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February 5, 2006
Ideas & Trends
Pity the Scientist Who Discovers the Discovered
By GINA KOLATA
IN 1996, Rakesh Vohra, a professor at Northwestern University, and his colleague Dean Foster published "A Randomized Rule for Selecting Forecasts," a paper in the journal Operations Research. It illustrated how a random investor could outperform a group of professional stock pickers simply by following a "buy and hold" investment strategy.
It was important research, the authors believed, until they learned that the same discovery had been made at least 16 times since the 1950's. And no one, Dr. Vohra said, ever realized they were not doing original work.
The discovery that your discovery has already been discovered is surprisingly common, said Stephen Stigler, a statistician at the University of Chicago who has written about the phenomenon. Not only does it occur in every scientific field, he said, the "very fact of multiple discoveries has been discovered many times."
The result of duplicative research may be no more serious than chagrin over wasted time. But in other cases, say those involving medical research, there can be a real risk of harm to patients.
It may seem odd that scientists in the Internet age spend years on a line of research, even bet their careers on it, without having first determined that their mountain had not already been climbed. But Dr. Stigler said that scientists often are ignorant of the work being done by others in their field, and searches of scientific literature can be hard to conduct. Web search engines, for example, look for words, not ideas, and Dr. Vohra said he discovered that every researcher who had made his discovery had given it a different name and description.
In 1957, for example, a statistician named James Hanna called his theorem Bayesian Regret. He had been preceded by David Blackwell, also a statistician, who called his theorem Controlled Random Walks. Other, later papers had titles like "On Pseudo Games," "How to Play an Unknown Game," "Universal Coding" and "Universal Portfolios," Dr. Vohra said, adding, "It's not obvious how you do a literature search for this result."
In a recent paper in Clinical Trials, Dean Fergusson, an epidemiologist at the Ottawa Health Research Institute in Canada, and his colleagues found 64 clinical trials had been conducted on the drug aprotinin, all asking if patients who received it during surgery had fewer transfusions. The answer was always yes.
It is easy to see why these studies were done, said Dr. Steven Goodman, an epidemiologist at Johns Hopkins University and an editor of Clinical Trials. Nearly all were so small, with perhaps a few dozen subjects, that they did not need a sponsor to finance them.
"They are already doing surgery and the drug is used at the discretion of the surgeon," Dr. Goodman said. "The only cost is maintaining a small database."
But Dr. Goodman said the larger issue is whether later medical researchers who studied aprotinin erred in giving placebos to some patients when there already was research showing that the drug resulted in fewer transfusions.
"It's a double betrayal," he said, "first to ignore the contribution of patients in past studies and then to ask for the same contribution from future patients."
Moreover, he said, in this case researchers could have found all the previous studies simply by typing "aprotinin" into a medical database.
In addition, despite the previous studies, a recent statistical analysis of 4,374 patients, led by Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation in San Bruno, Calif., found that aprotinin may increase the risk of heart attacks, strokes and kidney failure. The statistical evidence that led to this conclusion, however, could not have shown up in the many small-scale studies of the drug.
But Dr. Gregory Nuttall of the Mayo Clinic said that while it may seem that the time for using placebos in aprotinin studies had come and gone, that question "is never as cut and dried as it seems."
"Just because something works in one type of surgery doesn't mean it works in another," he said. "Different surgeries have different risks for bleeding and different risks for having blood clots."
Dr. Nuttall did look at the aprotinin literature, he said, and suspects that other doctors who studied the drug did so, too. But it was not always obvious from the study results, he said, that aprotinin was beneficial.
Finally, there is one more problem with duplicative science. It's about credit. Who gets it?
Dr. Stigler notes that renowned scientists have often been credited with results achieved first by others. This goes back to Pythagoras, he said, and includes august figures like Fourier and Laplace, as well as household names among mathematicians, like Cauchy and Chebyshev.
Of course, it can be embarrassing to learn that your discovery isn't one. But the best defense may be a good offense.
For example, there is the oft-told story about Larry Shepp, a famous mathematician at Rutgers University. Dr. Shepp, when told that a piece of work he thought was his discovery actually duplicated another mathematician's breakthrough, replied: "Yes, but when I discovered it, it stayed discovered." |
Bayer: cardiovascular concerns could run deep
3rd February 2006
Bayer looks set to face legal action following the release of study results linking the company's blood clot drug Trasylol to adverse events including heart and kidney failure. The study findings, and the potential impacts of litigation, pose a significant threat to Bayer's cardiovascular portfolio, and thus could signal trouble for the company overall.
In a 4,374-patient assessment, Ischemia Research and Education Foundation (IREF) researchers found that Trasylol (aprotinin) more than doubled the risk of patients suffering renal failure requiring dialysis. Trasylol was also associated with a 55% increase in the risk of myocardial infarction or heart failure and a 181% increase in the risk of stroke or encephalopathy.
In contrast, neither of the other agents evaluated, namely aminocaproic acid and tranexamic acid, were associated with an increased risk of renal, cardiac or cerebral events. Furthermore, these generically available drugs are much cheaper than Trasylol, costing $11 and $44 per dose, respectively, compared to $1,300 per dose of Trasylol.
In light of this, the researchers estimate that abandoning Trasylol in favor of the generic alternatives would reduce healthcare costs by $250 million per year, as well as enabling over 11,000 patients to avoid kidney dialysis each year.
Although Bayer has argued that the study results are inconsistent with its own data, the drug's sales are bound to suffer. Indeed, if the IREF's findings result in Trasylol being replaced, the drug's sales - estimated to be around $600 million in 2005 - will be significantly effected.
The impact of this would be felt throughout the company, corresponding to a possible 6% reduction in Bayer's overall revenues. The costs of litigation could also mean bad news for the company's bottom line, which has been struggling to make up for the withdrawal of cholesterol drug Baycol.
To make matters worse, the FDA recently asked Bayer to add a black-box warning to its stroke drug Nimotop after medication administration errors were found to increase the risk of serious, and even fatal, adverse events. While this warning relates specifically to the drug's route of administration, it still raises the issue of safety concerns within the company's cardiovascular franchise.
As this franchise is set to become Bayer's largest in the next few years, these drug safety issues are especially alarming and, although the company has some promising pipeline tricks up its sleeve, the pressure on these new drugs will now be even greater.
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Hospitals cautious about Bayer drug
Reuters
Jan. 29
FRANKFURT - Three large German heart clinics want to either avoid using Bayer drug Trasylol completely or confine its use only to patients with a high risk of blood loss, German magazine Der Spiegel said on Saturday.
A study published in the New England Journal of Medicine this week showed that Trasylol, widely given to heart surgery patients to prevent excessive blood loss, doubled the risk of kidney failure.
It also raised the chance of heart failure or heart attack by 55 percent, according to the study.
Der Spiegel, in a preview of an article due to appear in its Monday edition, cited Peter Sawicki, director of the independent scientific institute IQWiG as saying that until Bayer illustrated the safety of the medicine in a new study, the drug should not be used.
”The results of the study appear to be right,” the magazine quoted Bruno Reichart, head of heart surgery at Munich-Groshadern, as saying.
It said Roland Hetzer of the German Heart Institute in Berlin felt the drug could be avoided, especially as it was costlier than comparable products.
Analysts say the result of the New England Journal of Medicine study increases the risk for investors from Bayer’s pharmaceuticals business, which is recovering from a $1 billion recall of cholesterol drug Baycol over patient deaths.
A Bayer spokesman reiterated that the company needed to analyse the data from the study further in close cooperation with regulators.
”We are have just managed to reach the authors of the study and are trying to get the data from them,” he said.
Bayer Healthcare said earlier in the week that the results were ”not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug”.
Trasylol had sales of 171 million euros in 2004, up 8.9 percent.
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German Regulator Says to Study Bayer Drug Trasylol
Mon Jan 30, 2006 3:05 PM ET
FRANKFURT (Reuters) - Germany's top drug regulator BfArM wants information from Bayer AG <BAYG.DE> about the drugmaker's Trasylol medication, a BfArM official said on Monday, after a scientific journal study raised safety concerns.
The New England Journal of Medicine said last week that Trasylol, widely given to heart surgery patients to prevent excessive blood loss, doubled the risk of kidney failure and stroke.
Ulrich Hagemann, head of drug safety at BfArM, said the regulator was reviewing Trasylol in Germany and would have a look at the journal study as well.
He said the agency wanted to be involved in an exchange of information with Bayer and would take a decision on the drug's future based on data it received.
"At the moment, with the data available from the study, there is not a situation that warrants a ban on the drug," he said, adding that examining data could take weeks given the complexity of the material.
A Bayer spokesman said that the regulator had asked it to get further data on the Journal study from the researchers.
"We are in contact with the researchers, and if we get data we will pass it on to the regulators," he said.
"We are working closely with BfArM and other European regulators. We have offered all the data currently available and will offer any further analyzes that we make to them."
WestLB analyst Andreas Theisen said that he expected Trasylol sales to at least slow down.
"One should at least expect somewhat weaker sales in coming quarters," he said, adding that the Bayer stock price could lose 0.7 euros based on a net present value of 500 million euros for Trasylol.
He said he estimated Trasylol sales of 230 million euros for 2005.
Bayer stock was down 1.4 percent at 34.22 euros at 1449 GMT, underperforming a flat DAX index <.GDAXI>.
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From NASDAQ.com
Study Finds Bayer Blood Drug Raises Kidney-Failure Risk
By Jennifer Corbett Dooren, Of DOW JONES NEWSWIRES
WASHINGTON -(Dow Jones)- A Bayer Pharmaceuticals drug used in some patients undergoing open-heart surgery more than doubled the risk of kidney failure, according to a study that will be published in Thursday's New England Journal of Medicine.
The drug, Trasylol, is used to control bleeding during surgery. However, researchers said the risk of kidney failure is too great and recommended that Trasylol not be used in heart surgery. The drug, known generically as aprotinin, was approved by the FDA in 1993 for use during surgery to bypass clogged heart arteries. The company is studying it for use in other settings such as hip- replacement surgery and spinal-fusion surgery.
The research was led by Dennis Mangano, a physician who runs the Ischemia Research and Education Foundation, an independent nonprofit group based in San Bruno, Calif.
The organization studied 4,374 patients undergoing bypass surgery from about 1996 through 2000. They were given Trasylol or the generic drugs aminocaproic acid or tranexamic acid. The generic drugs are also designed to limit blood loss. Dr. Mangano said that not all patients undergoing bypass surgery need such drugs.
Overall, researchers found that patients receiving Trasylol had a 2.59 times greater risk of kidney failure than those receiving the other drugs. Mangano recommended that doctors stop using Trasylol and use the generic drugs instead, which controlled bleeding and were not linked to kidney failure. Trasylol also increased risk for heart attacks and strokes, but Mangano said the key finding was the doubling of the kidney-failure risk.
In a statement, Bayer Healthcare, a U.S. unit of Bayer AG (BAY), said it had not yet had the chance to fully review the findings but that they were "not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug." The company said it has studied the drug in almost 6,500 patients.
Still, the company said it will contact the study authors for more details and has told health regulatory authorities about the study.
A Food and Drug Administration spokeswoman said the agency was reviewing the study, but would need some time to complete the review of the "complex" data contained in the study.
While Trasylol has been on the market for several years, Bayer has started more aggressively marketing of the drug and sales have risen in recent years. The drug had about $210 million in worldwide sales in 2004 and company officials have projected the drug could reach about $600 million in annual sales this year.
- By Jennifer Corbett Dooren, Dow Jones Newswires; 202-862-9294; jennifer.corbett@dowjones.com
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Associated Press Article
Study Questions Safety of Heart Drug
By ALICIA CHANG, AP Science Writer 4 minutes ago
A drug commonly used to prevent excessive bleeding in heart surgery patients greatly increased the risk of kidney failure, a new international study found.
The drug aprotinin — marketed under the brand name Trasylol — is the second clotting medication in two weeks linked to serious complications.
Heart bypass patients who were injected with Trasylol during surgery had double the risk of kidney failure and an increased risk of heart problems compared to those who got other drugs, researchers reported in Thursday's New England Journal of Medicine.
"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, which led the study.
The San Bruno-based foundation is a nonprofit organization founded in 1987 that funds cardiovascular research.
The Food and Drug Administration approved Trasylol in 1993 to control bleeding in patients undergoing open heart surgery and minimize the need for blood transfusions. The drug works by blocking enzymes that dissolve blood clots.
Trasylol's maker, Germany-based Bayer AG, insists the drug is safe based on its own experiments, but said it alerted regulatory authorities in the United States, Canada, Australia and Europe about the latest research.
Trasylol is the latest clotting drug to spark safety concerns. Last week, 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 hemorrhages.
In the Trasylol study, researchers examined 4,374 heart surgery patients worldwide who received either one of three clotting drugs, including Trasylol, or a dummy medication.
Patients who took Trasylol had twice the risk of developing kidney failure that required dialysis and a 55 percent increased risk of a heart attack or heart failure. In contrast, those who took one of the two cheaper generic clotting medications had no harmful side effects.
In an editorial in the journal, Dr. Gus Vlahakes of Harvard Medical School, who had no role in the research, noted that the study is the most comprehensive, independent analysis yet of Trasylol's safety.
"Some surgeons and anesthesiologists who use the drugs have been concerned about its potential risks since it was first approved," Vlahakes wrote. "Yet ... sufficient data have not been available for an analysis of the risks and benefits of aprotinin (Trasylol)."
Global sales for the drug reached $210 million in 2005, according to Bayer. Last month, chief executive Werner Wenning put the sales potential for the blood thinning drug at more than $600 million.
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On the Net:
New England Journal of Medicine: http://content.nejm.org
Trasylol page: http://www.trasylol.com
Copyright © 2006 The Associated Press. All rights reserved. The information contained in the AP News report may not be published, broadcast, rewritten or redistributed without the prior written authority of The Associated Press. |
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Serious Risks Are Found in Heart Drug
Widely Used Medicine Increases
Chance of Kidney Failure, Stroke;
Generics Are as Effective and Safer
By DAVID ARMSTRONG
Staff Reporter of THE WALL STREET JOURNAL
January 26, 2006; Page D1
A widely used heart-surgery medicine that is standard treatment in many hospitals has been found to carry serious health risks, according to a new study.
The drug, Trasylol from Bayer AG, of Germany, is used to stem blood loss in patients undergoing heart-bypass surgery. Approved in the U.S. in 1993, the drug is given to about a quarter of the one million people world-wide who undergo bypass surgery each year, the study's author estimates.
Recently, Bayer has aggressively marketed the drug and funded research to expand its use to joint and spine surgeries. In the first nine months of this year, Trasylol -- whose chemical name is aprotinin -- was Bayer's fastest-growing drug, with world-wide sales of just less than $200 million during that period. Bayer says 150,000 patients received the drug last year in the U.S.
The study of 4,374 patients, published in this week's New England Journal of Medicine, found patients taking Trasylol were at an increased risk of kidney failure, heart attacks and strokes, compared with patients taking alternative drugs or no drugs at all. The researchers also found that cheaper alternatives to Trasylol were just as effective in limiting blood loss but didn't cause any of the dangerous side effects associated with the more expensive brand medication.
The authors estimate that using the alternative drugs, which are generics unrelated to Trasylol, would prevent kidney failure in 11,050 patients a year world-wide, saving $1 billion in the cost of dialysis. They also claim the use of cheaper alternatives would result in direct savings of $250 million a year.
 SIDE EFFECTS
In a study of heart- surgery drug Trasylol:
• 5% of patients on Trasylol required kidney dialysis vs. 1% of those on one of two alternative drugs.
• 16% of Trasylol patients had a myocardial infarction (heart attack) vs. 12% and 13% of those on alternatives.
• 9% of Trasylol patients experienced heart failure vs. 6% and 5% on alternatives.
Source: The New England Journal of Medicine
The study is significant because it was conducted without drug-industry funding at 69 medical centers, including many of the top U.S. hospitals. It raises safety concerns that weren't flagged in company-sponsored research over the course of more than a decade of clinical use.
An accompanying editorial in the medical journal calls on the U.S. Food and Drug Administration to improve the safety testing of drugs after they have been approved, saying that "too many pharmacologic agents have entered into clinical practice for which considerable and potentially life-threatening outcomes were recognized only after a large number of patients had been treated."
The FDA's handling of safety issues is already under scrutiny following the withdrawal in 2004 of Vioxx, the once-popular pain medication from Merck & Co. that was linked to an increased risk of heart attacks. In another case, the multiple sclerosis drug Tysabri from Biogen Idec Inc. was pulled from the market last year after its use was associated with a rare brain disorder. The FDA is considering a request to return Tysabri to the market. In response to concerns about safety monitoring, the FDA recently created a new Drug Safety Oversight Board to review safety issues related to drugs already approved by the agency.
Regarding Trasylol, the FDA released a statement calling the new study a "complicated analysis based on a large observational database" and said the agency is working to gather all available information and to evaluate the drug's safety. The statement said the agency "will make recommendations for best use as soon as possible."
Observational Study
One issue in that review is certain to be the fact that the study was an "observational" one, in which doctors dictate which treatment a patient will get, rather than a "randomized" trial in which patients are randomly assigned to receive either the drug being tested or a placebo. Bayer HealthCare, the U.S. pharmaceutical subsidiary of Bayer, cited the "limitations" of observational studies in a statement. The company also says it "believes that Trasylol is a safe and effective treatment" and that the study's results "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug." Nonetheless, the company says it "takes publications of this nature very seriously" and plans to discuss the results with the study authors.
Gus Vlahakes, chief of cardiac surgery at Massachusetts General Hospital, says the new study will cause clinical practices to "change a lot" and "will slow down the routine use" of Trasylol. "There is enough of a safety indication raised that I wouldn't use it unless there is a clearly defined indication for it," says Dr. Vlahakes, who also wrote the accompanying editorial in the journal regarding the study.
The study was sponsored by the Ischemia Research and Education Foundation in San Bruno, Calif., a nonprofit foundation known for studying heart attacks and strokes. Dennis Mangano, chief executive and the lead author of the Trasylol study, says the foundation's funding is its endowment, built by doing clinical-trial work for drug companies in the 1990s. He says the group no longer does that work for drug companies.
This new trial compared Trasylol to two generic drugs, aminocaproic acid and tranexamic acid, which are also used to control blood loss. The study found that 8% of the 1,295 patients receiving Trasylol suffered kidney dysfunction or required dialysis, which was twice the rate of the 1,705 patients receiving the generic drugs.
About 29% of the Trasylol patients suffered a stroke or heart-related complication, compared with about 21% of the patients taking the generic drugs and 19% getting no drugs. The study didn't give the actual number of patients suffering these complications. After adjusting for the varying risk factors of the patients being compared, the study determined there was a 55% increase in the risk of heart attacks among the Trasylol group and a 181% increase in the risk of strokes.
Post-Approval Issues
The clinical trials required to win FDA approval of a new drug are often too small to detect potentially rare and dangerous side effects, says Dr. Mangano. Once a drug is on the market, he says there is little incentive for pharmaceutical companies to aggressively work to discover previously undetected side effects or to compare their products with competing therapies.
"The problem today is what happens with drug safety once a drug is approved," he says.
Dr. Mangano says it would have been too difficult to make his study a randomized, controlled clinical trial -- considered the gold standard of medical studies -- because many hospitals have deemed Trasylol effective and would consider it unethical to allow a patient to get a placebo instead.
However, he attempted to mimic the effect of a randomized trial by gathering 7,500 pieces of information on every patient. This allowed him to "match" like patients across the study groups to control for other risk factors, such as age, gender and additional health problems.
Write to David Armstrong at david.armstrong@wsj.com |
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January 26, 2006
Doctors Urge Ending Use of Heart Surgery Drug
By DENISE GRADY
A drug used worldwide to reduce bleeding during heart surgery can increase the risk of kidney failure, heart attacks and strokes, and should be abandoned, doctors are reporting today. They say other medicines are safer and cheaper, and should be used instead.
The drug, aprotinin, is sold under the brand name Trasylol and made by Bayer. The company disputed the new findings.
Heart surgeons said the new report, being published today in The New England Journal of Medicine, was important and persuasive, but not definitive. Although the drug has risks, they said, it may still be helpful in some surgical patients who have an unusually high risk of severe bleeding.
The Food and Drug Administration is examining the data on aprotinin, a spokeswoman, Susan Cruzan, said, "and will make recommendations for best use as soon as possible."
Aprotinin (pronounced a-PRO-ti-nin) has been on the market for 13 years. The report in the journal is based on a study of 4,374 patients having bypass surgery in Canada, Colombia, Europe, Israel, Mexico, Thailand and the United States. To limit blood loss, 1,295 were given aprotinin and 1,705 one of two other drugs, both generics, aminocaproic acid or tranexamic acid. A control group, 1,374 patients, had no drugs to prevent bleeding.
Compared with the other patients, those given aprotinin had twice the rate of kidney failure, 5 percent. They also had increases in other serious problems, including heart attacks, heart failure, strokes and a diffuse type of brain damage called encephalopathy.
The article said halting aprotinin use globally would prevent 10,000 to 11,000 cases of kidney failure a year and save more than $1 billion a year in dialysis costs, as well as nearly $250 million spent on the drug itself.
"It would be nearly impossible for me to recommend using the drug in this patient population," said Dr. Dennis T. Mangano, the director of the study and the founder of a group that paid for it, the Ischemia Research and Education Foundation.
Bayer said in a statement, "Bayer believes that Trasylol is a safe and effective treatment."
One potential flaw in the study is that the patients were not picked at random to have one treatment or the other. Rather, their doctors made the decision about which drug to use.
That means that in theory the groups could be skewed. Doctors might have assigned sicker patients to a particular drug that could make the results for that drug look especially bad.
On the other hand, the study was large, with copious figures collected for each patient in an effort to minimize biases.
"The study shows the drug has risks," said Dr. Gus J. Vlahakes, chief of the division of cardiac surgery at Massachusetts General Hospital, who wrote an editorial that accompanied Dr. Mangano's article. "You shouldn't give it to everybody having heart surgery."
Instead, Dr. Vlahakes said, it should be reserved for patients with unusual bleeding problems, because it works better at stopping bleeding than the other two drugs. At his hospital, with about eight heart operations a day, he said, Trasylol is probably used less than once a day.
Worldwide, about one million people a year have bypass surgery, and two-thirds to three-quarters of them are given Trasylol or one of the other two drugs to limit blood loss, Dr. Mangano said.
Use of Trasylol has varied, with some doctors favoring it and others avoiding it because of concerns that it may cause clots. Some doctors have also resisted using Trasylol because of its cost, more than $1,000 a patient, as opposed to $10 to $50 for the other drugs.
Last year, sales totaled $200 million. This year, Bayer projections are much higher, $600 million. In recent years, the company has been marketing Trasylol to prevent inflammation, as well as bleeding, in bypass patients.
Its Web site suggests using the drug in all patients put on heart-lung machines for bypass surgery and explains the drug's role in inhibiting inflammation.
Dr. Vlahakes said preventing inflammation might require higher doses of the drug than those now being used. In view of the new safety information, he said, "I think there's no way" that the drug could be so broadly used, particularly at higher doses.
Bayer is also studying Trasylol in hopes of having it approved to prevent blood loss from hip replacement and spinal surgery.
Currently, Trasylol is given to heart-surgery patients intravenously along with a plethora of other medicines, and most people do not even know that they are receiving it. Doctors do not need special permission to administer it.
Given his findings, Dr. Mangano said, doctors should warn patients about the potential risks and ask for their consent to use it.
"I cannot see how a patient would elect to use this drug as opposed to the others," he said.
Dr. Timothy J. Gardner, the medical director of the Center for Heart and Vascular Health at the Christiana Care Health System in Newark, Del., and a spokesman for the American Heart Association, said the article would have substantial effects on medical practice.
Dr. Gardner said the findings were worrisome because many patients had been taking other drugs that increased the tendency to bleed, and surgeons sometimes need all possible help to stop excess blood loss.
Dr. Vlahakes agreed. "It's 2 o'clock in the morning and you can't stop the bleeding," he said. "That's every surgeon's nightmare." |
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Study Finds Risk to Kidneys In Drug That Limits Bleeding
Less Harmful Options Are Recommended
By Marc Kaufman
Washington Post Staff Writer
Thursday, January 26, 2006; A12
A popular drug given to more than a million people since 1993 to limit blood loss during heart surgery doubles a patient's risk of kidney failure and substantially increases the risk of a heart attack, a major study has found.
The research, being published today in the New England Journal of Medicine with a supportive editorial and commentary, concluded that use of the drug -- Bayer Corp.'s aprotinin -- causes more than 11,000 patients worldwide to need kidney dialysis each year.
The authors said that in light of their findings, and the fact that two other less harmful and far less expensive alternatives exist, it is no longer "prudent" for doctors to use the drug except in unusual circumstances. If they continue with the drug, the authors said, doctors have a moral obligation to inform patients about the risks.
The Food and Drug Administration said it is reviewing the study and "will make recommendations for best use as soon as possible." Bayer said that it had only recently become aware of the research, and that it is "not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug."
With the industry and the agency still reeling from the contentious withdrawal of the arthritis drug Vioxx in 2004 because of safety concerns, the new finding underscores how difficult it is to know the risks of a drug once it goes on the market.
"We have a real problem with safety once a drug is approved," said study lead author Dennis T. Mangano of the Ischemia Research and Education Foundation in California, a nonprofit group that has been collecting and analyzing the aprotinin data since 1996.
The FDA "can't mandate safety studies, and it's very expensive and risky for the drug company to do them on their own once a drug has been approved by the agency," Mangano said. "The system is not set up to assess safety in a general way once a drug is on the market."
Aprotinin, sold as Trasylol, has been widely studied since it was approved in 1993, but most of the research has focused on its effectiveness.
Mangano's research, however, found not only a greatly increased rate of kidney failure, but also a 50 percent increase in heart attacks and an almost 200 percent increase in strokes. The study also found that two other generic drugs in a different class were as effective as aprotinin in stanching bleeding after surgery, were safer and cost less than one-tenth the price. In its statement, the FDA said it will now compare the safety of aprotinin and the other products.
The study was based on data collected from 4,374 patients at 69 sites worldwide who underwent heart or coronary artery surgery. About 1,300 were given aprotinin, about 1,300 received no drug to stop bleeding, and more than 800 were treated with each of the two other generic anti-bleeding agents. Although the study was not a placebo-controlled and randomized clinical trial -- considered the gold standard for medical research -- it followed enough patients to give it "credibility," wrote Gus J. Vlahakes, chief of cardiac surgery at Massachusetts General Hospital, in an accompanying editorial.
Mangano said the increased risk of kidney failure makes sense physiologically because it is known that aprotinin, which is derived from the lung tissue of cows, generally stays in the kidneys for 24 hours and can cause damage. The two other drugs used to limit bleeding in the study are generally excreted quickly by the body.
Mangano said a 1998 study sponsored by Bayer had reported data that strongly suggested that aprotinin increased the risk of blood clotting, which can lead to heart attacks. He said the authors dismissed the results as reflecting extraneous issues.
In the Vioxx case, an early study sponsored by Merck & Co. similarly found a higher risk of heart attack and stroke in patients on its drug than in those on a comparison medication. In that case, the authors contended the control drug, Naproxen, had lowered the risks, not that Vioxx had raised them.
"I believe there was a safety signal coming out of the [1998 Bayer] study, maybe a pink flag rather than a red flag," Mangano said. "I think at that point more attention should have been paid."
Under current FDA policies, drug companies generally establish the effectiveness and safety of their products in clinical trials that include hundreds, and sometimes thousands, volunteers -- many of them healthy. Once drugs are on the market, however, they are often taken by millions of patients, many of them sick and weakened.
Bayer officials have been upbeat about ongoing and future sales of aprotinin, projecting $275 million in worldwide sales for 2005 and double that figure for this year. The company has been conducting trials of the drug to limit bleeding in hip replacement surgery, and hopes to apply for FDA approval for this use soon.
The company did not have international statistics on use of aprotinin, but said about 150,000 American patients were given the drug in 2005. |
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Drug 'doubles kidney failure risk'
From correspondents in Boston
26-01-2006
From: Reuters
THE Bayer drug Trasylol, widely given to heart surgery patients to prevent excessive blood loss, doubles the risk of kidney failure and stroke, researchers reported today.
It also raises the chance of heart failure or heart attack by 55 per cent, according to the study published in this week's New England Journal of Medicine.
Because 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 study concluded.
Bayer HealthCare released a statement saying it had just become aware of the finding and needed time to study it.
But the company said the results "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug".
Chief study author Dennis Mangano of the Ischemia Research and Education Foundation in San Bruno, California, said the results were clear.
"It's a serious situation," he said.
"The question is, how are the clinicians and regulators going to respond to this?"
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, he said.
The drug study, involving 4,374 patients undergoing heart bypass surgery at 69 medical centres around the world, is the largest ever done where the goal was to specifically look at safety issues.
It also comes at a time when Bayer is pushing to have the drug used in all surgery, not just in cases where there is a high risk of excessive blood loss. |
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Study: Cardiac Drug Doubles Risk of Kidney Failure
January 26, 2006
Aprotinin -- a drug approved by the FDA, marketed internationally for the last 13 years, and given to an estimated one million surgery patients to limit bleeding -- has now been proven to double a patient's risk of kidney failure, and increase the risk of heart attack, heart failure, and stroke.
The results, published in this week's New England Journal of Medicine, are based on an independent, non-commercial, observational study conducted by The Ischemia Research and Education Foundation (IREF).
"Our study provides compelling evidence of aprotinin's serious risks, and strongly suggests discontinuation of use and replacement with either of the two alternative generic and far less costly medications proven safe in this study," said IREF founder and principal scientist, Dennis T. Mangano, Ph.D., M.D.
"Certainly, our findings -- coming on the heels of the Vioxx(http://www.consumeraffairs.com//news04/vioxx.html) experience -- indicate that the problem of drug safety is not only ubiquitous, but also much more elusive than previously thought."
In fact, Mangano said, the findings raise even more troubling concerns, for:
(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.
The article states that replacing aprotinin with one of two safe generic drugs would annually prevent as many as 11,050 dialysis complications, save at least $1 billion in healthcare (dialysis) costs, and reduce drug costs by at least $250 million.
Each year approximately one million patients worldwide undergo surgical treatment following a heart attack, with the majority of these patients receiving one of three antifibrinolytic agents to limit blood loss during surgery: aprotinin (Bayer Healthcare Pharmaceuticals, Inc.), aminocaproic acid (generic), or tranexamic acid (generic).
The two generic drugs have proven safe in limiting blood loss, and do not have the harmful effects of aprotinin. Patients scheduled for cardiac surgery should consult their physicians and avoid this risk, Mangano said.
Aprotinin was approved by the U.S. Food and Drug Administration in 1993 and is manufactured by Bayer under the brand name Trasylol. Over the past three years, Trasylol sales have accelerated, with 2006 sales projected in excess of $600 million.
"We estimate that as many as 10,000 patients may be unnecessarily on dialysis today due to aprotinin use. This serious impact on human lives 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," said Mangano.
"This is easier said than done, however, for the economic forces are -- and will continue to be -- substantial, with little corporate incentive to identify safety problems once drugs are approved and marketed."
The New England Journal of Medicine article documents how aprotinin use was associated with a two-fold increase in renal failure requiring dialysis in patients undergoing both complex coronary artery surgery and primary surgery, excluding prior cardiac and current valve surgery.
Among primary surgery patients, Dr. Mangano and colleagues found that aprotinin use also increased risk of myocardial infarction (48 percent), heart failure (109 percent), and stroke (181 percent).
Neither of aprotinin's generic competitors, aminocaproic acid and tranexamic acid, was associated with increased renal, cardiac or cerebral events.
Aprotinin is at least ten times more expensive than its generic competitors.
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San Francisco Chronicle
Heart surgery drug said to be a risk to kidneys
- Keay Davidson, Chronicle Science Writer
Thursday, January 26, 2006
A drug used to control internal bleeding in heart surgery patients increases the risk of kidney failure, according to a study by a San Bruno research foundation reported in today's New England Journal of Medicine.
The study by Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation in San Bruno reports that during heart bypass operations, patients who received injections of the drug aprotinin during surgery were twice as likely to suffer kidney failure as patients treated with other drugs.
The patients also had a higher chance of heart problems compared with those receiving other medications, the Mangano study says.
The study suggests "serious concerns" about the safety of aprotinin, which is commercially marketed as Trasylol, said Mangano and two colleagues, Julia C. Tudor, Ph.D. and Dr. Cynthia Dietzel.
The study involved 4,374 patients in hospitals around the world.
An accompanying editorial in today's issue of the Journal says that "until the report by Mangano (and colleagues), sufficient data have not been available for an analysis of the risks and benefits of aprotinin." The editorial by Dr. Gus J. Vlahakes says that for the time being any increase in the prescribed dosages of aprotinin "may be premature."
Trasylol is manufactured by a German firm, Bayer AG. Representatives for the firm could not be reached for comment. However, the Associated Press reported Wednesday that Bayer AG "insists the drug is safe based on its own experiments, but said it alerted regulatory authorities in the United States, Canada, Australia and Europe about the latest research."
Mangano told The Chronicle that the San Bruno foundation is a California nonprofit foundation that "has been in existence nearly 20 years. It's associated with around 250 centers around the world which are the leading cardiac surgery centers."
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CNN's Health Section MedPage
This week in the medical journals
Possible cystic fibrosis treatment from inexhaustible supply
By Peggy Peck
MedpageToday.com Managing Editor
Editor's note: CNN.com has a business partnership with MedPageToday.com, which provides custom health content. A medical journal roundup from MedPage Today appears each Thursday.
Drug safety questioned
The major medical journals this week published studies that raised serious questions about the safety of two drugs and debunked some popular theories about the value of two of the gods of nutrition, soy and fish oil.
Safety issue for heart surgery drug
A team of independent researchers in California sounded the alarm about Trasylol (aprotinin), a drug used to control bleeding during heart surgery. According to the report in the New England Journal of Medicine, patients treated with Trasylol had almost twice the risk of death, kidney failure, or stroke and a 50 percent higher risk of heart attack.
The researchers based their report on a review of records from more than 4,300 patients who had heart surgery at 69 institutions worldwide.
But Bayer, the maker of Trasylol, denied the charge. The drug company said the drug has had a good safety record for 15 years and pointed out that the California researchers are basing their conclusion on observational data, not on more reliable placebo-controlled studies. |
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Heart Surgery Drug Raises Kidney Failure Risk
26 Jan 2006
Trasylol (aprotinin) is a drug surgeons use to control bleeding during heart surgery. New research has found that aprotinin also doubles the risk of kidney failures. The researchers who took part in this new study say the drug should be dropped.
Aprotinin has other risks: Patients have a 48% higher risk of a heart attack, heart failure risk is 109% higher and stroke a whopping 181%.
Aprotinin is produced and owned by Bayer Corp.
Every year, over 11,000 patients need kidney dialysis as a result of having been given this drug during heart surgery.
You can read about this study in The New England Journal of Medicine.
Other cheaper and safer drugs are available, say the scientists. They said doctors should inform the patient about the drug's risks if they still wish to use it. Aprotinin has been on the market for over 12 years.
In this study over four thousand patients were looked at - they had all had heart operations. Areas covered included North America, Europe Colombia, Israel and Thailand.
The FDA says the drug is under review.
Written by: Christian Nordqvist
Editor: Medical News Today |
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Doctors Say Widely Used Clotting Drug Raises Stroke Risk
By Thomas H. Maugh II
Times Staff Writer
2:55 PM PST, January 25, 2006
A physicians group is urging surgeons to abandon a drug widely used to control bleeding during heart surgery because the drug sharply increases the risk of severe side effects, including kidney damage and strokes.
The drug, known as aprotinin or Trasylol, causes such severe kidney damage that an estimated 10,000 patients every year are forced onto dialysis, the group reports Thursday in the New England Journal of Medicine.
The clotting agent also increases the risk of heart attack by 48%, heart failure by 109% and stroke by 181%, increasing medical costs by more than $1 billion per year, according to a study among nearly 4,400 patients around the world.
And the drug is not needed in most cases, the researchers said, because two generic drugs that cost only a tenth as much as Trasylol and are nearly as effective at stopping bleeding produce no increase in risks.
"I wonder how we can ethically prescribe aprotinin when there are alternatives that are safer," said Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation, who led the study.
Some surgeons were concerned about the risk of aprotinin, but "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.
"This is pretty much undebatable."
A spokesman for the Food and Drug Administration said the agency is aware of the study and is reviewing the data.
Bayer Healthcare, which manufactures Trasylol, said in a statement that it had not had time to analyze the data, but that the results were not consistent with its experience. Bayer has predicted about $606 million in sales of the drug this year, nearly triple the $213 million of 2004.
The study was conducted by a consortium of surgeons called the Multicenter Study of Perioperative Ischemia Research Group, sponsored by the Ischemia Research and Education Foundation, which receives no money from pharmaceutical companies.
In other recent studies, 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 Cox-2 inhibitor Bextra is associated with stroke and impaired wound healing.
Mangano said the team started the study because the medical and surgical treatment of heart attacks were contradictory. Medical treatment uses clot-dissolving agents and a class of drugs called anti-fibrinolytics that inhibit clotting to forestall further attacks.
If surgeons use a bypass or other surgical treatment for the heart attack, however, they employ fibrinolytics such as aprotinin to promote clot formation. "But isn't the patient who received aprotinin likely to [have a heart attack inducing clot]?" Mangano asked. "It seems very logical.
The team enrolled 4,374 patients at 69 medical centers who were undergoing surgery to reopen a blocked artery — typically angioplasty. The control group, which totaled 1,374 patients, received a placebo, while 1,295 received aprotinin, 883 received epsilon-aminocaproic acid, and 822 received tranexamic acid.
Epsilon-aminocaproic acid and tranexamic acid are generic drugs that promote clot formation. A dose of the former costs $11 and a dose of the latter $44, while a full dose of Trasylol costs $1,300.
The most common side effect was kidney dysfunction or failure, occurring in 8% of those receiving aprotinin, compared to 4% of those receiving tranexamic acid and 3% of those receiving epsilon-aminocaproic acid or a placebo.
That result is probably not surprising, Mangano said, because other studies have shown that aprotinin is taken up by tubules in the kidneys and stays there for 24 hours or longer, interfering with normal organ functions. The problem was not seen in earlier studies, he said, because they were too small to illuminate the relatively small difference in incidence between the two groups of patients.
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Health Business
Bayer's Trasylol may cause kidney failure
By STEVE MITCHELL
UPI Senior Medical Correspondent
WASHINGTON, Jan. 25 (UPI) -- A major independent study indicates Bayer's antifibrinolytic agent Trasylol doubles the risk of kidney failure and causes other serious adverse events, including stroke and heart attack.
The finding is likely to significantly impact sales of the drug, which were expected to be more than $600 million this year.
"The study raises serious questions about the continued use of Trasylol and suggests far less expensive alternatives are available that are equally effective and safe," the study's lead author, Dennis Mangano of the Ischemia Research and Education Foundation in San Bruno, Calif., told United Press International.
Trasylol, which has been on the market for 13 years, reduces the loss of blood during surgery and is typically used during certain heart operations.
Two generic drugs -- aminocaproic acid and tranexamic acid -- were just as effective and safer, the research team concluded in the Jan. 26 issue of The New England Journal of Medicine.
Mangano and colleagues stated in the article that using one of the generic drugs instead of Trasylol worldwide could prevent as many as 11,050 dialysis complications, save $1 billion in healthcare costs and reduce drug costs by $250 million.
The team also estimates that as many as 10,000 patients may now be on dialysis due to Trasylol. "I'm concerned about that, but I'm even more concerned about -- now that we know there is a problem -- how many new patients that receive the drug will develop renal failure," Mangano said.
He noted the life-threatening side effects associated with Trasylol occurred more frequently than those associated with Merck's Vioxx, which was taken off the market in 2004 after it was linked to an increased risk of heart attacks and strokes.
Asked whether he thought Trasylol should be withdrawn from the market, Mangano said that was a regulatory matter that he could not address. But he added, "In good conscience, I could not administer (Trasylol) to this group of patients, especially given the availability of safer alternatives."
If a physician still wants to use the medication, Mangano said, "The least that should be done is to inform the patient that the risk of going on dialysis is increased 2-3 fold and there are alternatives."
In the study, data was collected from more than 4,300 patients undergoing revascularization surgery at more than 69 centers around the world between 1996 and 2000. The patients received either Trasylol, aminocaproic acid, tranexamic acid or no treatment.
The Trasylol group had double the risk of renal failure requiring dialysis usually observed in patients undergoing complex coronary-artery surgery or primary surgery. The group also had a 48-percent increased risk of heart attack, a 109-percent increased risk of heart failure and a 181-percent increased risk of stroke or encephalopathy.
Neither group that received the generic drugs exhibited these increased risks.
Bayer was quick to defend its drug and shed doubt on the new study. The company said it "believes that Trasylol is a safe and effective treatment" and that the "increases in renal failure, myocardial infarction, congestive heart failure and stroke or encephalopathy associated with use of (Trasylol) in patients undergoing coronary-artery surgery are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug."
Bayer noted that clinical trials it has conducted with Trasylol have included more than 3,800 patients who received the drug whereas this current study only consisted of 1,295 patients. The company also faulted the study design, saying it was an observational trial and not a double-blind, randomized controlled trial.
Mangano, however, pointed out that Bayer's trials were small and no one study included as many patients as his current report. Regarding the study design, he said it is nearly impossible to do a randomized, double-blind study once a drug is on the market.
Mangano's colleagues seem to agree with him. Writing in an accompanying perspective, David Hunter, an epidemiologist at the Harvard School of Public Health, said it is an example of the type of study that may be a model for the future.
"Studies such as the one by Mangano and colleagues point the way to the prospective design of studies to assess drug safety and to the collection of as much information as necessary to provide answers of the highest quality," Hunter wrote.
"Substantial questions remain about how to fund and administer these studies, but we need to ensure that skepticism about the value of observational studies does not engender nihilism," he added. "In the absence of evidence from randomized trials, the best-quality data must be made available to ensure the safety of medications."
Gus Vlahakes, of Harvard Medical School and Massachusetts General Hospital, concurred, saying the study illustrates the importance of conducting phase 4 studies.
Noting that efforts are under way to expand Trasylol's indications, which could require higher doses of the drug, Vlahakes wrote in an accompanying editorial, "Phase 4 clinical trials should be required before the indications for pharmaceutical agents are expanded, particularly when increased doses are required or administration in high-risk patients is proposed."
He also encouraged the FDA to support the use of independent clinical research in phase 4 testing. Referring to the recent problems with Vioxx and other COX-2 inhibitors, he said, "Too many pharmacologic agents have entered into clinical practice for which considerable and potentially life-threatening outcomes were recognized only after a large number of patients had been treated." |
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Commonly Used Drug in Heart Surgery May Increase Risk of Death
By Jeff Minerd , MedPage Today Staff Writer
Reviewed by Robert Jasmer, MD; Assistant Professor of Medicine, University of California, San Francisco
Source News Article: Forbes, LA Times, San Francisco Chronicle
MedPage Today Action Points
• Carefully weigh the risk suggested by this study when prescribing Trasylol (aprotinin) to reduce bleeding in patients undergoing heart surgery.
• Consider less expensive, generic options such as the antifibrinolytic agents aminocaproic acid or tranexamic acid.
Review
SAN BRUNO, Calif., Jan. 26 - Trasylol (aprotinin), a drug commonly given during heart surgery to control bleeding, increases the risk of serious adverse events and death, reported investigators here.
Compared with controls, heart surgery patients receiving the serine protease inhibitor had nearly double the risk of death, renal failure, or stroke and a more than 50% increased risk of heart attack, said Dennis T. Mangano, M.D., Ph.D., and colleagues of the Ischemia Research and Education Foundation, an independent, non-profit research organization.
The drug was approved by the FDA in 1993. However, the clinical trials establishing its safety were not adequately powered to detect rare events, Dr. Mangano and colleagues wrote in the Jan. 26 issue of the New England Journal of Medicine.
Their observational study involved more than 4,300 patients undergoing coronary-artery bypass surgery with cardiopulmonary bypass at 69 medical institutions worldwide.
About 1,300 patients received Trasylol, about 900 received the generic antifibrinolytic drug aminocaproic acid, about 800 received the generic antifibrinolytic drug tranexamic acid, and about 1,300 control patients received no drug to control bleeding. Data were gathered throughout each patient's hospital stay.
Compared with the control groups, patients receiving Trasylol had double the risk of renal failure requiring dialysis (odds ratio=2.34; 95% confidence interval=1.27-4.31).
Similarly, Trasylol was associated with a 55% increase in the risk of myocardial infarction or heart failure (OR and 95% CI not given; P<0.001) and a 181% increase in the risk of stroke or encephalopathy (OR and 95% CI not given; P=0.001).
Overall, Trasylol was associated with an increased risk of all-cause death (2.8% versus 1.3% on the control group; P=0.02).
Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events, the researchers said. All three agents reduced blood loss to similar extents.
"Thus, our findings indicate that reconsideration of the safety of aprotinin among patients undergoing cardiac surgery is warranted and indicate replacement of aprotinin with either aminocaproic acid or tranexamic acid," the authors concluded.
The generic drugs are significantly less expensive, they added.
In an accompanying editorial, Gus J. Vlahakes, M.D., 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."
The editorial added, "Although this observational study was not a randomized trial, the incorporation of a large number of patients gives it credibility," he added.
Dr. Vlahakes noted that efforts are underway to expand the indications for Trasylol, based on evidence that it modulates the systemic inflammation response to cardiac surgery. The new indication may require a higher dose, he said.
"Until the safety of higher doses is fully explored in a prospective study, the expansion of indications for aprotinin may be premature," Dr. Vlahakes warned.
Bayer, the maker of Trasylol, said in a statement that the company “believes that Trasylol is a safe and effective treatment when used in accordance with the product labeling.” It said 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."
Bayer said it has studied Trasylol in a series of prospective, randomized, double-blind, placebo-controlled clinical trials that including almost 6,500 open- heart surgery patients worldwide, looking at 3,817 Trasylol patients versus 2,682 patients taking placebo. It compared that clinical history with Dr. Mangano’s observational results.
"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,” said Bayer. “Such trials do not suffer from the limitations that can exist in observational studies."
Primary source: New England Journal of Medicine
Source reference:
Mangano DT et al. The risk associated with aprotinin in cardiac surgery. NEJM. 2006; 354:352-365.
Additional source: New England Journal of Medicine
Source reference:
Vlahakes G. The value of phase 4 clinical testing. NEJM. 2006; 354:413-415.
Disclaimer
The information presented in this activity is that of the authors and does not necessarily represent the views of the University of Pennsylvania School of Medicine, MedPage Today, and the commercial supporter. Specific medicines discussed in this activity may not yet be approved by the FDA for the use as indicated by the writer or reviewer. Before prescribing any medication, we advise you to review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse effects. Specific patient care decisions are the responsibility of the healthcare professional caring for the patient. Please review our Terms of Use.
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Heart-Surgery Drug Poses Risks: Study
By Ed Edelson
HealthDay Reporter 6 minutes ago
WEDNESDAY, Jan. 25 (HealthDay News) -- A widely promoted drug used to prevent bleeding during heart surgery doubles the risk of kidney failure and increases the risk of heart attack, heart failure and stroke, a study finds.
Two less expensive generic drugs used for the same purpose do not carry the same dangers, said a report in the Jan. 26 issue of the New England Journal of Medicine.
The study looked at data on 4,374 patients who had surgery after heart attacks and is "the largest study yet done," said Dr. Dennis T. Mangano, director of the Ischemia Research and Education Foundation, a California-based nonprofit organization, and lead author of the report.
It compared the outcomes of operations in which patients undergoing coronary artery surgery were given either one of three drugs to reduce bleeding: aprotinin, the newer agent; aminocaproic acid; tranexamic acid; or no drug at all.
The incidence of kidney failure in patients who got aprotinin was more than double that of those who got either of the two other drugs or no drugs at all, the report said. The risk of stroke was 181 percent higher, while the incidence of heart attack or heart failure was 55 percent higher.
The study was done because previous, smaller trials indicated an increased risk associated with aprotinin, but none of them was large enough to be definitive, Mangano said.
Aprotinin was approved by the U.S. Food and Drug Administration in 1993. It is marketed by Bayer HealthCare under the brand name Trasylol.
A statement from Bayer said it "has only just become aware of this observational study" and has not yet reviewed its findings. But the company said the reported increases in risks "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug." Bayer said its claim of safety was based on controlled trials including almost 6,500 heart-surgery patients.
Mangano countered by saying those studies looked at the effectiveness of the drug, not at its safety. "There is no financial incentive for the drug industry to do safety trials after approval," he said.
And a study looking at safety "would find it very difficult to enroll patients," Mangano said. "You would be telling patients they would get a protein that promotes kidney failure."
The fact that aprotinin is a protein, while the other drugs are different chemically, could account for the reported kidney damage, he said. A protein is taken up by the kidney, where it remains for 24 hours and can change kidney function, Mangano said. He estimated that 10,000 Americans now require artificial kidneys because they were given aprotinin.
The Bayer statement said the new study was not the kind of randomized, controlled trial that is "the accepted standard for the safety and efficacy of drugs."
In an accompanying editorial in the journal, Dr. Gus J. Vlahakes of Massachusetts General Hospital said that "regulatory requirements and the desire to ensure approval often dominate the design of clinical trials."
The desire to get a drug approved quickly often leads to selection in trials of patients who are least likely to have adverse reactions, said Vlahakes, who is chief of cardiac surgery at the hospital. But once a drug is approved, the company is free to push for expanded uses, he said.
The new study shows the need for continued testing of drugs after their first approval, Vlahakes said. "This process of phase 4 testing [after approval] I think is very important and something the FDA might want to require," he said.
In the case of aprotinin, Bayer has proposed its use for all heart-surgery patients, saying the drug can prevent an inflammatory reaction often caused by use of a heart-lung machine during the operation, Vlahakes said. The results of the study "are a strong suggestion that you can't just put aprotinin in the repertoire for all patients," he said.
At Massachusetts General Hospital, heart-surgery patients are generally given one of the older drugs, with aprotinin used "only in select circumstances where we expect to have particular difficulty with bleeding," Vlahakes said. Experience has shown that half the recommended dose is fully effective, he said.
More information
You can learn about heart attack from the National Library of Medicine.
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