Drug warnings fall flat
Bayer hides bad news; a researcher doesn't, and takes heat.
By KRIS HUNDLEY, Times Staff Writer
Published August 5, 2007
When William "Sonny" Morrill went in for heart bypass surgery, his wife was so sure he would recover she bought him new pajamas.
But three days after the operation, the 61-year-old Sarasota resident died from kidney failure and a triple whammy of heart attacks.
Melissa Morrill ultimately came to grips with her loss. Then last year she read about two studies suggesting a link between Trasylol, a drug used to reduce bleeding during bypass procedures, and the unexplained symptoms that killed Sonny.
The studies fueled her suspicions. But it was how Bayer AG, the drug company that makes Trasylol, reacted to those studies -- and how federal regulators handled it -- that pushed her over the top.
"I see Bayer's ads for aspirin now," Morrill said, "and I just want to throw up."
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Raised in Clearwater, Sonny Morrill made his career flying and instructing others on L-1011 jets. A Delta Airlines pilot, he underwent his first bypass operation in 1995. In October 2003 he suffered a second heart attack, resulting in a second bypass surgery at Sarasota Memorial Hospital.
"One reason why I really was not overly concerned about this surgery being successful is that he'd been through it once before," his widow said.
Morrill said her first hint something was awry came when they put her husband on a dialysis machine after the operation.
The morning of the third day, the surgeon, Dr. Thomas Kelly, left Morrill a message that he wanted to call in another specialist. When she returned the call, she got the news: Sonny was dead.
"When I talked to Dr. Kelly, I could just sense the anguish in his voice," said Morrill, who has only praise for the surgeon and the hospital staff. "He didn't know what had happened and was obviously very upset."
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More than two years later, in January 2006, the New England Journal of Medicine published research by Dr. Dennis Mangano, founder of the nonprofit Ischemia Research and Education Foundation in San Bruno, Calif.
Mangano headed an international team of researchers that compared data on more than 4,000 patients treated with Trasylol versus two other agents used to reduce the need for transfusions during bypass surgery.
Mangano concluded that compared with the other two drugs, Trasylol put patients at higher risk of heart attacks, stroke and renal failure.
Not only were the alternatives safer and as effective, the study said, they were less expensive: $11 to $44 a dose compared with $1,400 for Trasylol. Mangano said a switch would save $250-million a year in health care costs and an additional $1-billion in dialysis.
"The association between aprotinin Trasylol and serious end-organ damage indicates that continued use is not prudent," he wrote.
The same month, the journal Transfusion published another study that linked Trasylol to kidney failure.
Such concerns stretched back to 1993, when the U.S. Food and Drug Administration first approved the drug and noted, "Kidney toxicity was also a problem in some patients in the (pre-approval) trials."
Mangano's article immediately elicited two phone calls: the first from Bayer, the second from the FDA. Both wanted access to his data.
In September 2006, nine months after publishing his study, Mangano defended it during a contentious FDA advisory committee meeting.
An anesthesiologist with a doctorate in math, Mangano described how his group analyzed millions of pieces of data to arrive at its conclusions about Trasylol. The work cost nearly $50-million and was underwritten by private donations and his foundation's endowment.
"This has been an entirely consuming effort of my life for the last 15 years," Mangano told the group.
The FDA advisory panel was not impressed. Panelists attacked Mangano's methodology, saying he had not sufficiently accounted for the high-risk nature of patients receiving Trasylol.
In a recent interview, Mangano said he was shocked by the panel's harsh reception of his work.
"The whole thing was a set-up," he said. "We did not have anything to gain financially by this. We were making an observation about safety."
Mangano noted that the chairman of the panel, Dr. William R. Hiatt, has written papers underwritten by Bayer, and that three committee members received waivers to vote because of financial interests in drug companies.
"The system is ridiculous," he said. "It's all pro-industry. Who's protecting the patient?"
After hearing from Mangano, the committee listened to several Bayer representatives, including Dr. Pamela Cyrus, vice president for U.S. medical affairs. Trasylol had been Bayer's seventh-best- selling drug in 2005, with U.S. sales up 32 percent. Before Mangano's bombshell, the company had estimated the drug's 2006 sales would more than double, to $600-million.
Cyrus reviewed the company's own studies of Trasylol and concluded, "Bayer remains convinced that the benefits of aprotinin (Trasylol) outweigh the risk."
The FDA's advisers voted 18-0 in support of the "safety and efficacy" of Trasylol. Panel member Dr. Norman Kato, a surgeon from Encino, Calif., gushed that he was "relieved and encouraged" that Bayer had come forward with so much data.
The company, Kato said, had made an attempt "to be almost overly transparent, which I find refreshing in this day and age."
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Bayer, it turned out, had been less than transparent.
Days after the advisory meeting, the FDA was contacted by a researcher who said Bayer had hidden important evidence from regulators.
Dr. Alexander Walker, a professor at Harvard School of Public Health, said Bayer hired him six months earlier to review an enormous database of 67,000 bypass patients. The study compared the side effects of Trasylol with those of the two other anti-bleeding drugs.
Walker said his analysis matched Mangano's: Trasylol patients seemed to be at increased risk for death, kidney failure, congestive heart failure and stroke.
When contacted by the FDA, Bayer said it had "mistakenly" neglected to mention the giant study. The company said the data was "preliminary in nature and raised significant questions on the study population, outcomes and methodology."
That response sounds hollow to several advisory committee members still stung by Bayer's behavior. Dr. Michael Lincoff, vice chairman of cardiovascular research at Cleveland Clinic in Ohio, said that several panelists had commented during the meeting on the need for more data.
"At no point did the Bayer folks say, 'It's on its way,'" he said.
Steve Findlay, a panel member and health care analyst with Consumers Union, said Bayer's actions were "intentional and very disingenuous."
"Absolutely no one would say it was in the public interest, or the interest of people having heart surgery, for that information not to be made public."
Findlay said the incident reinforces the need for a bill pending in Congress that would give the FDA more power to require postapproval drug studies.
It's often not until a drug is in widespread use that problems arise. Vioxx, recalled in 2004 after being linked to heart attacks, had been taken by 80-million people. Trasylol has been administered to more than 4-million.
"Bayer's action is yet another example, and an egregious one, that shows the lack of transparency regarding important data," Findlay said. "We need a system that makes all this publicly available."
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Bayer suspended two unidentified employees following the revelation of Walker's study. It also said it was investigating the incident, a review the company says is still under way.
After Bayer was forced to admit its deception, the FDA strengthened the warning label on Trasylol to include the risk of renal dysfunction. It makes no mention of increased risk of heart attack or stroke, the two other warnings raised by Mangano.
His team's latest research on Trasylol was published in February in the Journal of the American Medical Association. Tracking patients for five years post-surgery, the researchers found a substantially higher risk of death among those treated with Trasylol.
If surgeons substituted less risky drugs, Mangano projected that over the next five years, some 10,000 deaths could be prevented.
The FDA has scheduled a meeting Sept. 12 to discuss Mangano's latest research.
Mangano said he's not surprised that it would take seven months for regulators to consider his new warnings.
"You just wonder how many heart failures and strokes are going to happen because this drug is still on the market," he said. "But bringing up drug safety issues is not for the weak-hearted. There are a lot of interested parties that go against you. You just keep moving forward."
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Among Mangano's detractors is Sonny Morrill's surgeon at Sarasota Memorial. Kelly, a heart surgeon for 30 years, declined to comment on Morrill's case. But he said he routinely uses Trasylol on repeat open-heart patients or people on blood thinners. Morrill fit both criteria.
"Bleeding is a tremendous problem in surgery," Kelly said. "And I've seen right along that, in certain populations, there is much less need for transfusions with Trasylol. The alternatives are not nearly as effective."
Kelly said Mangano's research raised unnecessary concerns, with worried patients calling his office to see if they got the drug, which is administered under anesthesia.
"This drug is used on high-risk people; that's why there's a higher incidence of death," the surgeon said. "I think a terrible disservice has been done to a very helpful drug."
Though he thinks the recent studies "unfairly impugned" Trasylol, Kelly said he is using the drug more selectively and reading all the research available on the topic.
"I've told the Bayer reps, as well as all drug reps, that I want every report on this drug on my desk," he said. "I want to look at this objectively."
Asked if he had seen the damaging study Bayer kept from the FDA, Kelly paused.
"I don't remember that one," he said.
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Morrill's widow is among a dozen patients or their families that have sued Bayer, claiming that the use of Trasylol caused death or irreparable injuries, charges Bayer denies.
Morrill said Bayer's effort to hide damaging evidence shook her confidence in the legendary company.
"Bayer knew this drug caused this sort of complication and they still kept it on the market," said Morrill, a 53-year-old flight attendant for Delta. "My husband was just a number, a form of income for them."
Mangano said pharmaceutical companies need to know that they face consequences for not being open with regulators. He proposes that any drugmaker that hides data from the FDA should be banned immediately from submitting new drug applications for three years.
"The pharmaceutical industry would straighten up in a matter of seconds because you'd be hitting them in the pocketbook," he said.
"If you don't give drug companies boundaries, they'll do anything they want. Only the end user here is the patient, and I think it's critical for the government to assume the goal of protecting patients."
The FDA has taken no action against Bayer.
Information from wire stories and Times researcher Carolyn Edds was used in this report. Kris Hundley can be reached at firstname.lastname@example.org or (727) 892-2996.
BY THE NUMBERS
- 4.3-million people who have received Trasylol - Bayer AG
- 227,774 heart bypass surgeries in the United States, 2005 - Agency for Healthcare Research and Quality
- 10,000 deaths that could be prevented over the next five years if safer drugs are used - Dr. Dennis Mangano, a researcher
FAST FACTS: Trasylol (aprotinin)
- Who makes it? Bayer AG, Leverkusen, Germany
- What is it? A clear, injectable solution made from cow lung tissue
- When is it used? To reduce blood loss during heart bypass operations
- How often has it been used? On more than 4-million patients worldwide
The drug's history
- 1993: FDA approves use of Trasylol to reduce bleeding during bypass operations.
- Jan. 20, 2006: Transfusion article suggests that Trasylol causes renal failure.
- Jan. 26, 2006: New England Journal of Medicine article by Dr. Dennis Mangano ties the use of Trasylol to renal toxicity, heart attack and stroke.
- Sept. 21, 2006: FDA advisory board supports Trasylol's safety.
- Sept. 26, 2006: A whistle-blower tells the FDA Bayer has hidden a 67,000-patient Trasylol study that confirms Mangano's findings.
- Sept. 29, 2006: Bayer acknowledges that the study was not disclosed, calls it a "mistake."
- Dec. 15, 2006: FDA approves a revised label for Trasylol warning of renal failure.
- Jan. 25, 2007: Bayer announces that it is ending three clinical trials for use of Trasylol in other types of surgery.
- Feb. 6, 2007: A study in the Journal of the American Medical Association by Mangano says Trasylol raises the risk of death within five years after surgery.
- Sept. 12, 2007: FDA Advisory Committee is scheduled to reconsider Trasylol.