Overall, the new treatment cut the risk of clots alone by 64 percent and the risk of clots, major internal bleeding or death together by 48 percent.
Dr. Stephan Moll, director of the Thrombophilia Program at the University of North Carolina at Chapel Hill's Center for Thrombosis & Hemostasis, was one of the principal investigators for the trial, which involved 52 centers mainly across the United States, but also in Canada and Switzerland.
Moll and UNC School of Medicine colleagues enrolled the third highest number of patients in the study. Dr. Paul M. Ridker of Brigham and Women's Hospital in Boston served as chairman for the trial described Monday (Feb. 24) in the New England Journal of Medicine.
"Usually we treat patients who have had a blood clot in their legs or in their lungs with blood thinners for six months and then stop the thinning medication," said Moll, assistant professor of medicine. "Doctors have been reluctant to give warfarin (Coumadin) long term, however, since it can be dangerous and has a relatively high side effect rate.
"Until now, we had to accept that about 20 to 25 percent of patients would go on and have another blood clot once blood thinners were stopped. We wanted to learn whether we could improve that treatment without increasing the risk of bleeding. "
The new study, called PREVENT, was a randomized, double-blind trial that involved two groups of patients who suffered blood clots for no apparent reason and who had received standard full-dose anticoagulation for at least three months, the physician said.
One group then received an inactive compound known as a placebo, he said. The second group continued to take a small maintenance dose of warfarin.
"We found the later maintenance dose to be not only safe in that it did not increase the risk of major bleeding, but also effective in preventing a recurrence of clots," Moll said. "That means a maintenance dose should become the new standard of care for patients following a first blood clot and the current treatment."
The average length of follow-up with the 508 enrolled patients was more than two years, and the maximum was 4.3 years. The medical scientists were most interested in how many of them suffered recurring clots, and how many suffered serious internal bleeding episodes.
Of the 253 patients assigned to the placebo -- or inactive substance -- group, 37 had a new clot (7.3 percent per year) compared to 14 of the 255 in the low-dose warfarin group (2.6 percent per year). Eight deaths occurred among members of the former group, and four occurred in members of the latter.
"For ethical reasons, we stopped the study three years ahead of schedule so that all patients with blood clots of unknown origin would get the chance to go on low-dose warfarin," Moll said. "About 100,000 patients in the United States suffer blood clots every year. Many of those are triggered by surgery, but we were interested in the roughly 50,000 who had a spontaneous clot without a known triggering factor."
A second unrelated study, called THRIVE V, recently concluded. Moll also participated as a principal investigator. That was a phase III trial -- the final stage before the FDA approves a drug for routine use -- of a promising new medication for treating blood clots. The potential drug, ximelagatran (Exanta), does not require the monitoring that warfarin does, Moll said. It seems to work immediately, while warfarin requires between five and seven days to build up to the appropriate level in the body.
"If, as we expect, this new drug is as effective as warfarin and causes fewer side effects and lowers the risk of bleeding, it could make specialized blood testing to determine the appropriate dose of warfarin obsolete," he said.
Another potential benefit of ximelagatran is that it will allow patients to be less vigilant about their diets, the physician said.
Warfarin interferes with vitamin K, and so patients have to watch what they eat. Ximelagatran thins the blood through a vitamin K-independent mechanism.
The National Heart, Lung and Blood Institute supported the warfarin research.
By DAVID WILLIAMSON
UNC News Services
Note: Moll can be reached at 919-966-3311 or smoll@med.unc.edu. Ridker's number is 617-734-1508. Details on the PREVENT study can be found at www.nhlbi.nih.gov/studies/prevent1.htm.
Center for Thombosis & Hemostasis Contact: Margo Price, 919-966-6011
News Services Contact: David Williamson, 962-8596