Trasylol caused thousands of deaths that could have been avoided
|Cardiac surgeons will have to rely on alternatives now that Bayer pulled Transylol from the shelves. Source: MSNBC|
The BART (Blood conservation using Antifibrinolytics in a Randomized Trial) was a randomized-controlled, multicenter, blinded trial. Lead author Dean A. Fergusson, MHA, PhD, from Ottawa Health Research Institute, the University of Ottawa in Ontario, and colleagues randomly assigned 2,331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid and 780 received aminocaproic acid. Pfizer markets tranexamic acid as Cyklokapron and Xanodyne markets aminocaproic as Amicar.
In the three-arm study, aprotinin was compared in high-risk cardiovascular surgical patients to one of two other lysine analogues. “We set out to determine which of these drugs was superior—comparing one against the other—in terms of their ability to stop massive post-operative bleeding,” co-author Paul Hébert, MD, told Cardiovascular Business News.
“Our secondary endpoint included renal failure and death,” he added.
“It would have been far better for someone to conduct a trial like ours 10 years ago. We could have easily known these answers 10 years ago—that’s the striking part,” Hébert said.
On Oct. 17, 2007, the Data and Safety Monitoring Board terminated the trial early because of a higher rate of death in patients receiving aprotinin. Following that action, Bayer, based on the recommendations of the FDA, suspended international sales of its Trasylol. Trasylol was limited only to investigational use.
Hébert said that Trasylol’s suspension of sales was not globally uniform—in the U.S. and Canada, aprotinin was voluntarily suspended from use. However, he noted that in certain countries, like Germany, the regulatory agencies pulled it from the market.
In the BART results published today, the researchers found that a total of 74 patients (9.5 percent) in the aprotinin group had massive bleeding, as compared with 93 (12.1 percent) in the tranexamic acid group and 94 (12.1 percent) in the aminocaproic acid group. At 30 days, the rate of death from any cause was 6 percent in the aprotinin group, as compared with 3.9 percent in the tranexamic acid group and 4 percent in the aminocaproic acid group—nearly a double percentage in the aprotinin group.
The previous observational studies, “compared the difference in rates as compared to placebo—we had no placebo. So, the observational studies were not only confounded by indication, they were asking a different question,” he said.
Hébert also said that the previous meta-analyses that any drug, especially aprotinin, proved more effective than placebo. “In our trial, which did not have a placebo arm, the patients were all considered high-risk, and they would have received one of the three drugs,” he noted. Hébert added that aprotinin is proven to be far better than placebo in high-risk patients, “it’s just worse in comparison to the other two drugs in high-risk patients.”
In terms of reducing bleeding risks, Hébert said that “tranexamic acid is likely to be effective, or close to as effective as aprotinin, when the systematic reviews are examined—aprontinin might have been a bit better, but not by much.... Overall, aprotinin is more effective than tranexamic acid and Amicar than reducing massive bleeding, but by all accounts, that estimate may not be as reliable as it should be.” Hébert and his fellow authors encouraged their readers that “cautious interpretation of this trend [decrease in bleeding] is warranted,” mainly due to the increase in deaths.
He noted that the 2 percent increase in deaths with aprotinin is a “robust and real finding.”
As a result of their findings, Hébert said that in general for cardiac surgery, aprotinin should not be recommended for use. For the additional medical procedures for which aprontinin is indicated, he said that “the regulatory agencies should perform the risk-benefit calculations, overall.”
Following the pre-publication of the BART study in the May 14 online issue of NEJM, Bayer Pharmaceuticals notified the FDA of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses.
Trasylol has now been linked to up to 22,000 U.S. deaths and kidney failure in patients undergoing open heart surgery's and hip replacement surgery, according to the news program 60 Minutes.
According to Hébert, the FDA made the correct decision at the right time because prior to the BART study, aprotinin had only been compared to placebo in clinical testing. “It’s no doubt that it’s a better drug than placebo. They [previous clinical studies] suggested the right thing for the wrong reason; the entire analysis was confounded by indications.”
The authors of the BART study are recommending either tranexamic acid or aminocaproic acid as an alternative to aprontinin. “These two other drugs are perfect. They don’t kill people and they stop bleeding. While we haven’t done a true comparison of the drugs compared to one another within our own data, they both look to be equally effective,” Hébert said.
However, he noted that “Amicar is at least ten times less expensive than tranexamic acid [Cyklokapron.] Amicar is dollars-per-dose compared to $1,000 to $1,500 per dose for aprotinin. Depending on where you buy Amicar from, it could be in the $50-$70 range, as compared to tranexamic acid [Cyklokapron], which probably costs in the range of $300-$400 for a treatment dose based on our calculations at the time of the study.”
Hébert concluded that “the striking part is that this [type of clinical study] wasn’t done earlier. Why are we the ones doing this 20 years after this drug is on the market? Why didn’t the NIH take up this cause—the RCHR, the [Canadian] NIH equivalent, did fund our trial—but aprotinin was still being administered in placebo-comparison trials.”