February 1998

Cost-benefit and efficacy of aprotonin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial.
Bennett-Guerrero E, Sorohan JG, Gurevich ML, Kazanjian PE, Levy RR, Barberi AV, White WD, Slaughter TF, Sladen RN, Smith PK, Newman MF;
Anesthesiology 1997; 87:1373-80.
Commentary by Dr. Sladen

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[ see abstract below ]

Coagulopathy and bleeding continue to represent an important complication of cardiac surgery with cardiopulmonary bypass (CPB). Over the years, various theories emerged to explain the pathogenesis of CPB-induced coagulopathy. During the 1960's and 1970's it became routine in some centers to administer "prophylactic" platelets and fresh frozen plasma immediately following CPB in the belief that this would avert bleeding. In the 1980's there was a flurry of interest in the hemostatic powers of DDAVP (8-deamino-D-arginine vasopressin). Today, these approaches are considered archaic, wasteful and even dangerous. Although it is accepted that some platelet destruction and dysfunction is an established by-product of CPB, contact activation of fibrinolysis has emerged as the most likely proximate cause of bleeding after CPB.

In the late 1980's, David Royston and his colleagues in the United Kingdom serendipitously observed that aprotonin significantly decreased bleeding after CPB. Aprotinin (Trasylol ®) is a serine protease inhibitor which was used as an antiinflammatory agent in acute pancreatitis in the 1960's and 1970's. During CPB it appears to inhibit fibrinolysis by kallikrein inactivation (it is dosed in kallikrein inactivator units or KIU), and also spares platelet destruction. Given in high doses, aprotonin appears to decrease bleeding by anything from 30-50% from control subjects (1). Unfortunately, aprotonin has two major drawbacks. First, it is extremely expensive, and the per patient cost may be as much as $1200. Second, there is a rare but finite incidence of anaphylactic reactions to aprotonin, which increases the risk of repeat administration in individual patients.

For a number of years there has also been an interest in the peri-CPB hemostatic administration of simple antifibrinolytic agents such as epsilon aminocaproic acid (Amicar ®) or tranexamic acid. Initially used as a "last resort" for uncorrected bleeding after CPB, there are now considerable data indicating that the prophylactic administration of these antifibrinolytic agents decreases postoperative bleeding by about 20-30% (2). Although not as effective as aprotonin, epsilon aminocaproic acid and tranexamic acid are cheap (about $4 a vial) and not associated with anaphylaxis.

In the December 1997 issue of Anesthesiology, Bennett-Guerrero et al. posed the question: is the high cost of aprotonin justified by its superior hemostatic effect, compared with epsilon aminocaproic acid? In a multicenter study performed at Duke University, the University of Michigan and the Fundacion Favaloro in Buenos Aires, Argentina, they prospectively studied 204 patients undergoing repeated ("redo") cardiac surgery. Redo procedures were selected because of the inherently increased risk of postoperative bleeding.

In a blinded fashion, patients were randomized to receive either high-dose aprotonin or epsilon aminocaproic acid (EACA) as follows:

	APROTONIN	EACA
skin incision	2 million KIU	150 mg/kg
CPB prime	2 million KIU	saline placebo
CPB (over 4 hr)	2 million KIU	120 mg/kg
1996 Red Book cost	$1,080	$11

Red cell transfusions were administered if the hematocrit (Hct) was < 18% on CPB or < 25% after CPB, and platelets were given if the platelet count was < 100,000/mcL.

As expected, patients receiving aprotonin had significantly less bleeding than those receiving epsilon aminocaproic acid. But not by much: 511 mL vs. 655 mL (p = 0.016). Moreover, although the surgeon considered the field to be free of bleeding more often (44% vs. 26%, p = 0.012) and fewer platelet transfusions were required, there were no significant differences in red cell transfusions or the time required for chest closure.

When the median cost of aprotonin + required blood products was compared to that of epsilon aminocaproic acid + required blood products, the latter emerged as superior: $1,813 vs. $1,088 (p < 0.001). Even when a half-dose regimen of aprotonin (which has not been shown consistently to provide the same protection as a full dose regimen) was subjected to cost-benefit analysis, epsilon aminocaproic acid therapy remained more cost-effective.

What conclusions should we draw from these data and how should they affect our management of cardiac surgical patients? Bennett-Guerrero's study serves as an important reminder that the "cost" of any new drug should not simply be based on the acquisition cost alone, but also on its impact on measures of patient outcome. When aprotonin is used in redo cardiac procedures it provides superior hemostasis compared with epsilon aminocaproic acid. However, there is no difference in an important measure of outcome (red cell transfusion requirement and donor exposure) and its high cost does not appear to justify its routine use in redo procedures. Rather, these data suggest that its use should be confined to patients who have a particularly high risk of bleeding, or in whom (such as those with poor cardiac function) even a moderate amount of bleeding would be poorly tolerated. For most redo procedures, the administration of epsilon aminocaproic acid appears to provide adequate hemostasis at a substantially lower cost.

References:

1. Royston D: High dose aprotonin therapy: a review of the first five years experience. J Cardiothoracic Vasc Anesth 1992; 6:76-100.
2. Vander Salm TJ, Kaur S, Lancey RA et al. Reduction of bleeding after open-heart operations through the prophylactic use of epsilon-aminocaproic acid. J Thorac Cardiovasc Surg 1996; 112:1098-107.
3. Bennett-Guerrero E, Sorohan JG, Gurevich ML et al. Cost-benefit and efficacy of aprotonin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial. Anesthesiology 1997; 87:1373-80.

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ABSTRACT