No drug probably is cheaper and more effective in preventing strokes in a large and growing patient population than the anticoagulant warfarin, more commonly known by its brand name Coumadin, and probably no drug is more of a money-loser and thankless chore for hospitals.
Patients would probably be thrilled to get out from under the incessant monitoring and dosage readjustment associated with the drug, too.
Steven Almany, vice chief of cardiology at 226-bed William Beaumont Hospital in Royal Oak, Mich., says the hospital's anticoagulation management service monitors about 2,600 patients taking warfarin for a variety of reasons. The drug probably costs patients less than $1 a day, compared with perhaps $3 a pill for what an alternative will probably cost, Almany says, but dosage monitoring is the costliest part. The Beaumont service was created five years ago to relieve the burden from doctors who didn't have the time and received nearly no reimbursement beyond the costs of the blood test. The rationale was that the hospital would do a better job and would also have better success in getting payment from insurers for keeping their patients out of the hospital, Almany says. That thought was soon dashed: Beaumont's anticoagulation management service was losing $500,000 annually until two years ago when the hospital began to charge patients $60 per calendar quarter for three or four routine but essential blood checks. Now the anticoagulation management service is merely a break-even operation, he says.
"Have we shown less complications? No question about it. Have the insurance companies anted up and defrayed the costs? No," Almany says. "The hospital is doing it more as a public service than anything else."
Similarly, Geno Merli, director of the division of internal medicine at 816-bed Thomas Jefferson University Hospital and Jefferson Medical College in Philadelphia, says that although the hospital's anticoagulation service charges $20 for blood testing, insurance reimburses only $8. The test costs $6, not including the physician's time.
To remedy the burden for patients, drug companies for years have been working to develop an alternative drug that doesn't require constant dosage monitoring, that doesn't adversely interact with a multitude of foods and drugs and that doesn't come with deadly side effects of bleeding and stroke. But conquering the business proposition of warfarin may prove even more daunting than conquering the clinical proposition.
The first drug up to the plate as a pinch-hitter for Coumadin, which is manufactured by Bristol-Myers Squibb, was Ximelagatran, developed by AstraZeneca. It struck out when the Food and Drug Administration declined to approve it in September 2004, apparently because of worrisome side effects. However, this simply marks the beginning of the ballgame, experts say. Ximelagatran might get another chance at bat, and there also is a roster of other players in the dugout, although they are less-seasoned.
Based on a review of the available literature and interviews with experts, the Health Technology Center, or HealthTech, in San Francisco, a not-for-profit think tank focused on medical and information technology, is forecasting that a more convenient anticoagulant treatment will emerge within the next two years. Still, full adoption and the elimination of the need for Coumadin clinics are another story, says Wade Aubry, a HealthTech senior adviser.
"It will take a while for the current infrastructure and method of managing patients to change," Aubry says. "One of the issues, of course, is whether coverage and reimbursement will be favorable for physicians and hospitals. ... One thing we've found is there is a resistance from physicians to change a mode of practice to something new, particularly if there are barriers such as reimbursement and coverage."
Anticoagulant drugs such as warfarin are widely used for a broad array of cardiovascular problems, and most commonly for cardiac rhythm disorders, says Jonathan Halperin, director of clinical cardiology services at Mount Sinai Medical Center in New York. The drug is also recommended for patients with mechanical heart valves, deep vein thrombosis or pulmonary embolisms. Typically, Aubry notes, hospital patients suffering from blood clots will be put on intravenous heparin for immediate effect, then will be sent home with Coumadin pills. Doctors must monitor the Coumadin dosage frequently those first few days, then less frequently as the dose becomes more stabilized, he says.
Halperin, a co-chairman of the executive committee that oversaw two clinical trials for Ximelagatran, estimates about several million Americans are taking or should be taking warfarin, which is colloquially referred to as a blood-thinner but in actuality interrupts the formation of blood clots. For more than half a century, he notes, it has been the only available drug in its class of so-called Vitamin K antagonists.
Peter McCullough, chief of the division of preventive medicine at William Beaumont, says warfarin is the third most-prescribed cardiovascular drug, but "it doesn't get much fanfare because there is no commercial driver behind it," meaning it's a relatively inexpensive, generic drug. Hospital executives would welcome an alternative "because a cost center for them in all likelihood would go away," he says.
Warfarin's most dangerous side effect is internal bleeding. The drug is tricky because it interacts with many other drugs and food, especially leafy green vegetables with Vitamin K, such as broccoli, Halperin says. The vagaries of diet and medication can increase or decrease the drug's clotting ability, requiring a minimum of once-a-month blood testing.
The difficulties associated with monitoring patients on warfarin were tragically apparent in 2001 when at least two patients died at St. Agnes Medical Center in Philadelphia, now defunct as a hospital, because of a miscalculation in coagulation studies. Because of a tragic series of errors not likely to be replicated at other laboratories, lab tests did not accurately measure the blood-clotting ability of 932 patients who had such lab tests performed over a three-week period. As a result, an untold number of patients were given too much of the drug.
"You buy a whole bunch of baggage" with warfarin, says Halperin, who notes that it tops most lists of medicines associated with medication errors. Doctors don't like to prescribe the drug, so it's estimated that at least half of the 1 million patients in the U.S. who have atrial defibrillation -- an irregular heartbeat -- and should be taking the drug are not, he says. Of those patients who do take the drug, less than half "are taking the right dose at any given moment," Halperin says. "The price you pay is an increased risk of stroke or major bleeding. It represents a very important unmet need to find a drug that is easier to manage, safer overall, and a more friendly medicine than warfarin."
AstraZeneca began developing Ximelagatran in 1985 and it entered the advanced stage of clinical trials in the past five years, Halperin says. The studies involved 7,000 patients with atrial defibrillation in 23 countries. Compared with warfarin "on its best behavior," the new drug proved at least as effective and caused less bleeding, even though it was given in a fixed dose without the need for constant adjusting, Halperin says. "It looked like a winner" except for the troublesome fact that 6% of the patients who took Ximelagatran in clinical trials experienced an elevation of liver enzymes. Halperin says he believes the liver toxicity problem was its main impediment to FDA approval. McCullough of Beaumont notes that three patients enrolled in the clinical trials died, although they all were already sick with a variety of illnesses before they entered the trials.
"Clearly we're disappointed," but AstraZeneca is working with the FDA and other regulatory bodies "to identify the best path forward for Ximelagatran," says Julia Walker, an AstraZeneca spokeswoman. The drug is approved in 17 countries, including eight European nations, for the short-term prevention of blood clots for patients undergoing hip or knee replacements, she says.
Halperin says there are other drugs on the horizon but none as far in development as Ximelagatran. In his view, "there is no question of its efficacy and it looked good compared to warfarin," he says. The question is how many strokes would Ximelagatran prevent and does that outweigh the risks associated with the liver toxicity problem. "We don't have enough information to answer that vital question, so the future is unclear," Halperin says.
McCullough, who reviewed Ximelagatran in 2004 for Reviews in Cardiovascular Medicine, says that drug's shortcomings do not rule out the entire class. "This is one of many in the class (oral direct thrombin inhibitors) that is being brought forward by many, so we're hopeful," he says.
An alternative drug that requires no monitoring and causes no drug interactions would be "a positive step" for the 1,000 patients who are monitored by the hospital's anticoagulation service, says Jefferson's Merli, but Merli nevertheless isn't so sure there is a panacea. Ximelagatran was a good start, but it's going to take more work on the part of pharmaceutical companies to come up with an alternative "that makes us all comfortable," he says. Merli says he is "cautiously optimistic" that a new agent will be found.
Nevertheless, a new drug won't necessarily erase all the side effects, Merli says. And unlike warfarin, Ximelagatran does not have an antidote such as Vitamin K to reverse the effects of bleeding, which can cost $10,000 per case, he says. "The question is economically how much it would be saving and, economically, my personal feeling is not" very much, Merli says. The alternatives may obviate the need for dosage monitoring, but patients will still require blood tests to determine the drug's effect on internal organs, he says.
Like Aubry of HealthTech, Merli says conversion in medicine doesn't happen overnight. For example, low-molecular-weight heparin has been around as a better alternative to heparin for nearly a generation. Low-molecular-weight heparin doesn't require the intensive monitoring heparin requires, but it's still not fully adopted after 20 years, Merli says. Why?
"Cost is a big thing," Merli says. "Heparin is very cheap."