By Marc Kaufman
Washington Post Staff Writer
Thursday, January 26, 2006
A popular drug given to more than a million people since 1993 to limit blood loss during heart surgery doubles a patient's risk of kidney failure and substantially increases the risk of a heart attack, a major study has found.
The research, being published today in the New England Journal of Medicine with a supportive editorial and commentary, concluded that use of the drug -- Bayer Corp.'s aprotinin -- causes more than 11,000 patients worldwide to need kidney dialysis each year.
The authors said that in light of their findings, and the fact that two other less harmful and far less expensive alternatives exist, it is no longer "prudent" for doctors to use the drug except in unusual circumstances. If they continue with the drug, the authors said, doctors have a moral obligation to inform patients about the risks.
The Food and Drug Administration said it is reviewing the study and "will make recommendations for best use as soon as possible." Bayer said that it had only recently become aware of the research, and that it is "not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug."
With the industry and the agency still reeling from the contentious withdrawal of the arthritis drug Vioxx in 2004 because of safety concerns, the new finding underscores how difficult it is to know the risks of a drug once it goes on the market.
"We have a real problem with safety once a drug is approved," said study lead author Dennis T. Mangano of the Ischemia Research and Education Foundation in California, a nonprofit group that has been collecting and analyzing the aprotinin data since 1996.
The FDA "can't mandate safety studies, and it's very expensive and risky for the drug company to do them on their own once a drug has been approved by the agency," Mangano said. "The system is not set up to assess safety in a general way once a drug is on the market."
Aprotinin, sold as Trasylol, has been widely studied since it was approved in 1993, but most of the research has focused on its effectiveness.
Mangano's research, however, found not only a greatly increased rate of kidney failure, but also a 50 percent increase in heart attacks and an almost 200 percent increase in strokes. The study also found that two other generic drugs in a different class were as effective as aprotinin in stanching bleeding after surgery, were safer and cost less than one-tenth the price. In its statement, the FDA said it will now compare the safety of aprotinin and the other products.
The study was based on data collected from 4,374 patients at 69 sites worldwide who underwent heart or coronary artery surgery. About 1,300 were given aprotinin, about 1,300 received no drug to stop bleeding, and more than 800 were treated with each of the two other generic anti-bleeding agents. Although the study was not a placebo-controlled and randomized clinical trial -- considered the gold standard for medical research -- it followed enough patients to give it "credibility," wrote Gus J. Vlahakes, chief of cardiac surgery at Massachusetts General Hospital, in an accompanying editorial.
Mangano said the increased risk of kidney failure makes sense physiologically because it is known that aprotinin, which is derived from the lung tissue of cows, generally stays in the kidneys for 24 hours and can cause damage. The two other drugs used to limit bleeding in the study are generally excreted quickly by the body.
Mangano said a 1998 study sponsored by Bayer had reported data that strongly suggested that aprotinin increased the risk of blood clotting, which can lead to heart attacks. He said the authors dismissed the results as reflecting extraneous issues.
In the Vioxx case, an early study sponsored by Merck & Co. similarly found a higher risk of heart attack and stroke in patients on its drug than in those on a comparison medication. In that case, the authors contended the control drug, Naproxen, had lowered the risks, not that Vioxx had raised them.
"I believe there was a safety signal coming out of the [1998 Bayer] study, maybe a pink flag rather than a red flag," Mangano said. "I think at that point more attention should have been paid."
Under current FDA policies, drug companies generally establish the effectiveness and safety of their products in clinical trials that include hundreds, and sometimes thousands, volunteers -- many of them healthy. Once drugs are on the market, however, they are often taken by millions of patients, many of them sick and weakened.
Bayer officials have been upbeat about ongoing and future sales of aprotinin, projecting $275 million in worldwide sales for 2005 and double that figure for this year. The company has been conducting trials of the drug to limit bleeding in hip replacement surgery, and hopes to apply for FDA approval for this use soon.
The company did not have international statistics on use of aprotinin, but said about 150,000 American patients were given the drug in 2005.