Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: yes

In cardiac surgery, older, more complex patients, often receiving anticoagulants and antiplatelet agents, pose a risk for significant bleeding and the need for allogeneic blood products [1,2]. Multiple approaches and pharmacologic agents have been reported to reduce bleeding and the need for allogeneic transfusions following cardiac surgery. Blood products incur costs and are associated multiple risks because of immune and non-immune complications [3–6]. Immune complications may produce acute inflammatory injury, including hypersensitivity reactions, transfusion related acute lung injury, and anaphylactic reactions. Even though blood products are routinely administered to treat bleeding, studies to document their efficacy are still forthcoming. The increasing off label use of recombinant factor VIIa in cardiac surgery is an important example of transfusion failures [7,8]. Nonetheless, we treat bleeding with blood components without well-designed studies proving transfusions are helpful or assessing their risk–benefit profile. Cardiac surgery and cardiopulmonary bypass (CPB) generate proinflammatory responses that can present as a systemic inflammatory response syndrome [9]. Hemostasis is also closely linked with inflammation [10,11]. Every patient following CPB manifests elements of disseminated intravascular coagulation with elevated D-dimers, thrombocytopenia with dysfunctional platelets, decreased antithrombin, and abnormal hemostatic tests [1]. Cardiac surgical patients represent a unique opportunity to treat prophylactically with pharmacologic agents that modify the inflammatory response [12]. Preventive strategies for reducing bleeding during cardiac surgery and CPB include administration of the lysine analogs such as epsilon aminocaproic acid (EACA) or tranexamic acid, or aprotinin (Trasylol ; Bayer, Leverkusen, Germany) [13]. Multiple meta-analyses including thousands of patients report preventive pharmacological therapies used to reduce bleeding and transfusions in cardiac surgery [13–17]. Aprotinin, a serine proteinase inhibitor, inhibits multiple proteases including plasmin, trypsin, kallikrein, chymotrypsin, activated protein C, and thrombin. Aprotinin has been studied extensively in cardiac [14,18–23], orthopedic [24], and hepatic transplant surgery [25]. Aprotinin is the only FDAapproved pharmacological treatment to reduce blood transfusion in coronary artery bypass grafting (CABG) associated with CPB. Multiple studies and meta-analyses of the randomized double-blinded clinical studies have reported the efficacy of aprotinin. However, studies are also important to determine safety as well as efficacy. One of the important adverse effects of aprotinin is anaphylaxis on re-exposure, with a risk of approximately 0.9% if re-administered after 6 months [26]. To summarize on three major meta-analyses of aprotinin and other agents, Levi et al. [15] reported aprotinin, as compared with placebo, decreased mortality almost 2-fold, the frequency of surgical re-exploration and allogeneic blood transfusions without increasing the risk of perioperative myocardial infarction (MI). From the Cochrane database, Henry et al. [16] reported in 61 trials (7027 patients) that aprotinin significantly reduced the need for re-operation and red blood cell (RBC) transfusion. In 18 trials, (n 1⁄4 1342), tranexamic acid reduced RBC transfusion by 34%, and four trials (n 1⁄4 208) EACA did not decrease in RBC transfusion. Eight trials made comparisons between tranexamic acid and aprotinin with no significant difference between the two drugs in RBC transfusions. However, in nine tranexamic acid trials and five EACA trials, re-operation for bleeding in patients treated with tranexamic acid, compared to control, was not significant. Henry reported that aprotinin was not associated with an excess risk of adverse effects, including thromboembolic events or renal failure, and noted safety data were not available for tranexamic acid and EACA. Sedrakyan et al. [14] evaluated clinical outcomes in 35 CABG trials (n 1⁄4 3879). Aprotinin was not associated with increased or decreased mortality, MI, or renal failure risk, but it was associated with a reduced risk of transfusions and stroke. Correspondence: J. H. Levy, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Road NE, Atlanta, GA 30322, USA. Tel: +1 404 778 3934; fax: +1 404 7785194; e-mail: jerrold.levy@ emoryhealthcare.org Journal of Thrombosis and Haemostasis, 4: 1875–1878