Hematological Agents

Description: Aprotinin is a proteolytic enzyme inhibitor obtained from bovine lung that has multiple effects on the coagulation system. Aprotinin is indicated for use during repeat coronary artery bypass graft surgery (CABG), when patients are likely to sustain excessive bleeding. It is useful during the initial surgery if there is an especially high risk of bleeding (e.g., impaired hemostasis, or pretreatment with aspirin or NSAIDs) or when transfusion is unacceptable or unavailable.[355] Use of aprotinin reduces the need for blood transfusion and its associated risks, and also allows for a clearer field of view during surgery. Aprotinin also inhibits clotting, although therapy with aprotinin does not replace heparinization. In January 2006, Mangano et al reported that in patients undergoing coronary artery bypass graft (CABG) surgery, patients who received aprotinin versus tranexamic acid, aminocaproic acid, or no treatment had a significantly higher risk of renal failure, myocardial infarction, heart failure, stroke, and encephalopathy.[8704] In addition, the risk of death over a 5-year period was increased in patients receiving aprotinin after CABG surgery vs. no treatment; in contrast, an increased risk of death was not demonstrated in patients receiving tranexamic acid or aminocaproic acid as compared to no treatment.[9946] Similarly, Karkouti et al reported that the use of aprotinin versus tranexamic acid was associated with a significantly increased risk of renal dysfunction in patients undergoing CABG.[8705] Furthermore, a contract research organization for Bayer conducted a comparative study of hospital data from 30,000 patients receiving aprotinin and 37,000 patients receiving other drugs; preliminary findings suggest that patients receiving aprotinin were at increased risk for death, kidney failure, congestive heart failure, and stroke. In 2006, several public health advisories were issued by the FDA recommending that physicians limit using aprotinin to those situations where the clinical benefit of reduced blood loss is essential to the medical management of the patient and its use outweighs any potential risks. If aprotinin is used, health care providers are advised to carefully monitor patients for renal, cardiovascular, or central nervous system toxicity. Any occurrence of toxicity should be reported to Bayer or the FDA MedWatch system. Aprotinin was originally approved by the FDA in December 1993; in December 2006, the indication for aprotinin was modified to limit its use to those patients who are at high risk for blood loss or blood transfusion. Furthermore, recommendations to minimize the risk of anaphylaxis and renal failure were made. In response to the update in labeling, Bayer has discontinued investigating aprotinin for use in patients undergoing spinal fusion surgery, pneumonectomy, esophagectomy for cancer, and cystectomy for bladder cancer.

Mechanism of Action: The precise mechanisms governing the action of aprotinin are unclear but involve many interrelated processes: Aprotinin directly affects fibrinolysis by (a) inhibiting the kallikrein-kinin system and (b) inhibiting plasmin-induced lysis of fibrin by reducing conversion of plasminogen to plasmin. Aminocaproic acid, another potent inhibitor of fibrinolysis, appears to exert its effects on formed plasmin. Aprotinin also decreases bleeding by stabilizing glycoproteins in the platelet membrane.[356] The release or synthesis of thromboxane A2, which in turn stimulates platelet aggregation, is also inhibited by aprotinin.[357] Thus, aprotinin also can decrease possible thrombotic events. Aprotinin inhibits superoxide production and the release of lysosomal enzymes from leukocytes. Aprotinin antagonizes lymphocyte activation.

When blood is subjected to extracorporeal circulation during cardiopulmonary bypass surgery, certain changes in normal coagulation and clotting properties take place. Smooth vascular circulation in vivo is maintained by secretions from normal vascular endothelium, which are disrupted when blood is circulated through an artificial environment. Clotting mechanisms that are activated through surface-media contact (during extracorporeal circulation) require the presence of Factor XII, prekallikrein, high molecular weight kininogen, and Factor XI. This activation increases thrombotic and fibrinolytic activity and is responsible for excessive bleeding. The hemostatic defects generated commence during CPB surgery and continue afterwards.

Pharmacokinetics: Aprotinin is delivered by IV infusion and is rapidly dispersed into extracellular space. Pharmacokinetics are linear over the dose range 50,000 KIU—2 million KIU (Kallikrein Inhibitor Units). Animal studies indicate that a large proportion of aprotinin accumulates in the kidneys. Aprotinin is filtered by the glomeruli followed by reabsorption in the proximal tubules to be stored in phagolysosomes. Proteolytic degradation slowly inactivates aprotinin. The plasma half-life of aprotinin reflects biphasic elimination; an initial half-life of about 65 minutes followed by a terminal elimination phase half-life of 12.16 hours was reported in preoperative cardiac surgical patients receiving aprotinin.[819]

•Special populations: The pharmacokinetics of aprotinin in patients with renal-function impairment have not been studied. The elderly with compromised renal function may have altered parameters, but no dosage amendment is suggested.

355. Royston D, Taylor KM, Bidstrup BP et al. Effect of aprotinin on need for blood transfusion after repeat open heart surgery. Lancet 1987:2:1289—91.

356. Blauhut LB, Gross C, Necek S. et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958—67

357. van Oeveren W, Harder MP, Roozendaal KJ et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788—97

819. Levy JH, Bailey JM, Salmenper� M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994;80:1013—8.

8704. Mangano DT, Tudor JC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353—65.

8705. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327—38.

9946. Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass surgery. JAMA 2007;297:471—9.

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Gold Standard, Inc. � 2007