Aprotinin has demonstrated a 48% increase in the risk of 5-year mortality following coronary artery bypass graft (CABG) surgery, according to a study published in the Journal of the American Medical Association (JAMA).

"Our study, assessing the long-term safety of antifibrinolytic agents, demonstrated that aprotinin— but not amino-caproic acid or tranexamic acid— is associated with an increased risk of death during the first 5 years following surgery," the authors stated.

In a previous study published in the New England Journal of Medicine (NEJM), aprotinin use during CABG surgery was associated with a 2.5-fold risk of renal dysfunction, a 55% increase in the risk of coronary heart disease, and a 181% increase in the risk of stroke.

As a result of the earlier study, the labeling for aprotinin was revised in late 2006 to strengthen its safety warnings and to limit the drug's approved usage to "patients who are at increased risk for blood loss and blood transfusion in association with cardiopulmonary bypass in the course of coronary artery bypass grafting."

The most recent study involved a large observational cohort of 3,876 patients who underwent CABG surgery at 1 of 62 medical centers in North or South America, Europe, or Asia between November 1996 and December 2006. The primary objective of this analysis was to compare the rate of survival at 5 years among patients receiving any of the 3 antifibrinolytic (blood-sparing) agents and among patients who did not receive any of these agents.

Aprotinin use was associated with a statistically significant increased risk of mortality (20.8% incidence of death over 5 years) compared with no antifibrinolytic agent use (12.7% incidence over 5 years; adjusted HR=1.48; 95% CI, 1.19–1.85; P<.001). Neither amino-caproic acid (15.8% incidence over 5 years; adjusted HR=1.03; 95% CI, 0.80–1.33; P=.81) nor tranexamic acid (14.7% incidence over 5 years; adjusted HR=1.07; 95% CI, 0.80–1.45; P=.64) was associated with increased mortality compared with no antifibrinolytic therapy. The association between aprotinin and an increased risk of death was also observed in subgroup analysis of patients with diverse risk profiles and surgical factors.

It is estimated that >4 million patients worldwide have received aprotinin since 1985. Based on the apparent increase in the rate of mortality with aprotinin compared with either aminocaproic acid or tranexamic acid (approximately 1% absolute increase per year over 5 years), the authors stated: "In 2006 alone, had aprotinin been replaced with either of these generic agents, we estimate that approximately 2,000 deaths per year for the next 5 years (or 10,000 total deaths) might have been avoided."

SOURCES

Mangano DT, Miao Y, Vuylsteke A, et al; for the Investigators of The Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA. 2007;297:471–479.

Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group;Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006;354:353–365.

Aprotinin injection (marketed as Trasylol) information: FDA Alert. Food and Drug Administration website. Available at: http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm. Accessed March 1, 2007.