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.