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FDA to Review Clotting Drug After Trial Suggests Death Risk

THURSDAY Oct. 25, 2007 -- The U.S. Food and Drug Administration said Thursday that it will review the safety of the clotting drug aprotinin (Trasylol), after a major Canadian trial was stopped early due to an increase in deaths for cardiac surgery patients placed on the drug.

Trasylol, first approved by the FDA in 1993, is typically used to limit blood loss in patients undergoing cardiac surgery.

While less bleeding was noted in the aprotinin group versus patients assigned one of two other drugs, "a trend toward increased mortality in the aprotinin group had been observed throughout the study," the FDA noted in a statement released Thursday.

That elevated 30-day and overall death risk caused the Canadian study's Data Safety Monitoring Board (DSMB) to recommend stopping patient enrollment in the so-called BART trial. The trial was set to recruit about 3,000 adults who were candidates for a variety of cardiac surgeries and were at high risk of bleeding.

"The DSMB concluded that continued enrollment of patients into the aprotinin group was unlikely to significantly change the study findings," the FDA said.

Trasylol's maker, Bayer, also issued a new "guidance" to doctors on Thursday. The German company advises "that physicians use Trasylol only in accordance with approved product labeling." Bayer said it believes the drug "remains a safe and effective treatment option for physicians," but it is working with the FDA and international health authorities to see if any label changes might become necessary as new data emerges.

Trasylol has had a checkered history since it was first approved by the FDA in 1993.

On Sept. 12, a U.S. Food and Drug Administration advisory panel recommended that aprotinin remain on the market, despite evidence that it might have serious side effects.

In February, a study published in the Journal of the American Medical Association found patients on the drug were at greater risk of dying over the next five years than those given two other medications. The same researchers linked aprotinin to an increased risk of kidney failure, heart failure and stroke in a study published in 2006.

"Our present findings deal with death," one of the JAMA study's authors, Dr. Dennis T. Mangano, said at the time. Mangano, director of the Ischemia Research and Education Foundation, a California-based nonprofit group, said that "the death rate for aprotinin patients far outstrips that for the other two drugs."

His team's study tracked the long-term survival of nearly 3,900 heart patients who underwent coronary artery bypass surgery at 62 medical centers worldwide. The researchers tabulated survival at six weeks, six months, and then annually for five years.

The five-year death rate for patients given aprotinin was 20.8 percent, compared to 15.8 percent for those given another drug, aminocaproic acid, and 14.7 percent for those given tranexamic acid. Both alternative drugs are available in generic versions.

After the 2006 report from Mangano's group, the FDA advised doctors to carefully monitor aprotinin patients for kidney, heart and brain damage -- an action taken after Bayer disclosed study data showing that it increased the risk of death, kidney damage, congestive heart failure and stroke.

The 2006 report led to a 37 percent reduction in surgeons' use of aprotinin, Mangano said. "Clinicians, more than anyone else, will decide whether this drug should be on the market or its use should be limited," he said.

Aprotinin does have its defenders.

Dr. T. Bruce Ferguson Jr., associate director of cardiothoracic and vascular surgery at East Carolina University, wrote an accompanying editorial to the JAMA study. He believes the study "was inadequate to address the question they were asking because of the way the database was designed."

"The most important factor they were unable to control was why patients got aprotinin," Ferguson said. "There were no data to address that issue, and therefore it cannot account for physician-related bias."

For example, the higher rate of death and other complications linked to the drug might be due to aprotinin being prescribed for "higher-risk patients who could be expected to have a worse outcome and higher mortality," Ferguson said. Other studies have shown that "in carefully selected patients, aprotinin is a good drug," he said.

The information used in the study was thorough and complete, Mangano countered. "In terms of the database, we had between 7,000 and 10,000 pieces of data per patient from 59 centers in 16 countries, including 23 of the 25 top cardiac centers in the United States."

"The findings speak for themselves," Mangano said. "I think they are as accurate as you can get."

He believes that aprotinin's use should be restricted to about 5 percent of patients in whom other drugs could not be used.

"And the surgeon would have to tell each patient before using this drug that there is literature out there showing that this drug is associated with renal [kidney] failure and death," Mangano said. "For the vast majority of patients, there are the two other alternatives."

More information

There's more on cardiac surgery at the U.S. National Library of Medicine.

Posted: October 2007


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