Aprotinin Versus Lysine Analogues: The Debate Continues

Aprotinin Versus Lysine Analogues: The Debate Continues David Royston, MD Department of Cardiothoracic Anesthesia, Harefield Hospital, Harefield, England

The decision to use any pharmacologic intervention inevitably rests on balancing the efficacy and safety of the intervention. The advent of the acquired immunodeficiency syndrome epidemic greatly increased awareness of transfusion-related illnesses and focused attention on methods to prevent the need for blood and blood products. This has led, especially in the last decade, to increased use of drugs to help reduce perioperative bleeding. This chapter focuses on the lysine analogues and aprotinin as the serine protease inhibitor currently available in clinical practice. Both groups of compounds have recently shown promise in reducing surgical bleeding. However, the reader will notice that none of these agents are new; they have all been available for more than 30 years. What is new is their use in preventing bleeding. We therefore have considerable knowledge regarding the safety of these compounds. The first part of this review will compare the actions of these two types of agents on the processes related to thrombosis, hemostasis, and fibrinolysis. This is followed by a comparison of the efficacy of each intervention and any dose-response relationship. This section highlights the reported reduction in postoperative bleeding with both classes of agent.

There is, however, no obvious or consistent reduction in the transfusion of blood and blood products in patients given lysine analogues. In contrast, there is a consistent reduction in the need for blood transfusions in patients given aprotinin therapy. The next major section will discuss the evidence to suggest that these drugs may, because of their known effects on the processes related to inflammation, hemostasis, and cellular repair, contribute to an improvement or worsening of outcome after cardiac operations. In particular, this section focuses on the antiinflammatory actions and modifications in vascular tone associated with aprotinin therapy. These effects may be related to improved outcome in patients by reducing the incidence of permanent neurologic deficit or stroke after heart operations, as well as inhibiting pulmonary vascular hyperreactivity and hypertension in susceptible individuals. Finally, this brief review discusses the safety issues that have been raised in regard to each of these classes of agents, specifically problems associated with abnormal renal function, hypersensitivity reactions, and thrombotic complications. (Ann Thorac Surg 1998;65:S9 –19) © 1998 by The Society of Thoracic Surgeons

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inhibition of fibrinolysis. Once a fibrin surface has formed, fibrinolysis is activated with the generation of plasmin. Plasmin can escape from its fibrin-binding site fairly easily, and therefore a mechanism exists to neutralize this enzyme. The body’s naturally occurring inhibitor is a2-antiplasmin or a2-plasmin inhibitor (a2-PI), which has a number of properties related to inhibition of site-specific activation. In particular, it is now well recognized that if free plasmin is found in the circulation, then a2-PI will react and neutralize it with a time constant of approximately 0.01 second. This is the fastest enzyme/ inhibitor reaction found thus far in the universe. Free plasmin is a digestive enzyme and will degrade a number of intravascular proteins, including clotting factors. In contrast to this extraordinarily rapid inhibition of free plasmin, if this enzyme is generated in its normal position on the fibrin strand via the action of tissue plasminogen activator (t-PA), then the naturally occurring antiplasmin will only slightly inhibit this process. This natural inhibitor therefore has little if any action on bound plasmin; indeed, the time constant for this reaction is greater than 5 minutes. It is therefore apparent that a2-PI is a powerful inhibitor of free plasmin (associated with “pathologic” fibrinolysis) but does not act as an

he decision to use any pharmacologic intervention will depend on the efficacy and safety of the drug relative to the situation for which it will be used. The two groups of agents commonly used to prevent bleeding associated with cardiac operations are lysine analogue antifibrinolytics, either e-aminocaproic acid (EACA) or tranexamic acid (AMCHA), and serine protease inhibitors, notably aprotinin. This presentation will compare the efficacy and safety of these drugs for use in patients undergoing open heart operations with cardiopulmonary bypass (CPB).

Mechanism of Action There is considerable difference between the mechanism of action of lysine analogues and that of serine protease inhibitors in relation to how they affect hemostasis and clot lysis. Of particular relevance is their role in the Presented at the Fifteenth Annual Symposium: Clinical Update in Anesthesiology, Advances in Techniques of Cardiopulmonary Bypass, Acapulco, Mexico, January 21, 1997. Address reprint requests to Dr Royston, Department of Anesthesia, Harefield Hospital, Harefield, Middlesex, England UB9 6JH.

© 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

0003-4975/98/$19.00 PII S0003-4975(98)00071-X

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Fig 1. Effect of a2-plasmin inhibitor (alpha 2 PI) on tissue plasminogen activator (t-PA) clot lysis (top) and induced bleeding (bottom). (Graphs have been drawn based on data from Weitz et al [1].)

antifibrinolytic agent for “appropriate” or “physiologic” fibrinolysis (Fig 1) [1]. a2-Plasmin inhibitor does, however, have an interesting effect on the hemostatic process. Administration of t-PA produces an increase in both the amount and duration of bleeding from cut wounds. Administration of a2-PI inhibits this process and returns the duration and quantity of skin bleeding toward normal values (see Fig 1) [1]. This site specificity of a2-PI ensures that hemostasis will be maintained and physiologic or appropriate clot lysis will not be prevented. Aprotinin and the serine protease inhibitors act in the same way as the naturally occurring inhibitor to rapidly inactivate free plasmin but have little effect on bound plasmin when t-PA was used to induce fibrin breakdown. Separate studies have shown that clot lysis induced by t-PA is not significantly inhibited in the presence of high doses of aprotinin (Fig 2) [2]. Nonetheless, and as found with a2-PI, the hemostatic defect induced by t-PA (prolonged and increased bleeding from cutaneous wounds) is inhibited in the presence of high doses of aprotinin (see Fig 2) [3, 4]. Aprotinin’s effect on functional fibrinolysis has been demonstrated in patients before, during, and at the conclusion of CPB [5]. Although aprotinin decreased fibrinolytic activity throughout the procedure, the increased lytic activity observed at the end of bypass was not inhibited by the presence of aprotinin. These data support the concept that in physiologic terms aprotinin is not an antifibrinolytic agent but will improve the hemostatic defect associated with excess fibrinolytic activity. The mode of action of the lysine analogue antifibrinolytics is in complete contrast to the actions of plasmin inhibitors. The lysine analogues are designed to prevent excessive plasmin formation by mimicking lysine, fitting into plasminogen’s lysine-binding site and thus preventing the binding of plasminogen to fibrin.

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Fig 2. Effect of aprotinin on tissue plasminogen activator (t-PA) clot lysis (top) and induced bleeding (bottom). (Data for clot lysis are from Fears et al [2] and data for bleeding times from de Bono et al [4].)

It is thus not surprising that results from animal studies similar to those described above, but using lysine analogue antifibrinolytics, contrast with those achieved with plasmin inhibitors (a2-PI or aprotinin). The lysine analogues had no effect on t-PA–associated bleeding (Fig 3) [4]. Indeed, there is evidence to show that more chronic administration of these agents is associated with an increase in the bleeding time. For example, administration of EACA for 3 to 7 days was associated with a twofold increase in duration of bleeding [6, 7]. As expected, and unlike the natural enzyme inhibitors, EACA acts primarily to inhibit t-PA–induced fibrinolysis (see Fig 3) [2].

Fig 3. Effect of the lysine analogues tranexamic acid and e-aminocaproic acid on tissue plasminogen activator (t-PA)-induced bleeding (top) and clot lysis (bottom). (Data for bleeding times are from de Bono et al [4] and clot lysis data from Fears et al [2].)

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These differences in the mechanisms of action between aprotinin and the lysine analogues may also explain certain of the data related to reported thrombotic events in patients to whom these agents have been administered. This aspect is discussed more fully later.

Comparative Efficacy The efficacy of any pharmacologic agent will exhibit a dose-response effect. In the United States, the Food and Drug Administration asks for data regarding safety and efficacy and always requires a “no-effect” dose to be specified. It is assumed that with increasing dosage there will be increasing benefit until a plateau is reached. With the majority of chemical entities, the higher the dose, the greater the likelihood of a toxic effect, and this will define the upper-dosage limit. Dose response for efficacy can be demonstrated for aprotinin by analysis of the data provided in the package insert for Trasylol (Bayer Corporation, West Haven, CT; data on file) and obtained from placebo-controlled, randomized, double-blind studies conducted in patients in North America [8, 9]. Efficacy to reduce perioperative blood loss (Fig 4) and the need for blood-product transfusions (Fig 5) against the total administered dose of aprotinin follow a tight relationship. However, this relationship was defined from multicenter studies and thus may not be predictive for any one center or specific surgeon. The data for drains losses showed that the pump-prime-only regimen was not of significant benefit in reducing total drains [9]. This dose can thus be considered the “no-effect” dose. The so-called half-dose had statistically significant benefits compared with control losses and transfusion requirements, which were further increased with the increased dosage. In addition, these data suggest that the plateau for efficacy has not been achieved with the doses studied thus far, and my personal practice is to further increase the recommended dose in higher-risk patients to enhance this improved efficacy.

Fig 4. Relationship between total aprotinin dose and postoperative drains loss (mL/h) for patients enrolled in randomized, double-blind, placebo-controlled studies of aprotinin use in reoperations conducted in North America. Doses of aprotinin are 0 mg (placebo patients; n 5 156), 280 mg (pump-prime dose; n 5 68), 420 mg (half Hammersmith dose; n 5 113), and 840 mg (full Hammersmith dose; n 5 143). The line was derived by regression analysis. (Data on file, Bayer Corporation.)

Fig 5. Relationship between total aprotinin dose and total bloodproduct transfusion (units) for patients enrolled in randomized, double-blind, placebo-controlled studies of aprotinin use in reoperations conducted in North America. Doses of aprotinin are 0 mg (placebo patients; n 5 156), 280 mg (pump-prime dose; n 5 68), 420 mg (half Hammersmith dose; n 5 113), and 840 mg (full Hammersmith dose; n 5 143). The line was derived by regression analysis. (RBC 5 red blood cells.) (Data on file, Bayer Corporation.)

Analysis of dose response for the lysine analogue agents is confounded by a lack of truly placebocontrolled, randomized, double-blind studies. However, recently a number of reports in the literature have summarized the efficacy of AMCHA in total doses ranging from about 0.5 mg to 20 mg [10 –20]. When the results from these studies are pooled together, an analysis of AMCHA dose versus chest-tube drainage does not demonstrate a dose-response effect. Above a total dose of 1.5 g of AMCHA, a 20% to 30% reduction in drains losses can be anticipated compared with an untreated population [11]. This reduction in drains losses was not further enhanced by increasing dosage in other studies. In addition, studies by Horrow and colleagues [11] also failed to show any benefit of the reduction in drains losses in relation to the transfusion requirements of their patients. Unfortunately, an analysis for blood and blood-product transfusion—similar to that for aprotinin therapy and the Philadelphia group—is more difficult, as many of the additional reports provide no records of the amount of blood or products given to the patients but simply report the proportion of patients who received transfusions. These data, again, show an absence of a dose-response effect. Despite any supporting efficacy data, or any comparison with a lower-dose administration, the most commonly used total dose of AMCHA in recent reports is about 10 g. Analysis of the most recent reports in the literature on the efficacy of this dose [15–17, 19, 20] show wide variability (75% to 30%) in blood and blood-product requirements in patients not treated with AMCHA. The transfusion-sparing effects of AMCHA were also variable, from no effect in one report [16] to a two-thirds reduction in the need for blood products in another [17]. Significantly, the greatest effect was seen in the center with the lowest basal or control transfusion rates. In patients in whom the transfusion trigger is higher, there is less or no significant benefit in AMCHA use. This impression is confirmed by other studies using EACA. In particular, Daily and colleagues [21] noted a significant benefit for EACA on transfusion requirements in their patients. With a transfusion trigger of a hemato-

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crit of 21%, only about 25% of their control population received donor blood. This was reduced to about 10% in patients receiving therapy with EACA. This reduction is in keeping with the AMCHA-related data, where intentto-transfuse hematocrit was reported to be between 18% and 22%. Where a more conservative transfusion trigger of 11 g/dL was used, as suggested in one study from Minneapolis [22], all patients received red blood cells with or without EACA therapy. It is therefore easy to see, in regard to efficacy, that with aprotinin the higher the dose, the more benefit to the patient in terms of reduced bleeding and transfusion requirements. With the lysine analogues, a relatively small dose will produce an effect to reduce drains losses. The only benefit to the patient in reducing the amount of blood and blood products given is if one’s current practice is to treat patients as one would a Jehovah’s Witness patient, ie, allow significant anemia.

Nonhemostatic Drug Actions Serine protease enzymes are fundamental to all the hemostatic and inflammatory processes that occur in the plasma of higher animals. A basic rule of mammalian biochemistry is that for every enzyme there is a cognate inhibitor, and, therefore, serine protease inhibitors are present in all plasma and tissue fluids. One of these inhibitors, found throughout the whole of the natural animal kingdom, is aprotinin. It is therefore not surprising that aprotinin is able to modify and manipulate a vast number of processes involved in hemostasis and the inflammatory response.

Action of Aprotinin on Neutrophil Function The potential for aprotinin to modulate the inflammatory response may be of benefit in reducing the unwanted side effects of CPB. The white blood cell can produce tissue injury by several mechanisms: (1) occlusion of the microvasculature by abnormal clumping of the cells, (2) release of cytotoxic products, and (3) a reperfusion injury in association with unblocking of the capillary as the white blood cells unclump. Vascular occlusion will be potentiated by (1) vasoconstriction and (2) an increase in the expression of adhesion molecules on the surface of the white blood cell.

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Fig 6. Effect of aprotinin on vascular reactivity of coronary artery bypass grafts. (5-HT 5 5-hydroxy tryptamine.) (Data from Allen et al [24].)

Serine protease inhibitors such as aprotinin may also indirectly affect vascular tone by inhibition of the conversion of arachidonic acid to potent constrictors such as thromboxane. Reductions in the concentration of the stable metabolite thromboxane A2 are known to be produced with aprotinin therapy [25].

Direct Effects on Neutrophils Adhesion of neutrophils to the endothelium is promoted by specific adhesion molecules on the surface of both of these cell types. A number of these adhesion molecules on both the endothelium and the white blood cell have been well categorized. Some are expressed at all times on the cell surface; the expression of others can be upregulated by stimuli associated with open heart operations, eg, hypoxia, hypothermia, and cytokine release. A growing body of evidence shows that aprotinin use can inhibit the expression and activity of these adhesion molecules, thereby preventing white blood cells from becoming sticky and binding to the endothelium [26, 27]. A study [28] investigating the transit of white blood cells through filters (used to represent the capillaries of the body) showed that after open heart operations with CPB, the cells were less deformable and became stuck or held up in the filters. This effect was still seen at 6 days postoperatively. Aprotinin therapy, in high dose but not half dose, was able to inhibit this activity to allow normal white blood cell traffic (Fig 7).

Release of Cytotoxic Products Activated white blood cells secrete cytotoxic products such as oxygen-derived free radicals and proteases. The

Occlusion of the Microvasculature by Abnormal Clumping of the Cells Rapid, large-dose administration of aprotinin is associated with a small but significant decrease in blood pressure in humans [23]. Recent data from our laboratory at Harefield Hospital in the United Kingdom have shown that aprotinin has a direct dilating effect on preconstricted conduits used for bypass procedures such as the human saphenous vein (Fig 6) [24]. This ability of aprotinin to reduce vascular tone, particularly if infused rapidly, may have deleterious effects in patients in whom the maintenance of coronary perfusion is deemed important, eg, those with severe aortic stenosis or left main stem lesions.

Fig 7. Effect of high-dose aprotinin on blood cell filterability in association with cardiopulmonary bypass. (Data from Liu et al [28].)

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Fig 8. Action of aprotinin to reduce lipid peroxidation products during cardiopulmonary bypass in humans. (AoXC 5 aortic crossclamp; TBARS 5 thiobarbituric acid reactive substances.) (Data from Royston et al [29].)

cytotoxic action of activated neutrophils on the endothelium is reduced about threefold in the presence of aprotinin therapy [27]. This protective effect is similar, but of slightly greater magnitude, to that measured for the naturally occurring serine protease inhibitor a-1antitrypsin [27]. Other studies [29] also demonstrated that tissue injury, measured as lipid peroxidation products (ie, the products of oxidation of membrane lipids after free-radical attack), is increased during periods of CPB and this increase was prevented with aprotinin therapy (Fig 8). Neutrophils will also release proteolytic enzymes, of which elastase is the one most commonly implicated in tissue injury. Aprotinin will inhibit elastase in vitro at high concentrations [23], and earlier clinical studies suggested a reduction in elastase activity in patients having open heart operations with high-dose aprotinin [30]. However, subsequent studies have not been able to reproduce these original results [31, 32]. At present, there is no evidence to support the view that aprotinin is able to inhibit the release of potent proteolytic substances such as elastase at concentrations used during CPB. These actions of serine protease inhibitors, such as aprotinin, would suggest that administration of these compounds might reduce the effective bactericidal activity of the neutrophil and may thus compromise the patient. However, this concern appears not to be borne out by observations from other studies. Studies with human white blood cells have demonstrated that the process of phagocytosis is accelerated in the presence of the protease inhibitor FOY (gabexate mesilate) [33]. Observations of the white blood cells of patients having major vascular operations show that the ability of the neutrophil to migrate toward a chemoattractive stimulus is impaired. However, this important white blood cell function was preserved in the white blood cells from patients who received aprotinin therapy [34]. Of more interest was the observation in this study [34] that aprotinin therapy had no effects on the reduction of nitroblue tetrazolium (an index of free-radical production) in the resting state but augmented this action when the neutrophil was stimulated. This implies that aprotinin therapy increased the production of oxygen-free radicals into the phagosome of the neutrophil after stimulation. This is opposite to the effects of aprotinin predicted from the studies on free-radical activity discussed above.

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This conflict has been partially resolved by studies from Japan showing that in the presence of a serine protease inhibitor there was reduced surface free-radical activity together with a significant increase in activity in the neutrophil phagosome when these inhibitors were present [35, 36]. The precise mechanism by which this occurs is unknown at present. Overall these data suggest that administration of protease inhibitors will reduce the deleterious effects of white blood cells stimulated by the foreign surface of the bypass circuit during cardiac operations. However, and at the same time, the phagocytic and bactericidal functions of the neutrophil are enhanced and accelerated.

Can Aprotinin’s Antiinflammatory Actions Translate Into Improved Function Outcome? The above evidence suggests that serine proteases can modify the inflammatory response to CPB. However, the important question to address is whether these biochemical actions can translate into benefits in terms of organ or tissue function and patient outcome. The ability to produce vascular dilation may also be of benefit in regard to certain vascular beds by increasing organ and tissue perfusion. Included in this section, therefore, is discussion of studies investigating the possible role of improved organ perfusion, either as a direct action of the drug under study or by preventing inflammation and possible reperfusion injury. A number of studies have looked specifically at the effect of aprotinin on tissues and organs after a period of ischemia and reperfusion.

Myocardial Performance Studies focusing on the myocardium have shown reduced tissue injury. Myocardial perfusion and blood flow were also improved after a period of ischemia with aprotinin therapy [37]. This effect was associated with greater contractility, as shown by the rate of change of left ventricular pressure, and reduced evidence of myocardial injury, as shown by reduced creatine kinase-MB release. Human studies have suggested that outcome is improved after acute myocardial ischemia in patients treated with aprotinin [38, 39]. There are no data on the effects of lysine analogues on myocardial recovery after ischemia.

Pulmonary Circulation Respecting the pulmonary vascular bed, studies show that pulmonary hypertension and elevated transpulmonary pressure gradients are reduced with aprotinin therapy, both in pediatric operations associated with singleventricle palliation such as bidirectional Glenn shunt or Fontan procedures [40] and in heart transplantation in adults (Fig 9) [41]. A study of implantation of left ventricular assist devices showed significant reduction in the need to use a right ventricular assist device at the same time, which may be related to the action of aprotinin to reduce abnormally high pulmonary vascular tone [42].

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Fig 9. Action of aprotinin to reduce mean pulmonary artery pressure (PAP) and improve pulmonary and right heart function in patients during the posttransplantation period (A) and during operation for single ventricle palliation (B). (Data from Prendergast et al [41] [A] and from Tweddel et al [40] [B].)

Splanchnic Circulation Improved renal perfusion after open heart operations was shown as an increase in sodium and free-water clearance in the immediate postbypass period [25]. Creatinine clearance was also higher in patients given aprotinin therapy in the early postoperative period [43]. These early benefits may convert to later biochemical abnormalities, as discussed below.

Cerebral Circulation The use of lysine analogue antifibrinolytic agents in patients with subarachnoid hemorrhage is associated with an increase in mortality and morbidity due to the development of cerebral vasospasm and ischemia [37, 44, 45]. This is in contrast with the vasodilating effects of aprotinin and other serine protease inhibitors that have been advocated as a therapy to improve outcome after subarachnoid hemorrhage [46 – 48]. The concept that aprotinin can potentially reduce the incidence of stroke after cardiac operations came from studies in the United Kingdom [49]. In a 1993 report [49], my colleagues and I delineated the efficacy and safety of aprotinin therapy in high-risk cardiac surgical procedures. More than 400 patients undergoing reoperations and nearly 80 who had septic endocarditis at the time of their operation were included in this report. The incidence of stroke of less than 0.5% was in striking contrast with the expected 2% to 3% reported by other studies in which aprotinin had not been administered [50 –52]. This observation has been confirmed by data pooled from multicenter double-blind, placebo-controlled trials of the safety and efficacy of aprotinin conducted in North America [53]. Approximately a quarter of the patients were undergoing reoperations and about 90% were having coronary artery bypass grafting only. Data from these studies (1,721 patients in total) show that 2.4% of patients in the control group suffered stroke. This was reduced to 1.0% of patients with high-dose aprotinin therapy [53]. This reduction achieved statistical significance (p 5 0.027). This improvement in cerebral outcome may not be principally related to improved perfusion. For example, cerebral edema was reduced after aprotinin therapy after a prolonged period of ischemia in an animal model, with a preservation of adenosine diphosphate and adenosine triphosphate [54]. Similar data showed preservation of

cerebral high-energy phosphates in an animal model of CPB and profound hypothermic circulatory arrest [55]. The lack of randomized, prospective studies investigating the use of lysine analogues in similar groups of cardiac patients prevents a comparative analysis of the incidence of stroke between the two different pharmacologic therapies. The data available for AMCHA report a control stroke incidence of 1.1% in these studies [11–13, 15–17, 19, 20]. This is less than half of that from other large series of patients reported over the same period from multicenter studies, such as that of the Veterans Administration [56] or the Perioperative Ischemia Research Group [50], or those from single large centers [51, 52].

Areas of Concern Relating to Lysine Analogues and Aprotinin The lysine analogues and aprotinin have different chemical, pharmacokinetic, pharmacodynamic, and safety profiles. Three specific unresolved areas of concern relating to the differing mode of action of these drugs in patients undergoing open heart operations are effects on the kidney, risks associated with drug reexposure, and risk of an acute thrombotic event.

Kidney and Renal Function Early studies with aprotinin use in patients reported an increase in creatinine clearance, free water, and sodium clearance in the first 12 to 24 hours after operation [25, 43]. Despite this apparent benefit, there is also a body of evidence suggesting that there is a biochemical abnormality implying an altered renal function some 3 to 5 days after the procedure, with an increase in plasma creatinine level at that time. Typically, plasma creatinine values are within the normal range but are about 0.5 mg higher in aprotinin-treated patients than in placebotreated patients [57]. This rise in creatinine level is not associated with, or dependent on, the baseline creatinine concentration, nor is it associated with any deleterious event or need for renal support with dialysis. Examination of data from all patients enrolled in efficacy and safety studies of aprotinin therapy in North America have shown no overall effect of aprotinin on plasma creatinine concentrations [53]. Nonetheless, data reported after insertion of a left ventricular assist device

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with aprotinin therapy show a significant rise in creatinine concentration outside the normal range, without any concomitant change in the blood urea nitrogen level or increase in morbidity or early mortality in these patients [42]. It may be that this rise in creatinine level is unrelated to alterations in renal function but may reflect the action of aprotinin on other aspects of creatinine metabolism, eg, muscle injury [58]. Whatever the mechanism, this aspect requires further investigation. This is especially the case with more recent preliminary data suggesting that the pharmacokinetics of aprotinin may be altered in patients with dialysis-dependent renal failure [59]. The effect of lysine analogues on renal function in association with cardiac operations has been less well categorized. There have been reports of acute renal failure [60] and severe proteinuria [61] associated with the use of EACA. Similar articles caution against the use of such agents because of the potential renal toxicity profile [62]. Indeed, AMCHA is excreted predominantly via the kidney, and the package insert and product information that is approved by the Food and Drug Administration highlight this caution and recommend that the AMCHA dose administered be reduced if preoperative renal dysfunction exists. More recent studies have suggested that EACA is associated with a significant increase in excretion of b2 microglobulin, a protein linked to specific tubular injury and damage [63]. This effect is also noted after administration of aprotinin, although the raised excretion was not statistically significant [64].

Hypersensitivity Responses The published evidence concerning hypersensitivity and anaphylactic reactions to the lysine analogue antifibrinolytics is sparse [65, 66]. In contrast, there have been a number of reports of cardiovascular effects when highdose aprotinin has been administered. Hypersensitivity reactions are rarely reported in patients with no prior exposure to aprotinin. In the recent literature, three reports of large numbers of patients treated with highdose aprotinin suggest that the incidence of hypersensitivity reactions, varying from minor skin rashes and minor changes in blood pressure to true anaphylactic reactions, is between 0.3% and 0.6% [49, 67, 68]. These figures approximate those anticipated with use of muscle relaxants [69] or synthetic volume replacement [70] during cardiac operations. Four case reports in the literature discuss severe cardiovascular collapse after aprotinin administration [71– 74]. However, careful study of these reports would suggest that only one was a true anaphylactic reaction [73]; the other three may have been the result of incorrect administration of the drug [71, 72, 74]. A worrisome aspect of these reports is that it would appear that the manufacturer’s instructions to administer a small (1 mL) test dose were not followed, as the major cardiovascular collapse was reported as having occurred after the administration of 200 mL, 75 mL, and 50 mL of the aprotinin loading dose, respectively [71, 72, 74]. It is well recognized in the literature from the 1960s that rapid infusion

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Table 1. Abnormal Clot Formation Associated With Hemostatic Drug Therapya Thrombus Site (main organ affected) Lysine analogues Liver Brain Brain Brain Renal artery Brain Skin Central venous catheter Pulmonary artery catheter Aorta/circulation Cardiac chambers Aprotinin Pulmonary artery catheter Vein grafts Vein grafts Aortic cannula

Study

Year

Tytgat et al [82] Scott and Garrido [76] Fodstad and Liliequist [77] Hoffman and Koo [78] Tubbs et al [79] Tanghetti et al [80] Brooke et al [81] Hayhurst [89] Dentz et al [83] Hocker and Saving [84] Prah et al [85]

1971 1977 1979 1979 1979 1985 1992 1983 1995 1995 1995

Bohrer et al [87] Cosgrove et al [43] Umbrain et al [86] Gitter et al [88]

1990 1992 1994 1996

a

Anecdotal reports suggest abnormal clot formation is more widespread by organ or system with lysine analogues than the focused problems reported with aprotinin therapy.

of aprotinin can produce vasodilation [23]. This is particularly important in the presence of prior vasoconstriction, or in patients with critical coronary stenosis or an ischemic myocardium. Precautions to avoid rapid administration of large volumes of aprotinin should be taken, in line with the practice for administering other drugs used for induction and maintenance of anesthesia in this high-risk group of patients. There are, however, reports of true anaphylactic reactions to aprotinin on readministration to patients who have had a definite prior exposure. The overall incidence in the most recent report from Germany was estimated to be 2.5% [75]. The vast majority of the patients had received aprotinin within 3 to 6 months of their first exposure, and the incidence in this subgroup was 5.0%. The incidence of anaphylaxis after a guaranteed reexposure to the drug with a time frame greater than 6 months fell to 0.9%. Certain precautions should be taken in the management of patients requiring repeat operations within 3 to 6 months after the first operation and in whom aprotinin therapy is indicated. The test dose of aprotinin solution, and therefore the loading-dose administration, should be delayed either until the sternum has been reopened or until conditions for rapid cannulation are present, thus ensuring rapid heparinization and the institution of CPB if a severe cardiovascular problem occurs. Other authors suggest the use of steroids, prophylactic antihistamine therapy, or both before the test dose. The relative benefits of these strategies have yet to be proved.

Thrombotic Episodes It is not surprising that the majority of reports of thrombotic complications have been anecdotal. Reports of

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Table 2. Focused Studies of Effects of Aprotinin on Graft Patency After Myocardial Revascularization Control Study

Year Occluded

Bidstrup et al [49] Havel et al [93] Lemmer et al [8] Lass et al [94] Kalangos et al [92]

1993 1994 1994 1995 1994

Total

Aprotinin

Total

Occluded

Total

4 3 8 13 1

138 40 163 74 139

5 5 14 8 2

131 81 176 97 270

29

554

34

755

thrombotic episodes in patients receiving lysine analogue antifibrinolytics cover a wide range of vascular beds, although the cerebral circulation predominates (Table 1). Notwithstanding this, there is increasing literature, probably related to the increasing use of these agents, showing that abnormal clot formation can occur in any organ or tissue [76 – 82] as well as in association with indwelling vascular catheters [83– 85]. In contrast with this broad spectrum of clinically relevant clot formation in a variety of tissues and organs, current literature shows that with aprotinin therapy reported problems are confined to native and grafted myocardial blood vessels [43, 86] and to indwelling catheters [87, 88]. The true incidence of catheter-related thrombosis is unknown. Nonetheless, a number of studies have used techniques such as echo diagnosis and have suggested up to 30% of all catheters will show some evidence of thrombosis formation. This also appears to apply to catheters that are heparin-coated or bonded. There have been a number of reports of catheter-associated thrombosis when both aprotinin [87] and the lysine analogue antifibrinolytics [83, 89] have been used. Why should this be? The most likely answer was suggested in the review by Youngberg [90]. He argued that thrombus formation became apparent to the clinician as the prior administration of a drug with a potential antifibrinolytic action made the thrombus more adherent to the catheter. It is obvious that plastic catheters do not have a covering of endothelium. If a thrombus forms in this situation then (unlike the intact vascular system) natural fibrinolytic agents such as t-PA are not released from the endothelium by the action of thrombin at the site of fibrin formation. In this situation, the prior administration of a lysine analogue will inhibit any lytic activity as discussed in the first section of this article. This action has been demonstrated, again in animals, with a twofold increase in thrombus weight gain on an intravascular wire in animals that received EACA [91]. As also discussed previously, with aprotinin therapy there is less likelihood of an antiplasmin action to inhibit t-PA–induced fibrinolysis. However, there may be a tendency to inhibit the conversion of the precursor of urokinase to its active form. In this way, aprotinin may also inhibit the process of clot lysis at this site. In relation to cardiac operations, a recent report detailing the efficacy of EACA therapy in patients undergoing

myocardial revascularization specifically noted that the surgeons observed clot formation of a greater magnitude and frequency before the period of CPB when the internal mammary artery was being taken down [22]. e-Aminocaproic acid has no known procoagulation effect, and this observation must therefore imply that clot formed during tissue trauma was not being broken down at the normal rate. This observation follows the known pharmacology of this lysine analogue. In contrast, most observers have noted that the “dry field” with the protease inhibitors is associated with reduced clot formation. This reflects the natural anticoagulant and improved hemostatic action of aprotinin therapy. Thus far, focused studies [8, 49, 92–94] of the effects of aprotinin on graft patency after myocardial revascularization have not shown any consistent detriment attached to its use (Table 2).

Summary Therapy with aprotinin or the lysine analogues is associated with a reduction in postbypass drains losses. Only aprotinin therapy has shown to have consistent proven benefits in the reduction of blood and blood-product transfusions. The lysine analogue agents may be of benefit in this regard only if the patient is allowed to become profoundly anemic. Aprotinin therapy has other major pharmacologic actions to reduce the inflammatory response to the period of extracorporeal circulation and operation. In particular, the ability to reduce the incidence and severity of pulmonary hypertension and reduce the inflammatory actions to the heart and brain is in direct contrast with the lysine analogues. Aprotinin has antigenic potential, and special care should be taken if the drug is readministered to a patient within 6 months after the first exposure. The effects of aprotinin on renal function are complex, and there is a need to investigate further the significance and possible prevention of the rise in plasma creatinine level that occurs in patients who have received aprotinin therapy.

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