Evelyn Pringle January 2006
Experts are sounding the alarm that patients who received the drug Trasylol (generic aprotinin), during a surgical procedure may have suffered kidney failure, a heart attack, heart failure, or a stroke as an adverse event caused by the drug.
The results of a study, published last month in the New England Journal of Medicine, by the independent, non-commercial, Ischemia Research and Education Foundation (IREF), found Trasylol associated with a 2-fold increase in renal failure requiring dialysis in patients undergoing major surgery.
The study data was gathered from patients who had surgery between 1996 and 2000, at more than 69 medical centers around the world, and received either Trasylol, aminocaproic acid, tranexamic acid, or no drug treatment.
The study's control group of 1,374 patients, received a placebo, while 1,295 patients received Trasylol, 883 others received aminocaproic, and 822 patients received tranexamic.
The study found that the use of Trasylol increased the risk of stroke by 181%, myocardial infarction by 48%, and heart failure by 109%, when compared to people who received the 2 alternate drugs.
The researcher's determined that patients treated with Trasylol, had a risk of kidney failure 259% greater than patients who received no drugs.
German based drug maker, Bayer Pharmaceuticals, has said the results of the IREF study are inconsistent with its own clinical data. In fact, prior to the release of the study, the company had filed a request for FDA approval for the use of Trasylol during spinal and hip surgery. Experts say that approval is unlikely now.
The new study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, in San Bruno, California.
Surgeons and anesthesiologists had suspected problems with the drug for years, but the number of side effects was lost among the huge number of patients given the drug. "We didn't have good, hard data to prove it," said Dr. O. Wayne Isom, chairman of the department of cardiac and thoracic surgery at New York Presbyterian Hospital/Weil Cornell Medical College, to the Baltimore Sun on January 26, 2006.
The new results are "pretty much undebatable," Dr Isom added.
Dennis Mangano, PhD, MD, the founder of the IREF, and the study's lead researcher said that the study's findings -- "coming on the heels of the Vioxx experience -- indicate that the problem of drug safety is not only ubiquitous, but also much more elusive than previously thought," according to Consumer Affairs.com. In fact, Mangano said, the findings raise even more concerns than Vioxx because:
(1) aprotinin has been on the market for three times as long as Vioxx, yet few comprehensive safety studies have been conducted since approval;
(2) the life-threatening complications with aprotinin occurred far more frequently than those with Vioxx; and
(3) far less expensive generic alternatives to aprotinin which are equally effective in limiting bleeding have been available, but have been underused, Consumer wrote.
Although Trasylol use is approved in more than 60 countries worldwide, in the US, it gained FDA approval in 1993, but only for use to control bleeding in patients undergoing coronary artery bypass graft surgery (CABG), to reduce the need for blood transfusions. The drug is said to work by blocking enzymes that dissolve blood clots.
CABG is the most commonly performed major surgery in the US, with approximately half a million patients undergoing the procedures each year, according to Heart Disease and Stroke Statistics - 2005 Update.
Experts say the IREF study provides compelling evidence of serious risks caused by Trasylol, and calls for the discontinuation of the drug and replacement with one of the 2 alternative products.
Neither aminocaproic or tranexamic was associated with an increased risk of renal, cardiac or cerebral events and both are much cheaper, costing $11 and $44 per dose, respectively, compared to the $1,300 per dose price tag of Trasylol.
The researchers estimate that by switching from Trasylol to the alternatives, $250 million a year could be saved in health care costs, in addition to helping over 10,000 patients a year to avoid the dangers and cost of kidney dialysis.
The findings of the Trasylol study is the 4th major cost-saving discovery by Dr. Mangano and his IREF-McSPI colleagues over the past ten years.
In other studies, according to the Baltimore Sun, "the group has shown that giving inexpensive beta-blockers after major surgery could save 250,000 lives per year, that aspirin use after heart surgery reduces the risk of blood clots and that the painkiller Bextra is associated with stroke and impaired wound healing."
In 1996, the team found that generic beta-blockers reduced death after major surgery, saving 250,000 lives a year at a cost of a mere $15 per patient, according to the New England Journal of Medicine.
In 2002, Dr. Mangano recommended giving heart patients aspirin immediately after surgery to reduce the threat of thrombosis. This is now a standard practice and saves over 25,000 lives a year at a cost of pennies per patient.
In 2003, IREF- McSPI reported for the first time that Bextra, was associated with stroke and impaired wound healing, eventually leading to the drug's recall, according to J Thoracic and Cardiovascular Surgery.
For 2005, according to Bloomberg News, Bayer predicted Trasylol sales to bring in $614 million. However, on January 26, 2006, Bloomberg reported that shares of Bayer, "the German drugmaker that invented aspirin, fell 48 cents ... at the close of trading in Frankfurt after U.S. researchers published their findings in this week's New England Journal of Medicine."
If the IREF's findings result in the removal of Trasylol, the loss in sales could push Bayer stock-value into a free-fall during 2006.
The problem for surgery patients who may have been harmed by Trasylol, is that most people are never told what drugs they received during surgery. And while Trasylol is only approved for heart surgery, the drug has been used off-label during many other types of surgeries as well.
So who knows how many unsuspecting victims have been injured by this drug while under the knife.
Showing posts with label Bayer. Show all posts
Showing posts with label Bayer. Show all posts
Monday, August 2, 2010
Trasylol Patients and Clinical Trial Subjects Beware
Evelyn Pringle January 2006
Thirteen years ago, the FDA approved Trasylol (aprotinin) for use in patients undergoing heart bypass surgery. In January 2006, doctors, consumer advocates and a medical research group called for the removal of the drug from the market after a study found it to have deadly side effects.
Heart bypass surgery is performed to redirect blood around clogged arteries to increase blood flow and oxygen to the heart. A patient may undergo one, two, three or more bypasses depending on how many arteries are blocked. It is the most commonly performed major surgery in the US, with approximately 500,000 procedures conducted each year, according to Coronary Artery Bypass Graft Surgery at Heart Center Online.
The FDA approved Trasylol in 1993 to control bleeding in patients undergoing heart surgery by blocking enzymes that dissolve blood clots. Although it was only approved for heart surgery, the drug has been administered off-label to patients undergoing other types of surgery.
Because the majority of patients are unaware of the drugs they receive during surgery, and also because of Trasylol's off-label use, medical experts say patients need to check with their doctors to see whether they received the drug.
Since Trasylol was approved, an estimated 1 million people world-wide have received the drug. The new study published in the January 26, 2006 New England Journal of Medicine (NEJM), found patients who received Trasylol (aprotinin) have experienced potentially deadly side effects including:
A twofold increase in kidney failure
A 48-percent increase in risk of heart attack
A 109-percent increase in heart failure
A 181-percent increase in stroke
Researchers estimates that as many as 10,000 heart surgery patients have experienced kidney failure and are now on dialysis because they were given Trasylol.
The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, sponsored by the California-based Ischemia Research and Education Foundation (IREF), and led by IREF founder Dr Dennis Mangano, MD, Ph D.
"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 Mangano in the NEJM.
Another study published in the January 20, 2006 online edition of the journal Transfusion reported a similar increase in renal problems among patients given Trasylol while undergoing cardiac surgery with cardiopulmonary bypass.
Trasylol was the second clotting medication in two weeks linked to serious complications. according to the Associated Press on January 26, 2006. Other researchers reported that the hemophilia drug Novoseven was linked to deaths, heart attacks and strokes in patients who took the drug to treat other types of excessive bleeding such as cerebral hemorrhagesm, it wrote.
Trasylol is manufactured by German-based Bayer Healthcare Pharmaceuticals. The FDA has so far refused to remove the drug from the market, but on February 8, 2006, it posted a public health advisory on its web site that said, while FDA is continuing its evaluation, we are providing the following recommendations to healthcare providers and patients:
Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or to the FDA MedWatch program, as described at the end of this advisory.
Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.
The NEJM study comes at a time when Bayer is pushing to have the drug approved for other surgery. The company recently filed a request seeking FDA approval for the use of Trasylol for hip and spinal surgery.
On December 8, 2005, Bayer announced the initiation of a Phase III clinical trial to evaluate the safety and efficacy of Trasylol in reducing blood loss and the need for transfusion in adult patients undergoing elective spinal fusion surgery, in a press release.
According to the press release, over 450 adult patients will participate in the study in 40 investigational centers in North America. The company says Trasylol is currently approved for use in more than 60 countries.
In an editorial accompanying the study in the NEJM, Dr Gus Vlahakes, MD, of Harvard Medical School noted that efforts were underway to expand the indications for Trasylol and that the new indications may require a higher dose.
"Until the safety of higher doses is fully explored in a prospective study, the expansion of indications for aprotinin may be premature," he warned in the editorial.
According to IREF, each year nearly 1 million people worldwide undergo surgery following a heart attack and the majority of the patients receive one of 3 different drugs used to limit blood loss: aprotinin, aminocaproic acid, and tranexamic acid.
The IREF researchers studied 4,374 patients from around the world, comparing Trasylol with 2 alternative drugs or no drugs at all, and determined that the alternatives did not have the harmful side effects of Trasylol.
In light of these findings, IREF said that the other 2 drugs are "underused", although they are "equally effective in limiting bleeding," have been proven safe, and are readily available. In addition, the two alternatives drugs cost only a tenth of the cost of Trasylol.
Trasylol is a $600 million per year drug, Dr Mangano told Reuters News on January 25, 2006. "It would have been a blockbuster for them," he said.
The two alternative drugs are much cheaper. A full dose of Trasylol costs $1,300 per patient, while the other two are just $11 and $44, according to Dr Mangano.
The study contends that replacing Trasylol with one of the drugs could prevent as many as 11,050 dialysis complications each year and save at least $1 billion in health care costs and reduce drug costs by at least $250 million.
IREF says it provided all the funding for the study, totaling more than $35 million. The 69 participating cardiac centers also contributed through reduced research and data collection fees and that none of the study's authors received direct or indirect support from any of the manufacturers of the three drugs studied.
According to the January 26, 2006 Baltimore Sun, surgeons and anesthesiologists had suspected potential problems with Trasylol for many years, "but the number of adverse side effects was lost among the huge number of patients given the drug."
The "associations between aprotinin and serious end-organ damage indicates that continued use is not prudent," Dr Mangano wrote in the study. "In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives."
Thirteen years ago, the FDA approved Trasylol (aprotinin) for use in patients undergoing heart bypass surgery. In January 2006, doctors, consumer advocates and a medical research group called for the removal of the drug from the market after a study found it to have deadly side effects.
Heart bypass surgery is performed to redirect blood around clogged arteries to increase blood flow and oxygen to the heart. A patient may undergo one, two, three or more bypasses depending on how many arteries are blocked. It is the most commonly performed major surgery in the US, with approximately 500,000 procedures conducted each year, according to Coronary Artery Bypass Graft Surgery at Heart Center Online.
The FDA approved Trasylol in 1993 to control bleeding in patients undergoing heart surgery by blocking enzymes that dissolve blood clots. Although it was only approved for heart surgery, the drug has been administered off-label to patients undergoing other types of surgery.
Because the majority of patients are unaware of the drugs they receive during surgery, and also because of Trasylol's off-label use, medical experts say patients need to check with their doctors to see whether they received the drug.
Since Trasylol was approved, an estimated 1 million people world-wide have received the drug. The new study published in the January 26, 2006 New England Journal of Medicine (NEJM), found patients who received Trasylol (aprotinin) have experienced potentially deadly side effects including:
A twofold increase in kidney failure
A 48-percent increase in risk of heart attack
A 109-percent increase in heart failure
A 181-percent increase in stroke
Researchers estimates that as many as 10,000 heart surgery patients have experienced kidney failure and are now on dialysis because they were given Trasylol.
The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, sponsored by the California-based Ischemia Research and Education Foundation (IREF), and led by IREF founder Dr Dennis Mangano, MD, Ph D.
"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 Mangano in the NEJM.
Another study published in the January 20, 2006 online edition of the journal Transfusion reported a similar increase in renal problems among patients given Trasylol while undergoing cardiac surgery with cardiopulmonary bypass.
Trasylol was the second clotting medication in two weeks linked to serious complications. according to the Associated Press on January 26, 2006. Other researchers reported that the hemophilia drug Novoseven was linked to deaths, heart attacks and strokes in patients who took the drug to treat other types of excessive bleeding such as cerebral hemorrhagesm, it wrote.
Trasylol is manufactured by German-based Bayer Healthcare Pharmaceuticals. The FDA has so far refused to remove the drug from the market, but on February 8, 2006, it posted a public health advisory on its web site that said, while FDA is continuing its evaluation, we are providing the following recommendations to healthcare providers and patients:
Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or to the FDA MedWatch program, as described at the end of this advisory.
Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.
The NEJM study comes at a time when Bayer is pushing to have the drug approved for other surgery. The company recently filed a request seeking FDA approval for the use of Trasylol for hip and spinal surgery.
On December 8, 2005, Bayer announced the initiation of a Phase III clinical trial to evaluate the safety and efficacy of Trasylol in reducing blood loss and the need for transfusion in adult patients undergoing elective spinal fusion surgery, in a press release.
According to the press release, over 450 adult patients will participate in the study in 40 investigational centers in North America. The company says Trasylol is currently approved for use in more than 60 countries.
In an editorial accompanying the study in the NEJM, Dr Gus Vlahakes, MD, of Harvard Medical School noted that efforts were underway to expand the indications for Trasylol and that the new indications may require a higher dose.
"Until the safety of higher doses is fully explored in a prospective study, the expansion of indications for aprotinin may be premature," he warned in the editorial.
According to IREF, each year nearly 1 million people worldwide undergo surgery following a heart attack and the majority of the patients receive one of 3 different drugs used to limit blood loss: aprotinin, aminocaproic acid, and tranexamic acid.
The IREF researchers studied 4,374 patients from around the world, comparing Trasylol with 2 alternative drugs or no drugs at all, and determined that the alternatives did not have the harmful side effects of Trasylol.
In light of these findings, IREF said that the other 2 drugs are "underused", although they are "equally effective in limiting bleeding," have been proven safe, and are readily available. In addition, the two alternatives drugs cost only a tenth of the cost of Trasylol.
Trasylol is a $600 million per year drug, Dr Mangano told Reuters News on January 25, 2006. "It would have been a blockbuster for them," he said.
The two alternative drugs are much cheaper. A full dose of Trasylol costs $1,300 per patient, while the other two are just $11 and $44, according to Dr Mangano.
The study contends that replacing Trasylol with one of the drugs could prevent as many as 11,050 dialysis complications each year and save at least $1 billion in health care costs and reduce drug costs by at least $250 million.
IREF says it provided all the funding for the study, totaling more than $35 million. The 69 participating cardiac centers also contributed through reduced research and data collection fees and that none of the study's authors received direct or indirect support from any of the manufacturers of the three drugs studied.
According to the January 26, 2006 Baltimore Sun, surgeons and anesthesiologists had suspected potential problems with Trasylol for many years, "but the number of adverse side effects was lost among the huge number of patients given the drug."
The "associations between aprotinin and serious end-organ damage indicates that continued use is not prudent," Dr Mangano wrote in the study. "In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives."
Oops - Bayer Forgot to Tell FDA About Lethal Side Effects of Trasylol
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.
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.
What Did Bayer Know About Trasylol?
Evelyn Pringle November 2006
In January, 2006, the FDA issued a Public Health Advisory for Trasylol, based on the serious health risks found in two studies, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," by Karkouti et al, in the Journal of Transfusion, and "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, in the New England Journal of Medicine.
After the studies were published, the FDA scheduled a meeting on September 21, 2006, of the FDA's Cardiovascular and Renal Advisory Committee to discuss the findings and other relevant data.
At the meeting, FDA briefing officials advised the panel that in 2005, "about 250,000 patients received Trasylol in the U.S."
The NEJM study compared outcomes the groups of patients receiving the drugs aprotinin, aminocaproic acid and tranexamic acid, and one group of patients receiving no drug.
In the study, Trasylol was found to be associated with a 109% increase in heart failure, a 48% increase in myocardial infarction, a 181% increase in strokes, and a risk of kidney failure 259% greater than patients who received no drugs.
The study was conducted at the Ischemia Research and Education Foundation in San Bruno, California. Study leader, Dr Dennis Mangano, founder of the Foundation, told Consumer Affairs.com, that the results raised even more concerns than Vioxx because: (1) aprotinin has been on the market three times as long as Vioxx, yet few studies have been conducted; (2) the life-threatening complications occurred far more frequently; and (3) equally effective less expensive alternatives are available, but they are underused.
At the Advisory Committee meeting, Dr Mangano informed the panel that both aminocaproic and tranexamic showed blood-sparing capabilities equal to aprotinin. "Yet," he stated, "head-to-head comparisons were few and far between despite the enormous difference in cost between these agents with aprotinin between $500 and $1,200 a patient and the others, less than $50 a patient."
The NEJM study estimates that ending the use of Trasylol could prevent kidney failure in as many as 11,000 patients a year, which in turn would save more than $1 billion annually in dialysis costs.
Dr Keyvan Karkouti, presented the findings of the Transfusion study and told the panel, "Our primary outcome was efficacy transfusions and our hypothesis was that we would see a marked superiority with aprotinin mainly because that was the clinical impression and it still is at probably most places across Canada."
"But what we found," he reported, "was that there was really no difference in the
transfusion rates."
He said going in, their hypothesis was that if aprotinin is better, it should show a reduction in the risk of MI, stroke, renal failure, infection and death. "We didn't find any reduction of these adverse events with aprotinin use," he told the Committee.
"We did find a renal dysfunction increase with aprotinin," he said, "and a trend toward increased renal failure."
"So, in conclusion," he advised, "there is as yet no conclusive evidence that aprotinin is better than tranexamic acid in our opinion."
For Bayer's presentation to the FDA Committee, Mike Rozycki, Bayer's Director of US Regulatory Affairs, said that when the company learned of the new studies, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted," he stated, "in very close association and under the guidance of the FDA."
"All that information has been submitted and is under review by the FDA," he added.
Mr Rozycki specified that the company's presentation that day was based on the data available to Bayer.
On Bayer's behalf, Dr Robert Makuch, a Professor of Biostatistics at the Yale School of Public Health, discussed the methodological considerations of randomized, controlled clinical trials and dismissed the NEJM study as unreliable. "In summary," he said, "the Mangano study results should not be considered reliable at this time."
While not revealing Bayer's hidden study, he noted the discussions about the need for further analysis and independent access to Dr Mangano's study data and said, "I certainly would endorse that recommendation, as well."
Dr Pamela Cyrus appeared on behalf of Bayer and thanked the committee for having Bayer "here today to review our clinical trial data."
As to safety information on Trasylol provided to the FDA, she specifically said, that Bayer had "submitted data on an ongoing basis to our NDA, as well as with our ongoing pharmacovigilance additional data."
"With the two recent observational studies," she told the panel, "we have also conducted a very thorough analysis of our global CABG data base."
"We have submitted that analysis," she noted, "as well as our data sets, to the FDA for their review."
Dr Cyrus denied that Trasylol was associated with the same adverse effect revealed in the hidden study. "Bayer's summary on cardiac safety is very simple," she said, "Aprotinin was not associated with an increased incidence of myocardial infarction looking across all CABG patients."
"Bayer's conclusions on cerebrovascular safety," she told the Committee, "is that aprotinin was not associated with an increased incidence of either stroke or encephalopathy with encephalopathy also including coma."
Dr Jerrold Levy, Professor of Anesthesiology, Director of Cardiothoracic Anesthesiology and Deputy Chair of Research at Emory University, also appeared on behalf of Bayer to discuss the risk-benefit assessment and also flat-out denied the increased risk of adverse effects associated with Trasylol found in the hidden study, going so far as to say it decreased the risk of stroke.
Dr Levy told the panel, "if you look at the clinical studies of the randomized clinical trials in CABG surgery, there is no greater risk of mortality, MI, or renal failure and, at least from this data, there was a reduction in stroke in these patients."
Regarding stroke, if you look at four different meta-analysis of studies," he said, "there was a significant reduction in stroke."
Committee member, Dr Valluvan Jeevanandam, asked Bayer representatives whether there were other studies. "Could you comment on other trials other than CABG trials where there might have been an effect on renal function," he asked, "because a lot of the questions we had in our first presentation by Dr. Mangano was perhaps concomitant procedures with higher incidence of renal dysfunction, so do you have other trials other than just CABG trials looking at renal function?"
Dr Cyrus described one study as "the most recent" stating, "Probably the most recent study where you could just remove the effect of bypass totally is a study that was just conducted by Bayer in hip surgery."
"So, if you forget the bypass effect on the kidneys and let's look at a patient population that may not be at increased risk," she stated, "there were no differences between the groups in that patient population."
Dr Susan Heckbert also asked whether there were other studies stating, "I have a quick question about your global database, clinical trial database."
"It looks to me like the U.S. studies in that database," she said, "most of them are from the early nineties and they would reflect the kind of patient that would present and might be considered for a clinical trial in those days."
Dr Heckbert specifically asked, "You don't have anything beyond the early nineties in the United States in that database."
"What about from other countries," she inquired, "are we seeing the kind of patients that now go for CABG?"
"Do we have data in your global database from more contemporary types of patients?" she asked.
Dr Cyrus said, "The bulk of our clinical trial experience that I shared with you in the safety database was between the late eighties and late nineties."
"There were a few studies that went to 2001," she added.
"We do not have randomized clinical trials beyond 2001," she responded, "in the database that I shared with you today."
In the end, the Committee decided that there was no need for additional warnings on Trasylol labeling and Bayer quickly put out a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
The Committee agreed that the data are consistent with an association with aprotinin use and renal impairment, however, most members said they were not convinced that there was a definite increased risk of renal failure requiring dialysis.
Without the hidden study that proved otherwise, the Committee agreed that overall, there was no association between aprotinin and an increased risk of myocardial infarction, heart failure, stroke or encephalopathy.
Additionally, the Committee commented that these are short-term outcomes and that there is little or no data on the long-term cardiovascular outcomes in these patients.
Recommendations were made that, because there is limited current and long-term data, Bayer should be encouraged to sponsor such prospective studies to gather this information.
The Committee vote was taken to answer the specific question: "Based upon the presentations today, do you regard the totality of clinical data as supporting acceptable safety and efficacy for Trasylol usage among certain CABG/CPB patients?"
After being notified of the hidden study, the FDA issued another Advisory warning that the results of the study demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes."
Committee members were rightly outraged when they learned of the hidden study. Dr Robert Harrington, from Duke University, told Heartwire on October 6, 2006, "The process of evaluation, comment, and advice on important drug efficacy and safety data, only works when all of the involved parties are open and honest about their data."
He noted that he found Bayer's failure to disclose the study especially troubling, "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."
He called it "ironic" that the Committee spent part of the day criticizing Dr Mangano for failing to allow the FDA to analyze his database, "yet Bayer failed to even acknowledge the existence of these data."
Committee member, Dr Michael Lincoff, from the Cleveland Clinic, made similar comments to Heartwire. “It was astounding to me," he said, "that they did not disclose the information that the study had been conducted 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."
Dr Lincoff said it was "inconceivable," that Bayer representatives did not know of the study or its potential relevance to the Committee.
In the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn, published an opinion paper and stated, "The analysis completed in time for the FDA meeting, reached conclusions similar to those of Mangano et al."
"But neither Bayer nor its contractor," he wrote, "had provided the report to the FDA or even acknowledged its existence before the meeting."
Dr Avorn points out that a confirmatory observational study would have lent key support to the conclusions of Mangano et al — "if its findings had been aired," he added.
Bayer has admitted that suppressing the study was "a mistake," but Dr Avorn explains that this is not the first time the drug maker has been caught hiding research. When Bayer was accused of hiding data on its cholesterol-drug Baycol before it was taken off the market, litigation later unearthed a memo from a Bayer executive arguing against performing a study that would reveal its risk.
"If the FDA asks for bad news, we have to give," the memo states, "but if we don't have it, we can't give it to them
If patients or family members suspect that injuries or death may have been caused by Trasylol, they need to ask the surgeon whether the drug was administered during surgery.
In January, 2006, the FDA issued a Public Health Advisory for Trasylol, based on the serious health risks found in two studies, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," by Karkouti et al, in the Journal of Transfusion, and "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, in the New England Journal of Medicine.
After the studies were published, the FDA scheduled a meeting on September 21, 2006, of the FDA's Cardiovascular and Renal Advisory Committee to discuss the findings and other relevant data.
At the meeting, FDA briefing officials advised the panel that in 2005, "about 250,000 patients received Trasylol in the U.S."
The NEJM study compared outcomes the groups of patients receiving the drugs aprotinin, aminocaproic acid and tranexamic acid, and one group of patients receiving no drug.
In the study, Trasylol was found to be associated with a 109% increase in heart failure, a 48% increase in myocardial infarction, a 181% increase in strokes, and a risk of kidney failure 259% greater than patients who received no drugs.
The study was conducted at the Ischemia Research and Education Foundation in San Bruno, California. Study leader, Dr Dennis Mangano, founder of the Foundation, told Consumer Affairs.com, that the results raised even more concerns than Vioxx because: (1) aprotinin has been on the market three times as long as Vioxx, yet few studies have been conducted; (2) the life-threatening complications occurred far more frequently; and (3) equally effective less expensive alternatives are available, but they are underused.
At the Advisory Committee meeting, Dr Mangano informed the panel that both aminocaproic and tranexamic showed blood-sparing capabilities equal to aprotinin. "Yet," he stated, "head-to-head comparisons were few and far between despite the enormous difference in cost between these agents with aprotinin between $500 and $1,200 a patient and the others, less than $50 a patient."
The NEJM study estimates that ending the use of Trasylol could prevent kidney failure in as many as 11,000 patients a year, which in turn would save more than $1 billion annually in dialysis costs.
Dr Keyvan Karkouti, presented the findings of the Transfusion study and told the panel, "Our primary outcome was efficacy transfusions and our hypothesis was that we would see a marked superiority with aprotinin mainly because that was the clinical impression and it still is at probably most places across Canada."
"But what we found," he reported, "was that there was really no difference in the
transfusion rates."
He said going in, their hypothesis was that if aprotinin is better, it should show a reduction in the risk of MI, stroke, renal failure, infection and death. "We didn't find any reduction of these adverse events with aprotinin use," he told the Committee.
"We did find a renal dysfunction increase with aprotinin," he said, "and a trend toward increased renal failure."
"So, in conclusion," he advised, "there is as yet no conclusive evidence that aprotinin is better than tranexamic acid in our opinion."
For Bayer's presentation to the FDA Committee, Mike Rozycki, Bayer's Director of US Regulatory Affairs, said that when the company learned of the new studies, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted," he stated, "in very close association and under the guidance of the FDA."
"All that information has been submitted and is under review by the FDA," he added.
Mr Rozycki specified that the company's presentation that day was based on the data available to Bayer.
On Bayer's behalf, Dr Robert Makuch, a Professor of Biostatistics at the Yale School of Public Health, discussed the methodological considerations of randomized, controlled clinical trials and dismissed the NEJM study as unreliable. "In summary," he said, "the Mangano study results should not be considered reliable at this time."
While not revealing Bayer's hidden study, he noted the discussions about the need for further analysis and independent access to Dr Mangano's study data and said, "I certainly would endorse that recommendation, as well."
Dr Pamela Cyrus appeared on behalf of Bayer and thanked the committee for having Bayer "here today to review our clinical trial data."
As to safety information on Trasylol provided to the FDA, she specifically said, that Bayer had "submitted data on an ongoing basis to our NDA, as well as with our ongoing pharmacovigilance additional data."
"With the two recent observational studies," she told the panel, "we have also conducted a very thorough analysis of our global CABG data base."
"We have submitted that analysis," she noted, "as well as our data sets, to the FDA for their review."
Dr Cyrus denied that Trasylol was associated with the same adverse effect revealed in the hidden study. "Bayer's summary on cardiac safety is very simple," she said, "Aprotinin was not associated with an increased incidence of myocardial infarction looking across all CABG patients."
"Bayer's conclusions on cerebrovascular safety," she told the Committee, "is that aprotinin was not associated with an increased incidence of either stroke or encephalopathy with encephalopathy also including coma."
Dr Jerrold Levy, Professor of Anesthesiology, Director of Cardiothoracic Anesthesiology and Deputy Chair of Research at Emory University, also appeared on behalf of Bayer to discuss the risk-benefit assessment and also flat-out denied the increased risk of adverse effects associated with Trasylol found in the hidden study, going so far as to say it decreased the risk of stroke.
Dr Levy told the panel, "if you look at the clinical studies of the randomized clinical trials in CABG surgery, there is no greater risk of mortality, MI, or renal failure and, at least from this data, there was a reduction in stroke in these patients."
Regarding stroke, if you look at four different meta-analysis of studies," he said, "there was a significant reduction in stroke."
Committee member, Dr Valluvan Jeevanandam, asked Bayer representatives whether there were other studies. "Could you comment on other trials other than CABG trials where there might have been an effect on renal function," he asked, "because a lot of the questions we had in our first presentation by Dr. Mangano was perhaps concomitant procedures with higher incidence of renal dysfunction, so do you have other trials other than just CABG trials looking at renal function?"
Dr Cyrus described one study as "the most recent" stating, "Probably the most recent study where you could just remove the effect of bypass totally is a study that was just conducted by Bayer in hip surgery."
"So, if you forget the bypass effect on the kidneys and let's look at a patient population that may not be at increased risk," she stated, "there were no differences between the groups in that patient population."
Dr Susan Heckbert also asked whether there were other studies stating, "I have a quick question about your global database, clinical trial database."
"It looks to me like the U.S. studies in that database," she said, "most of them are from the early nineties and they would reflect the kind of patient that would present and might be considered for a clinical trial in those days."
Dr Heckbert specifically asked, "You don't have anything beyond the early nineties in the United States in that database."
"What about from other countries," she inquired, "are we seeing the kind of patients that now go for CABG?"
"Do we have data in your global database from more contemporary types of patients?" she asked.
Dr Cyrus said, "The bulk of our clinical trial experience that I shared with you in the safety database was between the late eighties and late nineties."
"There were a few studies that went to 2001," she added.
"We do not have randomized clinical trials beyond 2001," she responded, "in the database that I shared with you today."
In the end, the Committee decided that there was no need for additional warnings on Trasylol labeling and Bayer quickly put out a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
The Committee agreed that the data are consistent with an association with aprotinin use and renal impairment, however, most members said they were not convinced that there was a definite increased risk of renal failure requiring dialysis.
Without the hidden study that proved otherwise, the Committee agreed that overall, there was no association between aprotinin and an increased risk of myocardial infarction, heart failure, stroke or encephalopathy.
Additionally, the Committee commented that these are short-term outcomes and that there is little or no data on the long-term cardiovascular outcomes in these patients.
Recommendations were made that, because there is limited current and long-term data, Bayer should be encouraged to sponsor such prospective studies to gather this information.
The Committee vote was taken to answer the specific question: "Based upon the presentations today, do you regard the totality of clinical data as supporting acceptable safety and efficacy for Trasylol usage among certain CABG/CPB patients?"
After being notified of the hidden study, the FDA issued another Advisory warning that the results of the study demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes."
Committee members were rightly outraged when they learned of the hidden study. Dr Robert Harrington, from Duke University, told Heartwire on October 6, 2006, "The process of evaluation, comment, and advice on important drug efficacy and safety data, only works when all of the involved parties are open and honest about their data."
He noted that he found Bayer's failure to disclose the study especially troubling, "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."
He called it "ironic" that the Committee spent part of the day criticizing Dr Mangano for failing to allow the FDA to analyze his database, "yet Bayer failed to even acknowledge the existence of these data."
Committee member, Dr Michael Lincoff, from the Cleveland Clinic, made similar comments to Heartwire. “It was astounding to me," he said, "that they did not disclose the information that the study had been conducted 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."
Dr Lincoff said it was "inconceivable," that Bayer representatives did not know of the study or its potential relevance to the Committee.
In the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn, published an opinion paper and stated, "The analysis completed in time for the FDA meeting, reached conclusions similar to those of Mangano et al."
"But neither Bayer nor its contractor," he wrote, "had provided the report to the FDA or even acknowledged its existence before the meeting."
Dr Avorn points out that a confirmatory observational study would have lent key support to the conclusions of Mangano et al — "if its findings had been aired," he added.
Bayer has admitted that suppressing the study was "a mistake," but Dr Avorn explains that this is not the first time the drug maker has been caught hiding research. When Bayer was accused of hiding data on its cholesterol-drug Baycol before it was taken off the market, litigation later unearthed a memo from a Bayer executive arguing against performing a study that would reveal its risk.
"If the FDA asks for bad news, we have to give," the memo states, "but if we don't have it, we can't give it to them
If patients or family members suspect that injuries or death may have been caused by Trasylol, they need to ask the surgeon whether the drug was administered during surgery.
Bayer Excuse For Hiding Trasylol Study Not Good Enough
Evelyn Pringle November 2006
In October 2006, the German-based drug maker, Bayer AG, said it was a "mistake" to withhold a study from the FDA that showed the drug, Trasylol, can cause lethal side effects and that the company had suspended two employees involved in the fiasco.
Critics say that's not good enough.
An October 4, 2006 editorial, titled, "Bayer’s Duplicity on Drug Safety," in the New York Times said: "Bayer A.G.’s limp excuse for withholding data suggesting that a heart-surgery drug is dangerous won’t wash."
"The failure by the German pharmaceutical giant," it states, "to inform the Food and Drug Administration of the disquieting results of a large observational study cannot be sloughed off as a mere 'mistake on the company’s part.'"
In a paper titled, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," in the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn, a professor of medicine at Harvard Medical School, points out that:
"Many aspects of the aprotinin saga are familiar to observers of the drug-evaluation process: a product is approved because it is more effective than placebo, worries emerge about its safety, few or no adequately powered controlled trials are conducted to address these issues, and payers spend huge sums on the drug, despite the dearth of evidence that it is better than older, cheaper agents."
"The health care system," Dr Avorn says, "has a hard time performing drug-safety analyses, in large part because it relies on the pharmaceutical industry to conduct most research on the risks and benefits of medications."
He says it is naive to think that drug companies will voluntarily fund studies that could sink lucrative products, and that the FDA lacks the regulatory clout to require them.
Aprotinin was approved by the FDA in 1993, for reducing blood loss and the need for blood transfusion in patients undergoing coronary-artery bypass surgery.
By the time the news of the hidden Bayer study was made public in late September 2006, the FDA had been reassessing the safety of Trasylol for 9 months, following the publication of two studies that linked the drug to heart attack, stroke and kidney disease.
The agency began its reassessment of Trasylol after a paper titled, "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, was published in the New England Journal of Medicine and described a study of 4,374 patients scheduled for coronary artery bypass graft surgery in multiple centers in multiple countries in which patients received either no medication, or one of 3 drugs intended to reduce blood loss, including aprotinin, aminocaproic acid, tranexamic acid.
The study reported an association of Trasylol with an increased risk of cardiovascular events such as myocardial infarction or heart failure, and cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure.
The researchers reported that patients taking Trasylol experienced a 2-fold increase in kidney failure, as well a 48% higher chance of heart attack and 181% increase in stroke. They also pointed out that Trasylol is 10 times more expensive than the 2 generic drugs used in the study.
The study was the first comprehensive, non-industry sponsored analysis of Trasylol’s safety, and was based on a systematic sampling scheme at 69 of the world’s leading cardiac centers in North and South America, Europe, the Middle East and Asia.
Dr Dennis Mangano, of the non-profit Ischemia Research and Education Foundation, who led the study, told the Senior Journal on January 26, 2006, "Unfortunately, comprehensive observational studies also are very costly, and given that there truly is no mandate or incentive for the pharmaceutical industry to aggressively find safety problems once a drug is marketed, it is up to society to find creative ways to independently assess safety."
"Otherwise," he stated, "the Vioxx—and now Aprotinin—sagas will only be but the first of a series of public health drug-safety failures.”
The Ischemia Foundation provided all of the funding for the Mangano study, totaling more than $35 million, including site grants, central analysis and data disposition and manuscript grants.
At the very least, doctors should be informing their patients about the risks posed by Trasylol and the fact that safer generic alternatives are available, Dr Mangano told Reuters on January 25, 2006.
Neither aminocaproic or tranexamic acid was found to be associated with an increased risk of renal, cardiac or cerebral events and both are much cheaper, at $11 and $44 per dose respectively, compared to up to $1,400 a dose for Trasylol.
The researchers concluded that stopping the use of Trasylol could prevent more than 11,000 cases of kidney failure annually, and save more than $1 billion in dialysis costs each year, as well as nearly $250 million spent on Trasylol itself.
The second Trasylol study titled, "A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery," by Karkouti et al was published in the journal, Transfusion, in January 2006.
This study used a statistical methodology to compare outcomes from patients undergoing CABG who received either Trasylol or another drug intended to decrease the risk of bleeding and found that Trasylol increased the risk for renal dysfunction or failure.
The study that Bayer withheld also found that Trasylol increased the risk of death, kidney damage, heart failure and stroke, but the results were not disclosed at a September 21, 2006, meeting of an FDA Advisory Committee, held to assess the safety of the drug.
Bayer scientists even appeared at the meeting to discuss the possibility that Trasylol, might have serious risks and never mentioned a word about their newest study. Bayer was forced to make the results public a week later after Dr Alexander Walker, a professor at Harvard's School of Public Health, who was involved in the study informed the FDA of the study's existence.
In a statement at the time, Bayer claimed that it "mistakenly" did not tell the FDA about a study that included the evaluation of roughly 67,000 hospital records saying:
“This. . . was not shared immediately with the agency because it was preliminary in nature and raised significant questions on the study population, outcomes, and methodology. Bayer believes that despite the highly preliminary nature of data, the information should have been shared with the FDA prior to the September 21 advisory-committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the company’s part.”
The study withheld, was a review of a large database of patients, comparing the side effects of several drugs including Trasylol, used to control excess bleeding, Bayer told Bloomberg News on October 6, 2006.
A company spokeswoman said that Bayer contracted Ingenix, a company that specializes in data-mining hospital databases, to conduct the analysis in the first half of 2006, according to Forbes.com on September 29, 2006.
In a Public Health Advisory issued when the research became known, the FDA said that the study linked Trasylol to increased risk of death, serious kidney damage, congestive heart failure and strokes.
Without seeing the results of the study commissioned by Bayer, a week earlier, the FDA advisory panel voted against strengthening the warning label on Trasylol.
A statement in an email from Bayer quoted by Bloomberg News on November 22, 2006, now claims: "Bayer is committed to sharing all safety information with relevant regulatory agencies."
However, following the publication of the two studies in January 2006, back in February, 2006, Thomas Segerson, MD, Vice President, Medical & Scientific Affairs at Bayer, sent out a "Dear Health Care Professional," letter in Canada saying the same thing and stating in part: "We have been working and will continue to work closely with regulatory authorities in countries where Trasylol is marketed to address questions regarding product safety."
"We share the company's data on Trasylol," Dr Segerson stated, "with regulatory authorities on an ongoing basis and welcome their evaluation of these published reports."
So what is the public to believe since those statements were obviously false when made. The truth is that Bayer tried to hide the results of the study until it could figure out some way to discount them and only came clean after Dr Walker blew the whistle.
On December 15, 2006, the FDA issued a press release addressing the hidden study that said in part, "The preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
"The FDA review of this additional Trasylol safety information," the agency said, "is continuing and it may result in other actions, including additional changes to the labeling."
Critics say that's not good enough; that its time for drug makers who conceal studies to be held criminally responsible for the injuries and deaths associated with their products.
In October 2006, the German-based drug maker, Bayer AG, said it was a "mistake" to withhold a study from the FDA that showed the drug, Trasylol, can cause lethal side effects and that the company had suspended two employees involved in the fiasco.
Critics say that's not good enough.
An October 4, 2006 editorial, titled, "Bayer’s Duplicity on Drug Safety," in the New York Times said: "Bayer A.G.’s limp excuse for withholding data suggesting that a heart-surgery drug is dangerous won’t wash."
"The failure by the German pharmaceutical giant," it states, "to inform the Food and Drug Administration of the disquieting results of a large observational study cannot be sloughed off as a mere 'mistake on the company’s part.'"
In a paper titled, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," in the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn, a professor of medicine at Harvard Medical School, points out that:
"Many aspects of the aprotinin saga are familiar to observers of the drug-evaluation process: a product is approved because it is more effective than placebo, worries emerge about its safety, few or no adequately powered controlled trials are conducted to address these issues, and payers spend huge sums on the drug, despite the dearth of evidence that it is better than older, cheaper agents."
"The health care system," Dr Avorn says, "has a hard time performing drug-safety analyses, in large part because it relies on the pharmaceutical industry to conduct most research on the risks and benefits of medications."
He says it is naive to think that drug companies will voluntarily fund studies that could sink lucrative products, and that the FDA lacks the regulatory clout to require them.
Aprotinin was approved by the FDA in 1993, for reducing blood loss and the need for blood transfusion in patients undergoing coronary-artery bypass surgery.
By the time the news of the hidden Bayer study was made public in late September 2006, the FDA had been reassessing the safety of Trasylol for 9 months, following the publication of two studies that linked the drug to heart attack, stroke and kidney disease.
The agency began its reassessment of Trasylol after a paper titled, "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, was published in the New England Journal of Medicine and described a study of 4,374 patients scheduled for coronary artery bypass graft surgery in multiple centers in multiple countries in which patients received either no medication, or one of 3 drugs intended to reduce blood loss, including aprotinin, aminocaproic acid, tranexamic acid.
The study reported an association of Trasylol with an increased risk of cardiovascular events such as myocardial infarction or heart failure, and cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure.
The researchers reported that patients taking Trasylol experienced a 2-fold increase in kidney failure, as well a 48% higher chance of heart attack and 181% increase in stroke. They also pointed out that Trasylol is 10 times more expensive than the 2 generic drugs used in the study.
The study was the first comprehensive, non-industry sponsored analysis of Trasylol’s safety, and was based on a systematic sampling scheme at 69 of the world’s leading cardiac centers in North and South America, Europe, the Middle East and Asia.
Dr Dennis Mangano, of the non-profit Ischemia Research and Education Foundation, who led the study, told the Senior Journal on January 26, 2006, "Unfortunately, comprehensive observational studies also are very costly, and given that there truly is no mandate or incentive for the pharmaceutical industry to aggressively find safety problems once a drug is marketed, it is up to society to find creative ways to independently assess safety."
"Otherwise," he stated, "the Vioxx—and now Aprotinin—sagas will only be but the first of a series of public health drug-safety failures.”
The Ischemia Foundation provided all of the funding for the Mangano study, totaling more than $35 million, including site grants, central analysis and data disposition and manuscript grants.
At the very least, doctors should be informing their patients about the risks posed by Trasylol and the fact that safer generic alternatives are available, Dr Mangano told Reuters on January 25, 2006.
Neither aminocaproic or tranexamic acid was found to be associated with an increased risk of renal, cardiac or cerebral events and both are much cheaper, at $11 and $44 per dose respectively, compared to up to $1,400 a dose for Trasylol.
The researchers concluded that stopping the use of Trasylol could prevent more than 11,000 cases of kidney failure annually, and save more than $1 billion in dialysis costs each year, as well as nearly $250 million spent on Trasylol itself.
The second Trasylol study titled, "A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery," by Karkouti et al was published in the journal, Transfusion, in January 2006.
This study used a statistical methodology to compare outcomes from patients undergoing CABG who received either Trasylol or another drug intended to decrease the risk of bleeding and found that Trasylol increased the risk for renal dysfunction or failure.
The study that Bayer withheld also found that Trasylol increased the risk of death, kidney damage, heart failure and stroke, but the results were not disclosed at a September 21, 2006, meeting of an FDA Advisory Committee, held to assess the safety of the drug.
Bayer scientists even appeared at the meeting to discuss the possibility that Trasylol, might have serious risks and never mentioned a word about their newest study. Bayer was forced to make the results public a week later after Dr Alexander Walker, a professor at Harvard's School of Public Health, who was involved in the study informed the FDA of the study's existence.
In a statement at the time, Bayer claimed that it "mistakenly" did not tell the FDA about a study that included the evaluation of roughly 67,000 hospital records saying:
“This. . . was not shared immediately with the agency because it was preliminary in nature and raised significant questions on the study population, outcomes, and methodology. Bayer believes that despite the highly preliminary nature of data, the information should have been shared with the FDA prior to the September 21 advisory-committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the company’s part.”
The study withheld, was a review of a large database of patients, comparing the side effects of several drugs including Trasylol, used to control excess bleeding, Bayer told Bloomberg News on October 6, 2006.
A company spokeswoman said that Bayer contracted Ingenix, a company that specializes in data-mining hospital databases, to conduct the analysis in the first half of 2006, according to Forbes.com on September 29, 2006.
In a Public Health Advisory issued when the research became known, the FDA said that the study linked Trasylol to increased risk of death, serious kidney damage, congestive heart failure and strokes.
Without seeing the results of the study commissioned by Bayer, a week earlier, the FDA advisory panel voted against strengthening the warning label on Trasylol.
A statement in an email from Bayer quoted by Bloomberg News on November 22, 2006, now claims: "Bayer is committed to sharing all safety information with relevant regulatory agencies."
However, following the publication of the two studies in January 2006, back in February, 2006, Thomas Segerson, MD, Vice President, Medical & Scientific Affairs at Bayer, sent out a "Dear Health Care Professional," letter in Canada saying the same thing and stating in part: "We have been working and will continue to work closely with regulatory authorities in countries where Trasylol is marketed to address questions regarding product safety."
"We share the company's data on Trasylol," Dr Segerson stated, "with regulatory authorities on an ongoing basis and welcome their evaluation of these published reports."
So what is the public to believe since those statements were obviously false when made. The truth is that Bayer tried to hide the results of the study until it could figure out some way to discount them and only came clean after Dr Walker blew the whistle.
On December 15, 2006, the FDA issued a press release addressing the hidden study that said in part, "The preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
"The FDA review of this additional Trasylol safety information," the agency said, "is continuing and it may result in other actions, including additional changes to the labeling."
Critics say that's not good enough; that its time for drug makers who conceal studies to be held criminally responsible for the injuries and deaths associated with their products.
Sunday, August 1, 2010
High Death Rate Reported With Bayer's Trasylol
Evelyn Pringle January 2008
For over a year, Bayer has been under fire over the drug Trasylol, and now Dr Dennis Mangano, the lead author of new study in the February 7, 2007, Journal of the American Medical Association, says the drug may be responsible for 10,000 deaths over five years.
Trasylol (aprotinin) was FDA approved for sale in the US in 1993, as an anti-clotting medication for limited use with patients who at a high risk of blood loss while undergoing coronary artery bypass surgery.
The intended effects of Trasylol during surgery include reduced bleeding, a decreased need for re-exploration surgery for bleeding, which in turn should lessen the need for transfusions. The drug works by disabling the enzymes that dissolve blood clots.
Despite the approval for limited use, Trasylol has been used off-label with many patients undergoing other types of surgery. In fact, the rate of off-label use far exceeds the rate of on-label use. The FDA's Adverse Event Reporting System shows that the majority of adverse events reported, or about 75%, occurred in patients who received Trasylol for an unapproved use, with heart valve replacement being the most frequent.
According to Dr Mangano, Trasylol was administered to 246,000 patients in the US in 2006. Bayer had been seeking FDA approval for Trasylol to be used with patients undergoing spinal fusion and hip replacement surgery until 2 negative studies were published early last year.
The latest JAMA study was conducted by the Multicenter Study of Perioperative Ischemia Research Group, and sponsored by the California-based Ischemia Research and Education Foundation, between November 11, 1996, and December 7, 2006, and patient survival was assessed at 6 weeks, 6 months, and annually for 5 years after surgery.
The researchers compared long-term all-cause mortality in patients receiving aminocaproic acid, tranexamic acid, Trasylol or no drug at all.
A previous study by the same research team evaluated 4,374 patients undergoing coronary artery bypass surgery found patients who received Trasylol were at an increased risk for serious kidney problems, heart attack, stroke, and deaths, compared to patients who were given the same 2 alternative anti-clotting agents or no drugs at all.
The study was the first comprehensive, observational, non-industry funded analysis of Trasylol’s safety and was based on a systematic sampling of 69 of the world’s leading cardiac centers and institutions in North and South America, Europe, the Middle East and Asia.
When broken down into separate categories, the analysis showed that Trasylol use was associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, a 181% increase in strokes, and a 2-fold increase in renal failure. The study was published in the New England Journal of Medicine in January 2006, and reported that the alternatives drugs did not cause the side effects identified with Trasylol.
After reviewing the results, the research team pointed out that although the other 2 drugs were available, safe and "equally effective in limiting bleeding," they are "underused."
There is one major difference in the medications and that is the price. According to Dr Mangano, Trasylol costs roughly $1,300 per patient and the prices for the other drugs are $11 and $44.
“We estimate that as many as 10,000 patients may be unnecessarily on dialysis today due to aprotinin use," Dr Mangano said in Senior Journal.com.
"This serious impact on human lives," he says, "underscores once again the necessity for meticulous, post-approval surveillance, as well as ongoing, unbiased analysis of drug safety—all conducted by entirely independent entities."
He reports that by replacing Trasylol with one of the alternative drugs, at least $1 billion in health care costs could be saved and at least $250 million more would be saved from the reduced cost of the drug itself.
Another study published in the January 20, 2006 online edition of the journal Transfusion also found an increase in kidney problems among patients who received Trasylol while undergoing heart surgery.
Following the release of the results from these earlier studies last year, a number of physicians, consumer advocates, and Dr Mangano's research group called on the FDA to remove Trasylol from the market
The FDA opted not to recall the drug but the agency did begin a reassessment of the safety risks associated with Trasylol. In September, 2006, Bayer submitted new data on the drug to the FDA and company officials also testified about their own positive studies regarding the safety of the drug before an FDA advisory committee and made a series of accusations against the reliability of Dr Mangano's study.
However, within days of their testimony, a researcher on a study that Bayer did not share with the FDA panel, alerted the media about the existence of a study that produced far different results than those reported by Bayer representatives at the hearing.
As it turns out, Bayer paid a contract research organization to conduct a study of existing hospital records from 67,000 patients and apparently was not happy with the results.
Of that group, 30,000 patients were treated with Trayslol, and 37,000 were treated with alternate drugs, and according to the FDA's December 15, 2006, announcement of the new labeling for Trasylol, "preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
The latest study by Dr Mangano's team, compared the death rates of 1,072 patients on Trasylol, 834 on aminocaproic acid; 442 patients on tranexamic acid, and 1,374 patients who did not receive any medication.
The alarming results found patients who received Trasylol were about 50% more likely to die within the five years following surgery. At the five year mark, there were 223 deaths in Trayslol group, 132 in the aminocaproic acid patients, and 65 in the Cyklokapron group.
And once again, the study found that neither of the other drugs showed a significantly higher death rate when compared to patients who receive no medication and the authors concluded:
Use of aprotinin ... does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.
These findings indicate 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.
It should be noted that Bayer said the findings of the new study are unreliable because the study did not adequately reflect the complexity of illness in patients given its drug.
However, some surgery centers had already quit using Trasylol before the latest study was published. For instance in Florida, surgeons at the Lakeland Regional Medical Center and Winter Haven Hospital stopped using the drug last year after studies said it increased the possibility of kidney failure, heart attacks and strokes, hospital spokespersons told The Ledger on February 10, 2007.
In the Trasylol label changes announced on December 15, 2006, the FDA said it should only be given to patients who are at an increased risk for blood loss and transfusion in the setting of coronary bypass graft surgery when patients undergo cardiopulmonary bypass. The FDA also warned that patients should not be given Trasylol if they had already received the drug within the past year.
For over a year, Bayer has been under fire over the drug Trasylol, and now Dr Dennis Mangano, the lead author of new study in the February 7, 2007, Journal of the American Medical Association, says the drug may be responsible for 10,000 deaths over five years.
Trasylol (aprotinin) was FDA approved for sale in the US in 1993, as an anti-clotting medication for limited use with patients who at a high risk of blood loss while undergoing coronary artery bypass surgery.
The intended effects of Trasylol during surgery include reduced bleeding, a decreased need for re-exploration surgery for bleeding, which in turn should lessen the need for transfusions. The drug works by disabling the enzymes that dissolve blood clots.
Despite the approval for limited use, Trasylol has been used off-label with many patients undergoing other types of surgery. In fact, the rate of off-label use far exceeds the rate of on-label use. The FDA's Adverse Event Reporting System shows that the majority of adverse events reported, or about 75%, occurred in patients who received Trasylol for an unapproved use, with heart valve replacement being the most frequent.
According to Dr Mangano, Trasylol was administered to 246,000 patients in the US in 2006. Bayer had been seeking FDA approval for Trasylol to be used with patients undergoing spinal fusion and hip replacement surgery until 2 negative studies were published early last year.
The latest JAMA study was conducted by the Multicenter Study of Perioperative Ischemia Research Group, and sponsored by the California-based Ischemia Research and Education Foundation, between November 11, 1996, and December 7, 2006, and patient survival was assessed at 6 weeks, 6 months, and annually for 5 years after surgery.
The researchers compared long-term all-cause mortality in patients receiving aminocaproic acid, tranexamic acid, Trasylol or no drug at all.
A previous study by the same research team evaluated 4,374 patients undergoing coronary artery bypass surgery found patients who received Trasylol were at an increased risk for serious kidney problems, heart attack, stroke, and deaths, compared to patients who were given the same 2 alternative anti-clotting agents or no drugs at all.
The study was the first comprehensive, observational, non-industry funded analysis of Trasylol’s safety and was based on a systematic sampling of 69 of the world’s leading cardiac centers and institutions in North and South America, Europe, the Middle East and Asia.
When broken down into separate categories, the analysis showed that Trasylol use was associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, a 181% increase in strokes, and a 2-fold increase in renal failure. The study was published in the New England Journal of Medicine in January 2006, and reported that the alternatives drugs did not cause the side effects identified with Trasylol.
After reviewing the results, the research team pointed out that although the other 2 drugs were available, safe and "equally effective in limiting bleeding," they are "underused."
There is one major difference in the medications and that is the price. According to Dr Mangano, Trasylol costs roughly $1,300 per patient and the prices for the other drugs are $11 and $44.
“We estimate that as many as 10,000 patients may be unnecessarily on dialysis today due to aprotinin use," Dr Mangano said in Senior Journal.com.
"This serious impact on human lives," he says, "underscores once again the necessity for meticulous, post-approval surveillance, as well as ongoing, unbiased analysis of drug safety—all conducted by entirely independent entities."
He reports that by replacing Trasylol with one of the alternative drugs, at least $1 billion in health care costs could be saved and at least $250 million more would be saved from the reduced cost of the drug itself.
Another study published in the January 20, 2006 online edition of the journal Transfusion also found an increase in kidney problems among patients who received Trasylol while undergoing heart surgery.
Following the release of the results from these earlier studies last year, a number of physicians, consumer advocates, and Dr Mangano's research group called on the FDA to remove Trasylol from the market
The FDA opted not to recall the drug but the agency did begin a reassessment of the safety risks associated with Trasylol. In September, 2006, Bayer submitted new data on the drug to the FDA and company officials also testified about their own positive studies regarding the safety of the drug before an FDA advisory committee and made a series of accusations against the reliability of Dr Mangano's study.
However, within days of their testimony, a researcher on a study that Bayer did not share with the FDA panel, alerted the media about the existence of a study that produced far different results than those reported by Bayer representatives at the hearing.
As it turns out, Bayer paid a contract research organization to conduct a study of existing hospital records from 67,000 patients and apparently was not happy with the results.
Of that group, 30,000 patients were treated with Trayslol, and 37,000 were treated with alternate drugs, and according to the FDA's December 15, 2006, announcement of the new labeling for Trasylol, "preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
The latest study by Dr Mangano's team, compared the death rates of 1,072 patients on Trasylol, 834 on aminocaproic acid; 442 patients on tranexamic acid, and 1,374 patients who did not receive any medication.
The alarming results found patients who received Trasylol were about 50% more likely to die within the five years following surgery. At the five year mark, there were 223 deaths in Trayslol group, 132 in the aminocaproic acid patients, and 65 in the Cyklokapron group.
And once again, the study found that neither of the other drugs showed a significantly higher death rate when compared to patients who receive no medication and the authors concluded:
Use of aprotinin ... does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.
These findings indicate 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.
It should be noted that Bayer said the findings of the new study are unreliable because the study did not adequately reflect the complexity of illness in patients given its drug.
However, some surgery centers had already quit using Trasylol before the latest study was published. For instance in Florida, surgeons at the Lakeland Regional Medical Center and Winter Haven Hospital stopped using the drug last year after studies said it increased the possibility of kidney failure, heart attacks and strokes, hospital spokespersons told The Ledger on February 10, 2007.
In the Trasylol label changes announced on December 15, 2006, the FDA said it should only be given to patients who are at an increased risk for blood loss and transfusion in the setting of coronary bypass graft surgery when patients undergo cardiopulmonary bypass. The FDA also warned that patients should not be given Trasylol if they had already received the drug within the past year.
Trasylol Fiasco - FDA Fails To Protect Americans Again - Part I
Evelyn Pringle February 2008
On November 5, 2007, the FDA announced that Bayer Pharmaceuticals had suspended the marketing of Trasylol after preliminary results of a Canadian study indicated that patients may also have a greater risk of death than patients taking either of two other drugs.
The Canadian study, Blood Antifibrinolytics Randomized Trial (BART), led by scientists at the Ottawa Health Research Institute was designed to test the efficacy of Trasylol (aprotinin) against tranexamic acid and aminocaproic acid.
The study was supposed to randomize 2,973 patients to receive one of the three drugs but a review by a safety monitoring board of preliminary data on 2,163 patients indicated a trend towards increased deaths in the Trasylol patients.
A statement on the Research Institute's website said that if the final analysis of data confirmed the trend, it would translate into 2 additional deaths per 100 patients on Trasylol, compared to patients who received the other agents. Based on those findings the monitoring board terminated enrollment in the trial and regulatory agencies were notified.
This announcement by the FDA that Trasylol will no longer be marketed in the US represents another “too little - too late” example of the Bush Administration placing industry profits over the safety of American citizens.
Medical experts having been calling for the removal of Trasylol from the market for 2 years, ever since two studies in January 2006, reported that patients who received the drug were at an increased risk of kidney failure, heart attack, heart failure, stroke, coma, and encephalopathy, a breakdown of brain tissue.
In fact, the lead author of one of the studies, Dr Dennis Mangano told Consumer Affairs that the results of the studies on Trasylol raised even more concerns than Vioxx because the drug had been on the market 3 times as long as Vioxx, the life-threatening complications occurred more frequently, and equally effective alternative drugs were available and underused.
A little more than a year after the first warnings appeared, Dr Mangano, as lead author on another study in the February 7, 2007 Journal of the American Medical Association, estimated that over 5 years, Trasylol may have been responsible for 10,000 deaths.
There was no excuse for allowing all these people to be killed and injured because at an FDA advisory committee meeting on September 21, 2007, several experts, along with Dr George Shashaty, the FDA’s medical reviewer for Trayslol, as much as said that other than eliminating the need for transfusions, the benefits of the drug are at best undocumented and at worst non-existent.
“The use of Trasylol for its labeled indication is based on the balance between its benefits and risks," Dr Shashaty told the panel. "Trasylol has consistently been shown to diminish blood loss and the need for transfusion when administered during CABG surgery with CPB.”
“Despite this benefit,” he told the panel, “Trasylol has never been demonstrated to improve survival which would seem to be its most desired salutary effect.”
The chairman of the committee, Dr Bob Harrington, a cardiologist at Duke University, pointed out that, "If everyone is up there passionately talking about how bad blood transfusion is and this stuff reduces blood transfusion, why aren't we reducing death."
"As an old-time guy," Dr Shashaty stated in the hearing, "I am interested in knowing, does the patient live or die?"
"Well," he continued, "the best information we have from randomized controlled trials from the sponsor is no, there is no difference in the rate of death."
"Okay." he stated, "if there is no difference in the rate of death, again, as an old-time guy, I fall back to, well, what was the benefit that we gained from your intervention, whatever it is."
"As best we can determine," he said, "and I think this has been demonstrated over and over and over again, is that there is a decreased need for the transfusion of blood on a percentage basis and the number of units of blood transfused per patient is reduced."
Dr Michael Lincoff, an interventional cardiologist from the Cleveland Clinic also pointed out that the calculations of lives saved per transfusion prevented brings up the question, "then why aren't we seeing the mortality benefit."
Dr Timothy Lesar, the Director of Pharmacy, at Albany Medical Center in New York, even suggested a label change with a statement that said, "aprotinin has not been demonstrated to reduce morbidity and mortality. An overall positive benefit-to-risk ratio has not been demonstrated despite reduction in transfusion needs. Some observational studies have suggested no benefit or harm."
Trasylol gained FDA approval on December 30, 1993, for limited use in patients undergoing coronary artery bypass graft surgery, to control bleeding based on 2 placebo controlled trials conducted in the US that demonstrated aprotinin effectively reduced blood loss and decreased the need for transfusions.
“In one study, 42 percent of patients treated with aprotinin needed at least one unit of blood, compared to 77 percent who did not receive the drug. The second study showed similar results,” the FDA wrote.
“Its use should be reserved for high risk patients,” the FDA stated in a press release announcing the approval, “because severe allergic reactions can result from using it more than once in a patient. Kidney toxicity was also a problem in some patients in the trials."
A briefing document submitted to the FDA for the September 12, 2007 advisory meeting shows that Bayer’s entire global randomized controlled database, which presumably consists of all clinical trials conducted before and since it was approved 15 years ago, includes only 2,249 patients tested with a full-dose of Trasylol to compare the drug against 2,164 placebo-treated patients.
However, as usual, the drug has been heavily promoted for numerous off-label uses and as a result tens of millions of patients received the drug during other types of surgery for unapproved uses.
In fact, the rate of off-label use vastly exceeds the rate of on-label use and the FDA's Adverse Event Reporting System shows that the majority, or about 75%, of adverse events developed in patients who received Trasylol off-label, with heart valve replacement surgery being the most frequent unapproved use.
The FDA issued the first February 8, 2006 advisory warning doctors to limit the use of Trasylol based on the January 2006 study, "The Risk Associated with Aprotinin in Cardiac Surgery," in the New England Journal of Medicine that found the use of Trasylol increased the risk of stroke by 181%, myocardial infarction by 48%, and heart failure by 109%, when compared to people who received the 2 alternate drugs.
The researcher's also reported that patients treated with Trasylol, had a risk of kidney failure 259% greater than patients who received no drugs.
On February 8, 2008, Health Gazette ran the headline: “FDA Issues Half-Hearted Public Health Advisory About Trasylol,” and stated:
“Once again the Food and Drug Administration (FDA) has issued a Public Health Advisory in a manner that appears decidedly grudging and half-hearted. One can only imagine how well drug company management and investors must sleep at night, knowing that even if highly reputable medical journals publish adverse findings about their products, their friends at the FDA are there to protect them.
“Too bad for consumers though, isn't it.”
“This Advisory is remarkable,” the author notes. “While acknowledging that adverse findings have been reported from two different studies in two different medical journals, the Advisory itself begins a critique of those studies in such a way as to undermine their credibility.”
The NEJM study was led by Dr Mangano at the California based non-profit, Ischemia Research and Education Foundation, and involved more than 4,300 patients at 69 cardiac centers worldwide. In the discussion portion of the study, the authors wrote:
“Our findings raise serious concerns regarding the safety of an approved drug intended to limit blood loss in at-risk patients undergoing surgery. Specifically, the use of aprotinin was associated with a dose-dependent doubling to tripling in the risk of renal failure requiring dialysis among patients undergoing primary or complex coronary-artery surgery.”
“Furthermore, for the majority of patients undergoing primary surgery, we found evidence of multiorgan damage involving the heart (myocardial infarction or heart failure) and the brain (encephalopathy) in addition to the kidneys, suggesting a generalized pattern of ischemic injury.”
The researchers reported that their analysis of the less costly aminocaproic acid and tranexamic acid demonstrated no such safety concerns and the agents were found to be equally effective in reducing blood loss.
“Given our findings,” the researchers advised, “especially with regard to serious renal events among patients undergoing either primary or complex surgery, and given the cost of aprotinin therapy, which is at least 10 times that of aminocaproic or tranexamic acid, we estimate that considerable global health care savings would accrue if aprotinin were replaced by either aminocaproic acid or tranexamic acid.”
“Specifically,” they wrote, “we estimate that for renal complications alone, the replacement of aprotinin with aminocaproic acid would prevent renal failure requiring dialysis in 11,050 patients per year, yielding an indirect savings (from the saved cost of dialysis) of more than $1 billion per year, in addition to direct savings (from reduced drug costs) of nearly $250 million per year.”
The authors also advised that replacement with tranexamic acid would prevent 9,790 complications necessitating dialysis each year, yielding similar direct and indirect savings.
The study titled, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," in the January 20, 2006 online edition of Transfusion, also found a decreased kidney function in patients treated with Trasylol when compared to another agent used to prevent bleeding.
For its part, in a January 26, 2006 statement, Bayer said that the observational study’s results in the NEJM "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug," in an online statement in MedPage Today.
"Double-blind, randomized controlled trials are the accepted standard for the assessment of the efficacy and safety of drugs and serve as the basis for approval of all new drugs,” Bayer stated.
“Such trials do not suffer from the limitations that can exist in observational studies," the company wrote in the statement.
An observational study observes what happens to people after they have received a treatment.
The explanations given by Bayer for higher adverse events in patients receiving Trayslol compared to placebo, are used all the time by drug companies and sound like a broken record. They always claim its the disease and that people who experienced adverse events may have been really sick. Well then common sense says if the drug is a life-saver, the patients who received no medication would be dead, not the other way around.
It took the FDA eight months to convene an advisory committee on September 21, 2006, to decide whether the drug should remain on the market. At that meeting, the panel discussed the findings from the two published studies, the Bayer worldwide safety review, and the FDA’s own review of the agency’s post-marketing database.
At the meeting, FDA briefing officials advised the committee that about 250,000 patients received Trasylol in the US in 2005.
The findings of the Transfusion study were presented by Dr Karkouti. "Our primary outcome was efficacy transfusions," he told the panel, "and our hypothesis was that we would see a marked superiority with aprotinin mainly because that was the clinical impression and it still is at probably most places across Canada."
"But what we found," he stated, "was that there was really no difference in the
transfusion rates."
He said the hypothesis going in was that if aprotinin was better, it should show a reduction in the risk of MI, stroke, renal failure, infection and death. "We didn't find any reduction of these adverse events with aprotinin use," he told the panel.
"We did find a renal dysfunction increase with aprotinin and a trend toward increased renal failure," Dr Karkouti stated.
Dr Mangano told the panel that both aminocaproic and tranexamic showed blood-sparing capabilities equal to Trasylol but said, "head-to-head comparisons were few and far between despite the enormous difference in cost between these agents with aprotinin between $500 and $1,200 a patient and the others, less than $50 a patient."
During Bayer's presentation, Mike Rozycki, the firm's Director of US Regulatory Affairs, stated that when Bayer learned of the studies, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted in very close association and under the guidance of the FDA," he told the committee. He also said that all information had been submitted and was under review by the FDA.
Bayer’s Dr Pamela Cyrus, Vice President for Trasylol and Non-Specialty Products, US Medical Affairs, told the panel, "With the two recent observational studies, we have also conducted a very thorough analysis of our global CABG data base."
"We have submitted that analysis, as well as our data sets, to the FDA for their review," she stated.
As to the safety information provided to the FDA, Dr Cyrus specifically said that Bayer had "submitted data on an ongoing basis to our NDA, as well as with our ongoing pharmacovigilance additional data."
Dr Cyrus testified that Bayer’s research did not show that Trasylol was associated with the adverse events revealed in the NEJM study. "Bayer's summary on cardiac safety is very simple," she stated, "Aprotinin was not associated with an increased incidence of myocardial infarction looking across all CABG patients."
"Bayer's conclusions on cerebrovascular safety," she stated, "is that aprotinin was not associated with an increased incidence of either stroke or encephalopathy with encephalopathy also including coma."
Dr Robert Makuch, a professor at the Yale School of Public Health, also testified on Bayer's behalf and dismissed the results of the NEJM study. "In summary," he told the panel, "the Mangano study results should not be considered reliable at this time."
In the end, the FDA sided with Bayer and claimed that there was not enough evidence to even support adding a warning to the label of Trasylol, because Dr Mangano's research was the only study to report an increased cardiovascular risk.
Nine days after the panel decided that there was not enough evidence to justify removing Trasylol from the market, on September 30, 2006, the New York Times reported that Bayer had conducted a study of its own but failed to inform the FDA of its existence.
Come to find out, four days after the NEJM study appeared, on February 1, 2006, Bayer officials, Dr Kuno Sprenger, a Risk Manager and Drug Safety Advisor, and Dr Ernst Weidmann, a Vice President for GDS, had emailed Dr Alexander Walker of the contract research organization, i3 Drug Safety, about working on an observational study for Bayer involving aprotinin, aminocaproic acid and tranexamic acid.
The damning report on the study, entitled, “Mortality and Cardiovascular and Renal outcomes in recipients of aprotinin, aminocaproic acid and tranexamic acid during CABG surgery: Report on Computerized Inpatient Data from the Premier Perspective Comparative Database,” was sent to Bayer on September 13, 2006, a full week before the advisory committee hearing.
When Dr Walker realized that Bayer had not made the FDA aware of the negative findings in the i3 study that basically verified the findings of the studies discussed at the hearing, he informed the FDA that Bayer had commissioned the study and had the results at the time of the hearing.
Based on that study, the FDA issued an immediate warning that the drug could cause renal failure, congestive heart failure, stroke and death and on December 15, 2006, the FDA announced new labeling for Trasylol, and stated, "preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
The Bush Administration’s protection of drug company profits by allowing dangerous drugs to remain on the market, as evidenced in cases where serious risks were known by the company but concealed including Vioxx, Avandia, Paxil, OxyContin, Zyprexa, Baycol, Ketek, and now Trasylol, is so transparent that it has become a bad joke in itself.
For instance, on October 13, 2006, less than a month after the company was busted for concealing the study, Bayer embarked on an all out CYA campaign and announced that it had retained attorney, Fred Fielding of the Washington law firm, Wiley Rein & Fielding, to investigate the matter.
But on January 8, 2007, Mr Fielding had to back out of the job when news came that he had moved up in the world through new employment as White House Counsel, appointed by President George W Bush. After that, Bayer hired Zuckerman Spaeder LLP to conduct the investigation.
On August 21, 2007, the Zuckerman firm issued a report on the investigation and answers several questions. The first being: "Who at Bayer knew of the existence of the i3 study and which of those persons, if any, were functionally responsible for informing FDA of its existence?"
In the answer, the report lists many names, but most importantly, it lists the names of every person who testified at the September 21, 2006 advisory committee meeting.
Bayer’s Global Regulatory Affairs department was responsible for communicating with the FDA about Trasylol through Dr Joseph Scheeren, the Senior Vice President of Global Regulatory Affairs and Dr Michael Rozycki, the Director of US Regulatory Affairs.
The report lists Dr Rozycki as Bayer’s primary liaison to the FDA on Trasylol throughout 2006, including all matters related to the advisory committee meeting.
That said, the report predictably states: "We conclude that the failure to disclose was not motivated by an intent to conceal the i3 study from FDA or the Advisory Committee but was regrettable human error."
On November 5, 2007, the FDA announced that Bayer Pharmaceuticals had suspended the marketing of Trasylol after preliminary results of a Canadian study indicated that patients may also have a greater risk of death than patients taking either of two other drugs.
The Canadian study, Blood Antifibrinolytics Randomized Trial (BART), led by scientists at the Ottawa Health Research Institute was designed to test the efficacy of Trasylol (aprotinin) against tranexamic acid and aminocaproic acid.
The study was supposed to randomize 2,973 patients to receive one of the three drugs but a review by a safety monitoring board of preliminary data on 2,163 patients indicated a trend towards increased deaths in the Trasylol patients.
A statement on the Research Institute's website said that if the final analysis of data confirmed the trend, it would translate into 2 additional deaths per 100 patients on Trasylol, compared to patients who received the other agents. Based on those findings the monitoring board terminated enrollment in the trial and regulatory agencies were notified.
This announcement by the FDA that Trasylol will no longer be marketed in the US represents another “too little - too late” example of the Bush Administration placing industry profits over the safety of American citizens.
Medical experts having been calling for the removal of Trasylol from the market for 2 years, ever since two studies in January 2006, reported that patients who received the drug were at an increased risk of kidney failure, heart attack, heart failure, stroke, coma, and encephalopathy, a breakdown of brain tissue.
In fact, the lead author of one of the studies, Dr Dennis Mangano told Consumer Affairs that the results of the studies on Trasylol raised even more concerns than Vioxx because the drug had been on the market 3 times as long as Vioxx, the life-threatening complications occurred more frequently, and equally effective alternative drugs were available and underused.
A little more than a year after the first warnings appeared, Dr Mangano, as lead author on another study in the February 7, 2007 Journal of the American Medical Association, estimated that over 5 years, Trasylol may have been responsible for 10,000 deaths.
There was no excuse for allowing all these people to be killed and injured because at an FDA advisory committee meeting on September 21, 2007, several experts, along with Dr George Shashaty, the FDA’s medical reviewer for Trayslol, as much as said that other than eliminating the need for transfusions, the benefits of the drug are at best undocumented and at worst non-existent.
“The use of Trasylol for its labeled indication is based on the balance between its benefits and risks," Dr Shashaty told the panel. "Trasylol has consistently been shown to diminish blood loss and the need for transfusion when administered during CABG surgery with CPB.”
“Despite this benefit,” he told the panel, “Trasylol has never been demonstrated to improve survival which would seem to be its most desired salutary effect.”
The chairman of the committee, Dr Bob Harrington, a cardiologist at Duke University, pointed out that, "If everyone is up there passionately talking about how bad blood transfusion is and this stuff reduces blood transfusion, why aren't we reducing death."
"As an old-time guy," Dr Shashaty stated in the hearing, "I am interested in knowing, does the patient live or die?"
"Well," he continued, "the best information we have from randomized controlled trials from the sponsor is no, there is no difference in the rate of death."
"Okay." he stated, "if there is no difference in the rate of death, again, as an old-time guy, I fall back to, well, what was the benefit that we gained from your intervention, whatever it is."
"As best we can determine," he said, "and I think this has been demonstrated over and over and over again, is that there is a decreased need for the transfusion of blood on a percentage basis and the number of units of blood transfused per patient is reduced."
Dr Michael Lincoff, an interventional cardiologist from the Cleveland Clinic also pointed out that the calculations of lives saved per transfusion prevented brings up the question, "then why aren't we seeing the mortality benefit."
Dr Timothy Lesar, the Director of Pharmacy, at Albany Medical Center in New York, even suggested a label change with a statement that said, "aprotinin has not been demonstrated to reduce morbidity and mortality. An overall positive benefit-to-risk ratio has not been demonstrated despite reduction in transfusion needs. Some observational studies have suggested no benefit or harm."
Trasylol gained FDA approval on December 30, 1993, for limited use in patients undergoing coronary artery bypass graft surgery, to control bleeding based on 2 placebo controlled trials conducted in the US that demonstrated aprotinin effectively reduced blood loss and decreased the need for transfusions.
“In one study, 42 percent of patients treated with aprotinin needed at least one unit of blood, compared to 77 percent who did not receive the drug. The second study showed similar results,” the FDA wrote.
“Its use should be reserved for high risk patients,” the FDA stated in a press release announcing the approval, “because severe allergic reactions can result from using it more than once in a patient. Kidney toxicity was also a problem in some patients in the trials."
A briefing document submitted to the FDA for the September 12, 2007 advisory meeting shows that Bayer’s entire global randomized controlled database, which presumably consists of all clinical trials conducted before and since it was approved 15 years ago, includes only 2,249 patients tested with a full-dose of Trasylol to compare the drug against 2,164 placebo-treated patients.
However, as usual, the drug has been heavily promoted for numerous off-label uses and as a result tens of millions of patients received the drug during other types of surgery for unapproved uses.
In fact, the rate of off-label use vastly exceeds the rate of on-label use and the FDA's Adverse Event Reporting System shows that the majority, or about 75%, of adverse events developed in patients who received Trasylol off-label, with heart valve replacement surgery being the most frequent unapproved use.
The FDA issued the first February 8, 2006 advisory warning doctors to limit the use of Trasylol based on the January 2006 study, "The Risk Associated with Aprotinin in Cardiac Surgery," in the New England Journal of Medicine that found the use of Trasylol increased the risk of stroke by 181%, myocardial infarction by 48%, and heart failure by 109%, when compared to people who received the 2 alternate drugs.
The researcher's also reported that patients treated with Trasylol, had a risk of kidney failure 259% greater than patients who received no drugs.
On February 8, 2008, Health Gazette ran the headline: “FDA Issues Half-Hearted Public Health Advisory About Trasylol,” and stated:
“Once again the Food and Drug Administration (FDA) has issued a Public Health Advisory in a manner that appears decidedly grudging and half-hearted. One can only imagine how well drug company management and investors must sleep at night, knowing that even if highly reputable medical journals publish adverse findings about their products, their friends at the FDA are there to protect them.
“Too bad for consumers though, isn't it.”
“This Advisory is remarkable,” the author notes. “While acknowledging that adverse findings have been reported from two different studies in two different medical journals, the Advisory itself begins a critique of those studies in such a way as to undermine their credibility.”
The NEJM study was led by Dr Mangano at the California based non-profit, Ischemia Research and Education Foundation, and involved more than 4,300 patients at 69 cardiac centers worldwide. In the discussion portion of the study, the authors wrote:
“Our findings raise serious concerns regarding the safety of an approved drug intended to limit blood loss in at-risk patients undergoing surgery. Specifically, the use of aprotinin was associated with a dose-dependent doubling to tripling in the risk of renal failure requiring dialysis among patients undergoing primary or complex coronary-artery surgery.”
“Furthermore, for the majority of patients undergoing primary surgery, we found evidence of multiorgan damage involving the heart (myocardial infarction or heart failure) and the brain (encephalopathy) in addition to the kidneys, suggesting a generalized pattern of ischemic injury.”
The researchers reported that their analysis of the less costly aminocaproic acid and tranexamic acid demonstrated no such safety concerns and the agents were found to be equally effective in reducing blood loss.
“Given our findings,” the researchers advised, “especially with regard to serious renal events among patients undergoing either primary or complex surgery, and given the cost of aprotinin therapy, which is at least 10 times that of aminocaproic or tranexamic acid, we estimate that considerable global health care savings would accrue if aprotinin were replaced by either aminocaproic acid or tranexamic acid.”
“Specifically,” they wrote, “we estimate that for renal complications alone, the replacement of aprotinin with aminocaproic acid would prevent renal failure requiring dialysis in 11,050 patients per year, yielding an indirect savings (from the saved cost of dialysis) of more than $1 billion per year, in addition to direct savings (from reduced drug costs) of nearly $250 million per year.”
The authors also advised that replacement with tranexamic acid would prevent 9,790 complications necessitating dialysis each year, yielding similar direct and indirect savings.
The study titled, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," in the January 20, 2006 online edition of Transfusion, also found a decreased kidney function in patients treated with Trasylol when compared to another agent used to prevent bleeding.
For its part, in a January 26, 2006 statement, Bayer said that the observational study’s results in the NEJM "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug," in an online statement in MedPage Today.
"Double-blind, randomized controlled trials are the accepted standard for the assessment of the efficacy and safety of drugs and serve as the basis for approval of all new drugs,” Bayer stated.
“Such trials do not suffer from the limitations that can exist in observational studies," the company wrote in the statement.
An observational study observes what happens to people after they have received a treatment.
The explanations given by Bayer for higher adverse events in patients receiving Trayslol compared to placebo, are used all the time by drug companies and sound like a broken record. They always claim its the disease and that people who experienced adverse events may have been really sick. Well then common sense says if the drug is a life-saver, the patients who received no medication would be dead, not the other way around.
It took the FDA eight months to convene an advisory committee on September 21, 2006, to decide whether the drug should remain on the market. At that meeting, the panel discussed the findings from the two published studies, the Bayer worldwide safety review, and the FDA’s own review of the agency’s post-marketing database.
At the meeting, FDA briefing officials advised the committee that about 250,000 patients received Trasylol in the US in 2005.
The findings of the Transfusion study were presented by Dr Karkouti. "Our primary outcome was efficacy transfusions," he told the panel, "and our hypothesis was that we would see a marked superiority with aprotinin mainly because that was the clinical impression and it still is at probably most places across Canada."
"But what we found," he stated, "was that there was really no difference in the
transfusion rates."
He said the hypothesis going in was that if aprotinin was better, it should show a reduction in the risk of MI, stroke, renal failure, infection and death. "We didn't find any reduction of these adverse events with aprotinin use," he told the panel.
"We did find a renal dysfunction increase with aprotinin and a trend toward increased renal failure," Dr Karkouti stated.
Dr Mangano told the panel that both aminocaproic and tranexamic showed blood-sparing capabilities equal to Trasylol but said, "head-to-head comparisons were few and far between despite the enormous difference in cost between these agents with aprotinin between $500 and $1,200 a patient and the others, less than $50 a patient."
During Bayer's presentation, Mike Rozycki, the firm's Director of US Regulatory Affairs, stated that when Bayer learned of the studies, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted in very close association and under the guidance of the FDA," he told the committee. He also said that all information had been submitted and was under review by the FDA.
Bayer’s Dr Pamela Cyrus, Vice President for Trasylol and Non-Specialty Products, US Medical Affairs, told the panel, "With the two recent observational studies, we have also conducted a very thorough analysis of our global CABG data base."
"We have submitted that analysis, as well as our data sets, to the FDA for their review," she stated.
As to the safety information provided to the FDA, Dr Cyrus specifically said that Bayer had "submitted data on an ongoing basis to our NDA, as well as with our ongoing pharmacovigilance additional data."
Dr Cyrus testified that Bayer’s research did not show that Trasylol was associated with the adverse events revealed in the NEJM study. "Bayer's summary on cardiac safety is very simple," she stated, "Aprotinin was not associated with an increased incidence of myocardial infarction looking across all CABG patients."
"Bayer's conclusions on cerebrovascular safety," she stated, "is that aprotinin was not associated with an increased incidence of either stroke or encephalopathy with encephalopathy also including coma."
Dr Robert Makuch, a professor at the Yale School of Public Health, also testified on Bayer's behalf and dismissed the results of the NEJM study. "In summary," he told the panel, "the Mangano study results should not be considered reliable at this time."
In the end, the FDA sided with Bayer and claimed that there was not enough evidence to even support adding a warning to the label of Trasylol, because Dr Mangano's research was the only study to report an increased cardiovascular risk.
Nine days after the panel decided that there was not enough evidence to justify removing Trasylol from the market, on September 30, 2006, the New York Times reported that Bayer had conducted a study of its own but failed to inform the FDA of its existence.
Come to find out, four days after the NEJM study appeared, on February 1, 2006, Bayer officials, Dr Kuno Sprenger, a Risk Manager and Drug Safety Advisor, and Dr Ernst Weidmann, a Vice President for GDS, had emailed Dr Alexander Walker of the contract research organization, i3 Drug Safety, about working on an observational study for Bayer involving aprotinin, aminocaproic acid and tranexamic acid.
The damning report on the study, entitled, “Mortality and Cardiovascular and Renal outcomes in recipients of aprotinin, aminocaproic acid and tranexamic acid during CABG surgery: Report on Computerized Inpatient Data from the Premier Perspective Comparative Database,” was sent to Bayer on September 13, 2006, a full week before the advisory committee hearing.
When Dr Walker realized that Bayer had not made the FDA aware of the negative findings in the i3 study that basically verified the findings of the studies discussed at the hearing, he informed the FDA that Bayer had commissioned the study and had the results at the time of the hearing.
Based on that study, the FDA issued an immediate warning that the drug could cause renal failure, congestive heart failure, stroke and death and on December 15, 2006, the FDA announced new labeling for Trasylol, and stated, "preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
The Bush Administration’s protection of drug company profits by allowing dangerous drugs to remain on the market, as evidenced in cases where serious risks were known by the company but concealed including Vioxx, Avandia, Paxil, OxyContin, Zyprexa, Baycol, Ketek, and now Trasylol, is so transparent that it has become a bad joke in itself.
For instance, on October 13, 2006, less than a month after the company was busted for concealing the study, Bayer embarked on an all out CYA campaign and announced that it had retained attorney, Fred Fielding of the Washington law firm, Wiley Rein & Fielding, to investigate the matter.
But on January 8, 2007, Mr Fielding had to back out of the job when news came that he had moved up in the world through new employment as White House Counsel, appointed by President George W Bush. After that, Bayer hired Zuckerman Spaeder LLP to conduct the investigation.
On August 21, 2007, the Zuckerman firm issued a report on the investigation and answers several questions. The first being: "Who at Bayer knew of the existence of the i3 study and which of those persons, if any, were functionally responsible for informing FDA of its existence?"
In the answer, the report lists many names, but most importantly, it lists the names of every person who testified at the September 21, 2006 advisory committee meeting.
Bayer’s Global Regulatory Affairs department was responsible for communicating with the FDA about Trasylol through Dr Joseph Scheeren, the Senior Vice President of Global Regulatory Affairs and Dr Michael Rozycki, the Director of US Regulatory Affairs.
The report lists Dr Rozycki as Bayer’s primary liaison to the FDA on Trasylol throughout 2006, including all matters related to the advisory committee meeting.
That said, the report predictably states: "We conclude that the failure to disclose was not motivated by an intent to conceal the i3 study from FDA or the Advisory Committee but was regrettable human error."
Trasylol Fiasco - FDA Fails To Protect Americans Again - Part II
Evelyn Pringle February 2008
In reading the report issued by the Zuckerman Spaeder law firm, one thing is perfectly clear. Bayer was willing to pay $700,000 to get a Trasylol study done in time for the September 21, 2006 advisory committee meeting, if it could refute the findings of the New England Journal of Medicine study.
However, unbeknownst to the contract research firm, i3 Drug Safety, it was decided early on that the study would not be mentioned to the FDA or the advisory panel unless and until Bayer was certain that it would achieve that goal.
In the NEJM study, Trasylol was found to be associated with a 109% increase in heart failure, a 48% increase in myocardial infarction, a 181% increase in strokes, and a risk of kidney failure 259% greater than patients who received no drugs.
As soon as the advisory panel voted against adding new warnings to the Trasylol label, Bayer issued a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
The committee agreed that the data were consistent with an association with Trasylol use and renal impairment, however, most members said they were not convinced that there was a definite increased risk of renal failure requiring dialysis.
Less than a year later, Dr Sebastian Schneeweiss told the September 12, 2007 advisory committee that the i3 study found a 60% increased risk for renal failure requiring dialysis and a 64% increase in the risk of in-hospital death with Trayslol.
The “Report on Computerized Inpatient Data from the Premier Perspective Comparative Database,” was sent to Bayer a week before the hearing and the preliminary results showed that in addition to serous kidney damage, Trasylol increased the risk of death, congestive heart failure, and stroke.
When Dr Alexander Walker, who led the study, learned that Bayer had not made the FDA or the committee aware of the negative findings that basically verified the findings of the studies discussed at the hearing, he revealed that Bayer had commissioned the study and that the results were sent in the time for the hearing.
The Zuckerman law firm took over the investigation of the Trasylol matter from the Wiley Rein & Fielding law firm after the original attorney hired for the job, Fred Fielding was appointed White House counsel by President Bush less than 3 months after the investigation began.
The Zuckerman report blames the whole mess on Dr Kuno Sprenger, a Risk Manager and Drug Safety Advisor, and Dr Ernst Weidmann, a Vice President for GDS. “Bayer did not disclose the findings and conclusions from the Preliminary Report on or before September 21, 2006, because Drs. Weidmann and Sprenger did not advise BPC, FDA, or the Advisory Committee that they had received the Preliminary Report,” the report concludes.
The fact is, this was not a 2-man job. Bayer received a pre-publication copy of the January 26, 2006 NEJM article by Dr Dennis Mangano and immediately mobilized to respond, according to the report. Bayer also created a separate Advisory Committee Steering Committee to coordinate preparation for the FDA advisory meeting.
The report answers the question: “Who at Bayer knew of the existence of the i3 study and which of those persons, if any, were functionally responsible for informing FDA of its existence?”
A list of all the names in the answer are included here only to show how absurd it is to try to blame the non-disclosure of the study on 2 lone employees.
Bayer personnel who knew about it include: Conny Berlin, Department of Integrated Analysis; Pam Cyrus, Vice President for Trasylol and Non-Specialty Products, US Medical Affairs; Howard Dorfman, Head of Patents, BPC Legal; Tomasz Dyszynski, International Drug Safety Manager for Aprotinin; Allen Heller, Vice President of Medical Science, US Pharma Division; Hans-Peter Kraemer, Head Systems and Operations, GDS; Paul MacCarthy, Vice President, Head of Medical & Scientific Affairs (North America); Kemal Malik, Global Head of Development and Chief Medical Officer; Andrea Nadel, Deputy Director of Statistics, BPC; Michael Rozycki, Director of US Regulatory Affairs; Joseph Scheeren, Senior Vice President of Global Regulatory Affairs; Anita Shah, Global Project Leader, BPC; Kuno Sprenger, Risk Manager and Drug Safety Advisor for GDS; Ed Tucker, Vice President, US Drug Safety Assurance; Terry Taylor, Vice President, Global Clinical Development; David van Veenhuyzen, Global Clinical Leader, Trasylol; and Ernst Weidmann, Vice President for GDS.
Another question asks: “Why was the existence of the i3 study not communicated to FDA in advance of the Advisory Committee meeting on September 21, 2006?”
“The highest levels of Bayer management responsible for preparing for the Advisory Committee meeting agreed that Bayer should and would disclose the ongoing study before the meeting,” the report states.
“The managers responsible for making that disclosure ultimately failed to do so,” it concludes.
Dr Scheeren and Dr Rozycki were responsible for communicating with the FDA about any Trasylol study, not Dr Weidmann and Dr Sprenger, and Dr Rozycki was the Trasylol liaison with the FDA during 2006, including all matters pertaining to the advisory committee meeting.
"Dr. Rozycki, the person responsible for actually making the regulatory contact with FDA, also had primary responsibility for overall coordination of Bayer’s preparation," the reports states.
"Dr. Rozycki freely acknowledges having neglected certain outstanding “action items” – including disclosure of the i3 study to FDA," it says.
Yet at the September 12, 2007 advisory committee meeting, Dr Malik also placed all the blame on Dr Weidmann and Dr Sprenger for not revealing the study stating:
“Unfortunately, shortly after last year's advisory committee, Bayer became aware that two individuals within our organization had received preliminary results of this study prior to the advisory committee. They chose not to share these data more widely within Bayer or with the advisory committee.
On behalf of Bayer, I would like to personally apologize for this error. As was publicly stated when we published the results of an independent investigation conducted by William Taylor, no other individuals other than these two people knew of the results of this study prior to the advisory committee meeting.
I would like to emphasize that those consultants who are with us at the meeting did not know about the existence of these data prior to the advisory committee meeting.”
Dr Malik fails to mention the fact that neither he nor anyone else at Bayer informed the FDA of the i3 study after the meeting either until Dr Walker did.
It's highly unlikely that the advisory panel was impressed by these comments because many members had already expressed in the press how appalled they were to learn that Bayer had failed to reveal the existence of the study a year earlier.
“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,” Dr John Teerlink, a professor at the University of California told the New York Times on September 29, 2006.
He also told Bloomberg on October 6, 2006, 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."
On October 6, 2006, committee chairman, Dr Bob Harrington, from Duke University, told Heartwire: “Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me."
"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 noted, "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."
Panel member, Dr Michael Lincoff, from the Cleveland Clinic, told Heartwire: “It was astounding to me that they did not disclose the information that the study had been conducted even if the findings were considered preliminary."
"It is inconceivable that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee," he added.
"They were in the midst of an entire day's discussions at the FDA on that precise topic where there was substantial comment regarding the desirability of more contemporary data than their older trials," Dr Lincoff pointed out.
At the hearing itself, Dr Valluvan Jeevanandam, a cardiac surgeon, specifically asked Bayer officials about other studies. "Could you comment on other trials other than CABG trials where there might have been an effect on renal function," he asked, "because a lot of the questions we had in our first presentation by Dr. Mangano was perhaps concomitant procedures with higher incidence of renal dysfunction, so do you have other trials other than just CABG trials looking at renal function?"
"Probably the most recent study where you could just remove the effect of bypass totally is a study that was just conducted by Bayer in hip surgery," Dr Cyrus responded.
Committee member, Dr Susan Heckbert also asked about other studies. "It looks to me like the U.S. studies in that database," she said, "most of them are from the early nineties and they would reflect the kind of patient that would present and might be considered for a clinical trial in those days."
"You don't have anything beyond the early nineties in the United States in that database?" she asked.
"The bulk of our clinical trial experience that I shared with you in the safety database was between the late eighties and late nineties," Dr Cyrus answered. "There were a few studies that went to 2001."
However, the dates in the Zuckerman report reveal that the study that Bayer officials conveniently forgot to mention was initiated 8 months earlier. Four days after the NEJM study was published, on February 1, 2006, Dr Sprenger and Dr Weidmann, contacted Dr Walker at i3 Drug Safety by email about performing an observational study for Bayer to compare Trasylol (aprotinin), aminocaproic acid and tranexamic acid.
On February 23, 2006, Dr Sprenger emailed Dr Walker and said Bayer was expecting an advisory committee meeting in late summer and asked Dr Walker to present the results of the study at the meeting.
On June 2, 2006, Dr Sprenger informed Dr Walker of Bayer’s approval of the study and that Bayer would like him to finish the study in time to meet the deadline of the September 21 advisory meeting.
On June 28, 2006, Bayer and the FDA held a conference call regarding the advisory meeting and Dr Scheeren recalled that a Bayer agenda item was to inform FDA about the study on that call. But according to Dr Scheeren, the conference call ended before Bayer could discuss the study.
On July 13, 2006, Dr Sprenger again asked Dr Walker whether he would be willing to present the study at the meeting and informed him that the briefing packet for the FDA was due by August 18.
On July 17, 2006, Dr Walker told Dr Sprenger in an email that he and Dr Seeger would be happy to present the results at the meeting. On the same day, Dr Seeger emailed Dr Sprenger and Dr Walker and explained that the results would not be ready in time for the briefing deadline on August 18, but said Dr Sprenger should provide a description of the study in the briefing package.
On July 16, 2006, Bayer held a meeting to prepare for a July 17 face-to-face meeting with the FDA and among the attendees were Dr Cyrus, Dr Heller, Dr MacCarthy, Dr Nadel, Dr Rozycki, Dr Scheeren, Dr Shah, Dr Sprenger, Dr Taylor, and Dr Van Veenhuyzen.
At this meeting, Dr Sprenger said that he gave the group a verbal overview of the study and he also told Dr Scheeren and Dr MacCarthy that preliminary results would be ready for the advisory committee meeting.
According to the report, Dr MacCarthy said the group decided to inform the FDA about the study at the July 17, 2006 meeting and Dr Scheeren told Dr Sprenger to be prepared to discuss the study when it came up.
On July 17, several Bayer scientists, regulatory leaders, and external consultants met at a hotel in Maryland to prepare prior to the meeting and the group agreed that Bayer should inform the FDA of the study during the meeting. Dr MacCarthy, Dr Scheeren, and Dr Rozycki were responsible for doing so, according to the report.
Dr Sprenger said he informed at least Dr Scheeren and Dr MacCarthy that the study results would be in before the advisory committee meeting.
However, once again, no one informed the FDA about the study at the July 17, meeting.
On August 17, 2006, Dr Seeger informed Dr Sprenger in an email that i3 was on track to meet the schedule for delivering the preliminary results of the study and the same day, Bayer submitted the briefing document to the FDA with no mention of the study.
On August 19, Bayer conducted a mock panel to rehearse for the advisory meeting and according to the report, Dr Sprenger remembered mentioning the status of the study to people during a pre-meeting to the mock panel, including Dr Scheeren and Dr MacCarthy.
Dr Weidmann said that several times between July 2006 and the advisory meeting, he asked Dr Scheeren why he had not yet told the FDA about the study and Dr Scheeren claimed that regulations did not require disclosure.
He also said that he told Dr Scheeren that the timelines for the study had been shortened to produce the preliminary results before the advisory meeting. Dr Sprenger also said he told Bayer colleagues on more than one occasion that the study results would be available before the meeting.
"Notwithstanding these discussions of the i3 study, however, they did not cause Dr. Rozycki or anyone else to take affirmative steps to tell FDA about it," the report states.
On August 23, 2006 Dr Sprenger emailed Dr Seeger and proposed that i3 meet with Dr Tomasz Dyszynski, the International Drug Safety Manager for Trayslol, and the report shows that Dr Dyszynski and Dr Conny Berlin did meet with i3 on August 26.
As far as nobody else knowing that the findings would be in before the meeting, the report specifically states that on September 6, 2006, "After hearing from Dyszynski that preliminary results will be available from the i3 study the first week in September, Sprenger emails Walker (copying Weidmann) proposing a meeting or conference call to discuss preliminary results."
In response, on September 7, 2006, Dr Walker emailed Dr Sprenger and Dr Weidmann and said i3 was ready to give Dr Sprenger a summary of findings.
The same day, Dr Weidmann sent an email containing the March 3, 2006, i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker, and Dr Sprenger separately re-forwarded his July 21 email with the i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker.
Dr Sprenger said that he sent the email to remind the others about the i3 study and the report says, "Nothing about the email would have led its recipients to understand that results would soon be forthcoming."
However, the report also notes that “within minutes” after receiving the i3 study proposal, Dr Scheeren forwarded the email to Dr Rozycki with the note, “Mike – We need to discuss this as well.”
Dr Scheeren admitted speaking to Dr Rozycki after this email. "Although Dr. Scheeren denied a detailed recollection of the conversation, he said that an “unconscious decision” “could have” been made to delay disclosure until after the Advisory Committee meeting," the report states.
"He thought Dr. Rozycki “could have” left that meeting with a sense that the timing of the disclosure was “in the air” (i.e., undecided), and “maybe” Dr. Rozycki thought disclosure could occur after the September 21 Advisory Committee meeting," the report notes.
One question in the report asks, "Which employees of Bayer received, or otherwise knew about, the findings and conclusions of the i3 study in advance of the Advisory Committee meeting on September 21, 2006?"
The report answers: “Only two people at Bayer received or otherwise knew about
the findings and conclusions of the i3 study in advance of the Advisory Committee meeting: Dr. Ernst Weidmann, the Vice President for GDS; and his associate Dr. Kuno Sprenger, Bayer’s Risk Manager and Drug Safety Advisory for GDS.”
“They received the Preliminary Report for the i3 study no later than September 14, 2006,” the report notes.
Those statements are totally false. The Zuckerman report itself shows that close to a month before September 21, Dr Dyszynski and Dr Berlin met with i3 on August 26, and the notes taken by Dr Dyszynski at the meeting identify some of the same problems with the study that were highlighted in Dr Sprenger's questions sent to i3 on September 14.
If he was not made aware of the preliminary findings at the meeting with i3, common sense says Dr Dyszynski would not have been able to identify any problems, much less the exact same ones that Dr Sprenger highlighted close to 3 weeks later.
The report goes on to say that neither Dr Weidmann nor Dr Sprenger recalled Dr Dyszynski discussing these issues in detail but they acknowledged that Dr Dyszynski briefed them on the August 26, meeting with i3.
On September 21, the advisory meeting took place and no one from Bayer mentioned the study. On September 22, 2006, Dr Seeger emailed Dr Sprenger asking for confirmation that Dr Sprenger had received i3's September 19 responses to Bayer’s questions.
On the same day, Dr Walker emailed Dr Sprenger, and copied Dr Weidmann, asking why the study had not been mentioned. On September 26, Dr Weidmann emailed Dr Walker and claimed that due to email problems, Bayer had not received i3’s responses until September 22, and that they wanted to review the study before any disclosure was made.
Dr Walker responded by email and said the preliminary report had public health implications and had to be communicated to the FDA and requested that Bayer submit the report to the FDA by September 28. The rest is history, because Dr Walker decided to reveal the existence of the study himself and the New York Times reported the story on November 29, 2006.
On January 23, 2007, the South Florida Business Journal reported that Florida and 29 other states had reached an $8 million settlement with Bayer resolving an investigation into the marketing of a drug to lower cholesterol.
As it turns out, at the exact same time that Bayer was concealing the existence and the results of the Trasylol study, the company was in negotiations to settle Medicaid fraud charges that included hiding studies that revealed the adverse effects of Baycol that was pulled off the market in 2001 after 100 deaths were reported.
As part of this settlement, Bayer agreed to post information on new clinical studies online in a trial registry. This registry was supposed to give physicians, consumers and researchers access to information on the efficacy of the drugs, type and severity of side effects, goals of treatment, and timing and reasons for termination of studies.
Bayer specifically agreed to register all Non-Exploratory Phase II trials and all Phase III and IV trials on www.ClinicalTrials.gov at the time the studies were initiated and post the results of all trials on www.ClinicalStudyResults.org.
A press release by the Illinois attorney general, Lisa Madigan, noted that, “Phase IV trials are performed after a drug or treatment is on the market to gain additional information about risks, benefits, and optimal use.”
Which obviously means that the initiation and the results of the i3 Trasylol study should have been posted online and Bayer should have been thrown out of the Medicaid program a year ago for violating the agreement.
In reading the report issued by the Zuckerman Spaeder law firm, one thing is perfectly clear. Bayer was willing to pay $700,000 to get a Trasylol study done in time for the September 21, 2006 advisory committee meeting, if it could refute the findings of the New England Journal of Medicine study.
However, unbeknownst to the contract research firm, i3 Drug Safety, it was decided early on that the study would not be mentioned to the FDA or the advisory panel unless and until Bayer was certain that it would achieve that goal.
In the NEJM study, Trasylol was found to be associated with a 109% increase in heart failure, a 48% increase in myocardial infarction, a 181% increase in strokes, and a risk of kidney failure 259% greater than patients who received no drugs.
As soon as the advisory panel voted against adding new warnings to the Trasylol label, Bayer issued a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
The committee agreed that the data were consistent with an association with Trasylol use and renal impairment, however, most members said they were not convinced that there was a definite increased risk of renal failure requiring dialysis.
Less than a year later, Dr Sebastian Schneeweiss told the September 12, 2007 advisory committee that the i3 study found a 60% increased risk for renal failure requiring dialysis and a 64% increase in the risk of in-hospital death with Trayslol.
The “Report on Computerized Inpatient Data from the Premier Perspective Comparative Database,” was sent to Bayer a week before the hearing and the preliminary results showed that in addition to serous kidney damage, Trasylol increased the risk of death, congestive heart failure, and stroke.
When Dr Alexander Walker, who led the study, learned that Bayer had not made the FDA or the committee aware of the negative findings that basically verified the findings of the studies discussed at the hearing, he revealed that Bayer had commissioned the study and that the results were sent in the time for the hearing.
The Zuckerman law firm took over the investigation of the Trasylol matter from the Wiley Rein & Fielding law firm after the original attorney hired for the job, Fred Fielding was appointed White House counsel by President Bush less than 3 months after the investigation began.
The Zuckerman report blames the whole mess on Dr Kuno Sprenger, a Risk Manager and Drug Safety Advisor, and Dr Ernst Weidmann, a Vice President for GDS. “Bayer did not disclose the findings and conclusions from the Preliminary Report on or before September 21, 2006, because Drs. Weidmann and Sprenger did not advise BPC, FDA, or the Advisory Committee that they had received the Preliminary Report,” the report concludes.
The fact is, this was not a 2-man job. Bayer received a pre-publication copy of the January 26, 2006 NEJM article by Dr Dennis Mangano and immediately mobilized to respond, according to the report. Bayer also created a separate Advisory Committee Steering Committee to coordinate preparation for the FDA advisory meeting.
The report answers the question: “Who at Bayer knew of the existence of the i3 study and which of those persons, if any, were functionally responsible for informing FDA of its existence?”
A list of all the names in the answer are included here only to show how absurd it is to try to blame the non-disclosure of the study on 2 lone employees.
Bayer personnel who knew about it include: Conny Berlin, Department of Integrated Analysis; Pam Cyrus, Vice President for Trasylol and Non-Specialty Products, US Medical Affairs; Howard Dorfman, Head of Patents, BPC Legal; Tomasz Dyszynski, International Drug Safety Manager for Aprotinin; Allen Heller, Vice President of Medical Science, US Pharma Division; Hans-Peter Kraemer, Head Systems and Operations, GDS; Paul MacCarthy, Vice President, Head of Medical & Scientific Affairs (North America); Kemal Malik, Global Head of Development and Chief Medical Officer; Andrea Nadel, Deputy Director of Statistics, BPC; Michael Rozycki, Director of US Regulatory Affairs; Joseph Scheeren, Senior Vice President of Global Regulatory Affairs; Anita Shah, Global Project Leader, BPC; Kuno Sprenger, Risk Manager and Drug Safety Advisor for GDS; Ed Tucker, Vice President, US Drug Safety Assurance; Terry Taylor, Vice President, Global Clinical Development; David van Veenhuyzen, Global Clinical Leader, Trasylol; and Ernst Weidmann, Vice President for GDS.
Another question asks: “Why was the existence of the i3 study not communicated to FDA in advance of the Advisory Committee meeting on September 21, 2006?”
“The highest levels of Bayer management responsible for preparing for the Advisory Committee meeting agreed that Bayer should and would disclose the ongoing study before the meeting,” the report states.
“The managers responsible for making that disclosure ultimately failed to do so,” it concludes.
Dr Scheeren and Dr Rozycki were responsible for communicating with the FDA about any Trasylol study, not Dr Weidmann and Dr Sprenger, and Dr Rozycki was the Trasylol liaison with the FDA during 2006, including all matters pertaining to the advisory committee meeting.
"Dr. Rozycki, the person responsible for actually making the regulatory contact with FDA, also had primary responsibility for overall coordination of Bayer’s preparation," the reports states.
"Dr. Rozycki freely acknowledges having neglected certain outstanding “action items” – including disclosure of the i3 study to FDA," it says.
Yet at the September 12, 2007 advisory committee meeting, Dr Malik also placed all the blame on Dr Weidmann and Dr Sprenger for not revealing the study stating:
“Unfortunately, shortly after last year's advisory committee, Bayer became aware that two individuals within our organization had received preliminary results of this study prior to the advisory committee. They chose not to share these data more widely within Bayer or with the advisory committee.
On behalf of Bayer, I would like to personally apologize for this error. As was publicly stated when we published the results of an independent investigation conducted by William Taylor, no other individuals other than these two people knew of the results of this study prior to the advisory committee meeting.
I would like to emphasize that those consultants who are with us at the meeting did not know about the existence of these data prior to the advisory committee meeting.”
Dr Malik fails to mention the fact that neither he nor anyone else at Bayer informed the FDA of the i3 study after the meeting either until Dr Walker did.
It's highly unlikely that the advisory panel was impressed by these comments because many members had already expressed in the press how appalled they were to learn that Bayer had failed to reveal the existence of the study a year earlier.
“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,” Dr John Teerlink, a professor at the University of California told the New York Times on September 29, 2006.
He also told Bloomberg on October 6, 2006, 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."
On October 6, 2006, committee chairman, Dr Bob Harrington, from Duke University, told Heartwire: “Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me."
"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 noted, "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."
Panel member, Dr Michael Lincoff, from the Cleveland Clinic, told Heartwire: “It was astounding to me that they did not disclose the information that the study had been conducted even if the findings were considered preliminary."
"It is inconceivable that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee," he added.
"They were in the midst of an entire day's discussions at the FDA on that precise topic where there was substantial comment regarding the desirability of more contemporary data than their older trials," Dr Lincoff pointed out.
At the hearing itself, Dr Valluvan Jeevanandam, a cardiac surgeon, specifically asked Bayer officials about other studies. "Could you comment on other trials other than CABG trials where there might have been an effect on renal function," he asked, "because a lot of the questions we had in our first presentation by Dr. Mangano was perhaps concomitant procedures with higher incidence of renal dysfunction, so do you have other trials other than just CABG trials looking at renal function?"
"Probably the most recent study where you could just remove the effect of bypass totally is a study that was just conducted by Bayer in hip surgery," Dr Cyrus responded.
Committee member, Dr Susan Heckbert also asked about other studies. "It looks to me like the U.S. studies in that database," she said, "most of them are from the early nineties and they would reflect the kind of patient that would present and might be considered for a clinical trial in those days."
"You don't have anything beyond the early nineties in the United States in that database?" she asked.
"The bulk of our clinical trial experience that I shared with you in the safety database was between the late eighties and late nineties," Dr Cyrus answered. "There were a few studies that went to 2001."
However, the dates in the Zuckerman report reveal that the study that Bayer officials conveniently forgot to mention was initiated 8 months earlier. Four days after the NEJM study was published, on February 1, 2006, Dr Sprenger and Dr Weidmann, contacted Dr Walker at i3 Drug Safety by email about performing an observational study for Bayer to compare Trasylol (aprotinin), aminocaproic acid and tranexamic acid.
On February 23, 2006, Dr Sprenger emailed Dr Walker and said Bayer was expecting an advisory committee meeting in late summer and asked Dr Walker to present the results of the study at the meeting.
On June 2, 2006, Dr Sprenger informed Dr Walker of Bayer’s approval of the study and that Bayer would like him to finish the study in time to meet the deadline of the September 21 advisory meeting.
On June 28, 2006, Bayer and the FDA held a conference call regarding the advisory meeting and Dr Scheeren recalled that a Bayer agenda item was to inform FDA about the study on that call. But according to Dr Scheeren, the conference call ended before Bayer could discuss the study.
On July 13, 2006, Dr Sprenger again asked Dr Walker whether he would be willing to present the study at the meeting and informed him that the briefing packet for the FDA was due by August 18.
On July 17, 2006, Dr Walker told Dr Sprenger in an email that he and Dr Seeger would be happy to present the results at the meeting. On the same day, Dr Seeger emailed Dr Sprenger and Dr Walker and explained that the results would not be ready in time for the briefing deadline on August 18, but said Dr Sprenger should provide a description of the study in the briefing package.
On July 16, 2006, Bayer held a meeting to prepare for a July 17 face-to-face meeting with the FDA and among the attendees were Dr Cyrus, Dr Heller, Dr MacCarthy, Dr Nadel, Dr Rozycki, Dr Scheeren, Dr Shah, Dr Sprenger, Dr Taylor, and Dr Van Veenhuyzen.
At this meeting, Dr Sprenger said that he gave the group a verbal overview of the study and he also told Dr Scheeren and Dr MacCarthy that preliminary results would be ready for the advisory committee meeting.
According to the report, Dr MacCarthy said the group decided to inform the FDA about the study at the July 17, 2006 meeting and Dr Scheeren told Dr Sprenger to be prepared to discuss the study when it came up.
On July 17, several Bayer scientists, regulatory leaders, and external consultants met at a hotel in Maryland to prepare prior to the meeting and the group agreed that Bayer should inform the FDA of the study during the meeting. Dr MacCarthy, Dr Scheeren, and Dr Rozycki were responsible for doing so, according to the report.
Dr Sprenger said he informed at least Dr Scheeren and Dr MacCarthy that the study results would be in before the advisory committee meeting.
However, once again, no one informed the FDA about the study at the July 17, meeting.
On August 17, 2006, Dr Seeger informed Dr Sprenger in an email that i3 was on track to meet the schedule for delivering the preliminary results of the study and the same day, Bayer submitted the briefing document to the FDA with no mention of the study.
On August 19, Bayer conducted a mock panel to rehearse for the advisory meeting and according to the report, Dr Sprenger remembered mentioning the status of the study to people during a pre-meeting to the mock panel, including Dr Scheeren and Dr MacCarthy.
Dr Weidmann said that several times between July 2006 and the advisory meeting, he asked Dr Scheeren why he had not yet told the FDA about the study and Dr Scheeren claimed that regulations did not require disclosure.
He also said that he told Dr Scheeren that the timelines for the study had been shortened to produce the preliminary results before the advisory meeting. Dr Sprenger also said he told Bayer colleagues on more than one occasion that the study results would be available before the meeting.
"Notwithstanding these discussions of the i3 study, however, they did not cause Dr. Rozycki or anyone else to take affirmative steps to tell FDA about it," the report states.
On August 23, 2006 Dr Sprenger emailed Dr Seeger and proposed that i3 meet with Dr Tomasz Dyszynski, the International Drug Safety Manager for Trayslol, and the report shows that Dr Dyszynski and Dr Conny Berlin did meet with i3 on August 26.
As far as nobody else knowing that the findings would be in before the meeting, the report specifically states that on September 6, 2006, "After hearing from Dyszynski that preliminary results will be available from the i3 study the first week in September, Sprenger emails Walker (copying Weidmann) proposing a meeting or conference call to discuss preliminary results."
In response, on September 7, 2006, Dr Walker emailed Dr Sprenger and Dr Weidmann and said i3 was ready to give Dr Sprenger a summary of findings.
The same day, Dr Weidmann sent an email containing the March 3, 2006, i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker, and Dr Sprenger separately re-forwarded his July 21 email with the i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker.
Dr Sprenger said that he sent the email to remind the others about the i3 study and the report says, "Nothing about the email would have led its recipients to understand that results would soon be forthcoming."
However, the report also notes that “within minutes” after receiving the i3 study proposal, Dr Scheeren forwarded the email to Dr Rozycki with the note, “Mike – We need to discuss this as well.”
Dr Scheeren admitted speaking to Dr Rozycki after this email. "Although Dr. Scheeren denied a detailed recollection of the conversation, he said that an “unconscious decision” “could have” been made to delay disclosure until after the Advisory Committee meeting," the report states.
"He thought Dr. Rozycki “could have” left that meeting with a sense that the timing of the disclosure was “in the air” (i.e., undecided), and “maybe” Dr. Rozycki thought disclosure could occur after the September 21 Advisory Committee meeting," the report notes.
One question in the report asks, "Which employees of Bayer received, or otherwise knew about, the findings and conclusions of the i3 study in advance of the Advisory Committee meeting on September 21, 2006?"
The report answers: “Only two people at Bayer received or otherwise knew about
the findings and conclusions of the i3 study in advance of the Advisory Committee meeting: Dr. Ernst Weidmann, the Vice President for GDS; and his associate Dr. Kuno Sprenger, Bayer’s Risk Manager and Drug Safety Advisory for GDS.”
“They received the Preliminary Report for the i3 study no later than September 14, 2006,” the report notes.
Those statements are totally false. The Zuckerman report itself shows that close to a month before September 21, Dr Dyszynski and Dr Berlin met with i3 on August 26, and the notes taken by Dr Dyszynski at the meeting identify some of the same problems with the study that were highlighted in Dr Sprenger's questions sent to i3 on September 14.
If he was not made aware of the preliminary findings at the meeting with i3, common sense says Dr Dyszynski would not have been able to identify any problems, much less the exact same ones that Dr Sprenger highlighted close to 3 weeks later.
The report goes on to say that neither Dr Weidmann nor Dr Sprenger recalled Dr Dyszynski discussing these issues in detail but they acknowledged that Dr Dyszynski briefed them on the August 26, meeting with i3.
On September 21, the advisory meeting took place and no one from Bayer mentioned the study. On September 22, 2006, Dr Seeger emailed Dr Sprenger asking for confirmation that Dr Sprenger had received i3's September 19 responses to Bayer’s questions.
On the same day, Dr Walker emailed Dr Sprenger, and copied Dr Weidmann, asking why the study had not been mentioned. On September 26, Dr Weidmann emailed Dr Walker and claimed that due to email problems, Bayer had not received i3’s responses until September 22, and that they wanted to review the study before any disclosure was made.
Dr Walker responded by email and said the preliminary report had public health implications and had to be communicated to the FDA and requested that Bayer submit the report to the FDA by September 28. The rest is history, because Dr Walker decided to reveal the existence of the study himself and the New York Times reported the story on November 29, 2006.
On January 23, 2007, the South Florida Business Journal reported that Florida and 29 other states had reached an $8 million settlement with Bayer resolving an investigation into the marketing of a drug to lower cholesterol.
As it turns out, at the exact same time that Bayer was concealing the existence and the results of the Trasylol study, the company was in negotiations to settle Medicaid fraud charges that included hiding studies that revealed the adverse effects of Baycol that was pulled off the market in 2001 after 100 deaths were reported.
As part of this settlement, Bayer agreed to post information on new clinical studies online in a trial registry. This registry was supposed to give physicians, consumers and researchers access to information on the efficacy of the drugs, type and severity of side effects, goals of treatment, and timing and reasons for termination of studies.
Bayer specifically agreed to register all Non-Exploratory Phase II trials and all Phase III and IV trials on www.ClinicalTrials.gov at the time the studies were initiated and post the results of all trials on www.ClinicalStudyResults.org.
A press release by the Illinois attorney general, Lisa Madigan, noted that, “Phase IV trials are performed after a drug or treatment is on the market to gain additional information about risks, benefits, and optimal use.”
Which obviously means that the initiation and the results of the i3 Trasylol study should have been posted online and Bayer should have been thrown out of the Medicaid program a year ago for violating the agreement.
FDA Ignores Bayer Trasylol Fraud
Evelyn Pringle December 19, 2006
On December 15, 2006, the FDA said a new label for Trasylol will specify that it should only be used during coronary artery bypass graft surgery but the agency said nothing about what it plans to do about the fraudulent conduct of Bayer Pharmaceuticals in concealing a study that showed the increased risks associated with the drug.
Right about now, a little help from the Bush Administration's FDA could go a long way so far as protecting profits. Trasylol (aprotinin), is a top-selling drug for the German-based, Bayer Healthcare Pharmaceuticals. In 2005, sales of the drug worldwide reached $210 million, according to the Associated Press on January 26, 2006.
The drug can cost $1,200 a dose, compared to the two generic drugs that do the same job without the increased risks associated with Trasylol, at only $11 for aminocaproic acid (Amicar), and $44 for tranexamic acid (Cyklokapron).
Trasylol was approved by the FDA in 1993, for patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery, but doctors have been widely using the drug "off-label," meaning for uses not FDA approved as being safe and effective, during other surgeries.
For protection against the unapproved use of Trasylol during surgery, experts now say patients need to inform the surgeon before surgery that the drug is not to be used.
According to the FDA, Trasylol is a protease inhibitor derived from bovine lung tissue and is approved for the following indication: "For prophylactic use to reduce perioperative blood loss and the need for blood transfusion." The drug is said to control bleeding by blocking enzymes that dissolve blood clots.
At the time of approval, the Indications section of the labeling on Trasylol, included a statement citing the reasons for limitation as being concerns for renal dysfunction and anaphylaxis.
In 1998 the FDA approved an expansion of the indication to the broad population of patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass but also added a black box warning to the labeling regarding hypersensitivity.
According to the FDA, hypersensitivity is the most frequently reported adverse event associated with Trasylol, accounting for 41% of reports in Bayer's worldwide database; with 85% of the reports coded as anaphylactic reaction or anaphylactic shock.
Most importantly, the FDA points out that the high percentage of risks are found in cases of off-label use stating that the "hypersensitivity reactions occurred when Trasylol was administered to patients undergoing surgeries other than CABG."
The Adverse Event Reporting System is a computerized database that consists of over 3 million reports of adverse events. Reports are voluntarily submitted to the FDA from health care professionals and consumers, but pharmaceutical companies are required to report adverse events of which they become aware.
According to the FDA, limitations of this reporting database include underreporting, biases in reporting, and the variable quality of the reports themselves.
Using specific criteria for inclusion, the FDA notes 70 reports of anaphylaxis identified as associated with Trasylol, and 23 had a fatal outcome. Here again, a majority of the reports were related to off-label use with the most frequently reported use being for heart valve surgery. In fact, the FDA found that only 25% of the patients had received the drug for the approved indication.
The FDA issued a Public Health Advisory on February 8, 2006, and recommended that physicians consider limiting Trasylol use to those situations where the clinical benefit of reduced blood is essential and this benefit outweighs the Trasylol risks.
The Advisory was based on the results of two studies, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," by Karkouti et al, in the Journal of Transfusion, and "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, in the New England Journal of Medicine.
In an accompanying editorial in the NEJM, Gus Vlahakes, of Harvard Medical School and the Massachusetts General Hospital wrote, "Some surgeons and anesthesiologists who use the drug have been concerned about its potential risks since it was first approved for clinical use; yet until the report by Mangano et al., sufficient data have not been available for an analysis of the risks and benefits of aprotinin."
Prior to the FDA Advisory, Bayer had applied for FDA approval for the use of Trasylol during spinal fusion surgery and hip replacement surgery.
After the studies were published, the FDA convened an a advisory committee to reassess the drug's safety. On September 21, 2006, the FDA's Cardiovascular and Renal Advisory Committee met to discuss the findings and other relevant data.
As presented at the meeting, the NEJM study compared the outcomes from 3 groups of patients receiving the drugs aprotinin, aminocaproic acid and tranexamic acid, and one group of patients receiving no drug.
The study involved nearly 70 medical institutions worldwide and found Trasylol to be associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, and a 181% increase in strokes, and a 2-fold increase in renal failure.
The researcher's determined that patients treated with Trasylol, had a risk of kidney failure 259% greater than patients who received no drugs.
The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, at the Ischemia Research and Education Foundation in San Bruno, California.
Dr Dennis Mangano presented the study results to the Advisory Committee and said that its specific aim "was to compare the relative safety between the three agents, which are used commonly to reduce blood loss during bypass, during CABG with bypass versus no agent."
"Safety was assessed," he advised, "by individual organ, heart, brain, kidney, GI tract and overall."
The secondary aim, he told the panel, was to assess the relative safety between the three agents on blood loss as assessed by total chest tube output over 24 hours.
Essentially, Dr Mangano said, "4,374 patients entered the study with approximately 1,300 in control and aprotinin and 800 to 900 in aminocaproic and tranexamic acid."
The study found that renal dialysis was significantly increased in the aprotinin patients versus the control group and that neither aminocaproic or tranexamic were associated with increased risk of renal dialysis, renal dysfunction, or renal composite.
"In terms of efficacy," Dr Mangano said, "I don't believe the blood-sparing abilities of these three agents are different, I believe they are all equally effective."
"If you replace aprotinin with aminocaproic acid in primary surgery, you could save about 4,800 dialyses a year," he told the panel.
"The association between aprotinin and serious end organ damage," he concluded, "indicates that continued use is not proved in this population especially given the less expensive generics, which are we believe safe."
The Committee members asked multiple questions of the presenters regarding the details of statistical methodology for the studies. Several noted that the analytical details were important considerations in interpretation of the meaningfulness of the findings.
Several members expressed concern that Dr Mangano had not shared his database with independent reviewers, including the FDA. During the question and answer portion of the presentation, Dr Mangano explained why he refused to turn over his study data to the FDA without restrictions. "You could take this data and pull anything you want out of it."
"You could say the drug is safe and don't ever worry about it again," he said, "but if the FDA is going to perform a series of analyses, we believe it important to get the design for those analyses presented to us in written form, so we know what the prospective question is, because don't forget, the FDA is under some pressure right here, which is that they have a drug that is marketed 13 years."
"There is a real bias on this committee," Mr Mangano pointed out when concluding his testimony.
For the study in the Transfusion Journal, Dr Keyvan Karkouti, presented the findings to the Committee. His was a single-center study, conducted at Toronto General Hospital, which does 2,000 to 3,000 adult cardiac surgeries per year.
"We didn't find any reduction of these adverse events with aprotinin use," he told the Committee.
"We did find a renal dysfunction increase with aprotinin," he said. "So, in conclusion," he advised, "there is as yet no conclusive evidence that aprotinin is better than tranexamic acid in our opinion."
When it came for Bayer to address the panel, Mike Rozycki, Director of US
Regulatory Affairs at Bayer, said that when the company learned of the studies under discussion, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted," he stated, "in very close association and under the guidance of the FDA."
"All that information has been submitted and is under review by the FDA," he added.
Mr Rozycki specifically said the information presented to the Committee was based on the available data that Bayer had. "Dr. Pamela Cyrus, of Bayer's U.S. Medical Affairs organization," he said, "will review the clinical data that Bayer has and that is in the literature for aprotinin."
In the end, the Committee decided that there was no need for additional warnings on Trasylol labeling and Bayer quickly put out a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
But as it turns out, while testifying before the Committee that day, not one of the Bayer representative disclosed the existence of a large Bayer study of 67,000 patients. In June 2006, Bayer commissioned the private research firm, i3 Drug Safety, to determine the cardiovascular risks of Trasylol, and Bayer received a copy of the study's report on September 14, 2006.
When the study was conspicuously not mentioned at the meeting, Harvard professor, Dr Alexander Walker, who worked on the study, informed the FDA of its existence.
After learning of the suppressed study, the FDA issued a second Public Health Advisory warning that the results of the study demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes."
Last month, in a paper titled, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," in the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn states, "September 30 is becoming a day of infamy for drug safety.
On that date in 2004, he notes, Merck announced that Vioxx doubled the risk of myocardial infarction and stroke, and the company withdrew the drug from the market after 5 years of use by more than 20 million patients.
Jumping ahead to September 30, 2006, he relates that a front-page article in the New York Times reported that the FDA had issued a warning that aprotinin could cause renal failure, congestive heart failure, stroke, and death.
"What put aprotinin on the front page," he wrote in the paper, "was the revelation that its manufacturer, Bayer, had hired a private contract research organization to perform its own large observational study of postoperative complications in patients given the drug."
Critics who are already incensed over the coziness between the Bush administration's FDA and the pharmaceutical industry, are now watching to see whether or not the FDA will hold Bayer accountable for its fraudulent conduct related to Trasylol.
On December 15, 2006, the FDA said a new label for Trasylol will specify that it should only be used during coronary artery bypass graft surgery but the agency said nothing about what it plans to do about the fraudulent conduct of Bayer Pharmaceuticals in concealing a study that showed the increased risks associated with the drug.
Right about now, a little help from the Bush Administration's FDA could go a long way so far as protecting profits. Trasylol (aprotinin), is a top-selling drug for the German-based, Bayer Healthcare Pharmaceuticals. In 2005, sales of the drug worldwide reached $210 million, according to the Associated Press on January 26, 2006.
The drug can cost $1,200 a dose, compared to the two generic drugs that do the same job without the increased risks associated with Trasylol, at only $11 for aminocaproic acid (Amicar), and $44 for tranexamic acid (Cyklokapron).
Trasylol was approved by the FDA in 1993, for patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery, but doctors have been widely using the drug "off-label," meaning for uses not FDA approved as being safe and effective, during other surgeries.
For protection against the unapproved use of Trasylol during surgery, experts now say patients need to inform the surgeon before surgery that the drug is not to be used.
According to the FDA, Trasylol is a protease inhibitor derived from bovine lung tissue and is approved for the following indication: "For prophylactic use to reduce perioperative blood loss and the need for blood transfusion." The drug is said to control bleeding by blocking enzymes that dissolve blood clots.
At the time of approval, the Indications section of the labeling on Trasylol, included a statement citing the reasons for limitation as being concerns for renal dysfunction and anaphylaxis.
In 1998 the FDA approved an expansion of the indication to the broad population of patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass but also added a black box warning to the labeling regarding hypersensitivity.
According to the FDA, hypersensitivity is the most frequently reported adverse event associated with Trasylol, accounting for 41% of reports in Bayer's worldwide database; with 85% of the reports coded as anaphylactic reaction or anaphylactic shock.
Most importantly, the FDA points out that the high percentage of risks are found in cases of off-label use stating that the "hypersensitivity reactions occurred when Trasylol was administered to patients undergoing surgeries other than CABG."
The Adverse Event Reporting System is a computerized database that consists of over 3 million reports of adverse events. Reports are voluntarily submitted to the FDA from health care professionals and consumers, but pharmaceutical companies are required to report adverse events of which they become aware.
According to the FDA, limitations of this reporting database include underreporting, biases in reporting, and the variable quality of the reports themselves.
Using specific criteria for inclusion, the FDA notes 70 reports of anaphylaxis identified as associated with Trasylol, and 23 had a fatal outcome. Here again, a majority of the reports were related to off-label use with the most frequently reported use being for heart valve surgery. In fact, the FDA found that only 25% of the patients had received the drug for the approved indication.
The FDA issued a Public Health Advisory on February 8, 2006, and recommended that physicians consider limiting Trasylol use to those situations where the clinical benefit of reduced blood is essential and this benefit outweighs the Trasylol risks.
The Advisory was based on the results of two studies, "A Propensity Score Case-Control Comparison of Aprotinin and Tranexamic Acid in High Transfusion Risk Cardiac Surgery," by Karkouti et al, in the Journal of Transfusion, and "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, in the New England Journal of Medicine.
In an accompanying editorial in the NEJM, Gus Vlahakes, of Harvard Medical School and the Massachusetts General Hospital wrote, "Some surgeons and anesthesiologists who use the drug have been concerned about its potential risks since it was first approved for clinical use; yet until the report by Mangano et al., sufficient data have not been available for an analysis of the risks and benefits of aprotinin."
Prior to the FDA Advisory, Bayer had applied for FDA approval for the use of Trasylol during spinal fusion surgery and hip replacement surgery.
After the studies were published, the FDA convened an a advisory committee to reassess the drug's safety. On September 21, 2006, the FDA's Cardiovascular and Renal Advisory Committee met to discuss the findings and other relevant data.
As presented at the meeting, the NEJM study compared the outcomes from 3 groups of patients receiving the drugs aprotinin, aminocaproic acid and tranexamic acid, and one group of patients receiving no drug.
The study involved nearly 70 medical institutions worldwide and found Trasylol to be associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, and a 181% increase in strokes, and a 2-fold increase in renal failure.
The researcher's determined that patients treated with Trasylol, had a risk of kidney failure 259% greater than patients who received no drugs.
The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, at the Ischemia Research and Education Foundation in San Bruno, California.
Dr Dennis Mangano presented the study results to the Advisory Committee and said that its specific aim "was to compare the relative safety between the three agents, which are used commonly to reduce blood loss during bypass, during CABG with bypass versus no agent."
"Safety was assessed," he advised, "by individual organ, heart, brain, kidney, GI tract and overall."
The secondary aim, he told the panel, was to assess the relative safety between the three agents on blood loss as assessed by total chest tube output over 24 hours.
Essentially, Dr Mangano said, "4,374 patients entered the study with approximately 1,300 in control and aprotinin and 800 to 900 in aminocaproic and tranexamic acid."
The study found that renal dialysis was significantly increased in the aprotinin patients versus the control group and that neither aminocaproic or tranexamic were associated with increased risk of renal dialysis, renal dysfunction, or renal composite.
"In terms of efficacy," Dr Mangano said, "I don't believe the blood-sparing abilities of these three agents are different, I believe they are all equally effective."
"If you replace aprotinin with aminocaproic acid in primary surgery, you could save about 4,800 dialyses a year," he told the panel.
"The association between aprotinin and serious end organ damage," he concluded, "indicates that continued use is not proved in this population especially given the less expensive generics, which are we believe safe."
The Committee members asked multiple questions of the presenters regarding the details of statistical methodology for the studies. Several noted that the analytical details were important considerations in interpretation of the meaningfulness of the findings.
Several members expressed concern that Dr Mangano had not shared his database with independent reviewers, including the FDA. During the question and answer portion of the presentation, Dr Mangano explained why he refused to turn over his study data to the FDA without restrictions. "You could take this data and pull anything you want out of it."
"You could say the drug is safe and don't ever worry about it again," he said, "but if the FDA is going to perform a series of analyses, we believe it important to get the design for those analyses presented to us in written form, so we know what the prospective question is, because don't forget, the FDA is under some pressure right here, which is that they have a drug that is marketed 13 years."
"There is a real bias on this committee," Mr Mangano pointed out when concluding his testimony.
For the study in the Transfusion Journal, Dr Keyvan Karkouti, presented the findings to the Committee. His was a single-center study, conducted at Toronto General Hospital, which does 2,000 to 3,000 adult cardiac surgeries per year.
"We didn't find any reduction of these adverse events with aprotinin use," he told the Committee.
"We did find a renal dysfunction increase with aprotinin," he said. "So, in conclusion," he advised, "there is as yet no conclusive evidence that aprotinin is better than tranexamic acid in our opinion."
When it came for Bayer to address the panel, Mike Rozycki, Director of US
Regulatory Affairs at Bayer, said that when the company learned of the studies under discussion, "We immediately began a comprehensive review of all the data that we had in CABG surgery for aprotinin."
"This was conducted," he stated, "in very close association and under the guidance of the FDA."
"All that information has been submitted and is under review by the FDA," he added.
Mr Rozycki specifically said the information presented to the Committee was based on the available data that Bayer had. "Dr. Pamela Cyrus, of Bayer's U.S. Medical Affairs organization," he said, "will review the clinical data that Bayer has and that is in the literature for aprotinin."
In the end, the Committee decided that there was no need for additional warnings on Trasylol labeling and Bayer quickly put out a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."
But as it turns out, while testifying before the Committee that day, not one of the Bayer representative disclosed the existence of a large Bayer study of 67,000 patients. In June 2006, Bayer commissioned the private research firm, i3 Drug Safety, to determine the cardiovascular risks of Trasylol, and Bayer received a copy of the study's report on September 14, 2006.
When the study was conspicuously not mentioned at the meeting, Harvard professor, Dr Alexander Walker, who worked on the study, informed the FDA of its existence.
After learning of the suppressed study, the FDA issued a second Public Health Advisory warning that the results of the study demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes."
Last month, in a paper titled, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," in the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn states, "September 30 is becoming a day of infamy for drug safety.
On that date in 2004, he notes, Merck announced that Vioxx doubled the risk of myocardial infarction and stroke, and the company withdrew the drug from the market after 5 years of use by more than 20 million patients.
Jumping ahead to September 30, 2006, he relates that a front-page article in the New York Times reported that the FDA had issued a warning that aprotinin could cause renal failure, congestive heart failure, stroke, and death.
"What put aprotinin on the front page," he wrote in the paper, "was the revelation that its manufacturer, Bayer, had hired a private contract research organization to perform its own large observational study of postoperative complications in patients given the drug."
Critics who are already incensed over the coziness between the Bush administration's FDA and the pharmaceutical industry, are now watching to see whether or not the FDA will hold Bayer accountable for its fraudulent conduct related to Trasylol.
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