Aprotinin use during cardiac surgery: a new or continuing controversy?

Charles W. Hogue, MD* Martin J. London, MD† Excessive bleeding during and after cardiac surgery is a serious complication that exposes patients both to the risks of transfusion of blood products and to those associated with mediastinal re-exploration (1,2). Cardiac anesthesiologists and cardiac surgeons, have thus long sought pharmacologic means to reduce bleeding resulting from nonsurgical sources. Interest in these efforts was intensified in 1982 when the transmission of the human immunodeficiency virus by allogeneic blood transfusion was reported (1,3). The use of aprotinin for reducing blood loss has been of particular interest. This serine protease inhibitor has a long history of use in clinical medicine including its use in cardiac surgery as far back as in the 1960s (4–6). There was a resurgence of interest in aprotinin in the 1980s following the reports from the United Kingdom by Royston et al. (7,8) who demonstrated its blood-sparing effects during cardiac surgery. Favorable results from randomized, double-blind and placebo-controlled trials in the United States led to the approval of aprotinin by the Food and Drug Administration (FDA) in 1993 for patients undergoing re-operative coronary artery bypass graft (CABG) surgery or for those at high-risk for excessive bleeding (9). This approval was later extended to all CABG patients in 1998. The international cardiac anesthesiology and cardiac surgery communities now face a controversy regarding aprotinin after the publication of two reports suggesting a higher incidence of adverse events (e.g., renal, cardiovascular, and central nervous system) in patients who receive aprotinin. Mangano et al. (10) performed a retrospective analysis of 4374 patients enrolled in the Multicenter Study on Perioperative Ischemia Research Group international database. In that study, aprotinin use was associated with an increased risk of renal dysfunction (controls, 2% vs aprotinin group, 5%, P 0.001) and renal failure (controls, 1% vs aprotinin group, 5%, P 0.01) for patients undergoing primary CABG or complex CABG surgery. Renal dysfunction was defined as serum creatinine level in the first postoperative week, of at least 177 mol/L (approximately 2 mg/dL) or an increase from baseline of 62 mol/L. They also noted a 55% increase in the risk for myocardial infarction or heart failure and a 181% increase in risk for stroke or encephalopathy for patients undergoing primary CABG surgery who received aprotinin when compared with control patients. Karkouti et al. (11) performed a propensity score casecontrol comparison of 898 high-transfusion risk patients undergoing cardiac surgery who received either aprotinin or tranexamic acid. They found that aprotinin did not result in higher rates of myocardial infarction, stroke, or death. A greater percentage of patients receiving aprotinin developed renal dysfunction in the first postoperative week when compared with those receiving tranexamic acid (24% vs 17%, P 0.01). They defined renal dysfunction as a 50% increase in creatinine concentration to 100 mol/L in women or 110 mol/L in men, or the use of renal dialysis. Others have suggested that the combination of preoperative angiotensin converting enzyme inhibitors and intraoperative aprotinin increases the risk for elevation in creatinine after cardiac surgery (12). Preoperative angiotensin converting enzyme inhibitor therapy was not included in the reports by Mangano et al. (10) or Karkouti et al. (11). Two articles (13,14) in this issue of Anesthesia & Analgesia addressing From the *Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland; and †Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California. Accepted for publication July 27, 2006. Dr. Hogue has received honorarium for participation in continuing medical education programs indirectly sponsored by Bayer Corporation. Dr. London reports no conflicts of interest. Address correspondence and reprint requests to Charles W. Hogue, MD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, 600 North Wolfe St, Tower 711, Baltimore, MD 21287. Address e-mail to chogue2@ jhmi.edu. Copyright © 2006 International Anesthesia Research Society