Aprotinin safety again in spotlight as new study suggests increased cardiac events

October 02, 2006

October 2, 2006 (updated October 6, 2006) ( West Haven, CT) - Just days after an FDA advisory committee effectively endorsed the safety of aprotinin (Trasylol, Bayer), a new study conducted for Bayer has come to light that suggests that there could be an increased risk of cardiovascular events with the drug after all.

A front-page story in the New York Times, headlined “FDA says Bayer failed to reveal drug risk study,” reports that the FDA only learned of the study because of a tip from a researcher involved in it [ 1 ].

That Bayer chose not to reveal these results before or at the advisory-committee meeting has angered some of the panel members. The company has now acknowledged that not sharing the data before the meeting was a “mistake.”

Update: Harvard researcher alerted FDA to Bayer study

A Harvard researcher who helped to conduct the new Bayer study of aprotinin told the FDA about its existence after noticing that it was not mentioned at the advisory committee meeting, Bloomberg News reports [ 2].

Dr Alexander Walker, a professor at Harvard's School of Public Health, helped run the study for i3 Drug Safety, a private clinical research company. Walker, previously head of Harvard's department of epidemiology and a former consultant to the New England Journal of Medicine, is quoted by Bloomberg as saying that notifying the FDA "seemed like the right thing to do.''

The Bloomberg report also quotes advisory-committee member Dr John Teerlink (University of California, San Francisco) as saying that Bayer’s failure to tell the FDA about the study before the advisory committee meeting "calls into question the honesty of Bayer and the honesty of the pharmaceutical industry in general. Teerlink adds: "I think the public health has been harmed in two ways. One, we didn't have complete information to make our decision. But second, it calls into question a process that all of us depend on.''

A September 29 letter to the panel members said the FDA may call for a second meeting of the advisory panel to review the new data, the report notes.

Bayer is said to have started the study in June. It received a preliminary copy of i3's report on September 14 and submitted questions aimed at getting clarifications on the data on September 18, Bloomberg notes. The company also claims that Bayer employees who presented information to the FDA panel did not know the study results were available.

The FDA’s cardiovascular and renal advisory committee met on September 21 to discuss two observational studies published earlier this year questioning the safety of aprotinin, an antifibrinolytic drug used to reduce bleeding risk in CABG patients. One study, by Mangano et al [ 3 ], suggested an increased risk of cardiovascular events and renal insufficiency with aprotinin; the other study, by Karkouti et al [ 4 ], suggested some renal toxicity but did not show any increasedcardiovascular risk.

Because of concerns about methodology in the Mangano study, because Mangano did not allow independent analysis of his data by the FDA, and because this was the only study that suggested an increased cardiovascular risk with the drug, the advisory committee concluded that there was not enough evidence to support changing the cardiovascular-safety labeling of the drug.

But just six days later, Bayer admitted to the FDA that it had commissioned an observational study of its own to investigate the cardiovascular safety of aprotinin and that preliminary results of that study suggested that the use of aprotinin increases the chance of death, serious kidney damage, congestive heart failure, and stroke.

FDA issues new safety warning

On September 29, the FDA issued a statement saying that it was not aware of these new data when the advisory-committee meeting was held and that it is now evaluating the new study and its implications for appropriate use of the drug [ 5 ].

In the meantime, the FDA offers the following advice:

  • Physicians who use aprotinin should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, and brain, and promptly report observed adverse-event information to Bayer or to the FDA MedWatch program.

  • Physicians should consider limiting aprotinin use to situations in which the clinical benefit of reduced blood loss is essential to the medical management of the patient and in which its benefits outweigh potential risks.

These recommendations are similar to those provided in a February 8, 2006 FDA Public Health Advisory, which was issued after the publication of the initial studies.

The FDA statement notes that, in the new Bayer study, which was conducted by a contract research organization, hospital data from 67 000 CABG patients were examined. Of these, 30 000 patients were treated with aprotinin and 37 000 were treated with other products. The report, which used complex epidemiological and statistical methods, suggested that patients receiving aprotinin were at increased risk for death, kidney failure, congestive heart failure, and stroke.

Advisory committee angry

Members of the cardiorenal advisory committee were understandably angry that Bayer had not revealed this information before the meeting.

Dr Robert Harrington (Duke University, Durham, NC) commented to heart wire : “Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me. The process of evaluation, comment, and [the provision of] advice on important drug efficacy and safety data only works when all of the involved parties are open and honest about their data. It is ironic that we spent part of the panel meeting criticizing Dr Mangano for failing to allow the FDA to perform an independent review of his database, yet Bayer failed to even acknowledge the existence of these data. It is especially troubling when several panel members, including me, commented that more data and more analyses were needed to fully understand the risks and benefits of the drug. I'd like to know if the Bayer team. . . present that day had knowledge of the existence of the data and why they chose not to even mention it.”

Dr Michael Lincoff (Cleveland Clinic, OH), also a member of the advisory panel, had similar views. “It was astounding to me that they did not disclose the information that the study had been conducted, even if the findings were considered preliminary. They were in the midst of an entire day's discussions at the FDA on that precise topic, where there was substantial comment regarding the desirability of more contemporary data than their older trials. It is inconceivable that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee,” he told heart wire .

The chair of the committee, Dr William Hiatt (University of Colorado Health Sciences Center, Denver), confirmed that he was unaware of these new data at the September 21 meeting. “While the new study does not change things at the moment, after full review by the FDA, it possibly could change our impression of the safety of aprotinin,” he said.

Teerlink is quoted in the New York Times as saying of Bayer: “For them not to mention that it was under way, that it was being analyzed, or that results were available is appalling and will do significant harm to their reputation for transparency.”

Bayer acknowledges "mistake"

Bayer issued a statement saying it was a mistake not to have informed the FDA about the study before the advisory-committee meeting. “This. . . was not shared immediately with the agency because it was preliminary in nature and raised significant questions on the study population, outcomes, and methodology. Bayer believes that despite the highly preliminary nature of [these] data, the information should have been shared with the FDA prior to the September 21 advisory-committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the company’s part,” the statement reads. It adds that the company will work with the investigators and other experts to examine the underlying source data and fully understand the results.

  1. Harris G. FDA Says Bayer failed to reveal drug risk study. New York Times, September 30, 2006. Available at: http://www.nytimes.com/2006/09/30/health/30fda.html?_r=1&oref=slogin.

  2. Blum J and von Schaper E. Harvard researcher forced Bayer to disclose drug toxicity study. Bloomberg News, October 6, 2006. Available at: http://www.bloomberg.com/apps/news?pid=20601103&sid=aLufHbinR8bI&refer=news.

  3. Mangano DT, Tudor IC, Dietzel C, et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353-365.

  4. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006; 46:327-338.

  5. US Food and Drug Administration. FDA Public Health Advisory: Aprotinin Injection (marketed as Trasylol). September 29, 2006. Available at: http://www.fda.gov/cder/drug/advisory/aprotinin20060929.htm.

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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