Trasylol (aprotinin) was FDA approved for sale in the US in 1993, as an anti-clotting medication for limited use with patients who at a high risk of blood loss while undergoing coronary artery bypass surgery.
The intended effects of Trasylol during surgery include reduced bleeding, a decreased need for re-exploration surgery for bleeding, which in turn should lessen the need for transfusions. The drug works by disabling the enzymes that dissolve blood clots.
Despite the approval for limited use, Trasylol has been used off-label with many patients undergoing other types of surgery. In fact, the rate of off-label use far exceeds the rate of on-label use. The FDA's Adverse Event Reporting System shows that the majority of adverse events reported, or about 75%, occurred in patients who received Trasylol for an unapproved use, with heart valve replacement being the most frequent.
According to Dr Mangano, Trasylol was administered to 246,000 patients in the US in 2006. Bayer had been seeking FDA approval for Trasylol to be used with patients undergoing spinal fusion and hip replacement surgery until 2 negative studies were published early last year.
The latest JAMA study was conducted by the Multicenter Study of Perioperative Ischemia Research Group, and sponsored by the California-based Ischemia Research and Education Foundation, between November 11, 1996, and December 7, 2006, and patient survival was assessed at 6 weeks, 6 months, and annually for 5 years after surgery.
The researchers compared long-term all-cause mortality in patients receiving aminocaproic acid, tranexamic acid, Trasylol or no drug at all.
A previous study by the same research team evaluated 4,374 patients undergoing coronary artery bypass surgery found patients who received Trasylol were at an increased risk for serious kidney problems, heart attack, stroke, and deaths, compared to patients who were given the same 2 alternative anti-clotting agents or no drugs at all.
The study was the first comprehensive, observational, non-industry funded analysis of Trasylol's safety and was based on a systematic sampling of 69 of the world's leading cardiac centers and institutions in North and South America, Europe, the Middle East and Asia.
When broken down into separate categories, the analysis showed that Trasylol use was associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, a 181% increase in strokes, and a 2-fold increase in renal failure. The study was published in the New England Journal of Medicine in January 2006, and reported that the alternatives drugs did not cause the side effects identified with Trasylol.
After reviewing the results, the research team pointed out that although the other 2 drugs were available, safe and "equally effective in limiting bleeding," they are "underused."
There is one major difference in the medications and that is the price. According to Dr Mangano, Trasylol costs roughly $1,300 per patient and the prices for the other drugs are $11 and $44.
"We estimate that as many as 10,000 patients may be unnecessarily on dialysis today due to aprotinin use," Dr Mangano said in Senior Journal.com.
"This serious impact on human lives," he says, "underscores once again the necessity for meticulous, post-approval surveillance, as well as ongoing, unbiased analysis of drug safety—all conducted by entirely independent entities."
He reports that by replacing Trasylol with one of the alternative drugs, at least $1 billion in health care costs could be saved and at least $250 million more would be saved from the reduced cost of the drug itself.
Another study published in the January 20, 2006 online edition of the journal Transfusion also found an increase in kidney problems among patients who received Trasylol while undergoing heart surgery.
Following the release of the results from these earlier studies last year, a number of physicians, consumer advocates, and Dr Mangano's research group called on the FDA to remove Trasylol from the market.
The FDA opted not to recall the drug but the agency did begin a reassessment of the safety risks associated with Trasylol. In September, 2006, Bayer submitted new data on the drug to the FDA and company officials also testified about their own positive studies regarding the safety of the drug before an FDA advisory committee and made a series of accusations against the reliability of Dr Mangano's study.
However, within days of their testimony, a researcher on a study that Bayer did not share with the FDA panel, alerted the media about the existence of a study that produced far different results than those reported by Bayer representatives at the hearing.
As it turns out, Bayer paid a contract research organization to conduct a study of existing hospital records from 67,000 patients and apparently was not happy with the results.
Of that group, 30,000 patients were treated with Trayslol, and 37,000 were treated with alternate drugs, and according to the FDA's December 15, 2006, announcement of the new labeling for Trasylol, "preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
The latest study by Dr Mangano's team, compared the death rates of 1,072 patients on Trasylol, 834 on aminocaproic acid; 442 patients on tranexamic acid, and 1,374 patients who did not receive any medication.
The alarming results found patients who received Trasylol were about 50% more likely to die within the five years following surgery. At the five year mark, there were 223 deaths in Trayslol group, 132 in the aminocaproic acid patients, and 65 in the Cyklokapron group.
And once again, the study found that neither of the other drugs showed a significantly higher death rate when compared to patients who receive no medication and the authors concluded:
Use of aprotinin ... does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.These findings indicate that in addition to the previously reported acute renal and vascular safety concerns, aprotinin use is associated with an increased risk of long-term mortality.
It should be noted that Bayer said the findings of the new study are unreliable because the study did not adequately reflect the complexity of illness in patients given its drug.
READ MORE LEGAL NEWS
In the Trasylol label changes announced on December 15, 2006, the FDA said it should only be given to patients who are at an increased risk for blood loss and transfusion in the setting of coronary bypass graft surgery when patients undergo cardiopulmonary bypass. The FDA also warned that patients should not be given Trasylol if they had already received the drug within the past year.