05/21/2008- Results of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), halted by the company [Bayer] last year, have now been published online May 15, 2008 in the New England Journal of Medicine, scheduled for its May 29, 2008 issue, confirming that aprotinin (Trasylol, Bayer Healthcare Pharmaceuticals), an antifibrinolytic agent designed to reduce major bleeding during coronary artery bypass graft (CABG), significantly increased the risk of death as compared with tranexamic acid or aminocaproic acid [1]. Experts now say BART is likely "the end of the aprotinin story" [2].

As previously reported by heartwire, the trial's data safety and monitoring board halted the trial in October 2007 after identifying the increased deaths; in response, Bayer opted to temporarily suspend aprotinin marketing. In fact, the drug, approved in 1993, has been under scrutiny ever since a postmarketing study by Mangano et al came out in early 2006 indicating that aprotinin appeared to increase the risk of serious end-organ damage, particularly renal failure. A series of FDA panels had agreed to let the drug remain on the market prior to Bayer's voluntary suspension; however, many hospitals still had large quantities of aprotinin in stock, and physicians in many countries were still permitted to use the drug by applying through a restricted-access protocol reinstated by Bayer and the FDA in late 2007/early 2008.

According to BART investigators, led by Dr Dean A Fergusson (Ottawa Health Research Institute, ON), the risks of aprotinin far exceed its benefits. "Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin as compared with lysine analogs precludes its use in patients undergoing high-risk cardiac surgery."

In BART, investigators randomly assigned 2331 high-risk cardiac-surgery patients to aprotinin, tranexamic acid, or aminocaproic acid. Analyses after the termination of the trial showed that while the number of patients with massive bleeding was numerically smaller in the aprotinin-treated group, as compared with the other two groups, the 30-day mortality was more than 50% higher in the aprotinin-treated patients (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.06-2.22).

Bleeding and deaths in BART (HR [95% CI])

A cause-of-death analysis in 2328 patients suggested that death was from cardiac causes in 3.2% of aprotinin-treated patients, but only 1.3% and 1.7% were cardiac in origin in the tranexamic acid and aminocaproic acid groups, respectively. The hazard ratio for cardiac death in the aprotinin group compared with the other two groups combined was 2.19 (95% CI 1.25 - 3.84).

Rates of other adverse events, including organ failure, renal failure/dysfunction, myocardial infarction (MI), and stroke, were no different between the three groups.

In an accompanying editorial, Drs Wayne Ray and C Michael Stein (Vanderbilt University, Nashville, TN) suggest that one reason the aprotinin controversy dragged out as long as it did was because other trials of the drug used a placebo as the comparator. An even more likely explanation is the inherent problems of combining multiple trials that had not been designed to study mortality rates—many trials, they note, had no deaths in either aprotinin-treated patients or the control group.

As for mechanisms, Ray and Stein speculate that aprotinin may have been too effective as an antifibrinolytic, offsetting the procoagulatory/anticoagulatory balance; alternatively, aprotinin, as a nonspecific serine protease inhibitor, may have adversely affected vasodilation, inflammation, and response to angiotensin-converting enzyme inhibitors.

Importantly, while BART enrolled high-risk patients, there is no suggestion from the study that any one subgroup may have benefited from aprotinin, including younger patients or those without comorbidities.

As the editorialists observed: "The conventional wisdom has been that aprotinin was most beneficial in high-risk surgeries that were likely to cause increased blood loss. It is precisely in this population that BART provides convincing evidence as to the superiority of the lysine analogs."

At a press conference on the trial's findings, held by the Ottawa Health Research Institute, Fergusson said that the trial's findings don't address the safety of aprotinin in surgical patients who are lower risk than those enrolled in BART. But in the trial, outcomes were poorer with aprotinin in "the lower-risk of the high-risk patients. So it seems unlikely it will have a role in lower-risk heart-surgery patients. But we cannot definitely answer that."

Trasylol to be removed from pharmacies

Following publication of the BART study, Bayer notified the FDA of its intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses [3]. Access to Trasylol is now limited to investigational use of the drug under a limited-use agreement. That agreement allows treatment for certain patients who are at increased risk of blood loss and transfusions during CABG and who have no acceptable alternative therapy. Physicians using Trasylol in this situation must verify that the benefits of the drug clearly outweigh the risks for their patients.