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November 5, 2007; Wall Street Journal

Bayer Halts U.S. Sale of Trasylol

Bayer AG will pull its antibleeding drug Trasylol from the U.S. market amid growing evidence it may be linked to a higher risk of death than that of competing drugs, according to people with knowledge of the matter.
It wasn't clear late yesterday if Bayer, based in Germany, would halt sales of the drug in other countries, although such a move would be likely in light of a suspension of U.S. sales.
Trasylol, which is supposed to reduce blood loss and allow patients undergoing heart-bypass surgery to avoid transfusions, would be the third drug this year whose sale in the U.S. was halted under scrutiny from the Food and Drug Administration, a signal of how the agency is weighing safety issues heavily in drug decisions. Still, the history of Trasylol, which was approved in the U.S. in 1993 and has been tied to high-profile safety concerns at least since early 2006, is likely to draw questions from Congress and plaintiff attorneys.
The drug had world-wide sales of $338 million in 2005. Sales dropped by about a third last year.
Last month, after a Canadian clinical trial stopped enrolling patients to take the drug because it appeared linked to a higher risk of death, the FDA said it was reviewing Trasylol.
The drug's safety became a high-profile issue with the publication of a study in the New England Journal of Medicine in January 2006, which found the drug might be linked to a doubled risk of kidney failure, as well as increased risk of heart attacks, heart failure and strokes. The authors concluded "continued use is not prudent" and said two generic medications were safe alternatives. However, the study didn't involve patients being randomly assigned to take the drug.
The FDA put out a notice about Trasylol in February 2006, urging doctors to closely monitor patients taking the drug. In September 2006, an agency advisory committee voted unanimously that the drug should remain on the market. After the meeting, the FDA said a safety study commissioned by Bayer hadn't been submitted to the agency in time to be reviewed by the committee.
The FDA made changes to Trasylol's label in December 2006, including a warning about potential kidney damage and a narrowing of the recommended population of patients.
In September, another advisory committee examined the drug, this time including the Bayer study, which suggested Trasylol might be tied to a higher risk of death and kidney damage. A follow-up to the earlier New England Journal study, this one published in the Journal of the American Medical Association in February, also tied Trasylol to mortality risk, and it advised that its use "does not appear prudent." Still, none of the safety studies were randomized.
The committee still voted, 16-1, that Trasylol remain on the market. Some doctors argued that the drug filled an important niche for patients who couldn't handle blood transfusions.
Finally, late last month, the FDA announced the new review in the wake of the early findings from the randomized Canadian trial, which suggested Trasylol "increases the risk of death" compared to the risk from other drugs, the agency said. Write to Anna Wilde Mathews at anna.mathews@wsj.com

23 November 2007, Pharma Times

EMEA advisors call for suspension for Bayer's Trasylol

Just a few weeks after Bayer decided to halt global marketing of Trasylol, advisors to Europe’s regulators has issued a statement saying that the blood loss agent should indeed be pulled.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has concluded that the benefits of systemic formulations of Trasylol (aprotinin) “no longer outweigh their risks” and it has recommended that all marketing authorisations should be suspended throughout Europe.

The CHMP has been reviewing the drug since November 5, when the German medicines regulatory authority suspended marketing authorisation for Trasylol, used as an infusion during bypass surgery. This decision was triggered by the preliminary results of the Canadian Phase III BART study, which is looking at the use of aprotinin in around 3,000 heart surgery patients to reduce post-operative bleeding.

That study was stopped after preliminary findings indicated a higher risk of death compared to two antifibrinolytic drugs used in the study, epsilon-aminocaproic acid and tranexamic acid. Bayer then responded by taking the drug off the market until it has analysed all the data.

The CHMP has looked at the data that its Pharmacovigilance Working Party (PhVWP) has already been considering in the context of its monitoring of the safety of medicines, plus new information from the BART study. It says that the PhVWP review had already identified some concerns and now the extra data has convinced the agency’s committee to recommended that Trasylol be suspended in all European Union and European Economic Area markets.

Bayer has still not given up on the drug and Bayer Healthcare chairman Arthur Higgins recently told PharmaTimes World News that it is waiting for the full data from BART to be evaluated which could take up to another month. However he noted that the US Food and Drug Administration has twice recently said that available data continue to support a favourable risk-benefit profile for Trasylol when used according to labelling.

further information

Oct 26, 2007; Foodconsumer.org

Bayer Trasylol trial halted due to high risk of death

Use of Trasylol also known as aprotinin may significantly increase risk of death in patients at an increased risk of blood loss and blood transfusion because of coronary artery bypass graft surgery with cardiopulmonary bypass, the Food and Drug Administration reported October 26.

The finding was derived from a trial titled Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study that planned to enroll approximately 3,000 adult Canadian patients who were to undergo various types of cardiac surgery that placed them at high risk for bleeding. As a result, the study was terminated earlier than planned.

Aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft (CABG) surgery who are at an increased risk for blood loss and blood transfusion.

The study was meant to determine if aprotinin is superior to other antifibrinolytic drugs such as epsilon-aminocaproic acid or tranexamic acid. It turned out that aprotinin imposed a higher risk of death compared to its two competitors.

The BART Executive Committee notified the FDA and the drug manufacturer of the increased death risk and its decision to discontinue the study on Trasylol.

According to the FDA, the findings resulting from the aborted study include:

The 30- day mortality in the aprotinin group nearly had reached conventional statistical significance at the interim analysis, when compared to either epsilon-aminocaproic acid or tranexamic acid;

A trend toward increased mortality in the aprotinin group had been observed throughout the study;

The use of aprotinin was associated with less serious bleeding than either of the comparator drugs; however, more deaths due to hemorrhage had been observed among patients receiving aprotinin;

Bayer Pharmaceuticals Corp., Leverkusen, Germany, the manufacturer of Trasylol, on October 26 issued additional guidance to physicians after the company was notified that use of aprotinin was linked to increased risk of mortality in high risk cardiac surgery patients.

Bayer said in its Guidance that physicians should use Trasylol in accordance with approved product labeling. Also they should consider the fact that the BART Trial has been discontinued due to increased all-cause mortality in patients who were treated with the drug compared to those who were treated with either aminocaproic acid or tranexamic acid.

The drug of concern was approved in 1993. And it’s been more than a year that the increased risk of death, serious kidney damage and stroke became public, according to Reuters. In 2006, the FDA revised the labeling for Trasylol to address the risk and limit its approved usage to patients at an increased risk for blood loss and blood transfusion during coronary bypass graft surgery.

On October 26, the FDA issued Early Communication about an Ongoing Safety Review of Aprotinin Injection saying that the federal agency was notified of the halted study due to the unexpectedly higher risk of death. It said "FDA anticipates further review of the risk and benefits of Trasylol, which may result in additional labeling or other regulatory action. FDA will work with the sponsor of the recently terminated study to evaluate the data fully."

In the meantime, the FDA recommends that physicians weigh the risks and benefits of Trasylol outlined in the label and in the Early Communication about an Ongoing Safety Review, and discuss the information with their patients. By Sue Mueller