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January 26, 2006; Los Angeles Times

Bayer´s Trasylol: Multiple Risks of Surgery Drug Seen

A drug widely used during heart surgery to control bleeding doubles the risk of kidney damage, forcing an estimated 10,000 patients onto dialysis each year, according to a study from a group calling for surgeons to abandon its use.

Known as aprotinin (Trasylol), the drug also increases the risk of heart attack by 48%, heart failure by 109% and stroke by 181%, the study of about 4,400 patients reports today in the New England Journal of Medicine.

The researchers added that the drug was not even needed in most cases because there were two generic drugs that cost a tenth as much and were nearly as good at stopping bleeding yet produced no increased risk.

"I wonder how we can ethically prescribe aprotinin when there are alternatives that are safer," said Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation, who led the study.

The drug, which is derived from the lung tissue of cows, was approved by the Food and Drug Administration in 1993. It is used in a significant number of the 1 million heart surgeries performed worldwide each year, largely because it is slightly more effective than alternative drugs and has been well-marketed by its manufacturer, Bayer Corp.

Surgeons and anesthesiologists had suspected potential problems with the drug for many years, but the number of adverse side effects was lost among the huge number of patients given the drug.

"We didn't have good, hard data to prove it," said Dr. O. Wayne Isom, chairman of the department of cardiac and thoracic surgery at New York Presbyterian Hospital/Weil Cornell Medical College. The results are "pretty much undebatable," Isom said.

The study estimated that the side effects from aprotinin had increased medical costs by more than $1 billion per year worldwide. A spokesman for the FDA said the agency was aware of the study and was reviewing the data.

Bayer, which sells aprotinin under the brand name Trasylol, said in a statement that it had not analyzed the study but the results were not consistent with its experience. Bayer, with annual sales of about $40 billion, has predicted about $606 million in sales of the drug this year, nearly triple the $213 million of 2004.

The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, sponsored by the Ischemia Research and Education Foundation in San Bruno, Calif. The groups receive no money from pharmaceutical companies.

In other recent studies, the consortium has shown that giving inexpensive beta blockers after major surgery could save 250,000 lives a year, that aspirin use after heart surgery reduces the risk of blood clots, and that the painkiller Bextra is associated with stroke and the impaired healing of wounds.

Mangano said the team started the study because the medical and surgical treatments of heart attacks were contradictory. Medical treatment uses clot-dissolving agents and a class of drugs that inhibit clotting, called antifibrinolytics, to forestall further attacks. But in heart surgery, drugs such as aprotinin are used to promote clot formation to prevent internal bleeding.

"But isn't the patient who received aprotinin likely" to have a heart-attack-inducing clot? Mangano asked. "It seems very logical."

The team enrolled 4,374 patients at 69 medical centers in seven countries who were undergoing coronary surgery to reopen a blocked artery.

The control group, which totaled 1,374 patients, received a placebo, while 1,295 received aprotinin, 883 were given epsilon-aminocaproic acid and 822 received tranexamic acid.

Epsilon-aminocaproic acid and tranexamic acid are generic drugs that promote clot formation. A dose of the former costs $11 and a dose of the latter $44; a dose of Trasylol costs $1,300.

The most common side effect in the study was kidney dysfunction or failure, occurring in 8% of those receiving aprotinin and in 4% of those receiving tranexamic acid and 3% of those receiving epsilon-aminocaproic acid or a placebo.

The result is not surprising, Mangano said, because other studies have shown that aprotinin is taken up by tubules in the kidneys and stays there for 24 hours or longer, interfering with normal organ functions.

The side effects were not seen in earlier studies, he said, because they were too limited to illuminate the relatively small difference in incidence between the two groups of patients. The other serious side effects caused by the drug involved even fewer patients.

"If this data is correct, it will change our practices," said Dr. Nicola D'Attellis, a cardiac anesthesiologist at Cedars-Sinai Medical Center in Los Angeles. "This is really going to push people to do other research."

The study also showed that the risk of serious side effects increased with larger doses. That is significant, Dr. Gus J. Vlahakes of the Harvard Medical School wrote in one of two editorials in the New England Journal of Medicine, because Bayer is initiating trials using aprotinin to reduce inflammation after cardiac surgery. The trials involve higher doses than are now used. "Now the onus is on (Bayer) to prove that, for any other application, the drug is safe," Mangano said. (By Thomas H. Maugh II, Writer)


New England Journal of Medicine, Number 4, Volume 354:353-365
January 26, 2006

The Risk Associated with Aprotinin in Cardiac Surgery

Dennis T. Mangano, Ph.D., M.D., Iulia C. Tudor, Ph.D., Cynthia Dietzel, M.D., for the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation

ABSTRACT
Background: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition - namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken.
Methods: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin (1295 patients), aminocaproic acid (883), and tranexamic acid (822)) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.)
Results: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss.
Conclusions: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

Source Information
From the Ischemia Research and Education Foundation, San Bruno, Calif.
Address reprint requests to Dr. Mangano at the Editorial Office, Ischemia Research and Education Foundation, 1111 Bayhill Dr., Ste. 480, San Bruno, CA 94066, or at dtb@iref.org .


New York Times, January 26, 2006

Study of Bypass Patients Urges Dropping Drug Used to Reduce Bleeding in Heart Surgery

A drug used worldwide to reduce bleeding during heart surgery can increase the risk of kidney failure, heart attacks and strokes, and should be abandoned, doctors are reporting today. They say other medicines are safer and cheaper, and should be used instead. The drug, aprotinin, is sold under the brand name Trasylol and made by Bayer. The company disputed the new findings.

Heart surgeons said the new report, being published today in The New England Journal of Medicine, was important and persuasive, but not definitive. Although the drug has risks, they said, it may still be helpful in some surgical patients who have an unusually high risk of severe bleeding. The Food and Drug Administration is examining the data on aprotinin, a spokeswoman, Susan Cruzan, said, "and will make recommendations for best use as soon as possible."

Aprotinin (pronounced a-PRO-ti-nin) has been on the market for 13 years. The report in the journal is based on a study of 4,374 patients having bypass surgery in Canada, Colombia, Europe, Israel, Mexico, Thailand and the United States. To limit blood loss, 1,295 were given aprotinin and 1,705 one of two other drugs, both generics, aminocaproic acid or tranexamic acid. A control group, 1,374 patients, had no drugs to prevent bleeding.

Compared with the other patients, those given aprotinin had twice the rate of kidney failure, 5 percent. They also had increases in other serious problems, including heart attacks, heart failure, strokes and a diffuse type of brain damage called encephalopathy. The article said halting aprotinin use globally would prevent 10,000 to 11,000 cases of kidney failure a year and save more than $1 billion a year in dialysis costs, as well as nearly $250 million spent on the drug itself.

"It would be nearly impossible for me to recommend using the drug in this patient population," said Dr. Dennis T. Mangano, the director of the study and the founder of a group that paid for it, the Ischemia Research and Education Foundation.

Bayer said in a statement, "Bayer believes that Trasylol is a safe and effective treatment." One potential flaw in the study is that the patients were not picked at random to have one treatment or the other. Rather, their doctors made the decision about which drug to use. That means that in theory the groups could be skewed. Doctors might have assigned sicker patients to a particular drug that could make the results for that drug look especially bad.

On the other hand, the study was large, with copious figures collected for each patient in an effort to minimize biases. "The study shows the drug has risks," said Dr. Gus J. Vlahakes, chief of the division of cardiac surgery at Massachusetts General Hospital, who wrote an editorial that accompanied Dr. Mangano's article. "You shouldn't give it to everybody having heart surgery." Instead, Dr. Vlahakes said, it should be reserved for patients with unusual bleeding problems, because it works better at stopping bleeding than the other two drugs. At his hospital, with about eight heart operations a day, he said, Trasylol is probably used less than once a day. Worldwide, about one million people a year have bypass surgery, and two-thirds to three-quarters of them are given Trasylol or one of the other two drugs to limit blood loss, Dr. Mangano said.

Use of Trasylol has varied, with some doctors favoring it and others avoiding it because of concerns that it may cause clots. Some doctors have also resisted using Trasylol because of its cost, more than $1,000 a patient, as opposed to $10 to $50 for the other drugs.

Last year, sales totaled $200 million. This year, Bayer projections are much higher, $600 million. In recent years, the company has been marketing Trasylol to prevent inflammation, as well as bleeding, in bypass patients. Its Web site suggests using the drug in all patients put on heart-lung machines for bypass surgery and explains the drug's role in inhibiting inflammation.

Dr. Vlahakes said preventing inflammation might require higher doses of the drug than those now being used. In view of the new safety information, he said, "I think there's no way" that the drug could be so broadly used, particularly at higher doses. Bayer is also studying Trasylol in hopes of having it approved to prevent blood loss from hip replacement and spinal surgery. Currently, Trasylol is given to heart-surgery patients intravenously along with a plethora of other medicines, and most people do not even know that they are receiving it. Doctors do not need special permission to administer it.

Given his findings, Dr. Mangano said, doctors should warn patients about the potential risks and ask for their consent to use it. "I cannot see how a patient would elect to use this drug as opposed to the others," he said.

Dr. Timothy J. Gardner, the medical director of the Center for Heart and Vascular Health at the Christiana Care Health System in Newark, Del., and a spokesman for the American Heart Association, said the article would have substantial effects on medical practice. Dr. Gardner said the findings were worrisome because many patients had been taking other drugs that increased the tendency to bleed, and surgeons sometimes need all possible help to stop excess blood loss. Dr. Vlahakes agreed. "It's 2 o'clock in the morning and you can't stop the bleeding," he said. "That's every surgeon's nightmare." (By DENISE GRADY)