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.”

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