http://www.medpagetoday.com/Cardiology/CHF/dh/2557
Commonly Used Drug in Heart Surgery May Increase Risk of Death
By Jeff Minerd, MedPage Today Staff Writer
Reviewed by
Robert Jasmer, MD; Assistant Professor of Medicine, University of California, San Francisco
January 26, 2006
Also covered by:
Forbes,
LA Times,
San Francisco Chronicle
Review
SAN BRUNO, Calif., Jan. 26 - Trasylol (aprotinin), a drug commonly given during heart surgery to control bleeding, increases the risk of serious adverse events and death, reported investigators here.
Compared with controls, heart surgery patients receiving the serine protease inhibitor had nearly double the risk of death, renal failure, or stroke and a more than 50% increased risk of heart attack, said Dennis T. Mangano, M.D., Ph.D., and colleagues of the Ischemia Research and Education Foundation, an independent, non-profit research organization.
The drug was approved by the FDA in 1993. However, the clinical trials establishing its safety were not adequately powered to detect rare events, Dr. Mangano and colleagues wrote in the Jan. 26 issue of the
New England Journal of Medicine.
Their observational study involved more than 4,300 patients undergoing coronary-artery bypass surgery with cardiopulmonary bypass at 69 medical institutions worldwide.
About 1,300 patients received Trasylol, about 900 received the generic antifibrinolytic drug aminocaproic acid, about 800 received the generic antifibrinolytic drug tranexamic acid, and about 1,300 control patients received no drug to control bleeding. Data were gathered throughout each patient's hospital stay.
Compared with the control groups, patients receiving Trasylol had double the risk of renal failure requiring dialysis (odds ratio=2.34; 95% confidence interval=1.27-4.31).
Similarly, Trasylol was associated with a 55% increase in the risk of myocardial infarction or heart failure (OR and 95% CI not given; P<0.001) and a 181% increase in the risk of stroke or encephalopathy (OR and 95% CI not given; P=0.001).
Overall, Trasylol was associated with an increased risk of all-cause death (2.8% versus 1.3% on the control group; P=0.02).
Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events, the researchers said. All three agents reduced blood loss to similar extents.
"Thus, our findings indicate that reconsideration of the safety of aprotinin among patients undergoing cardiac surgery is warranted and indicate replacement of aprotinin with either aminocaproic acid or tranexamic acid," the authors concluded.
The generic drugs are significantly less expensive, they added.
In an accompanying editorial, Gus J. Vlahakes, M.D., of Harvard Medical School and the Massachusetts General Hospital wrote, "Some surgeons and anesthesiologists who use the drug have been concerned about its potential risks since it was first approved for clinical use; yet until the report by Mangano et al., sufficient data have not been available for an analysis of the risks and benefits of aprotinin."
The editorial added, "Although this observational study was not a randomized trial, the incorporation of a large number of patients gives it credibility," he added.
Dr. Vlahakes noted that efforts are underway to expand the indications for Trasylol, based on evidence that it modulates the systemic inflammation response to cardiac surgery. The new indication may require a higher dose, he said.
"Until the safety of higher doses is fully explored in a prospective study, the expansion of indications for aprotinin may be premature," Dr. Vlahakes warned.
Bayer, the maker of Trasylol, said in a statement that the company “believes that Trasylol is a safe and effective treatment when used in accordance with the product labeling.” It said the observational study’s results in the NEJM "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug."
Bayer said it has studied Trasylol in a series of prospective, randomized, double-blind, placebo-controlled clinical trials that including almost 6,500 open- heart surgery patients worldwide, looking at 3,817 Trasylol patients versus 2,682 patients taking placebo. It compared that clinical history with Dr. Mangano’s observational results.
"Double-blind, randomized controlled trials are the accepted standard for the assessment of the efficacy and safety of drugs and serve as the basis for approval of all new drugs,” said Bayer. “Such trials do not suffer from the limitations that can exist in observational studies."
Primary source: New England Journal of Medicine
Source reference:
Mangano DT et al.
The risk associated with aprotinin in cardiac surgery. NEJM. 2006; 354:352-365.
Additional source: New England Journal of Medicine
Source reference:
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Commonly Used Drug in Heart Surgery May Increase Risk of Death
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