Feb. 17, 2008, CBS

Researcher: FDA Was Too Slow On Trasylol

Tells 60 Minutes He Estimates 22,000 Lives Could Have Been Saved

A renowned researcher calculates that 22,000 patients could have been saved if the Food and Drug Administration removed the heart surgery drug Trasylol two years ago, when his study revealed widespread death associated with it.

The researcher, Dr. Dennis Mangano, also tells 60 Minutes correspondent Scott Pelley that Bayer, the drug's maker, failed to tell the FDA about negative results of their own Trasylol study and that the company's failure placed the drug's success before patient well-being.

Mangano’s interview will be broadcast this Sunday, Feb. 17, at 7 p.m. ET/PT.

Bayer suspended sales of the expensive drug, used to limit bleeding in heart surgery, last year at the request of the FDA, after a Canadian study of Trasylol was stopped because of patient deaths, causing a ban of the drug in Germany, where Bayer is based. At the height of its use, Trasylol was given to about a third of all heart bypass patients in the United States. In Germany, the figure was far higher.

Mangano believes Trasylol should have been taken off the market when he published his study in January 2006, a study that associated the drug's use with kidney failure requiring dialysis and increased death of those patients. Between the study’s publication and November 2007, when Bayer removed the drug, "There were approximately 431,000 patients who received the drug," says Mangano. "As I calculated, 22,000 lives could have been saved. It’s about a 1,000 lives per month," he tells Pelley.

In September 2006, Mangano presented his observational study of 5,065 patients in 17 countries to the FDA in hopes it would persuade them to pull the drug. Bayer senior executives attended the meeting to defend their product and at the time, their company had results from its own research that confirmed Mangano’s results. But the Bayer executives failed to disclose the existence of the study. Mangano says this was irresponsible. "The Bayer representatives at the meeting…should have disclosed fully to the FDA that a study was done…even put the meeting in abeyance until the data were found or discussed," Mangano tells Pelley. "Good medicine demands that you protect the patient. That’s the issue here and not the drug and not the profit margin," he says.

The chairman of the FDA committee that held that meeting, Dr. William Hiatt, told 60 Minutes that he would have voted to remove Trasylol from the market if he had known about Bayer’s study. He also took issue with Bayer's failure to disclose it. "I thought it was unusual. I thought it was truly inappropriate," he tells Pelley.

Bayer was also made aware of Trasylol's potential to harm kidneys early in the drug's development, according to a German scientist. Dr. Juergen Fischer, the director of the Institute of Experimental Medicine at the University of Cologne, near the German city where Bayer is headquartered, found the drug caused severe kidney damage in animals. He said he told Bayer about his results in the early 1980s, but, "I felt that Bayer wasn't interested to examine these side effects," he says. "There was no study organized to look at these side effects specially," Fischer says.

The drug has always carried a warning of various side effects, including renal (kidney) effects.

Neither Bayer nor the FDA would speak to 60 Minutes for this story. Bayer sent a letter stating, in part: "The available data continue to support a favorable risk-benefit profile for Trasylol when used according to labeling."

The company plans to assess whether the drug can be remarketed after further research.

Interview with Dr. Fischer
Bayer Halts U.S. Sale of Trasylol
Bayer apologizes to FDA panel on Trasylol data
Bayer failed to report risks of drug
US reviewing safety of Bayer heart-surgery drug

Feb. 21, 2008, Bloomberg

Bayer's Trasylol Boosts Death, Kidney Risks After Heart Surgery

Bayer AG's Trasylol, a drug whose sales were halted last year, raises the risk of death and kidney damage when used to control bleeding in heart surgery, two studies in the New England Journal of Medicine found.
Trasylol patients were 27 percent more likely to die than those getting a rival drug a decade after open-heart surgery, according to a review of 10,275 consecutive patients at Duke University Medical Center. Another study of 78,199 patients, presented to regulators last year after Bayer initially withheld it, found a 78 percent higher death risk a week after surgery.
Trasylol was approved in the U.S. in 1993 to reduce transfusions and bleeding during open-heart surgery. It became a mainstay of care, generating about $333 million in 2005, until an international study the next year tied it to higher rates of heart attack, stroke, kidney failure and death. Leverkusen, Germany-based Bayer suspended sales in November after a pivotal Canadian trial linked it to higher death rates.
``It's become part of the fabric of cardiac surgery for the past decade,'' said Andrew Shaw, lead author of one study and associate professor of anesthesiology at Duke, in a telephone interview. ``Our study doesn't provide a definitive answer, but it intensifies the debate over the drug safety.''
Bayer challenged the findings from both studies, raising questions about how the researchers analyzed the data and accounted for differences between the patients getting Trasylol and those on the alternate, generic drug aminocaproic acid.

Sicker Patients
Trasylol patients were sicker, which could have altered the results even after researchers tried to adjust for differences, everyone involved agreed.
Two U.S. Food and Drug Administration advisory panels, including one that had information on the research, recommended keeping the drug on the market. The studies, which looked back at how patients fared without first putting them in treatment groups, aren't considered conclusive.
Bayer, Germany's largest drug company, is waiting for a detailed analysis of the more definitive Canadian trial that was halted last year to determine the most appropriate course of action, said Staci Gouveia, a company spokeswoman. Officials will work with the FDA after the information is available to see what impact it, and other recent research, should have on Trasylol, she said in a statement.
``At that time, the temporary marketing suspension will be re-evaluated,'' she said, adding that the company has no idea when the details will be available. ``Bayer believes that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol.''

200,000 Patients#
More than 200,000 bypass patients a year worldwide were getting Trasylol before sales were halted. The company has said 4.3 million people have been treated with the injectable drug. It costs 10 times more than its closest rival.
Sebastian Schneeweiss, the lead researcher of the second study and an associate professor of medicine at Harvard Medical School in Boston, defended his team's work. The study was done using data from one sixth of all hospitalizations in the U.S. by Schneeweiss and other researchers at i3 Drug Safety, a unit of Minnetonka, Minnesota-based UnitedHealth Group Inc.
``It is the largest cohort study ever on the issue, representing routine care,'' he said. ``It's another data point in the accumulating number of studies that show this increased risk of death,'' Schneeweiss said in a telephone interview.
He declined to say if he thought Trasylol should be permanently removed from the market. Currently, doctors can get it through a restricted access program in the U.S.

`Informed Decision'
``The data have to be reviewed and seen in the light of all the evidence,'' he said. ``The bottom line is there are still more people dying using this drug. FDA is the agency that has all the evidence together at this point, and they need to make an informed decision.''
The predicament with Trasylol underscores the need for more definitive studies on the safety of new products before they are widely used, Wayne A. Ray, director of drug epidemiology and professor of preventive medicine at Vanderbilt University School of Medicine, wrote in an editorial accompanying the studies. Such drugs should be compared directly to their rivals, he said.
``The manufacturer cannot be relied on to perform these studies voluntarily, because they frequently serve no commercial purpose,'' Ray wrote. As a result, the studies ``supervised by the FDA, should be mandatory. To limit the risk for patients, distribution of new drugs should be restricted while these trials are being conducted, with selective extension of patents to reduce the economic burden on manufacturers.'' By Michelle Fay Cortez