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Safety Concerns About Aprotinin

Prompted by troubling observational findings, the FDA has issued a public health advisory about aprotinin use in coronary-artery surgery.

Concerns about bleeding associated with elective coronary-artery surgery have led to the widespread use of lysine analogues (aminocaproic acid and tranexamic acid) and serine protease inhibition (with aprotinin; Trasylol) to reduce bleeding risk. However, safety concerns about these agents persist.

Now, in a multinational, nonrandomized, prospective study not sponsored by industry, researchers studied 4374 patients (80% men) scheduled for coronary-artery surgery with cardiopulmonary bypass: 1295 received aprotinin, 883 aminocaproic acid, 822 tranexamic acid, and 1374 no antifibrinolytic treatment (control). Outcome analyses, in which controls served as the reference group, were adjusted for multiple potential confounders, including patients’ likelihood of receiving antifibrinolytic treatment.

Aprotinin — but not aminocaproic acid or tranexamic acid — was associated with significantly increased risks for death (2.8%, vs. 1.3% of controls), renal events (5.5% vs. 1.8%), cardiovascular events (20.4% vs. 13.2%), and cerebrovascular events (4.5% vs. 1.6%) among the 69% of patients who underwent primary surgery (elective surgery that involved only coronary-artery revascularization or angioplasty). Among the 31% of patients who underwent other revascularization procedures (i.e., complex surgery), aprotinin — but not the other antifibrinolytic treatments — was associated with significantly increased risk for renal events. In the overall cohort, recipients of high-dose aprotinin were especially likely to experience adverse renal and cardiovascular events. Blood loss was significantly lower in each treatment group than in the control group.

Comment: Use of aprotinin was associated with increased risk for several types of adverse outcomes after coronary revascularization. This observational study is limited by apparent lack of adjustment for study site and lack of stratification of patients by whether they eventually underwent surgery or angioplasty. Still, the data raise significant concerns, enough to prompt an FDA public health advisory that warns about potential toxicity from aprotinin and suggests using it only when "the clinical benefit of reduced blood loss is essential to medical management . . . and outweighs the potential risks." The advisory also cites a recent observational study in the journal Transfusion showing increased renal toxicity associated with aprotinin use in cardiac surgery. FDA evaluation is ongoing.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology March 9, 2006

Citation(s):

Mangano DT et al. for the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006 Jan 26; 354:353-65.

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