Aprotinin safe in on-pump but not off-pump CABG

February 08, 2008

Bristol, UK - A new retrospective analysis of patients undergoing CABG in whom the antifibrinolytic aprotinin (Trasylol, Bayer) was used has found that the product appears to be safe during on-pump CABG surgery [1]. Dr Ronelle Mouton (Bristol Royal Infirmary, UK) and colleagues report their findings in the February 9, 2008 issue of the Lancet.

Although worldwide marketing of aprotinin was suspended by Bayer in November last year, after enrollment in the Canadian trial Blood Conservation Using Antifibrinolytics: A Randomized Trial in a Cardiac Surgery Population (BART) was halted in mid-October because of safety concerns with the product, senior author of the new paper, cardiac anesthetist Dr Kai Zacharowski (Bristol Royal Infirmary), told heart wire that many surgeons are still using it. "The general opinion [when marketing was suspended] was that it was a shame, we wanted to have aprotinin back on the market because a lot of high-risk patients would benefit from it. We are still prescribing it, because we have a huge batch still in the hospital."

However, Zacharowski and colleagues' work did show that there was an increased risk of renal dysfunction when patients received aprotinin and ACE inhibitors during off-pump CABG. As a result, his center is no longer using aprotinin in off-pump surgery, he noted.

In a comment accompanying the paper [2], Dr Derek J Hausenloy (University College London, UK) Dr Domenico Pagano (University Hospital Birmingham, UK), and Dr Bruce Keogh (Heart Hospital, London, UK), say the Bristol researchers "provide reassuring evidence . . . that aprotinin use does not worsen postoperative renal function in this [on-pump CABG] group of patients."

The chequered past of aprotinin
The general opinion [when marketing was suspended] was that it was a shame, we wanted to have the aprotinin back on the market.

Aprotinin was approved for preventing perioperative blood loss and cutting the need for transfusions during pump-supported CABG surgery in high-risk patients. But it has faced a rocky ride since a phase 4 study by Mangano et al came out in early 2006 indicating that despite 13 years on the market, the drug appeared to increase the risk of serious end-organ damage, particularly renal failure.

The US FDA subsequently issued a public-health advisory alerting doctors to the higher risk of renal failure, MI, and stroke. Late in 2006, an FDA advisory panel ruled that aprotinin was safe if used as indicated, only to learn of additional data that might have swayed its decision. Meeting again a year later, in September 2007, the FDA panel once more recommended that aprotinin stay on the market, with stronger warnings.

Just a month after that, a large meta-analysis of randomized trials indicated that aprotinin did not raise the risk of death. But barely a week later, enrollment in BART was suspended after more patients receiving aprotinin died within the first 30 days of the trial, as compared with patients taking the other antifibrinolytics, epsilon-aminocaproic acid or tranexamic acid.

Bayer then made the decision to temporarily suspend marketing. However, in some markets, aprotinin is still available to doctors under certain circumstances. For example, in the US there is a special protocol to allow physicians to access the product during the marketing suspension and until final data from BART are evaluated [3].

"Once the complete BART database has been compiled, received, and evaluated, Bayer will work with the FDA and other health authorities to evaluate whether these data have any impact on the positive benefit/risk assessment for Trasylol. At that time, the temporary marketing suspension will be reevaluated," says the company.

Renal dysfunction almost tripled in off-pump CABG using ACE inhibitors, too

In the new study in Bristol, the researchers retrospectively analyzed their large institutional observational database and included 9106 patients undergoing on-pump or off-pump CABG from January 2000 to September 30, 2007. Zacharowski told heart wire that his institute "performs about 1500 to 1600 CABG per year, and we have some of the best outcomes in the UK. Also, our unit is unique in that we do, on average, 50% of procedures on-pump and 50% off-pump, so we are ideally placed to detect differences in the groups—for example, due to different treatments."

They separately analyzed the incidence of renal dysfunction in patients receiving aprotinin, tranexamic acid, or no antifibrinolytic in the presence or absence of perioperative ACE-inhibitor treatment for both on-pump and off-pump surgery. "We analyzed the use, or not, of ACE inhibitors, because in the past it has been suggested that ACE inhibitors may act synergistically with aprotinin in causing renal problems," Zacharowski explained.

On-pump, we found that aprotinin, with or without ACE inhibitors, doesn't make any difference, it's fine.

In 5434 patients undergoing on-pump surgery, the odds ratio for an increased risk of renal dysfunction for aprotinin without an ACE inhibitor was 1.81 (95% CI 0.79-4.13; p=0.162) and with an ACE inhibitor was 1.73 (95% CI 0.56-5.32; p=0.342). "On-pump, we found that aprotinin, with or without ACE inhibitors, doesn't make any difference, it's fine," Zacharowski commented.

But in the 848 patients taking ACE inhibitors and undergoing off-pump CABG, aprotinin was associated with a greater than twofold increase in the risk of renal dysfunction (OR 2.87; p=0.013).

"Our findings suggest that in the subgroup of patients taking ACE inhibitors and undergoing off-pump cardiac surgery, aprotinin might be associated with increased postoperative renal dysfunction," say the researchers.

Flawed research led to aprotinin suspension?

Both Zacharowski and the editorialists are critical of the research that seems to have led to the temporary suspension of aprotinin.

Zacharowski told heart wire that he is somewhat suspicious of the BART trial. "It's very hard to get information on this trial. But I've heard that some of the centers participating are operating on fewer than 300 patients per year, which by our standards is unacceptable. If you operate on fewer than 800 patients per year, your outcomes will be worse—it has nothing to do with the drug. You can't have a few centers that are operating on so few patients coming up with a result that influences the whole world."

Hausenloy, Pagano, and Keogh agree. "Interim analysis of 2163 patients [in BART] suggested that 30-day mortality was higher in patients given aprotinin than in those given either of the two other drugs. We had little information on the size of the increased risk associated with aprotinin in BART, although an FDA statement indicates that this effect did not reach conventional levels of statistical significance."

Zacharowski is also critical of the original New England Journal of Medicine paper that sparked the whole debate on aprotinin, by Mangano et al. "Looking back on that paper, it's not good, there are a lot of questions. For example, they just said 'transfusion with blood products' and did not define whether that was one unit, five units, or 10 units of blood. Well, the risk is exponential; the more blood the patient receives, the higher the risk. Our work showed that in patients getting on-pump surgery and receiving aprotinin—we don't see any problem with it."

Hausenloy, Pagano, and Keogh note that the limitations of the study by Mangano et al and a long-term follow-up study by the same author "have been addressed by our group and others."

Cardiac surgeons: Waiting for BART

"Would the BART trial have been stopped and aprotinin withdrawn had it not been for Mangano and colleagues' reports?" wonder Hausenloy, Pagano, and Keogh. "The outcome of the BART analysis will not be known for some time—will the results support or refute the findings of 64 randomized trials [that have shown that aprotinin is safe and effective]?

"While waiting for that analysis, the use of aprotinin in the US and in some European countries has been necessarily restricted, with the consequence that some high-risk cardiac patients having cardiac surgery might not receive optimum therapy," they state.

Zacharowski said many cardiac surgeons who can't get hold of aprotinin "are complaining. It's a huge problem for them. If it would come back, they would all welcome it very much, that's the major message."

He adds that in the meantime, many centers are now using alternative products such as epsilon-aminocaproic acid or tranexamic acid, "but no one has really shown that they are safe."

Editorialist Pagano has received an honorarium from Bayer. The authors of the paper and the other editorialists have no disclosures.


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