Trasylol use discouraged after link to MI and stroke

Last Updated: 2006-01-25 17:00:10 -0400 (Reuters Health)

By Anthony J. Brown, MD

NEW YORK (Reuters Health) - Physicians should no longer use aprotinin (Trasylol) to reduce bleeding during cardiac surgery, as the drug appears to markedly raise the risk of MI, stroke, and renal failure, according to the authors of a report in The New England Journal of Medicine for January 26.

In an interview with Reuters Health, lead author Dr. Dennis T. Mangano likened the potential scenario with Trasylol, produced by Bayer AG, to what happened with Vioxx, Merck's COX-2 inhibitor that was pulled from the market in September 2004 after being tied to MI and stroke.

"It's a Vioxx 2, but it's a little bit different," Dr. Mangano, from the Ischemia Research and Education Foundation in San Bruno, California, said. "The frequency of (adverse) events we see is far greater with (Trasylol) than with Vioxx. The other thing that is disturbing is that the drug has been in use for 13 years and a million patients have received it. Why am I coming along now and finding these results and why haven't they been found before?"

Dr. Mangano noted that there was one study, in 1998, that did uncover risks with the drug, but the findings were dismissed. "That trial proved that aprotinin was associated with thrombosis, increasing the risk by about 40%." However, with various statistical analyses, which should never have been applied, he explained, the significant association disappeared. As a result, "the drug was never questioned in a regulatory way."

In the current study, which Dr. Mangano called "the biggest investigating aprotinin", 4374 cardiac surgery patients who received aprotinin, aminocaproic acid, tranexamic acid, or no agent were prospectively evaluated. The subjects included 3013 who underwent primary surgery, defined as elective surgery involving only coronary artery revascularization or angioplasty, and 1361 who underwent more complex procedures.

Among patients undergoing primary surgery, use of aprotinin raised the risk of MI or heart failure by 42%, stroke, encephalopathy or coma by 115%, and renal dysfunction or failure by 134% relative to treatment with no agent (p < 0.05 for all). By contrast, neither aminocaproic acid nor tranexamic acid was tied to significantly elevated risks.

In the complex surgery group, aprotinin use raised the risk of renal events by 159% (p = 0.004), but did not have a significant effect on the risks of cardiovascular and cerebrovascular events.

All three agents were comparable in their ability to reduce blood loss and significantly better than no treatment, the report shows.

As to why aprotinin might have a different side effect profile than the other agents, Dr. Mangano explained that aminocaproic acid and tranexamic acid are formally antifibrinolytic agents, whereas aprotinin has additional properties and is classified as a serine protease inhibitor. In animal studies, aprotinin had been shown to have renal effects that the other two drugs did not, he added.

"I think this study will affect use of aprotinin," Dr. Mangano said. "Because there are safer, far less expensive alternatives available, if, in the face of this study, you elect to give aprotinin and a patient develops renal failure, it will be very difficult to defend your actions from a medicolegal standpoint."

In a statement released to Reuters Health, Bayer AG commented that the present findings "are not consistent with the more than 15 years of clinical data and experience Bayer has amassed on this drug." The group emphasized that "double-blind, randomized controlled trials are the accepted standard for the assessment of the efficacy and safety of drugs and serve as the basis for approval of all new drugs. Such trials do not suffer from the limitations that can exist in observational studies."

Anticipating that Bayer might criticize the observational nature of his team's study, Dr. Mangano "said that once you have an embedded practice with a drug you cannot easily do a randomized trial to assess drug safety." He added that "he expects Bayer to put up a battle. You don't get a $600 million per year drug, well on its way to a blockbuster, and give it up easily."

In a related commentary, Dr. David Hunter, a statistician from Harvard School of Public Health in Boston, notes that observational studies may provide "the only source of evidence on the side effects of drugs" and calls the research by Dr. Mangano's team "the type of study that may be a model for the future." He goes on to list several reasons why observational studies may be better suited to uncovering side effects than randomized trials.

The present study "stands as an example of the importance of phase 4 clinical trials," Dr. Gus J. Vlahakes, from Massachusetts General Hospital in Boston, notes in an accompanying editorial. "Although the FDA can mandate the post-approval gathering of data, vendors are given the task of designing the subsequent clinical trials." He adds that "this conflict of interest creates a disincentive to fully explore the safety of a drug in various patient populations."

N Engl J Med 2006;354:329-331,353-365,413-415.