Bayer anti-bleeding drug linked to 50 % higher death rate than alternatives
TORONTO - An expensive drug used to minimize severe bleeding during heart surgery actually significantly increased the risk that patients would die during surgery or in the 30 days following, a Canadian study comparing the drug to two far cheaper alternatives shows.
Called the BART trial, the study found people who received Trasylol or aprotinin (its generic name) were 53 per cent more likely to die than people who received the other anti-bleeding agents, tranexamic acid or aminocaproic acid.
In absolute terms that means for every 100 patients who got aprotinin during high-risk cardiac surgery, six died. For every 100 patients getting tranexamic acid or aminocaproic acid, four died, according to the study, published electronically on Wednesday by the New England Journal of Medicine.
"The risks of aprotinin are greater than its benefits," said Dr. Paul Hebert, a critical care doctor at the Ottawa Health Research Institute and one of the principal investigators in BART (short for Blood Conservation using Antifibrinolytics in a Randomized Trial).
"The two other drugs are safe alternatives."
Given the number of such surgeries performed around the world every year, the difference could translate into thousands of lives. It is estimated that roughly 250,000 high-risk cardiac surgeries are performed annually; use of one of the anti-bleeding agents in high-risk cardiac surgery is standard care, said Dr. David Mazer, one of the lead researchers.
"The BART study has changed the way heart surgery will be done in Canada and around the world," predicted Mazer, a cardiovascular anesthesiologist and critical care physician at St. Michael's Hospital in Toronto.
Trasylol's manufacturer, Bayer HealthCare, suspended worldwide sales of the drug last November after Hebert and his research partners notified Health Canada and other international drug regulatory agencies that they were halting the BART trial.
The decision to end the trial early was made on the advice of an independent data safety monitoring board, which spotted the higher rates of death in the patients who received aprotinin.
Bayer has never said whether it plans to try to resuscitate aprotinin. And even with the release of the BART data, it is hedging its bets.
"Bayer will continue to carefully review this article, the editorial and (when available) the underlying data on which the authors have based their conclusions and continue to discuss both the restricted access programs for Trasylol and the worldwide temporary marketing suspension of the drug with regulatory authorities," the company said in a prepared statement.
"When further conclusions are reached, Bayer will communicate publicly."
But an editorial in the journal predicted the drug is done.
"In all likelihood this is the end of the aprotinin story," wrote Wayne Ray and Dr. Michael Stein of the Vanderbilt University Center for Education and Research on Therapeutics in Nashville, Tenn.
Aprotinin and the other anti-bleeding drugs have been used for years to try to lower the risk of major bleeding events during high-risk heart surgeries.
Cardiac surgeons and their teams are aggressive about trying to reduce the need for blood transfusions, said Dr. Martin London, an anesthesiologist who specializes in cardiovascular surgeries at the University of California, San Francisco.
"Bleeding in cardiac surgery has profound consequences and can cause mortality both acutely and then later on," London explained. "We've got plenty of observational data that suggests that the more blood you got during surgery the worse your outcome is long-term."
Over time it seemed aprotinin was more effective than the other two and Bayer marketed it aggressively, London said.
The drug cost substantially more than the alternatives. During the course of the study, aprotinin cost between $1,200 and $1,500 per patient, compared to about $150 per patient for tranexamic acid or aminocaproic acid. In places where aminocaproic acid is made - it is not made in Canada - that cost could be less than $4 per surgery, the study noted.
No head-to-head trial had been done on the effectiveness of the drugs. So, with funding from the Canadian Institutes of Health Research and Ontario's Ministry of Health and Long-term Care, Hebert and co-principal investigator Dr. Dean Fergusson of the Ottawa Health Research Institute started the BART trial.
"The Canadians stepped up to the plate in terms of doing the necessary randomized trials," said London, who was not involved in the study. "If the BART study hadn't been done, we probably would still be using aprotinin."
The original plan was to enrol 3,000 patients. At the time the enrolment was stopped, 2,331 patients had been randomly assigned to receive either aprotinin, tranexamic acid or aminocaproic acid during surgery.
Aprotinin did appear to be slightly more effective in preventing major bleeds. But that benefit was outweighed by the increased risk of death.
Hebert said the research doesn't show why deaths were higher among patients who got aprotinin, but the researchers believe the drug's apparent superiority at inducing clotting was both a positive and a negative in this setting.
"Our hypothesis at this point, although we can't prove it, we speculate that it worked a little bit better in preventing bleeding. It also worked a little bit better in causing clotting. And that's why a few more patients died."