in North America. All participants had atrial fibrillation and at least one other condition that put them at risk of stroke, Dr. Halperin said.
Patients were randomly assigned to receive either warfarin or ximelagatran. After two years, Dr. Halperin said, about 1.2 percent of those taking warfarin had a stroke — caused by either a clot or bleeding — or had some other blood-clot problem. In the ximelagatran group, the rate was 1.6 percent.
This difference is small enough that it could have been caused by chance, and therefore the two drugs are equally effective, Dr. Halperin said.
Ximelagatran is being developed by AstraZeneca, which has tested it on 30,000 patients around the world. Dr. Halperin said all results will be submitted soon to the U.S. Food and Drug Administration and similar agencies in Europe to seek approval to sell the drug.
So far, the drug has been tested only in patients with atrial fibrillation, blood clots in the leg, and pulmonary emboli (clots that break off from the leg and travel to the lung). Results do not apply to other patients who now take warfarin, including people with diseased or artificial heart valves.
During the new study, Dr. Halperin said, researchers monitored blood-clotting times so closely in patients taking warfarin that they remained in ideal ranges nearly 70 percent of the time. In the real world, he said, this occurs only about 30 to 40 percent of the time.
To make sure that patients did not know which drug they were getting, even those who took ximelagatran received fake tests and "dose adjustments," although the actual dose they got remained the same, Dr. Halperin said.
Study results did raise one concern about the new drug's possible effects on the liver for a small percentage of patients.
About 6 percent of the people taking ximelagatran showed sharply elevated levels of liver enzymes released into the blood, an indication of liver-cell injury, Dr. Halperin said. About half of those who had this problem had to stop the drug.
One of the patients developed significant liver-related complications. This patient was diagnosed with hepatitis some time after stopping the drug, he said. The patient was treated with steroids and later died from a perforated ulcer, he said.
It's impossible to say whether the drug caused the liver problem, Dr. Halperin said. "It's one patient, and stuff happens." If the drug presents any risk to the liver, this probably will not become apparent until it goes on the market and is used by many more patients, he said.
He said it probably would be good to monitor patients' liver function for the first six months.
Raymond J. Gibbons, M.D., chairman of the AHA committee that planned the conference, said this level of monitoring still would be far less than the tests that people taking warfarin must undergo now.
"Even if it means frequent monitoring for a year, that pales in comparison with monitoring for a lifetime," he said. People taking warfarin are supposed to get blood tests monthly — or even weekly for some patients, he said.
"You also have to be aware of this long list of drugs that interact with warfarin. It also affects your diet. If you eat more broccoli, suddenly you have to adjust the drug," he said.
Dr. Gibbons, who is on the faculty of the Mayo Clinic in Rochester, Minn., said that every summer he sees patients who suddenly need medicine adjustments because of the "broccoli epidemic" — a sudden increase of green, leafy vegetables from gardens. These vegetables contain high levels of vitamin K which counteracts the effects of warfarin.
AstraZeneca has not said how much the new drug would cost, if it is approved.
Whatever that cost may be, Dr. Gibbons said it should be weighed against not only the low cost of warfarin but also the extensive laboratory and other costs associated with frequent blood tests and dose adjustments.
On the other hand, "the patient doesn't see that as out-of-pocket costs," he said. Therefore, he said, most patients probably would find ximelagatran more expensive.
