A better way to prevent blood clots?

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A better way to prevent blood clots?

A drug derived from cobra venom offers an alternative to warfarin, although liver problems temper its benefits.

Since the 1950s the drug warfarin has been a key weapon in the battle against blood clots. Millions of Americans take it every day, making it one of the top 10 prescription drugs.

It’s also one of the most difficult drugs to use. Some foods block warfarin’s anticlotting action. So do a host of prescription and over-the-counter medications, as well as some herbal and dietary supplements. And the same dose of warfarin has different effects on different people.

This variability is important because warfarin (Coumadin, generic) has what doctors call a “narrow therapeutic index.” If there’s too little of the drug in your bloodstream, you run the risk of forming potentially dangerous blood clots. If there’s too much, you may be prone to serious bleeding problems.

Routine blood tests followed by dose adjustments can keep warfarin levels in their safe target zone. But the hassle and the potential problems cause many people and their doctors to shy away from warfarin. Up to two-thirds of people with the erratic heart rhythm known as atrial fibrillation don’t take the drug, putting themselves at risk for clot-caused strokes. And even among those who do use it, blood levels of warfarin are in the target zone only about half the time.

These drawbacks have kindled a search for alternatives to warfarin. An ideal replacement would be a pill that (1) works quickly, (2) affects everyone’s blood-clotting mechanism in much the same way, (3) isn’t affected by foods, other drugs, or dietary supplements, and (4) doesn’t have any side effects, says Dr. Victor Gurewich, professor of medicine at Harvard Medical School.

Benefits, and some risk

Pharmaceutical giant AstraZeneca has modified a substance in cobra venom into a warfarin alternative that achieves three of the four ideals. Cobras kill by injecting into their victims a powerful anticoagulant and a deadly nerve poison. Tinkering with the anticoagulant has led to a substance called ximelagatran (ZIE-mel-uh-GAT-tran), which AstraZeneca hopes to sell under the brand name Exanta.

The drug gets into the bloodstream quickly and is processed rapidly throughout the body. It appears to have the same anticlotting effect from person to person. And unlike warfarin, Exanta doesn’t seem to be affected by other drugs or food. These qualities mean there’s no need for routine blood tests.

In clinical trials that have included about 14,000 volunteers, twice-daily doses of the drug prevented blood clots as well as warfarin did among people with atrial fibrillation, those with unexplained clots in the legs or arms (deep-vein thrombosis), and those undergoing knee surgery or hip replacement. Serious bleeding was no more common with Exanta than with warfarin.

There’s just one hitch: Liver trouble crops up in 6%–10% of people who use the drug for more than a month or two. Most of the time the trouble is a spike in blood levels of proteins released by damaged liver cells. These levels usually fall back to normal whether or not the drug is stopped.

Sometimes, though, the problems are much more serious. In the clinical trials of Exanta, three volunteers died from liver failure. About 4 in 10,000 people who use Exanta for an extended period will die from liver failure, according to a cost-benefit analysis of Exanta published in the Feb. 9, 2005, Journal of the American Medical Association. This may be an underestimate, since none of the trials evaluated use of Exanta much beyond two years. Some people take warfarin for far longer than that.

The ball is in the FDA’s court

In the spring of 2004, the European Union approved Exanta for preventing clots after surgery. It got a chillier reception a few months later from the FDA. It denied AstraZeneca’s application to sell Exanta in the United States, citing worries about liver problems and the company’s plans to monitor and manage liver damage. According to a company spokesman, as of May 2005 AstraZeneca was having “ongoing discussions with the FDA to see if there is an appropriate path forward for U.S. approval for Exanta.”

A larger, longer clinical trial probably won’t add much to the discussion. We already know that Exanta prevents blood clots as well as warfarin and is easier to use. We also know that it may cause potentially deadly liver damage. We don’t know what other problems might surface with long-term use, especially outside of the relatively healthy and tightly scripted groups that usually make up the bulk of clinical trial participants.

Balancing benefits and risks

Exanta would simplify the prevention of blood clots and allow more people who need this protection to get it. At the same time, it would cause deadly liver damage in a small number of people who take the drug, and it wouldn’t come as a surprise if other serious side effects appeared with long-term use.

The FDA doesn’t use a single standard for determining whether a drug is too risky to be on the market. Factors such as the nature of the illness, whether alternatives are available for treating it, and how persuasive the information is on the risk influence the decision. For deadly diseases such as advanced cancer, drugs are sometimes approved with substantial side effects, while those for a more benign condition such as a sinus infection or toenail fungus must be much safer.

It will be interesting to see how the FDA juggles benefit and risk for Exanta. One thing is for certain: If it is approved, those who take it must do so with eyes wide open.

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Last updated:	August 21, 2006