Multiple Risks of Surgery Drug Seen
By Thomas H. Maugh II
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, 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.
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