Bayer halts sales of anti-bleeding drug after Canadian trial identifies risks
Reported November 05, 2007
TORONTO – Pharmaceutical giant Bayer AG suspended global sales of its anti-bleeding drug Trasylol on Monday after a clinical trial led by Ottawa researchers found the drug was linked to a higher risk of death than alternative medications.
The action followed requests from the U.S. Food and Drug Administration, Health Canada and the German Federal Institute for Drugs and Medical Devices that Bayer suspend sales in their jurisdictions while the regulatory agencies review the preliminary findings of the BART trial.
Jirina Vlk, a spokesperson for Health Canada, said while sales are suspended Health Canada will work with Bayer to ensure the drug is available for special needs surgeries.
“Bayer Inc. will work with Health Canada so that the drug can be made available to certain patients in cases where the doctor believes the substantial benefit clearly outweighs the risk,” Vlk said from Ottawa.
But a number of cardiac surgeons indicated Monday that given the BART trial findings they are already turning to alternatives.
“I would avoid it,” said Dr. Gideon Cohen, a cardiac surgeon at Toronto’s Sunnybrook Health Sciences Centre who until the BART results were made public used aprotinin (Trasylol’s generic name) in his surgeries but is now using an alternate drug, tranexamic acid.
“Because the cases now for cardiac surgeons are becoming more and more complex and more and more high risk. Although bleeding is a major risk, I think that I’d have to really believe that aprotinin is better than the other agents and have conclusive evidence that it is before I would use it again.”
A member of an FDA advisory panel that has twice studied the drug said he thinks it’s unlikely Trasylol will return to the market, except perhaps for use in a subset of heart bypass patients if it can be determined that for some the benefits outweigh the risks.
“I can’t think of drugs that have reached this point of being pulled and then come back,” said Dr. Michael Lincoff, director of cardiovascular clinical research at the renowned Cleveland Clinic.
The BART trial – the acronym stands for Blood conservation using Antifibrinolytics in a Randomized Trial – was designed to test the efficacy of aprotinin and two related drugs, tranexamic acid and aminocaproic acid. All three are used to reduce blood loss during bypass surgery with the aim of minimizing the need for blood transfusions.
It was the first head-to-head trial testing aprotinin against other drugs. Earlier trials had only tested it against placebos and those trials were too small to show serious but rare side-effects, Lincoff said.
The thinking in the medical community was that aprotinin – which is vastly more expensive than the other drugs – was likely going to be shown to be more effective than the alternative drugs, said Dr. Fraser Rubens, a professor of surgery and a cardiac surgeon at the University of Ottawa Hearth Institute.
But Rubens said the increased efficacy came at a cost.
“It’s a double-edged sword. This drug stops bleeding but then it causes clotting.”
The BART trial, which was led by scientists at the Ottawa Health Research Institute, was to randomize 2,973 heart surgery patients to receive one of the three drugs. But in a regularly scheduled safety monitoring board review, preliminary data on 2,163 patients showed a trend towards increased deaths in the Trasylol arm.
A statement on the institute’s website said that if the final analysis of the data confirms the increased-mortality trend, it would translate into two additional deaths per 100 patients getting Trasylol as compared to those who received one of the other antifibrinolytics.
Based on the findings the data safety monitoring board terminated enrolment into the trial. Regulatory agencies were informed and on Oct. 25 the FDA announced it was re-evaluating the drug.
The principal investigator is Dr. Paul Hebert, a cardiology researcher and editor of the Canadian Medical Association Journal. Hebert and his co-investigators declined to comment Monday.
A spokesperson for the institute said they are in the process of analyzing the data from the study and will not discuss the issue further until that work is completed.
A 2006 observational study – one which observes what happens to people who receive a treatment or follow a certain diet, for example – raised concerns that aprotinin was associated with higher rates of stroke, heart attack, kidney failure and death.
Based on that study, the FDA convened an advisory panel to investigate whether the drug should be withdrawn from the market. In September of 2006 and again a year later that panel decided there were grounds for concern and a need for better, bigger studies, but it decided not to recommend withdrawal.
Given the BART trial results, if the panel had met Monday the vote would have gone in the opposite direction, said Lincoff, who sat on the panel.
“I think it would be overwhelming. Because there was a lot of discussion about how we felt we absolutely needed more evidence and that if they (Bayer) weren’t willing to provide more evidence to do another trial in a serious fashion . . . we would consider that a reason to withdraw the drug.”
The study received funding from the Canadian Institutes of Health Research and the Ontario Ministry of Health and Long-Term Care. The pharmaceutical industry provided no funding for the trial and none of the makers of the three drugs had any role in its design, conduct or evaluation, the institute said.
