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NewsletterPRO: Aprotinin Use is Justified in All High-Risk Cardiac SurgeryPhilip E. Greilich, MD High risk cardiac surgery (redo, combined, transplants, mechanical assist devices) is associated with significantly greater blood loss than primary coronary revascularization and valve only procedures.1 The combination of profound coagulopathy (thrombocytopenia, platelet dysfunction, hyperfibrinolysis, coagulation factor and inhibitor deficiencies) and substantial hemostatic stress (reexploration through scar tissue, open cardiac chambers) are believed to be primarily causes for the increased blood loss observed in these patients. The use of a broad-spectrum protease inhibitor, like aprotinin, has been shown to reduce blood loss and transfusion requirements in patients undergoing high risk cardiac surgery.2-4 The demonstrated safety of aprotinin in high risk cardiac patients is the basis of Bayer's current FDA approval. Although aprotinin's use in valvular and transplant cases is widely accepted, early reports of higher venous graft occlusion rates still concern many surgeons. The risks of early graft occlusion (8-15%) with aprotinin must be viewed in the context of known early occlusion rates of (6-7%) without antifibrinolytic therapy.5 Furthermore any additional risk of graft occlusion that aprotinin may impart must be compared to known risks associated with transfusion of blood products4 and emergent reexploration.6 The risk of early venous graft occlusion in patients receiving aprotinin has been evaluated in several smaller and one large prospective trial (IMAGE).7 The data from the U.S. centers indicate that there were no significant differences in the overall early graft occlusion rates and myocardial infarction compared to patients not receiving any antifibrinolytic therapy. Although the data from this study also indicate that some patient (gender, vessel) and center-specific (volume, surgeon) characteristics could influence the occlusion rates, the relative risk associated with blood loss and transfusion of blood products must be kept in mind. The cost of aprotinin remains a significant issue. The cost:benefit analysis brings into focus several questions regarding minimum effective doses of aprotinin and use of less expensive antifibrinolytic therapy (lysine analogs).2-3 Proponents of lysine analogs have used a "macroeconomic" argument that suggests aprotinin's cost may not be justified.8 A more comprehensive understanding of the risks of using the lysine analogs and their relative cost effectiveness awaits additional study. In summary, current data indicate that aprotinin is a safe, effective, FDA-approved therapeutic intervention that decreases blood loss, transfusion of blood products and emergent reexploration in patients undergoing surgery requiring cardiopulmonary bypass. The risks of aprotinin are well characterized and suggest a clear benefit in reducing all causes morbidity in patients undergoing cardiac surgery that require blood transfusion. As such, aprotinin should be used in all high risk cardiac surgery patients.
References 1. Hardy JF, Trembley N, Robitaille D, Blain R, Carrier M. The stratification of cardiac surgical procedures according to use of blood products: a retrospective analysis of 1480 cases. Can J Anaesth 1991;38:511-7. 2. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: Metaanalysis using perioperative blood transfusion as an outcome. Anesth Analg 1997;85:1258-67. 3. Munoz JL, Birkmeyer JO, Birkmeyer JD, et al. Is epsilon aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery. Circulation 1999;99:81-89. 4. American Society of Anesthesiologists Task Force on Blood Component Therapy. Practice guidelines for blood therapy. 1996;84:732-747. 5. Goldman S, Copeland J, Moritz T et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy:results of a veterans administration cooperative study. Circulation 1988;77:1324-1332. 6. Moulton MJ, Creswell LL, Mackey ME et al . Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thor Cardiovasc Surg 1996;111:1037-46. 7. Alderman EL, Levy JH, Rich JB et al. Analysis of coronary graft patency after aprotinin use:results from the international multicenter aprotinin graft patiency experience (IMAGE) trial. 1998;116:716-30. 8. Bennett-Guerrero E, Sorohan JG, Gurevich ML et al. Cost-benefit and efficacy of aprotinin compared to epsilon-aminocaproic acid in patients having repeated cardiac operations: A randomized, blinded clinical trial. Anesthesiology 1997;87:1373-1380. CON: Aprotinin Use is Justified in All High-Risk Cardiac Surgery Elliott Bennett-Guerrero, MD Aprotinin has been demonstrated in several randomized clinical trials to decrease bleeding and the need for donor red blood cell transfusions in selected high-risk cardiac surgical procedures.1,2 It is not clear, however, if aprotinin should be used routinely in all "high-risk" cardiac surgery. Cost-effectiveness is an increasingly important issue. There is a marked difference in the average wholesale cost of aprotinin ($1080 full-dose, $540 half-dose) compared with synthetic antifibrinolytic agents (e.g. $11 for epsilon-aminocaproic acid). A multicenter double-blind clinical trial randomized 204 patients undergoing repeat median sternotomy to full-dose aprotinin or epsilon-aminocaproic acid (EACA).3 Although aprotinin therapy was slightly more efficacious, total bleeding related costs were significantly higher with aprotinin therapy, even taking into account the costs of blood and blood products, potential infectious disease transmission, operating room time, and even assuming the use of half-dose aprotinin. Although studies such as this one can help clinicians make an informed decision, additional factors should be taken into account. For example, it may not make sense to use aprotinin for routine "high risk" surgical procedures if you routinely order "prophylactic" blood products prior to discontinuation of CPB and reversal of heparin in these cases. It has been suggested that aprotinin may have additional effects (e.g., anti-inflammatory). To date, aprotinin has not been proven to confer additional benefits related to non-hematological complications, such as stroke. There is no evidence that aprotinin therapy reproducibly reduces hospital length-of-stay or duration of mechanical ventilation. Hence, it is unlikely that aprotinin reduces postoperative complications attributable to systemic inflammation. A final issue relates to the definition of "high-risk" patients. I place patients into one of three groups: Group 1 patients are at very high risk for bleeding (e.g., left ventricular assist device insertion) or would refuse life-saving blood products (e.g., Jehovah's Witnesses). I support the use of full-dose aprotinin in these patients, without regard for whether it is "cost-effective." Group 2 patients are at high risk for bleeding (e.g. repeat median sternotomy, endocarditis). It is reasonable to use aprotinin routinely in these patients under the assumption, however, that one is not concerned with cost-effectiveness. There is no convincing evidence that the less expensive alternatives (i.e., synthetic antifibrinolytic agents) are unsafe, cause stroke,4 or worsen graft patency. Group 3 patients are at slightly increased risk for bleeding (e.g. preoperative use of aspirin or heparin). I believe that the costs and risks associated with aprotinin therapy are not justified in these patients, especially given the alternatives. References 1. Levy JH et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation. 1995; 92:2236-44. 2. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth. 1992; 6:76-100. 3. Bennett-Guerrero E et al. Cost-effectiveness and efficacy of aprotinin as compared with epsilon-aminocaproic acid in patients undergoing repeat cardiac operation: A randomized, blinded clinical trial. Anesthesiology 1997; 87:1373-80. 4. Bennett-Guerrero E et al. Epsilon-aminocaproic acid administration and stroke following coronary artery bypass graft surgery. Ann Thorac Surg 1999; 7:1283-7. © Society of Cardiovascular Anesthesiologists Questions or comments? Please send email to webmaster@scahq.org |