Bayer has temporarily stopped marketing Trasylol. Source: www.dbtechno.com

A hemostatic agent commonly used during coronary-artery bypass grafting may cause twice as many deaths than other less expensive alternatives, according to two studies in the Feb. 21 New England Journal of Medicine. A commentary on the studies, however, calls into question the methodology used by the FDA to approve the drug and the design of subsequent studies to determine the drug’s efficacy. 

Trasylol, or aprotinin, was approved by the FDA in 1993 for reducing blood loss during CABG. By 2006, aprotinin was prescribed for approximately 200,000 patients undergoing cardiac surgery worldwide.

In October 2007, a large Canadian study comparing aprotinin with aminocaproic acid or tranexamic acid during cardiac surgery was stopped due to an increase in mortality in the first 30 days for the aprotinin group. Bayer subsequently suspended the worldwide marketing of aprotinin, pending a full review of trial data.

Other cohort studies and meta-analyses have not fared well for aprotinin.

The Canadian study, “coupled with the increased mortality associated with aprotinin use in three independent cohort studies, will make it difficult, in the absence of convincing new data, to prescribe this drug, except perhaps in limited circumstances,” according to an accompanying commentary by Wayne A. Ray, PhD, from the Vanderbilt Center for Education and Research on Therapeutics.

In the short-term follow-up study, Sebastian Schneeweiss, MD, ScD, from the division of pharmacoepidemiology and pharmacoeconomics, and colleagues at Harvard Medical School conducted an analysis – commissioned by Bayer – to retrospectively examine the association between aprotinin use and the risk of serious in-hospital events and to compare it with other anti-bleeding agents.

Researchers, who drew their study cohort from the Premier Perspective Comparative Database, a national repository, found that in all, 4.5 percent of the 33,517 aprotinin recipients and 2.5 percent of the 44,682 aminocaproic acid recipients died.

After adjustment for 41 characteristics of patients and hospitals, researchers found the estimated risk of death was 64 percent higher in the aprotinin group than in the aminocaproic acid group. The average follow-up period was 7.6 days in the aprotinin group and 8.2 days in the aminocaproic acid group.

Researchers also found that postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid.

In the long-term follow-up study, Andrew D. Shaw and colleagues in the departments of anesthesiology and surgery at Duke University Medical Center retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at their institution.

A total of 13.2 percent of patients received aprotinin, 66.8 percent received aminocaproic acid, and 20 percent received no antifibrinolytic therapy.

The overall mortality of those followed for 30 days was 2.9 percent. Of those, 6.4 percent received aprotinin, compared with 2.4 percent who received aminocaproic acid and 2.2 percent who were given no antifibrinolytic therapy.

The overall mortality of those followed for one year was 7.6 percent. Of those, 15.8 percent were in the aprotinin group, 6.4 percent the aminocaproic acid group, and 6.5 percent the no-therapy group.

At each time point, the difference between the percentage for the aprotinin group and that for each of the other two groups was significant, whereas the difference between the percentages for the aminocaproic acid group and the no-therapy group was not.

Shaw and colleagues also found that patients who received aprotinin had larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

In his commentary, Ray cited problems with various types of confounders in many studies of aprotinin. The two studies above reinforce this concern, he said. The cases in which aprotinin was given were more complicated than those in which another (or no) agent was given, and the relative-risk estimates decreased after adjustment for measured covariates.

He also said that premarketing testing leaves many important questions unanswered because of the frequent reliance on comparison with placebo (as in the case of aprotinin) and the limited numbers of patients studied.

Even around the time of aprotinin’s introduction, concerns were raised about adverse prothrombotic and renal effects, and some experts suggested that aminocaproic acid was a better therapeutic choice, Ray said.

“Nevertheless, there was no requirement for more definitive information on infrequent but serious complications, survival after surgery, and performance relative to then-available alternatives,” he added.

He concluded that head-to-head comparative trials with alternative therapies, powered for important clinical end points, are needed before the drug is routinely prescribed for large numbers of patients.

“The manufacturer cannot be relied on to perform these studies voluntarily, because they frequently serve no commercial purpose,” he said.