Doctors hopeful over improved blood thinners
By; Lauran Neergaard..Associated Press.
Associated Press Published: 7/21/2008 12:05 AM...July 21 2008 issue..Daily Herald
A trio of experimental drugs has doctors hopeful that for the first time in decades, millions of people at risk of lethal blood clots may soon get easier treatment.
The first goal is a pill option for people who now need daily blood-thinning shots for weeks after knee or hip replacement surgery.
But the ultimate goal is an alternative to that old standby warfarin, also called Coumadin, the nation's most troublesome lifesaver because of side effects and restrictions its 2 million users face.
Now in late-stage testing in thousands of Americans are three pills that work to prevent blood clots in ways that promise to be less burdensome. One of the trio, Boehringer Ingelheim's Pradaxa, just began selling in Europe.
The drug research comes as Medicare is considering withholding payment from hospitals when at-risk patients develop clots in their veins, usually the legs - a common preventable cause of hospital deaths. The National Quality Forum has estimated that only about a third of patients who need protective blood thinners while hospitalized get them.
Known medically as a "deep vein thrombosis" or DVT, such a clot can kill quickly if it moves up to the lungs. There aren't good counts, but recent estimates suggest that about 900,000 people a year suffer a vein clot, and nearly 300,000 die. Being immobile for long periods, such as during hospitalizations or even long airplane flights, can trigger a clot.
Vice President Cheney suffered one after a long trip last year. NBC correspondent David Bloom died of one in 2003 after spending days in a cramped military vehicle while covering the invasion of Iraq.
But there are a variety of risks, including increasing age, smoking, birth control pills, obesity - and especially, big surgeries like knee or hip replacements.
Doctors use faster acting shots of the blood thinner enoxaparin to protect orthopedic surgery patients. But warfarin is a top treatment once a vein clot strikes - and the leading protection for other types of clots, such as strokes caused by the irregular heartbeat atrial fibrillation.
But too many of those patients go unprotected, too, because warfarin is so hard to use. Dangerous bleeding is the worst side effect, but it requires monthly blood checks because diet and other factors can throw off the dose.
"The need is substantial" for an easier alternative, says Dr. Richard Becker, a hematology and cardiovascular specialist at Duke University Medical Center who is monitoring the pipeline.
"I don't know of a drug that has the inherent complexities and potential for harm that Coumadin does."
Hopes have been dashed before. Just a few years ago, the highly anticipated blood thinner Exantra was pulled off Europe's market, and rejected here, because of surprising liver damage. So while trial results have U.S. specialists optimistic about the three new attempts, they're watching closely for any hints of problems.
"There are some huge benefits to these drugs, all three of them - if they play out," says pharmacist John Fanikos of Boston's Brigham and Women's Hospital and the North American Thrombosis Forum.>/b>
In the pipeline
¤ Rivaroxaban tamps down action of a key player in blood clotting, called Factor Xa. Last month, the New England Journal of Medicine published two studies of more than 7,000 knee and hip replacement recipients who received either a daily rivaroxaban pill or today's standard injections. Pill users were less likely to suffer fatal and nonfatal vein clots. Bleeding and other side effects were similar.
Johnson & Johnson, which is developing rivaroxaban with Bayer Healthcare AG, plans to seek Food and Drug Administration approval later this summer.
¤ Pradaxa, or dabigatran, interferes with another blood clotting agent, called thrombin. European regulators cited research showing Pradaxa was as effective as standard shots in protecting orthopedic patients.
Duke's Becker cautions that one U.S. study didn't show as big an effect; other research is continuing. This drug works similarly to the ill fated Exantra, but Becker says there are no signs of liver toxicity so far.
¤ Bristol-Myers Squibb's apixaban works against the same clotting factor as rivaroxaban; its key studies are under way.
Orthopedic surgery is an easier hurdle - because vein clots are quick and common - than proving if these pills will work as well as warfarin for people who need longer term care.
Stay tuned: Large studies comparing warfarin to each have begun at hospitals nationwide.
If they work, their targeted action promises fewer side effects, dietary restrictions or dose problems than warfarin, Fanikos notes. But warfarin still will play an important role, he cautions - since the generic form sells for as little as $40 for a three-month supply.
Gene test may determine needed amount of blood thinner...Warfarin/Coumadin
It's the nation's most trouble some lifesaver. Every day, (*)two (2) million + Americans swallow a blood thinner called warfarin that puts them on a tightrope: Too little, and they won't be protected from lethal blood clots. Too much, and they can bleed to death.
Something as simple as a big serving of spinach or stressful travel can alter how much of the drug stays in the body, putting patients in a danger zone.
Even picking the best dose in the first place is perilous, as doctors basically use trial and error for each patient
That could soon change. Scientists have discovered two genes that help determine ,if someone can tolerate only a little warfarin or needs a lot.
So the Food and Drug Administration is launching a major study to see if testing new patients' genes will dramatically reduce side effects.
Even before that study gets under way this fall, the FDA is about to alter the warning labels on generic warfarin and the brand name version, Coumadin.
The message to doctors: Be aware that some patients' genes dictate far lower doses than you usually prescribe, and stay tuned for more precise instructions.
"It's a very difficult drug," says Dr. Brian Gage of Washington University in St. Louis, who is leading a pilot study of the gene testing for another government agency, the National Institutes of Health.
"Each person has a limited range where they have the 'right thinness of blood. ... It's hard to get right the first time."
The difficulty doesn't stop once doctors finally settle on an initial dose. Patients need regular blood tests - daily at first,then weekly or monthly - to check that their blood is clotting properly.
Few get those checks at specialized clinics trained to recognize impending side effects.
And a recent survey by the National Consumers League suggests too few underst and other basic steps they're supposed to take to avoid warfarin complications.
"Patients, some were absolutely clueless. It was scary I how much they didn't know," said Rebecca Burkholder, health publicy director at the consumer'group, which has begun a patient safe aignl;o try to change that. Among the leading myths: that warfarin users must avoid vitamin K-rich green, leafy vegetables.
Warfarin works by blocking a step in the blood clotting process that is largely regulated by vitamin K.
Actually, the key is consuming about the same amount of vitamin K all the time, learned Lynn Levitt, 32, of Highlands Ranch, Colo., who has used the drug for three years since developing a life threatening disorder.
Levitt initially thought if tests showed her blood wasn't too thin one week, "I could go celebrate with a big salad. Actually, I could eat salad every single day but I need to do it consistently," she now knows. Warfarin is one of the most widely used medicines, and doctors' top choice in blood thinners to prevent heart attacks, strokes and other lethal blood clots.
At the same time, warfarin is one of the most side effect prone drugs.
The FDA cites research suggesting warfarin alone accounts for 15 percent of severe drug side effects. For every 100 patients, there are anywhere from one to seven major bleeding episodes.
And most of the side effects occur in the first month of treatment, says FDA Pharmacology chief Dr. Lawrence Lesko.
A gene known as CYPZC9 produces an enzyme that helps the body metabolize a variety of medicines. Variations in that gene can make people metabolize warfarin more slowly, so that they need a smaller dose. But that's hot the only factor.
A vitamin K related gene called VKORC1 produces the bloodclotting protein that warfarin blocks.
People who produce less of that protein need less warfarin.
Say doctors start a 200 pound, 40 year old man on 10 milligrams of warfarin. But if he had the warfarin sensitive gene combination, he'd only need 3mg , the higher dose puts him at risk of a hemorrhage.
Today,doctors would know that only once routine blood tests show the patient's clotting levels out of whack, and it can take days for a dose adjustment to kick in.
In November,(* 2006) FDA funded researchers will begin enrolling up to 800 warfarin patients to see if gene testing gets them the right dose faster, with fewer side effects in that first month.