Evelyn Pringle October 26, 2006
On September 29, 2006, the New York Times reported that Bayer "failed to reveal to federal drug officials the results of a large study suggesting that a widely used heart-surgery medicine might increase the risks of death and stroke," citing an FDA announcement. That drug is aprotinin, marketed as Trasylol.
Bayer's memory lapse would be bad enough in itself, but it seems the FDA is particularly annoyed because Bayer scientists appeared at a public meeting with an FDA advisory committee on September 21, 2006, specifically set up to discuss the risks associated with Trasylol, and did not mention a word about the study or its negative findings.
The lethal side effects of Trasylol became public on February 8, 2006, when the FDA issued an advisory to healthcare professionals requesting that they limit the use of the drug based on research in the New England Journal of Medicine that found its use to be associated with a 2-fold increase in renal failure, a 48% increase in myocardial infarction, a 109% increase in heart failure, and a 181% increase in strokes.
This observational study involved more than 4,300 patients at 69 medical institutions worldwide. "Our findings raise serious concerns regarding the safety of an approved drug intended to limit blood loss in at-risk patients undergoing surgery," wrote Dr Dennis Mangano of the Ischemia Research and Education Foundation, who led the study.
The San Bruno, California foundation is a non-profit organization founded in 1987 that funds cardiovascular research. In other recent studies, the group has shown that giving inexpensive beta-blockers after major surgery could save 250,000 lives a year, that aspirin use after heart surgery reduces the risk of blood clots, and that Bextra is associated with stroke and impaired wound healing, according to the January 26, 2006 Baltimore Sun.
Another study in the January 20, 2006 online edition of Transfusion, Karkouti, et al, also found an association between Trasylol and renal toxicity among patients undergoing cardiac surgery with cardiopulmonary bypass.
Critics say the Trasylol matter is another example of how serious side effects often fail to become known until after a drug is widely used. Post-marketing studies by drug makers to assess side effects are seldom conducted according to Dr Mangano. "There's an enormous disincentive to finding safety problems," he told Reuters on January 25, 2006.
Trasylol is one of Bayer's top selling drugs with worldwide sales of $210 million in 2005, according to Bayer in a January 26, 2006 article by Associated Press.
On December 9, 2005, the Associated Press reported that Bayer's Chief Executive, Werner Wenning, predicted that sales for Trasylol in 2006 would reach $600 million. However, on January 26, 2006, Reuters reported that shares in Bayer fell more than 3% "after a study showed that its Trasylol drug doubled the risk of kidney failure."
Analysts said the result of the NEJM study increased the risk for investors in Bayer's pharmaceuticals business, which was already recovering from a $1 billion recall of cholesterol lowering medication Baycol. Bayer withdrew Baycol in August 2001 after a number of patients developed muscle weakening and kidney failure and the drug was linked to as many as 100 deaths.
The FDA approved Trasylol in 1993 to control bleeding in patients during heart surgery and minimize the need for blood transfusions. The drug works by blocking enzymes that dissolve blood clots. Trasylol is indicated for patients undergoing cardiopulmonary bypass (CPB) in the course of coronary artery bypass graft (CABG) surgery.
According to Heart Disease and Stoke Statistics 2005 Update, CABG is the most commonly performed major surgery in the US, with approximately half a million patients undergoing the procedures each year.
Trasylol was approved for heart surgery only but doctors have been routinely using the drug off-label when performing other surgeries. Prior to the NEJM study, Bayer was seeking FDA approval of the drug for patients undergoing hip replacement surgery and spinal fusion surgery.
Trasylol is extremely expensive with a full dose costing about $1,300, while the two generic drugs used in the NEJM study, aminocaproic acid, known by the brand name Amicar, and tranexamic acid, known as Cyklokapron, which turned out to be safer and as effective as Trasylol, at a fraction of the cost of just $11 and $44 respectively.
The "associations between aprotinin and serious end-organ damage indicates that continued use is not prudent," Dr Mangano wrote in the study. "In contrast," he said, "the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives."
Because the two alternative drugs that do the same job carry no such risks and are far less expensive, "continued use (of Trasylol) is not prudent," the NEJM study concluded.
The study authors predicted that halting the use of Trasylol could prevent as many as 11,000 cases of kidney failure a year and save more than $1 billion per year in dialysis costs, in addition to the nearly $250 million spent on the drug itself.
The FDA's cardiovascular and renal advisory committee met on September 21, 2006, to discuss the risks associated with Trasylol found in the two observational studies, Mangano et al and Karkouti et al, published in January 2006.
In the end, the committee concluded that there was not enough evidence to support changing the cardiovascular safety labeling on Trasylol, reportedly in large part because Mangano et al was the only study to find an increased cardiovascular risk with the drug - that is until the results of the Bayer study leaked out 6 days after the meeting.
A September 29, 2006 letter from the FDA to the advisory committee members said the agency may call a second meeting of the advisory panel to review the new data.
After being tipped off about the undisclosed study, the FDA also issued another public health advisory saying that it had learned of the study and that the preliminary results demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes."
The FDA advisory noted that the Bayer study was conducted by a contract research organization, and hospital data from 67,000 CABG patients were examined. Of these, it said, 30,000 patients were treated with aprotinin and 37,000 were treated with other drugs. The FDA's recommendations in the new advisory are similar to those in the February 8, 2006 advisory issued after the publication of the initial studies.
According to an October 6, 2006 report by Bloomberg News, Dr Alexander Walker, a Harvard professor and researcher who helped conduct the Bayer study for i3 Drug Safety, a private research company, told the FDA about the study's existence after noticing that it was not mentioned at the committee meeting. He is quoted by Bloomberg as saying that notifying the FDA "seemed like the right thing to do.''
According to Bloomberg, Bayer has admitted to the FDA that the company commissioned its own observational study to investigate the cardiovascular risks of Trasylol in June 2006, and received a copy of a preliminary report on the study on September 14, 2006.
Members of the advisory committee are understandably ticked off that Bayer failed to reveal this information before or during the meeting and several said they were shocked.
“For them not to mention that it was under way, that it was being analyzed or that results were available is appalling and will do significant harm to their reputation for transparency,” said Dr John Teerlink, a professor at the University of California, San Francisco, to the New York Times.
Bloomberg quotes him as saying that Bayer’s failure to tell the FDA about the study before the meeting "calls into question the honesty of Bayer and the honesty of the pharmaceutical industry in general."
"I think the public health has been harmed in two ways," Dr Teerlink said. "One, we didn't have complete information to make our decision," he stated. "But second," he told Bloomberg, "it calls into question a process that all of us depend on."
Committee member, Steven Findlay, a health care analyst at Consumers Union, told the Times that the FDA needed to investigate whether Bayer knowingly withheld the information from the committee. “The safety of this drug is called into further question now,” Mr Findlay said.
Dr Robert Harrington, a committee member from Duke University, in Durham, NC, told Heartwire: “Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me."
"The process of evaluation, comment, and advice on important drug efficacy and safety data," he said, "only works when all of the involved parties are open and honest about their data."
"It is ironic that we spent part of the panel meeting criticizing Dr Mangano for failing to allow the FDA to perform an independent review of his database," he told Heartwire, "yet Bayer failed to even acknowledge the existence of these data."
"It is especially troubling," Dr Harrington said, "when several panel members, including me, commented that more data and more analyses were needed to fully understand the risks and benefits of the drug."
"I'd like to know if the Bayer team present that day had knowledge of the existence of the data and why they chose not to even mention it,” he stated.
Another member of the panel, Dr Michael Lincoff, from the Cleveland Clinic, shared similar views with Heartwire. “It was astounding to me that they did not disclose the information that the study had been conducted," he stated, "even if the findings were considered preliminary."
"They were in the midst of an entire day's discussions at the FDA on that precise topic," he noted, "where there was substantial comment regarding the desirability of more contemporary data than their older trials."
"It is inconceivable," Dr Lincoff told Heartwire, "that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee."
Legal experts say the main problem for patients who are injured by Trasylol is that the serious injuries and death are often not attributed to the drug because most patients and their families are not informed that the patient received Trasylol during surgery and therefore, do not realize that the drug is to blame.
To avoid serious injuries or death, experts are recommending that patients request that Trasylol not be used prior to undergoing surgery, and for patients and their families who suspect that injuries or death may have been caused by the drug, to ask the surgeon whether Trasylol was administered.