New bloodthinners thicken the drug market
Monday, November 22, 2010; 4:32 PM
For decades, doctors have tended to rely on one very imperfect drug for patients who need to take a blood thinner to prevent clots from forming and traveling to their heart, lungs, legs or brain.
Warfarin, packaged and sold as the anticoagulant Coumadin, has been a lifesaver drug - "one of the most effective therapies in all of medicine," says Jonathan Halperin, a cardiology professor at Mount Sinai School of Medicine in New York - but it also can be hard to manage and poses serious risks of uncontrolled and potentially fatal bleeding. As a result, scientists have been searching for a simpler, safer alternative but without success.
Now, however, several new anticoagulants are poised to come to market in the United States - one hit pharmacies this month - that doctors say could revolutionize the treatment of blood clots and stroke prevention.
These new blood thinners require less monitoring and promise to be just as effective - if not more - at eliminating blood clots, and hopefully reducing stroke rates. The bleeding risks remain, but the frequent blood tests required for anyone using warfarin would be a thing of the past for patients on these new drugs.
"We've been waiting years," said Eric Prystowsky, director of the clinical electrophysiology laboratory at St. Vincent Hospital in Indianapolis and an unpaid consultant for one of the new drugs "We now have a drug that's close - it's not ideal - but it's close."
Warfarin was initially developed as a chemical to kill rats, which would bleed to death after eating it. It was first prescribed as a human anticoagulant in 1954. An oral tablet, warfarin blocks Vitamin K-dependent molecules that are necessary to get blood to thicken and clot.
Clotting is essential for bleeding to stop and wounds to heal.
"It's as essential for life as breathing," added John Mandrola, an electrophysiologist at Louisville Cardiology, who also writes the DrJohnM blog.
For those with the irregular heart rhythm known as atrial fibrillation, blood may pool too long in the heart, forming clots that can break away and cause strokes and other serious problems. Similarly, people with artificial heart valves risk clots forming on the actual device. In these cases, as well as for those with hypertension, history of stroke and heart attack, warfarin may be a lifesaver. It can reduce a patient's stroke risk by up to 70 percent, Halperin says.
Yet using it is tricky. Take too much warfarin and your risk for major bleeds jumps. If it occurs in the brain, it can cause a stroke. Take too little, and your risk for conditions such as deep vein thrombosis, lung embolisms and strokes rises. Change your diet, and your prescribed warfarin dose may not do its job since the drug interacts differently with different foods.
Foods such as green, leafy vegetables, rich with Vitamin K, may promote clotting. Therefore, patients need those regular blood tests, sometimes as often as every week, so doctors can monitor how quickly the blood clots and adjust the dose if necessary. Getting the dose right can be difficult - it's easy to overshoot or undershoot - and time-consuming. It may take days or weeks to find the best warfarin dose, and it poses real complications for anyone needing emergency surgery.
"Every doctor will tell you, warfarin is a difficult drug to use," Mandrola said. "It requires a motivated, educated patient and good systems like availability of [blood] testing."
As a result, there is much anticipation for the new drugs that promise few side effects, no dietary restrictions or drug interactions, and no need for blood tests. There are more than seven oral anticoagulants in development, according to a market analysis by Goldman Sachs, published this month.
In October, the FDA approved the first of them, dabigatran etexilate, sold as Pradaxa, to prevent stroke and blood clots in patients with only nonvalvular atrial fibrillation- not those with artificial valves. Last year, a study of 18,113 patients published in the New England Journal of Medicine and sponsored by the drugmaker, Boehringer-Ingelheim, found dabigatran etexilate to be more effective than warfarin at reducing stroke rates, and for some people, much safer at limiting bleeding - especially intracranial bleeds. According to the drugmaker, Pradaxa became available at pharmacies Nov. 3. It has been sold in Canada and Europe since 2008 to prevent blood clots following knee- and hip-replacement surgery.
"It'll be more of a simple, aspirin-like drug," Mandrola said. "You take it and your blood's thin, end of story; that's really exciting."
On Nov. 15, at an American Heart Association conference, Bayer AG and Johnson & Johnson announced that their once-a-day anticoagulant, rivaroxaban, could prevent strokes in patients with AF more effectively than warfarin, with similar bleeding risks.
These new oral anticoagulants are different from warfarin in that they target specific components of the multi-step clotting pathway rather than several Vitamin K-dependent molecules. Pradaxa inhibits the molecule, thrombin. The others inhibit the clotting Factor Xa (ten-ay). Because of their mechanism, these drugs don't interact with foods and other drugs, and blood tests are not necessary.
Unlike warfarin, which may take days to take effect, Pradaxa can start impeding the coagulation cascade within a few hours, says Prystowsky; but its effects last about 12 to 17 hours. Pradaxa's shorter chemical half-life requires patients to take a capsule twice a day (compared with the usual once a day dose of warfarin).
On Pradaxa, patients should limit contact sports and other forms of physical activity that pose bleeding risks - but according to the NEJM study, a 110 mg dose has a 20 percent lower bleeding risk when compared with warfarin, while providing similar prevention of strokes and blood clots. There was a 35 percent reduced rate of stroke, with similar bleeding risk, in patients taking the 150 mg dose of Pradaxa.
(Pradaxa does have some downsides, according to the NEJM study, including a small but significant increase in risk of heart attack and gastrointestinal bleeding.)
Yet, experts say warfarin is still, and will continue to be, a very effective drug - if managed properly.
"Don't blame the drug, blame the management system," said Henry Bussey, professor of pharmacotherapy at University of Texas at Austin and president of the nonprofit ClotCare.org. "The new agents provide an alternative, but if we want to achieve the very best outcomes, I still think [warfarin] under optimal management conditions is a better choice."
Such is the thinking of Don Sanders, who's been taking Coumadin since he had a stroke four years ago. "You think I'm going to take a drug that's just been approved?" said Sanders, 59, of Smithfield, N.C. "I'm going to take Coumadin . . . because I'm betting on the fact that the odds are in my favor to not have another stroke."
Sanders points out that warfarin has been around since Eisenhower was president, and it has no significant side effects for him other than the admittedly serious bleeding risk. If Sanders nicks himself, he says the cut may leak for a couple of hours. And when he gets in a car, he says he does feel a little paranoid - "That's the only side effect," Sanders added.
And although all patients on blood thinners need to stop taking their anticoagulant a few days prior to major or minor surgery, there is no antidote to reverse the blood-thinning effects of these new thrombin and Factor Xa inhibitors if a patient has a major trauma. Warfarin patients can get an infusion of Vitamin K or other clotting factors to speed the process.
"Even though we don't have an antidote, there are things we can do that accelerate blood clotting," Mount Sinai's Halperin, a consultant for the makers of Pradaxa, said, adding that "there's an advantage to wearing off quickly."
Then there's the cost.
Sanders pays about $4 a month for Coumadin. A daily dose of Pradaxa sells for $6.75, according to the drugmaker. However, a November study in the Annals of Internal Medicine suggested Pradaxa may be a cost-effective alternative to warfarin because it won't require regular blood testing, which can cost up to $250 a month, Prystowsky says. Most insurance plans pay for a significant portion of these tests.
Still, many patients have done well with warfarin, and will continue to do so. Those who have trouble with it will now have other possibilities.
"It'd be a mistake to think that warfarin is simply going to go away," said Douglas Packer, president of the Heart Rhythm Society and a professor of medicine at the Mayo Clinic. "I'm enthusiastic about the changes that are occurring, but the burden remains on us [clinicians] to manage patients appropriately."