The Trasylol-BART Connection

San Bruno, CAThe Trasylol debacle, and the anti-bleeding drug's impact on the lives of cardiac surgery patients, is the stuff of moviedom. One can just imagine the Keystone Cops-like scurrying on the part of expert panels convened at the behest of the US Food and Drug Administration (FDA), which twice reviewed and twice re-asserted the wisdom of keeping Trasylol (aprotinin) on the market in spite of mounting evidence suggesting aprotinin's shortcomings.

Then there was Bayer AG, the makers of Trasylol, keeping mum during a 2006 review panel at which panel participants were pining for more data, knowing all along that fresh data was available. That data wasn't presented for reasons known only to Bayer.

What finally brought Trasylol down was the Canadian-led BART trial, which had to be halted in October of last year after patients on Trasylol were dying. Yes, bleeding was reduced. But they appeared to be dying with greater regularity, which mitigates any advantage to the anti-bleeding properties of Trasylol.

Okay, so just who is BART, anyway?

Well, BART isn't so much a 'who,' as it is a 'what'—'Blood Conservation using Antifibrinolytics: A Randomized Trial in High-Risk Cardiac Surgery Patients.'

If you had to pronounce that mouthful, you'd have come up with the acronym, too.

Thus, you have the gold standard of clinical trials—a randomized and controlled trial comparing high-risk cardiac patients on Trasylol (aprotinin), with participants taking two other alternative anti-bleeding drugs: aminocaproic acid, and tranexamic acid. Participants numbered 3000 high-risk cardiac patients having either a repeat operation for coronary heart bypass graft (CABG), or requiring surgery to replace an aortic valve. A combined valve/CABG procedure was also part of the mix.

Trasylol had long been under the microscope for suspicion of cardiovascular and renal complications. Dr. Dennis Mangano, a noted researcher with the not-for-profit Ischemia Research and Education Foundation in San Bruno, California, conducted an observational study involving thousands of patients in dozens of countries that took years of study and millions of dollars to complete. Over a million points of data points were analyzed. The conclusion confirmed what had long been suspected: that aprotinin posed a serious risk.

Mangano's conclusions, however, were dismissed at the FDA-sanctioned advisory panel in September of 2006, primarily because it was an observational study of the actual hospital records of patients. A similar study, initiated by Bayer and conducted under the auspices of the Harvard School of Public Health, painstakingly studied some 75,000 patients and came to a similiar conclusion.

That was the study that was in Bayer's hands at the time of the review panel meeting, but was not presented. A year later, with both studies at their disposal, the FDA review panel again judged that the benefits of Trasylol outweighed the risks. The results of the two studies were insufficient to sway their posiitons.

But BART changed all that, and literally a month later. That's when the Canadian BART trial was halted by the trial's executive committee after it received a communique from the trial's safety board stating that the results were beginning to show that aprotinin reduced bleeding as advertised, but was also beginning to present a significant link to increased risk of death from all causes, compared with aminocaproic acid, and tranexamic acid.

It's one thing for a trail to be carried through to completion, the results of which posing serious concerns surrounding the safety of a drug. However, it's quite another when a gold-standard clinical trial has to be halted prematurely, because it's killng people. Well, not the trial, but allegedly one of the drugs being studied.

Bayer issued a communique to doctors advsing that Trasylol should be used only as directed, taking into account that the BART trial was halted due to "an increase in all-cause mortality in patients in the aprotinin treatment arm compared to patients who received either aminocaproic acid or tranexamic acid."

It wasn't long before Bayer, in consultation with the FDA and health regulators in Canada and Germany, agreed to a halt for the marketing of Trasylol.In the end, the halting of a clinical trial prior to its conclsuion carries certain weight, at least sufficient weight for the FDA, and Bayer to agree that Trasylol needed to be knocked off its pedestal.

While Trasylol has been pulled from global markets, surgeons can still use the drug on a case-by-case basis. Bayer views the recall as temporary, while it reviews the BART data. And the FDA, instead of putting the hammer down and banning Trasylol outright pending the BART data has left the door open, and has said that it would like to phase Trasylol out gradually, ensuring that it does not leave a void in the market for patients at high risk for bleeding.

Interestingly, there are alternatives—the two drugs assuming the comparative role in the BART trial. Aminocaproic acid and tranexamic acid, according to Dr. Mangano's study, are just as effective as aprotinin, without any of the risks.

And in a country where the cost of health care is on everyone's mind, the cost associated with aminocaproic acid or tranexamic acid are in a different world, at about fifty bucks per dose, vs. the reported $1000 per for Trasylol.

Yeah, I'd be calling my lawyer too...