Trasylol (Aprotinin) During Heart Surgery Shown Elevated Risk of Death After Operation
Trasylol (aprotinin) is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.
The effects of Trasylol (aprotinin) use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.
An anti-bleeding drug probably will stay off the market, experts say, after a rigorous study found patients getting the medication during heart surgery were much more likely to die than patients given other drugs.
Bayer AG, the maker of the drug Trasylol, said it is still deciding what to do and is awaiting details from the Canadian study. Bayer faces dozens of lawsuits claiming Trasylol led to excess deaths and that the company hid evidence of harm.
But experts in Canada and the United States say the study appears to seal the drug's fate, given that several prior studies linked Trasylol to an elevated risk of death after surgery — and studies that didn't find a higher risk had many weaknesses.
The latest study was the first head-to-head comparison of Trasylol (aprotinin), also known as aprotinin, and two other drugs that surgeons use to prevent massive blood loss during heart surgery. The findings were released Wednesday by the New England Journal of Medicine.
"In all likelihood, this is the end of the aprotinin story," Wayne A. Ray and C. Michael Stein of Vanderbilt University School of Medicine wrote in an editorial accompanying the study.
Trasylol was approved in 1993 but questions about its safety didn't surface until 2006, when one large study linked it to increased risk of death, heart attack, stroke and kidney failure.
The Canadian study, paid for by the government, included more than 2,300 patients who were at high risk of bleeding or had multiple health problems. They were chosen randomly to receive Trasylol or two other anti-bleeding drugs during heart surgery. The study was stopped early last October when preliminary results showed a higher rate of death in the Trasylol group. Bayer temporarily pulled the drug off the market two weeks later.
"There was no way we could ethically enroll (more patients) in the trial because we had our answer," said lead researcher Dean A. Fergusson, a transfusion medicine expert at the Ottawa Health Research Institute. "I think the results are quite definitive, certainly for high-risk cardiac surgery, and it's going to be very tough to justify its use in lower-risk surgery."
An analysis of the data showed Trasylol increased chances of death by 54 percent, compared to two much-cheaper drugs. Six percent of the Trasylol patients died within 30 days of surgery, compared with 4 percent who got either Amicar or Cyklokapron, despite a slightly lower percentage of the Trasylol patients suffering from massive bleeding or needing transfusions.
The researchers found those who died in the Trasylol group had a much higher proportion of heart complications after surgery, including heart attacks.
So far, Bayer said more than 80 lawsuits have been filed over Trasylol. About 200,000 patients worldwide received Trasylol in 2006, the peak year for sales.
Peper Long, a spokeswoman at the U.S. Food and Drug Administration, said the agency is awaiting details from the Canadian study to determine whether to continue allowing the drug to be used in research studies.
A study for mortality associated with Aprotinin during 5 Years following coronary artery bypass graft surgery; published in JAMA indicated 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 following CABG surgery. Use of aprotinin among patients undergoing CABG surgery does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.
In November 2007 Bayer AG suspended worldwide sales of Trasylol, a clotting drug using during heart surgery to prevent bleeding, following a request from the U.S. Food and Drug Administration to remove the drug from the American market for safety reasons.
"Studies have found that Trasylol can increase the risk of kidney damage compared with other drugs," Dr. Gerald Dal Pan, the FDA's director of the Office of Surveillance and Epidemiology, said during the news conference.
However, he added, "the suspension will include a slow phase-out of Trasylol from the marketplace to decrease the possibility of shortages of the alternative drugs." And he added that Bayer could continue to supply the drug if physicians can identify specific patients who would benefit from it.
In December 2006, the FDA updated the Trasylol label to include a black box warning - the agency’s strictest safety notice - stating that the drug placed patients at a high risk of kidney failure. Then in September 2007, even while agreeing with the assessment that Trasylol had a high risk of causing fatal side-effects, an FDA advisory panel voted that Trasylol should stay on the market.
Bayer faces nearly 80 lawsuits over Trasylol. As late as February, the company had maintained that it would eventually return Trasylol to the market. Yesterday, Bayer changed its tune, and said it was removing Trasylol supplies from all countries where it remained in the supply chain, except where local authorities wanted to keep it in the market for special access programs.