Aprotinin Reintroduction Puts Lives at Risk in Canada, EU

Shelley Wood

September 29, 2014

OTTAWA, ON — Investigators for the study that first led to the removal of aprotinin (Trasylol, Bayer) from worldwide markets say the decision by regulators in Europe and Canada to allow the reintroduction of the product is putting lives at risk[1].

As previously reported by heartwire , the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study was halted early by the trial's data safety and monitoring board (DSMB) in October 2007 after spotting increased deaths in the arm receiving the antifibrinolytic, intended to reduce the risk of major bleeding during CABG.

One month later, the manufacturer, Bayer, suspended the product worldwide. Both Health Canada in 2011 and the European Medicines Agency in 2012 elected to allow the drug to be used again in their jurisdictions, a decision that co–principal investigators Drs Paul C Hébert and Dean A Fergusson and their BART coinvestigators say is putting patients "at substantial risk."

"We stand by the results of BART," Fergusson told heartwire . "We owe it to the patients and everyone involved in the trial [to stand up for these results]. And to me the overall message, from not just BART but the cumulative evidence, suggests that aprotinin indeed increases the risk of death."

The Chain of Events

As Fergusson explained to heartwire , BART was terminated within a week of the DSMB's alert. Within a day of hearing from the DSMB, investigators contacted the FDA and Health Canada, ran their final analysis, published the paper, and "in due course," Health Canada convened a hearing. BART investigators as well as the sponsor, Bayer, made presentations to the panel, and, in the case of the trialists, also supplied answers to a number of follow-up questions.

Health Canada's subsequent report, however, contained "a number of criticisms and inaccuracies" about the trial, Fergusson said, that investigators have been trying to bring to the regulators' and public's attention for years.

In their paper, published today in CMAJ, BART investigators detail three key errors in Health Canada's report.

The first was based on allegations that BART investigators reclassified a full 75% of primary outcome events in the study. In fact, write Hébert et al, just 1.6% of events, or 38 out of the trial's 2438 patients, were reclassified during data cleaning, and this was done in a "nondifferential manner" between trial arms and did not have a major impact on primary study results.

Another concern in Health Canada's report was over the 137 patients excluded after randomization. In their paper today, Hébert et al provide an explanation for the exclusions as well as per-protocol and as-treated population analyses, showing that with or without the exclusion of these subjects, the trial's primary findings were unchanged.

Finally, Health Canada reviewers, in their report, raised concerns about a potential imbalance between treatment and placebo arms based on heparin use and/or anticoagulation monitoring. On this point, BART investigators undertook a series of post hoc analyses and, as they detail in their publication today, found no differences in mortality related to heparin use or heparin dose. They also reject assertions that anticoagulation was in some way mismanaged in the trial, saying "inadequate anticoagulation in any group in BART is highly unlikely."

Investigators' Concerns Fall on Deaf Ears

According to BART investigators, their attempts to get answers from the government reviewers to explain some of their calculations have gone unanswered. European regulators, meanwhile, made limited attempts to independently substantiate or verify information provided by Canadian regulators and never contacted the BART investigators directly, Fergusson said.

Hébert and colleagues argue that the most logical next step for regulatory bodies uncertain about the BART results would have been to mandate a second large trial comparing aprotinin with another active agent—something that has never come to pass.

According to Fergusson, aprotinin had been, prior to 2008, the most popular drug used in cardiac operating rooms for minimizing bleeding. Today, he said, while he did not have exact numbers, "I suspect it is used very little, but I don't know that for a fact."

Guidelines on blood conservation in cardiothoracic surgery, released by the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) in 2011, advise against the use of aprotinin.

What's clear, he continued, is that tranexamic acid—appropriately—"has become the drug of choice, and I think our concern is more directly related to the fact that now that we have tranexamic acid, why would you reintroduce aprotinin if it has a 50% increased risk of death? Why take that risk when there is an effective alternative?"

Fergusson believes that Health Canada has tried to come to terms with the data but that the agency is not accustomed to dealing with data from large, pragmatic trials.

"In this new era of comparative-effectiveness and patient-centered research, these large trials provide our best estimates of safety and effectiveness, and that doesn't necessarily fit in a regulatory model or framework, which is used to relying on smaller, placebo-controlled trials."

Of note, Fergusson added, the US FDA also convened an expert review after BART was published, "and to this day aprotinin remains off the market" in the US.

Hébert and Fergusson had no conflicts of interest. Disclosures for the coauthors are listed in the paper.

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