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Scientific Debate
 Roland Demeyere is one of the founders of EACTA and has represented Belgium for many years. He organized the very successful EACTA congress in Leuven in 1996. Roland, working with cardiothoracic anaesthesia in Leuven, Belgium, has been in the front particularly in the clinical testing of new drugs. The use of aprotinin in cardiac surgery has been controversial, not because the efficacy is questioned but because of side effects and cost. There are other drugs that seem to work at a lower cost. Roland Demeyere is summing up the experience with this interesting drug.Email: Aprotinin is a protease inhibitor isolated from bovine lung tissue. It inhibits trypsin, chymotrypsin, plasmin, tissue plasminogen activator, kallikrein, elastase, urokinase and thrombin (1).The drug was first used in cardiac surgery in the early 1960’s when it was thought that excessive post-operative bleeding was due to increased fibrinolysis. It was not until the late 1980’s that prophylactic use was reported. Multiple studies support aprotinin’s efficacy to decrease blood loss and transfusion requirements in cardiac surgery and in other types of major surgery (e.g., liver transplantation) (2). This hemostatic action of aprotinin is related to its effects on fibrinolysis and on platelet dysfunction. Mechanisms of action. Direct inhibition of plasmin is the major mechanism of the antifibrinolytic effects of aprotinin, while inhibition of the contact activation system via kallikrein inhibition is involved to a lesser extent. Suggested mechanisms by which aprotinin preserves platelet function and numbers and decreases platelet dysfunction and activation are reduction of thrombin generation, preservation of platelet surface adhesive receptor glycoprotein (GP)Ib function, reduction of thromboxane A2 release and prevention of heparin-induced platelet dysfunction. Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the protease-activated receptor 1 (PAR-1), the major thrombin receptor on platelets. These recent findings argue against aprotinin being prothrombotic and suggest that aprotinin may have antithrombotic effects. PAR-1 and thrombin have a critical role in platelet aggregation and proinflammatory effects of thrombin are mediated by PAR-1 (3). The drug has been shown to substantially attenuate multiple markers of the kinin-kallikrein pathway and to reduce the complement system activation in patients following exposure to CPB. Bradykinin formation is reduced, neutrophil release of elastase is decreased. The drug is associated with reduction of leukocyte accumulation in the lungs of patients exposed to CPB - possibly through inhibition of leukocyte extravasation and transmigration across endothelial surfaces. Potentially beneficial effects of aprotinin include decrease in tumour necrosis factor, decrease in interleukin-6 (IL-6) and IL-8, increase in IL- 10, reduction in CD11b and increase in CD18. Thus, the drug may reduce the cell-mediated inflammatory response of platelets indirectly through effects on plasma proteases and directly through protease-activated receptors on platelets. Thus, in addition to its haemostatic properties the antiinflammatory effects of aprotinin are being increasingly recognized (4). Aprotinin decreases the activation of neutrophils, as demonstrated by reduced release of elastase, tumour necrosis factor and IL-8. Aprotinin reduced lung reperfusion damage after CPB, diminished postischemic myocardial dysfunction in dogs and reduced the frequency and incidence of stroke in patients receiving high dose aprotinin (5). Pharmacological aspects. Aprotinin has been produced by recombinant techniques by genetic engineering but the bulk of the drug is derived from bovine lungs coming from countries without known cases of bovine spongioform encephalitis (BSE). According to the manufacturer the production process has an extremely high capacity for the inactivation and removal of the BSE agent. The question of BSE should not be a major concern. The biological activity of aprotinin is expressed as kallikrein inactivator or inhibitory units. (1 mg equals 7143 KIU). After intravenous administration the plasma half-life of aprotinin is less than 1 hour. The calculated VD is 26.4L with a rapid distribution out of the vascular compartment. Elimination is almost entirely renal. Aprotinin is filtered by the kidney and metabolized in the proximal convoluted tubule. Hence the clearance of aprotinin may be reduced in patients with renal insufficiency or end-stage renal disease. Dose modification may therefore be indicated. Haemofiltration does not significantly alter serum aprotinin levels probably because of aprotinin binding to albumin. Aprotinin has also a stabilizing function in several biological tissue sealants. Effects of aprotinin. Aprotinin may have the potential of preventing clinical morbidity associated with SIRS in patients undergoing cardiac surgery with CPB (4). In a meta-analysis of all randomized, controlled trials of the three most frequently used pharmacological strategies to decrease blood loss, aprotinin, lysine analogues and desmopressin, Levi included a separate meta-analysis of studies concerning complicated cardiac surgery treatment with aprotinin. Mortality decreased almost two-fold compared with placebo (Odds ratio 0.55 [95% CI 0.34-0.90]) (9). Possible indications for use Aprotinin’s hemostatic effects have been most consistently demonstrated in patients undergoing second-time heart operations. Aprotinin reduced postoperative blood loss and the use of blood products. In studies where patients had received aspirin, aprotinin reduced blood loss 49-75% and transfusion requirement from 49 to 77% (7,8). Aprotinin has been associated with reduced incidence of stroke in adult cardiac surgery (5). Although it is not definitely established that aprotinin has independent strokereducing capacity, there might also be an indirect effect as shed blood is a major cause of neurologic insult. Lipid microemboli cause small capillary and arteriolar dilatations (SCAD’s) related to focal ischemic changes. In my opinion the use of aprotinin is justified in patients with high risk factors for perioperative bleeding during cardiac surgery. These include:
Dosage and Administration Protocol Different dosing regimen have been advocated. Due to possible anaphylactic reactions it is recommended that a test dose of 10.000 kallikrein inactivator units KIU (1.4 mg) should be given at least 10 min before the first administration. The high dose regimen (Hammersmith) consists of a loading dose of 2x106 KIU (or 280 mg) administered over 20 to 30 min at the start of operation followed by an infusion of 5x105 KIU/hr (70 mg) that is maintained throughout surgery. Further, 2x106 KIU (or 280 mg) of aprotinin is added to the pump priming fluid of the CPB circuit. The so-called low dose aprotinin is the same regimen with half the dosage (loading dose of 1x106 KIU (or 140 mg) followed by 2.5x105 KIU/h (or 35mg/h) by intravenous IV infusion plus 1x106 (140 mg) in the priming). The pump prime only regimen consists of aprotinin 2x106 KIU (or 280 mg) in the pump priming fluid of the CPB circuit only. Both the high and the low dose regimens of aprotinin are superior to placebo. The safety of the low-dose regimens remains in question (6). Lower doses of aprotinin seem to be associated with an increase in the frequency of MI, early graft failure and renal complications.The pump-prime-only dose is not recommended because of a possible association with more frequent myocardial infarctions. Aprotinin and ACT Aprotinin is known to elevate the activated clotting time (ACT) value, particularly the celite activated system. Consequently, the previously recognized ACT value of >400 to >450 seconds may not reflect adequate heparinization in patients treated with aprotinin. Aprotinin is by no means a heparin-sparing agent and there is a general agreement that heparin dosage should not be decreased. Aprotinin generally does not affect kaolin ACT, most likely because kaolin binds aprotinin. Initial reports that aprotinin increased thromboembolic complications in cardiac patients whose heparin administration was based on celite ACT protocols may be caused by inadequate anticoagulation. Current recommendations are to maintain the celite ACT at >750 seconds or the kaolin ACT at >480 seconds. Side effects and concerns related to coagulation Aprotinin may potentially lead to a hypercoagulable state caused by inhibition of plasmin, protein C or both. Because inhibition of protein C may more likely occur at plasma concentrations more than 250 KIU/ml, weight-adjusted dosing regimens should be considered, especially in smaller patients. On the other hand, the high dosage of aprotinin seems to have fewer prothrombotic complications. The better-preserved haemostatic system may also demand an earlier onset of postoperative anticoagulant or antiplatelet treatment in patients treated with aprotinin. Differences in circulating levels of ATIII of individual patients may also affect a patient response to aprotinin. Heparin affects circulating levels of ATIII. Preoperative heparin administration decreases ATIII activity and CPB reduces it further. The use of aprotinin in patients with factor V Leiden could cause extreme dysfunction of the protein C regulatory pathway and result in clinical thrombosis. Earlier reports of higher venous graft occlusion rates with aprotinin are still a concern. The results of initial reports indicating that aprotinin therapy may increase MI rates and mortality have not been supported by subsequent and more recent studies specifically designed to investigate this outcome (10). A large prospective study on coronary graft patency after aprotinin use was recently reported in the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial (11). The results varied between the participating centres. Aprotinin should not be used in patients with extremely diffuse coronary artery disease and in patients with deficiency in factor V Leiden or activated protein C abnormalities. Aprotinin is definitely not routinely indicated for the first-time CABG patient who is at low risk of bleeding.Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA) raised concerns about hazards associated with its use. Whether aprotinin causes thrombosis in patients undergoing DHCA remains uncertain. Excessive mortality and complication rates have only been reported in series in which the adequacy of heparinization is questionable. Aprotinin is taken up by the renal tubule. There have been concerns about its possible effects on renal function especially using CPB and DHCA. More data suggests the safety of high-dose apro- tinin. There is no convincing evidence to withhold aprotinin for cardiac surgery utilising DHCA (12). There seems to be agreement that administration of both aprotinin and tranexamic acid / epsilon-aminocaproic acid (EACA) should be avoided. Possible prothrombotic effect in the presence of catheters has also been reported. Anaphylactic reactions. Aprotinin is a polybasic polypeptide derived from bovine lung and possesses antigenic properties. Antibody production in human beings is likely to occur. Severe anaphylactic reactions after systemic aprotinin exposure in cardiac operations have been reported. The use of aprotinin in first-time cardiac operations is widespread in Europe. Since there is an increasing rate of re-operations, the risk of anaphylaxis is increased. In a meta-analysis of US controlled clinical trials including 2285 patients without prior exposure to aprotinin, the incidence of hypersensitivity or anaphylactic reactions was less than 0.1% while it was 2.8% after reexposure. Recently Dietrich (13) examined the incidence of anaphylactic reactions in 121 patients re-exposed to aprotinin with measurements of IgG and IgE anti-aprotinin antibodies. The incidence of anaphylactic reactions after aprotinin re-exposure during cardiac surgery was 2.5%. The risk of an anaphylactic reaction is apparently not only related to previous exposure to the drug but also to the timing of the previous procedure (13). It therefore seems reasonable to recommend that with a re-exposure interval of less than 6 months, aprotinin should be used with definite caution only in exceptional cases, such as in patients at high risk for bleeding expected to benefit clinically from treatment during cardiac surgery. Aprotinin should not be infused until the patient is prepared for the initiation of CPB to allow a rapid onset of CPB in case a cardiovascular collapse should occur. Quantification of anti-aprotinin IgG antibody concentrations may identify those more likely to develop an anaphylactic reaction to this drug. The preoperative SC Prick-test and intradermal (ID) tests are not sensitive enough to predict the risk of adverse aprotinin reactions. Repeated applications of aprotinin should therefore be avoided and its use should be reserved for major high-risk operations. Conclusion. The question is not the efficacy of the drug - but determination of where the benefit justifies the potential risk and the cost of its use. In my opinion, based on current information, the benefit of aprotinin in reducing blood loss and inflammation in selected patients outweighs the risks and the costs involved in its use. Other antifibrinolytic agents like tranexamic acid and e-amino-caproic acid (EACA) may be effective but aprotinin is the drug that is best studied. In comparison with tranexamic acid, aprotinin was shown to negate the usual positive effect of CPB time on chest tube blood loss (14) Aprotinin is an expensive drug and the drug cost for aprotinin greatly exceeds the price for the lysine analogues. Despite the high cost, several studies have shown aprotinin to be cost-effective due to a decrease in the use of blood products, reduction in use of OR time, and shorter ICU and hospital stay (15). Careful evaluation of the risk-benefit potential to the individual patient is needed. Aprotinin is not indicated for the first-time CABG patient with a low risk of bleeding. References 1. Davis R, Whittington R. Aprotinin: a review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995; 49: 954- 83 2. Porte RJ, Molenaar IQ, Begliomi B et al.from the EMSALT Study Group. Aprotinin and transfusion requirements in orthotoptic liver transplantation: a multicenter randomised double-blind study. Lancet 2000;355:1303-1309 3. Pouillis M, Manning R, Laffan M, et al. The antithrombotic effect of aprotinin: actions mediated via the protease-activated receptor 1. J Thorac Cardiovasc Surg 2000;120: 370-8 |
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