Aprotinin associated with increased renal dysfunction, but not with increased cerebrovascular or cardiovascular events

Key Points

In a large cohort study published in the Journal of Thoracic and Cardiovascular Surgery, aprotinin was not associated with an increased risk of cerebrovascular events or myocardial infarction (MI) in patients undergoing cardiothoracic surgery. The study did, however, confirm the increased risk of renal dysfunction associated with aprotinin use.

This study follows 2 publications by the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation published in the Journal of the American Medical Association (JAMA) and the New England Journal of Medicine (NEJM), respectively, which suggested a link between aprotinin use during cardiothoracic surgery and negative postoperative outcomes including a 48% increased risk of death within the first 5 years after surgery and increased risks of renal, cardiovascular, and cerebrovascular events in the immediate peri- and postoperative periods. As a result of these and other studies, the aprotinin package insert was revised in December 2006 to strengthen the safety warnings for the drug and to limit aprotinin's use 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."

This most recent study retrospectively evaluated 3,348 patients who underwent cardiothoracic surgery (coronary artery bypass grafting [CABG] with or without valvular surgery) at a single US hospital between January 1, 2000, and December 31, 2005. The outcome measures evaluated in the study included the odds of experiencing an MI, a cerebrovascular event (including delirium, transient ischemic attack [TIA], or stroke), or renal dysfunction (defined as a doubling of serum creatinine or a new need for dialysis) before hospital discharge.

As demonstrated in the previous cohort studies, aprotinin was associated with an increased risk of postoperative renal dysfunction (adjusted OR=2.03; 95% CI, 1.37–3.01).

"It is not currently known whether the renal dysfunction seen with aprotinin reflects renal damage or a transient reduction in glomerular filtration pressure similar to that seen, for example, with angiotensin-converting enzyme inhibitors or receptor blockers," the authors stated.

According to the authors, a possible explanation for the differences between their study and prior analyses with regard to the risks for coronary and cerebrovascular events may be the lack of a celite-activated clotting time (ACT)-aprotinin drug interaction at their institution. A drug-lab test interaction occurs between aprotinin and celite-ACT that results in abnormally high ACT values, a result which may have led to heparin underdosing and more events in previous cohort studies.

It is estimated that >4 million patients worldwide have received aprotinin since 1985. Approximately 600,000 patients per year receive aprotinin to reduce blood loss and decrease the need for blood transfusions related to cardiothoracic surgery. Of these patients, nearly 250,000 undergo surgery in the United States.

SOURCES

Coleman CI, Rigali VT, Hammond J, Kluger J, Jeleniowski KW, White CM. Evaluating the safety implications of aprotinin use: The retrospective evaluation of aprotinin in cardio thoracic surgery (REACTS). J Thorac and Cardiovasc Surg. 2007;133:1547–1552.

Mangano DT, Miao Y, Vuylsteke A, et al; Investigators of The Multicenter Study of Perioperative Ischemia Research Group; 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 Eng J Med. 2006;354:353–365.

Aprotinin injection (marketed as Trasylol) information: FDA Alert. US Food and Drug Administration website. http:// http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm. Accessed June 7, 2007.