|New Clot Blockers Prove Their Mettle|
Modern drugs offer key advantages over older therapies
By Adam Marcus
WEDNESDAY, Oct. 29 (HealthDayNews) -- The new generation of blood thinners holds its own against the old guard, offering equal, if not better, protection against clots with fewer complications.
Three new studies show two of the new drugs lead to no more -- and often significantly fewer -- clots than warfarin or heparin, the standards of care for the condition. Patients on the new drugs also don't seem to suffer more bouts of serious bleeding, a major concern with blood-thinning medications.
Dr. Charles Francis, a clotting expert at the University of Rochester in New York, says the success of the drugs reflects the growing knowledge of how blood coagulates.
"The agents that we've been dealing with for 50 years were general anticoagulants that were almost discovered by chance. These new agents are based on what we know of biochemistry, the structure of clotting proteins" and other facets of the clotting process, says Francis, who helped conduct one of the new studies.
The three reports, which appear in the Oct. 30 issue of the New England Journal of Medicine, cover several different applications for blood thinners.
Warfarin, which was first developed as a rat poison in 1948, and heparin have been the anti-clotting agents of choice for five decades. Each drug is highly effective. But if heparin and warfarin, also known as Coumadin, are blunt instruments, the two new drugs, fondaparinux and ximelagatran, are honed scalpels.
Ximelagatran takes the straightest path, interfering with the protein thrombin, which is considered the blood's chief clotting molecule. [Thrombin shares its name with "thrombosis," the medical term for clotting.]
Fondaparinux disrupts an enzyme called Xa that's crucial for making thrombin. Fondaparinux, or Arixtra, developed by Sanofi-Synthelabo Inc. and Organon International, has won approval from the U.S. Food and Drug Administration and European regulators. Ximelagatran, developed by AstraZeneca as Exanta, has yet to be approved in either jurisdiction.
Even if they weren't more effective than older medications, the new drugs have an important advantage. Their highly specific mechanism of action avoids the need for frequent lab tests and dose tinkering that warfarin and certain versions of heparin demand, experts say.
Warfarin, which can be taken orally, interacts with a wide variety of other medications and even foods in ways that can harm patients. It's also slow to take effect and must be stopped several days before surgery to prevent excessive bleeding in the operating room.
Heparin, which must be injected, can trigger severe immune reactions in some patients and causes more bleeding problems than warfarin. Patients on either blood thinner must be carefully watched, and even small errors in dose can lead to potentially deadly complications.
Newer, smaller versions of the heparin molecule require little or no laboratory monitoring. Like heparin, Arixtra must be injected, which might deter some patients from long-term use. However, it can be given once a day.
In one of the new studies, Francis and his colleagues compared Exanta and warfarin in 1,851 people undergoing hip replacement surgery. Patients taking the new drug, which like warfarin comes in pill form, were about a third less likely to develop lung clots -- a common complication of major surgery -- or to die of any cause than those on warfarin.
Exanta "clearly was better," Francis says of the multi-center study. The rate of bleeding problems was the same for either drug, according to the researchers. Francis and several of his colleagues on the study have been paid consultants for AstraZeneca, which funded the research.
The second study, by a team of European scientists, also looked at Exanta, this time in the prevention of leg and lung clots in 1,233 men and women with a history of the problem. Half the patients received the drug and half took sugar pills.
After 18 months, 12 people on Exanta had developed new clots, compared with 71 in the other group, a difference of 84 percent. Bleeding trouble was slightly more likely in the group taking Exanta, but the risk of major bleeding was roughly the same.
Exanta, if approved, would be "an important alternative to warfarin, because it doesn't require dose adjustments and testing to see how thin the blood is," says study leader Dr. Sam Schulman, a researcher at the Karolinska Institute in Stockholm, Sweden. "Patients don't have to think about what they eat, what other drugs they get."
Schulman says scientists so far haven't found any other drugs that Exanta interferes with. What's more, even a double dose is safe and effective, whereas just a small increase in warfarin can have serious bleeding consequences.
The third study, by scientists in Europe, Australia and North and South America, compared injections of Arixtra with injections of conventional heparin to treat blood clots in the lungs. The new drug proved as effective as heparin at preventing clots from recurring, the researchers say, and seemed as safe.
Dr. Sandor Shapiro, a blood specialist at Jefferson Medical College in Philadelphia, says the new drugs "look very interesting," although much more research is needed to fully understand their risks and benefits. "It would really be a revolution to have an oral anticoagulant available that acts directly on thrombin," adds Shapiro, author of an editorial accompanying the journal articles.
A key area of future research, Shapiro says, is to see how well the new drugs, especially thrombin inhibitors, are tolerated over time. Long-term use of the medications could have harmful effects, but there's reason to believe they may prevent aggressive cancers.
Each of the studies was funded by the drug companies whose products were being tested.
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SOURCES: Charles Francis, M.D., professor, medicine, University of Rochester Medical Center, Rochester, N.Y.; Sam Schulman, M.D., Ph.D., associate professor, medicine, Karolinska Institute, Stockholm, Sweden; Sandor Shapiro, M.D., research professor, physiology, Jefferson Medical College, Philadelphia; Oct. 30, 2003, New England Journal of Medicine