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Experts are questioning a decision by Health Canada to allow a controversial drug with a history of safety problems back on the market.
The department announced last Wednesday that the benefits of anti-bleeding drug aprotinin, sold under the brand name Trasylol, outweigh the risks and that it can be used in patients once again.
The decision makes Canada the only country that has reauthorized Trasylol for use in patients. The drug was withdrawn worldwide in 2007 after a study linked it to an increased risk of death.
"I was surprised and I thought that the evidence that Health Canada reviewed suggested that it was maybe wiser not to re-release it," said Stephen Fremes, head of cardiac and vascular surgery at Sunnybrook Health Sciences Centre and professor of surgery at the University of Toronto, who was involved with the 2007 study. "I think every hospital will have to decide whether they're going to bring it back on the shelves or not."
Trasylol, sold by Bayer, was initially approved for use in low-risk coronary artery bypass graft (CABG) surgery, also known as heart bypass surgery, to reduce the chances of bleeding. But many surgeons began using it for riskier treatments, such as valve replacement or repair, or "situations where we generally think the risk of bleeding is higher," Dr. Fremes said. Using a drug in a capacity for which it was not specifically approved is called "off-label" use and is a common and legal practice in the medical community.
But then a Canadian study, titled Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), suggested the drug may be linked to a higher risk of death in patients given it. The study examined high-risk patients treated with either Trasylol or two other drugs.
The trial was halted early in 2007 after preliminary results suggested an additional two deaths per 100 patients would occur among those treated with Trasylol. Use of the drug was suspended worldwide. Final analysis put the increased relative risk of death at 53 per cent compared with patients who took the other drugs.
Other studies, including one published in the New England Journal of Medicine the following year, also found problems with the drug, including higher risk of kidney failure and death. This study looked specifically at patients undergoing CABG surgery, for which Trasylol was approved, as well as higher-risk procedures.
After the announcement that the drug was being pulled from the market, Michael Lincoff, director of cardiovascular clinical research at the Cleveland Clinic, one of the top hospitals in the U.S., told the Canadian Press: "I can't think of drugs that have reached this point of being pulled and then come back."
But last week, Health Canada said it had conducted a comprehensive safety review that determined the drug should be put back on the market.
Bayer will be required to add warnings to the drug's label that there "have been reports of an increased risk of death" when Trasylol is used "outside of its authorized indication" in risky operations. The warnings will also state that the drugs should only be used in CABG patients after careful consideration.
Health Canada said it is giving Trasylol the green light because evidence from clinical trials and post-market surveillance reports shows the benefits outweigh the risks and there are no data to show increased risk of death when the drug is used in CABG patients.
The department added the BART study was flawed because it was "not designed to reliably determine the risk of death" in Trasylol in relation to the two other drugs with which it was being compared.
But the co-principal investigator of the BART study, Paul Hébert, said the research clearly showed the drug was unsafe in high-risk surgery, the kind most doctors were using it for. "Frankly, nothing's changed," he said.
Although Health Canada said data show the drug is relatively safe when used in heart bypass surgery, those patients already have a low risk of bleeding and death. That's why most surgeons used Trasylol in high-risk procedures: The risk of bleeding and death is much higher, which warrants use of a drug to prevent serious problems.
As a result, use of Trasylol in low-risk patients is "still controversial" because the low mortality rate in that group makes it very difficult to accurately determine the risks, according to David Mazer, professor of anesthesia at the University of Toronto as well as a cardiac anesthesiologist and critical care physician at St. Michael's Hospital.
"Showing that this drug worsens mortality in a group of patients that has relatively low risk to start with would be difficult," he said.
Since Trasylol was taken off the market, doctors have used two effective, and often much cheaper, alternatives.
As a result, Dr. Hébert and others question the point of reauthorizing a pricey drug for which viable alternatives exist. "Are the benefits worth the costs and risks?" he asked.
Bayer did not return calls seeking comment.
It's unclear whether other countries will follow Canada's lead and reauthorize Trasylol. Doctors in Canada will have to figure out what to make of the drug's reappearance, Dr. Fremes said. There are still many unanswered questions about Trasylol, he said.
"The bigger question is, compared to alternatives, should [Trasylol]be used and in whom," he said. "I don't think we know that. If anything, I think the data suggest the alternatives are safer."