"Our findings raise very serious concerns about this drug," one of the study's authors, Dennis T. Mangano, M.D., Ph.D., tells WebMD.
The researchers conclude that "continued use of aprotinin in this population does not appear prudent, given that safer alternatives ... are available."
For the study, researchers examined outcomes among almost 4,000 bypass surgery patients followed for five years. More deaths occurred in patients treated with aprotinin than in those treated with two other blood-loss-limiting drugs — aminocaproic acid and tranexamic acid.
The scientists concluded that 10,000 deaths could have been avoided over the five-year period "had aprotinin been replaced with either of these generic agents."
The report is published in the Feb. 7 issue of The Journal of the American Medical Association.
But Bayer Pharmaceuticals, maker of Trasylol, the trade name for aprotinin, questioned the "methodological and analytical approaches" used in both this and an earlier study from the same researchers that also raised questions about the drug.
A statement from the drugmaker says that "based on this initial review (of the new research), Bayer believes that the results of this study should not serve as a basis for affecting the use of aprotinin in clinical practice."
Aprotinin is used during coronary artery bypass graft surgery — a procedure to improve blood flow to the heart muscle.
In surgery patients who undergo a cardiopulmonary bypass, in which a machine is used to help pump blood and to add oxygen to the blood during the bypass graft surgery, aprotinin is sometimes used to reduce blood loss and the need for a transfusion.
But, says Mangano, "This drug has been approved for use in the United States for the past 13 years, but its long-term safety has not been studied until now."
Early last year, Mangano and colleagues from the Ischemia Research and Education Foundation in San Bruno, Calif., reported that aprotinin use was associated with a doubling or tripling of the risk of kidney damage and kidney failure immediately following bypass surgery. Findings from this and one other study led the FDA to strengthen its safety warning for the drug, calling for its use only in patients "at increased risk for blood loss and blood transfusion."
But Mangano says the new labeling does little to increase patient safety. "Just about any patient undergoing bypass surgery is at risk for bleeding," he says.
The team's latest study was conducted using the same registry of heart bypass patients as its earlier one. The patients were treated at 69 cardiac surgery centers in North and South America, Europe, and Asia. Data from 3,876 patients were reviewed and postsurgical survival was assessed at six weeks, six months, and then annually for five years.
During this time, about 21 percent of the aprotinin-treated patients died, compared with 16 percent of patients treated with aminocaproic acid and 15 percent of patients treated with tranexamic acid. Roughly 13 percent of patients who did not receive blood-loss-limiting treatment died during the same period.
In Bayer's statement Tuesday, company officials say, "One of the limitations of both of these studies is that doctors chose whether to administer aprotinin or another treatment based on a patient's condition."Generally, sicker patients who were already at greater risk for mortality [death] were treated with aprotinin," according to Bayer.
However, in an earlier news release, Baer officials acknowledged withholding preliminary findings from its own safety study of the drug from an FDA advisory committee last September.
According to an FDA statement published in mid-December, results from Bayer's study suggest "that in addition to serious kidney damage [aprotinin] may increase the chance for death, congestive heart failure, and strokes."
That Bayer news release, issued just days after the September FDA committee meeting, acknowledged that withholding the information was "a mistake."
"Bayer believes that despite the highly preliminary nature of this data, the information should have been shared with the FDA prior to the Sept. 21st advisory committee meeting held to assess the safety and efficacy of (aprotinin)," the statement reads. "This was a mistake on the company's part."
Cardiac surgeon T. Bruce Ferguson Jr., M.D., of East Carolina University says the safety concerns surrounding aprotinin highlight the need for better ways to assess drug safety.
"Ultimately, going forward, the most important lesson learned from the aprotinin story is determining better ways to ensure drug safety and to eliminate and prevent these harms," he writes in an editorial, also published in the Feb. 7 issue of JAMA.
In an interview with WebMD, Ferguson says drug companies have no incentive to collect safety data on their products once they've been approved for sale.
"This is a huge piece of the puzzle that we don't have right now," he says. "Just because the FDA approves a drug or a medical device, that doesn't mean that the industries that market them don't have a responsibility to continue to collect this critical safety data."
SOURCES: Mangano, D., The Journal of the American Medical Association, Feb. 7, 2007; Vol. 297: pp. 471-479. Dennis T. Mangano, M.D., Ph.D., Ischemia Research and Education Foundation, San Bruno, Calif. T. Bruce Ferguson Jr., M.D., division of cardiothoracic and vascular surgery, East Carolina University, Greenville, N.C. Ferguson, T., The Journal of the American Medical Association, Feb. 7, 2007; Vol. 297: pp. 527-529. Mangano, D. The New England Journal of Medicine, 2006; Vol. 355: pp. 2171-2173. News release, Bayer. News releases, FDA.
By Salynn Boyles
Reviewed by Louise Chang, M.D