Aprotinin under fire: Two new observational studies point to mortality risk

Shelley Wood

February 20, 2008

Boston, MA - More fuel for the aprotinin controversy this week: two large, observational studies appearing in the February 21, 2008 issue of the New England Journal of Medicine (NEJM) point to an increased risk of mortality in patients given the drug—used to reduce bleeding risk during CABG—as compared with patients given other drugs or no antifibrinolytic [1][2].

As previously reported by heart wire , aprotinin safety has been under scrutiny ever since a postmarketing study by Mangano et al [3] 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. A series of FDA panels have agreed to let the drug remain on the market, but its manufacturer, Bayer, opted to temporarily suspend marketing after enrollment in the BART study was halted in 2007 when the trial's data safety and monitoring board identified an increase in deaths among patients randomized to aprotinin. Many hospitals, however, still have large quantities of aprotinin in stock, and physicians in many countries are still permitted to use the drug if they apply through a restricted-access protocol reinstated by Bayer and the FDA in the past few months.

Both of the papers in the NEJM this week are in keeping with the findings of Mangano et al's paper, but not that of another large retrospective analysis published in the Lancet earlier this month by Dr Kai Zacharowski and colleagues (Bristol Royal Infirmary, UK) suggesting that aprotinin is safe during on-pump CABG but may increase the risk of renal dysfunction in people undergoing off-pump procedures and taking ACE inhibitors [4].

Increased deaths with aprotinin

In the first of the two studies published this week, Dr Sebastian Schneeweiss (Brigham and Women's Hospital, Boston, MA) and colleagues reviewed records from a database of roughly one-sixth of all US hospitals to compare in-hospital and seven-day outcomes in patients who received aprotinin vs those who received aminocaproic acid. They report that 4.5% of more than 33 500 aprotinin recipients died, vs 2.5% of 44 682 aminocaproic-acid recipients.

"The most important finding in our study was that the risk of in-hospital deaths among people using the aprotinin medication is 64% higher as compared with patients who received aminocaproic acid," even after adjustment for patient and hospital-related characteristics, Schneeweiss told heart wire .

In the second study, Dr Andrew Shaw (Duke University, Durham, NC) and colleagues looked exclusively at patients treated at Duke University Medical Center—a smaller cohort, but with a much longer period of follow-up than that of Schneeweiss et al's study. Shaw et al reviewed data on more than 10 000 patients treated between January 1, 1996 and December 31, 2005—13.2% of this group received aprotinin. Long-term survival, out to 10 years, among aprotinin-treated patients was significantly lower than that of patients treated with either aminocaproic acid or no antifibrinolytic agent. Aprotinin-treated patients had a 32% greater risk of dying than patients who received no antifibrinolytic therapy and a 27% increased risk as compared with patients taking aminocaproic acid. Survival curves separated early on, pointing to a high perioperative risk of aprotinin; however, survival differences remained significant over the follow-up period. Of note, the authors point out, "aprotinin therapy did not appear to reduce the need for transfusion. . . . Although this may simply represent residual confounding, it may also mean that the potential risks associated with aprotinin use are not outweighed by the potential benefits."

Worsening renal function

In both studies, aprotinin was also associated with an increased risk of renal problems: in the first study, aprotinin-treated patients were more likely to require dialysis than patients treated with aminocaproic acid. In Shaw et al's study, investigators measured percentage increase in serum creatinine levels, which Shaw described to heart wire as a much more sensitive measure of renal dysfunction than other studies have attempted. They found that while there was no significant difference in rates of dialysis in aprotinin-treated subjects—something Shaw puts down to lack of statistical power—these patients had significantly greater increases in serum creatinine levels.

"We think this is very important, because it's a much more sensitive way of detecting a decline in kidney function," he told heart wire .

"The three large published cohort studies—and I include ours, the Mangano paper, and the [Schneeweiss et al] paper that accompanies ours in the NEJM—seem to suggest that there is an association between the use of aprotinin and adverse outcomes," Shaw said. "It's important to stress that you can't prove a causal relationship between those two from observational studies; however, it does set the stage very clearly for the BART trial results that everyone is eagerly anticipating."

Asked about the Zacharowski paper showing a difference in off-pump vs on-pump treated patients, Shaw stated that his own group conducted an analysis to look for a difference in off-pump/on-pump patients at Duke, and the results were the same whether off-pump patients were included or not. He pointed out that the Zacharowski paper did not use as sensitive a marker of kidney function as his group did, which may have influenced the study results. More important, he said, "the fact that they seemed to be using the drug routinely in off-pump cases is an interesting observation in itself, in that off-pump cases are not typically associated with a high risk of bleeding, so it would be difficult to see the potential advantages of using the drug in those cases. . . . We don't tend to use the drug in off-pump cases here."

In response, Zacharowski told heart wire , "We obviously have a different opinion, because we think that patients undergoing off-pump surgery do have bleeding problems, so we would use aprotinin off-pump."

Controversy continues

These two new papers "are going to make things more controversial," Zacharowski acknowledged. He takes issue with the fact that neither paper looked adequately at patient subgroups.

"We are still using aprotinin at our center, but in every single patient in whom we are using it, it needs to be justified," he said, adding that both the anesthesiologist and the cardiac surgeon are involved in the decision to use the drug. "Based on our paper and our database here, we are continuing to use it, and we don't see anything in these two papers to convince us to do otherwise."

Zacharowski agreed, however, that there is more work to be done to understand aprotinin's role and safety profile. "Obviously there must be some reason why they are seeing an increase in mortality and we don't. I'm not sure what it is, but we will continue to work on this."

Dr Wayne A Ray, however, who wrote an editorial accompanying the NEJM papers [5], is less convinced that there is much room for continued debate. The halting of BART, combined with the results of three independent cohort studies, "will make it difficult, in the absence of convincing new data, to prescribe this drug, except perhaps in limited circumstances," he writes.

Schneeweiss disclosed receiving consulting fees from Ingenix ' s i3 Drug Safety unit, which was contracted by Bayer to study aprotinin in 2006. Others interviewed by heartwire disclosed no relevant conflicts of interest.

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