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Aprotinin

An Update of its Pharmacology and Therapeutic Use in Open Heart Surgery and Coronary Artery Bypass Surgery

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Summary

Abstract

Cardiopulmonary bypass (CPB) is associated with defective haemostasis which results in bleeding and the requirement for allogenic blood product transfusions in many patients undergoing open heart surgery (OHS) and/or coronary artery bypass graft surgery (CABG) with CPB. Conservation of blood has become a priority during surgery because of shortages of donor blood, the risks associated with the use of allogenic blood products and the costs of these products.

Aprotinin is a serine protease inhibitor isolated from bovine lung tissue which acts in a number of interrelated ways to provide an antifibrinolytic effect, inhibit contact activation, reduce platelet dysfunction and attenuate the inflammatory response to CPB. It is used to reduce blood loss and transfusion requirements in patients with a risk of haemorrhage and has clear advantages over placebo or no treatment.

High dose aprotinin significantly reduces postoperative blood loss compared with aminocaproic acid and desmopressin, and decreases transfusion requirements compared with desmopressin. Results are less consistent with tranexamic acid: high dose aprotinin either reduces blood loss significantly more than, or to an equivalent level to, tranexamic acid. A variety of other lower aprotinin dosage regimens consistently result in similar reductions in blood loss to aminocaproic acid or tranexamic acid.

Data from clinical trials indicate that aprotinin is generally well tolerated, and the adverse events seen are those expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity reactions occur in <0.1 to 0.6% of patients receiving aprotinin for the first time. The results of original reports indicating that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to investigate this outcome. However, a tendency to early vein graft occlusion with aprotinin has been shown and care with anticoagulation and vessel grafts is required. No comparative tolerability data between aprotinin and the lysine analogues, aminocaproicacid and tranexamic acid, are available.

Conclusion: Comparative tolerability and cost-effectiveness data for aprotinin and the lysine analogues are required to more fully assess their individual rolesin reducing blood loss and transfusion requirements in patients undergoing CPB during OHS and/or CABG. However, clinical evidence to date supports the useof aprotinin over its competitors in patients at high risk of haemorrhage, in those for whom transfusion is unavailable or in patients who refuse allogenic transfusions.

Pharmacodynamic Properties

Aprotinin is a serine protease inhibitor which dose-dependently inhibits human trypsin, plasmin and kallikrein. In patients undergoing cardiopulmonary bypass (CPB), aprotinin has been shown to prevent plasmin-mediated fibrinolysis and inhibit the contact activation system via kallikrein inhibition, preserve platelet surface adhesive receptor glycoprotein (GP)Ib function and attenuate heparin-induced platelet dysfunction, and display anti-inflammatory and antioxidant effects. The antifibrinolytic effects of high dose aprotinin (see Dosage and Administration summary), as measured by reductions in D-dimer levels, are less than those of tranexamic acid, similar to those of aminocaproic acid and superior to those of desmopressin. Aprotinin has anti-inflammatory effects equivalent to methylprednisolone (1g before CPB) in patients undergoing CPB.

Pharmacokinetic Properties

Aprotinin cannot be administered orally because of gastric inactivation. Mean plasma aprotinin concentrations reported previously were 37 to 47 mg/L at the beginning of CPB and 26 to 27 mg/L at the end of CPB after administration ofhigh dose aprotinin (see Dosage and Administration summary). These concentrations are adequate to suppress plasmin throughout the procedure. As well, a more recent trial found high dose aprotinin produced concentrations needed to inhibit kallikrein throughout surgery.

After intravenous administration, aprotinin is rapidly distributed into theextracellular compartment, and plasma aprotinin concentrations then decrease biphasically. Distribution and elimination half-lives are 0.32 to 0.50 hours and 5.25 and 8.28 hours for the 2 phases, respectively.

Aprotinin is filtered by the glomeruli but then actively reabsorbed by the proximal tubules and gradually metabolised in the kidney. Approximately 25 to 40% of a single intravenous dose of 131I-labelled aprotinin was measured in the urine of healthy volunteers within 48 hours of administration. Aprotinin clearance was substantially reduced, and the elimination half-life and area under the plasma concentration-time curve increased in 2 patients with chronic renal impairment who received 140mg by intravenous infusion over 30 minutes. However, renal impairment did not affect peak plasma aprotinin concentrations or distribution half-life.

Therapeutic Use

The clinical efficacy of aprotinin has been evaluated in patients undergoing open heart surgery (OHS) and/or coronary artery bypass graft surgery (CABG), including those undergoing repeat sternotomy and those receiving aspirin. It has been compared with untreated controls and placebo as well as the lysine analogues tranexamic acid and aminocaproic acid, and the vasopressin analogue desmopressin.

An evaluation of comparative efficacy is difficult because dosage regimens of all active treatments vary between studies. However, high dose aprotinin (see Dosage and Administration summary) significantly reduces postoperative blood loss compared with aminocaproic acid and desmopressin, and decreases transfusion requirements compared with desmopressin. Results are less consistent in comparisons with tranexamic acid: high dose aprotinin reduced blood loss significantly more than tranexamic acid in some studies and to equivalent levels in others. A variety of other lower dose aprotinin regimens consistently result in similar reductions in blood loss to aminocaproic acid or tranexamic acid.

In patients undergoing CPB during OHS, no significant difference in the reduction in postoperative blood loss or transfusion requirements could be shown between high dose and low dose (50% of the high dose using the same protocol) regimens. Aprotinin 280mg [2 × 106 kallikrein inactivator units (KIU)] added to the pump priming fluid of the CPB circuit has usually been shown to decrease blood loss and transfusion requirements significantly more than placebo, although in a study in patients undergoing repeat CABG, no difference was seen.

While some studies using a variety of dosage regimens in paediatric patients undergoing OHS with CPB have shown significant reductions in blood loss and/or transfusion requirements, others have failed to demonstrate any advantage of aprotinin over no treatment. However, results available so far indicate that aprotinin may be beneficial in children undergoing repeat or very complicated OHS.

A recent meta-analysis suggests that high dose aprotinin, but not low dose or pump prime only aprotinin, significantly reduces the incidence of stroke in patients undergoing CPB.

Although no cost-effectiveness studies have been conducted for aprotinin, studies examining the effect on costs of aprotinin suggest that low dose aprotinin (50% of the high dose regimen) is cost saving compared with no treatment, aminocaproic acid and various anti-inflammatory strategies. In contrast, high dose aprotinin has been shown to increase costs compared with aminocaproic acid. However, neither study comparing the costs of aprotinin and aminocaproic acid included critical care or hospitalisation costs.

Tolerability

Aprotinin is generally well tolerated in clinical trials. Adverse events reported are generally consistent with those expected in patients undergoing CPB during OHS and/or CABG. Unfortunately, there are scant comparative tolerability data for aprotinin and aminocaproic acid, tranexamic acid or desmopressin. Aprotinin appears to be well tolerated in paediatric patients.

Some concerns remain regarding graft patency and myocardial infarction (MI) rates and allergic reactions. The trend toward a higher incidence of MI and mortality seen in some earlier trials has not been confirmed by further investigations specifically designed to investigate this outcome. However, a recent large multi-centre prospective study in patients undergoing primary CABG showed that high dose aprotinin increased the probability of early vein graft occlusion, particularly in patients with high risk factors. Surgical procedures used at different sites in this study may also have contributed to this effect and indicate that care with anticoagulation and vessel grafts is required when using aprotinin.

The reported incidence of hypersensitivity reactions in clinical trials in patients receiving mainly high dose aprotinin ranges from <0.1 to 0.6%. Most of the patients in these trials received aprotinin for the first time and it has been shown that reactions are more likely to occur in patients with prior exposure to aprotinin. Indeed, a retrospective analysis in 240 patients re-exposed to aprotinin a mean of 344 days after first exposure reported 7 allergic reactions (2.8%).

Increases in serum creatinine levels of ≥44 µmol/L (0.5 mg/dl) above pre-operative levels were more common in patients receiving aprotinin than those not receiving aprotinin in some but not all studies. However, these elevations in serum creatinine levels were generally small, and levels returned to baseline and did not predispose patients to renal dysfunction.

Drug Interactions

Aprotinin alters the results of coagulation assays that depend on contact activation, i.e. it prolongs the activated partial thromboplastin time and activated clotting time (ACT). Consequently, the previously recognised ACT value of >400 to >450 seconds may not reflect adequate heparinisation in patients receiving aprotinin. There is general agreement that heparin dosage should not be decreased during aprotinin administration, and current recommendations are to maintain the celite ACT at >750 seconds or the kaolin ACT at >480 seconds, or to use a fixed dose heparin regimen or to maintain heparin concentrations at ≥2.7 × 103 IU/L using heparin/protamine titration.

Dosage and Administration

Aprotinin is administered intravenously through a central line. The high dose regimen is a loading dose of aprotinin 280mg (2 × 106 KIU) administered as an infusion over 20 to 30 minutes after the induction of anaesthesia followed by an infusion of aprotinin 70 mg/h (5 × 105 KIU/h) that is then maintained throughout surgery. In addition, this regimen includes aprotinin 280mg added to the pump priming fluid of the CPB circuit.

A variety of lower dose regimens have been investigated but the most common are a standard low dose regimen of 50% of the high dose regimen using the same protocol or aprotinin 280mg in the pump prime only.

An intravenous test dose of aprotinin 1.4mg or lml is recommended at least 10 minutes before the loading dose in patients with known previous exposure to aprotinin, or in patients for whom this information is not available, because of the risk of anaphylactic reactions.

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    Dene C. Peters & Stuart Noble

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  1. Dene C. Peters
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Correspondence to Stuart Noble.

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Various sections of the manuscript reviewed by: M.E. Able, Department of Pathology, Mt Diablo Medical Center, Concord, California, USA; M.N. D’Ambra, Cardiac Anesthesia Group, Massachusetts General Hospital, Boston, Massachusetts, USA; B.P. Bidstrup, North Queensland Clinical School, University of Queensland, Townsville, Queensland, Australia; W. Dietrich, Institut für Anaesthesiologie, Deutsches Herzzentrum München, Munich, Germany; G.E. Hill, Department of Anesthesiology and Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA; J.H. Lemmer, Northwest Surgical Associates, Portland, Oregon, USA; J.H. Levy, Department of Anesthesiology, Emory University Hospital, Atlanta, Georgia, USA; J.M. Murkin, Department of Anaesthesia, University of Western Ontario, London, Ontario, Canada.

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Peters, D.C., Noble, S. Aprotinin. Drugs 57, 233–260 (1999). https://doi.org/10.2165/00003495-199957020-00015

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