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Aprotinin

A Review of its Pharmacology and Therapeutic Efficacy in Reducing Blood Loss Associated with Cardiac Surgery

  • Drug Evaluation
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Summary

Synopsis

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) experience transient haemostatic defects as a result of adverse changes to their blood components, blood cells and specific coagulation proteins. Aprotinin is a naturally occurring serine protease inhibitor isolated from bovine lung tissue which inhibits kallikrein and plasmin. A high dose aprotinin regimen (aprotinin 280mg loading dose over 20 to 30 minutes after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit) has been used during CPB in order to reduce perioperative bleeding.

Recent clinical trials confirm the efficacy of high dose aprotinin in reducing blood loss and transfusion requirements associated with primary cardiac procedures such as coronary artery bypass graft (CABG) or heart valve replacement surgery. High dose aprotinin is also effective in procedures known to possess a high risk for excessive blood loss, such as repeat CABG or heart valve replacement surgery, cardiac surgery in patients with infective endocarditis, or in patients receiving aspirin (acetylsalicylic acid) before surgery. Studies indicate that low dose aprotinin (280mg added to CPB pump prime fluid) is effective in reducing blood loss and transfusion requirements in patients undergoing primary CABG surgery. Additionally, low dose aprotinin regimens (both 280mg added to CPB pump prime fluid and 50% of the high dose regimen) have shown some benefit in repeat CABG surgery; however, more studies are needed to confirm these results.

Data from clinical trials indicate that aprotinin is well tolerated. The types and incidences of adverse events reported with aprotinin therapy are generally consistent with those associated with major cardiac surgery, and are not significantly different from those observed in control groups. A trend towards lower graft patency rates, detected by ultrafast computerised tomography (CT), has been observed in aprotinin recipients in 2 US trials. These differences did not reach statistical significance and should be interpreted with caution since the ability of ultrafast CT to determine graft patency has not been validated. Mildly elevated plasma creatinine levels are more commonly observed in aprotinintreated patients; these changes are transient in the majority of patients.

Both high dose and low dose aprotinin regimens (280mg added to CPB pump prime fluid or 50% of the high dose regimen) have reduced blood loss and transfusion requirements in patients undergoing primary and repeat cardiac surgery. The role of aprotinin in paediatric cardiac surgery needs further clarification, while well-designed studies comparing aprotinin with other agents which inhibit fibrinolysis are also awaited with interest. Preliminary pharmacoeconomic assessments of aprotinin appear favourable, and antigenic reactions occur in only a small proportion of patients. However, the achievement of a clear consensus regarding the routine use of aprotinin for primary cardiac surgery requires further clarification of these issues. Nonetheless, it is clear that high dose aprotinin should be considered a valuable adjunct to aggressive blood conservation programmes in patients undergoing cardiac surgery with the potential for excessive blood loss, in patients for whom transfusion is unavailable or in patients who refuse homologous transfusions.

Pharmacological Properties

Aprotinin is a serine protease inhibitor with effects on a number of biochemical systems. In patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), aprotinin has been shown to inhibit plasmin- and kallikrein-mediated fibrinolysis, as indicated by reductions in the formation of fibrin degradation products. In addition to effects on contact activation and fibrinolytic pathways, aprotinin is also thought to improve haemostasis during and after CPB by preserving the platelet membrane adhesive receptor (glycoprotein Ib).

Pharmacokinetic Properties

Following single dose intravenous administration of aprotinin 70 to 280mg to patients awaiting cardiac surgery or to female patients undergoing primary elective abdominal hysterectomy, mean maximum plasma concentrations (Cmax) ranged from 8.4 to 59.6 mg/L (60.0 to 425.7 KIU/ml). Linear pharmacokinetics over this dose range were observed. Following administration of high dose aprotinin (aprotinin 280mg loading dose after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit), mean plasma drug concentrations ranged from 37 to 47 mg/L at the beginning of CPB and 26 to 27 mg/L at the end of CPB.

Aprotinin is rapidly distributed into the extracellular compartment after intravenous administration. Plasma drug concentrations decrease biphasically, with distribution and elimination half-lives of 0.32 to 0.50 hours and 5.25 to 8.28 hours for the 2 phases, respectively.

Animal studies have shown that aprotinin is primarily accumulated within the proximal tubular epithelial cells of the kidneys. After undergoing glomerular filtration, aprotinin is actively reabsorbed by the proximal tubules, stored in phagolysosomes and then gradually metabolised by lysosomal enzymes in the kidney. Approximately 25 to 40% of a single intravenous dose of 131I-labelled aprotinin was found in the urine of healthy volunteers within the first 48 hours. However, the total urinary excretion of unchanged drug is low (range 1.1 to 8.7%), but appears to increase slightly when the infused dose is increased.

Therapeutic Efficacy

The therapeutic efficacy of aprotinin in both high and low dose regimens (mostly 50% of the high dose regimen or 280mg added to the CPB pump prime fluid) has been evaluated in patients undergoing cardiac surgery with CPB. Patients in these trials underwent primary cardiac surgery [both with and without aspirin (acetylsalicylic acid) pretreatment] or repeat cardiac operations or were patients with active infective endocarditis (high dose aprotinin only). Compared with control patients, high dose aprotinin significantly reduced postoperative blood loss (range 35 to 81%) and homologous transfusion requirements (range 35 to 97%) and markedly increased the percentage of patients who did not require homologous transfusions (range 40 to 88%). Significant reductions in blood loss and transfusion requirements and increases in the number of patients who did not require homologous transfusions were also seen in patients treated with low dose aprotinin (280mg added to the CPB pump prime fluid) who underwent primary coronary artery bypass graft (CABG) surgery. Low dose aprotinin regimens (both 50% of the high dose regimen and 280mg added to the CPB pump prime fluid) also showed encouraging results in a recent study in patients who underwent repeat CABG surgery. Although there was no clear correlation between dosage and overall efficacy, the observed reductions in the haemostatic measures of clinical efficacy were less marked in the studies that used low dose aprotinin regimens compared with those that used high dose aprotinin, particularly in patients at high risk for excessive blood loss.

Tolerability

Aprotinin was generally well tolerated in clinical trials. Adverse events associated with aprotinin usage in 4 pooled double-blind placebo-controlled US studies were generally consistent with those associated with major cardiac surgery, and no significant differences were noted between aprotinin and placebo recipients.

Although no clear pattern of serious adverse events with high dose aprotinin has emerged in clinical trials to date, there are still concerns about increased risks of graft occlusion and hypersensitivity reactions. A trend towards lower graft patency rates detected by ultrafast computerised tomography (CT) in aprotinin recipients than in placebo recipients has been observed in a 2 US studies; however, these differences did not reach statistical significance. These results should be interpreted with caution because the ability of ultrafast CT to determine internal mammary artery graft patency has not been validated.

The reported incidence of anaphylactic reactions in patients from recent placebo-controlled US studies who received aprotinin was 0.3%. In 2 large European reviews, the incidence of mild hypersensitivity reactions (skin rash, hypotension and/or bronchospasm) ranged from 0.3 to 0.6% in patients who received mostly high dose aprotinin. These reactions are more likely to occur in patients who have received prior aprotinin treatment.

Plasma creatinine concentration elevations ≥44 μmol/L (0.5 mg/dl) above baseline were more common in the aprotinin-treated patients than in those who received placebo; however, the observed renal dysfunction was mild, reversible and clinically insignificant in the majority of patients.

Dosage and Administration

The high dose regimen used in recent clinical trials is a loading dose of aprotinin 280mg infused over 20 to 30 minutes after induction of anaesthesia but before sternotomy, followed by a continuous infusion of aprotinin 70 mg/h until the surgical procedure is completed and the patient is removed from the operating room. Before initiation of CPB, aprotinin 280mg is added to the priming fluid of the CPB circuit by replacement of an aliquot of the priming fluid. Because of the risk of serious allergic reactions, test doses of 1.4mg administered by intravenous injection or 1.4 to 7mg administered as part of the initial intravenous loading dose have been recommended. Although a variety of low dose aprotinin regimens have been evaluated, the 2 most commonly used regimens include aprotinin administered as 50% of the high dose regimen and a. single dose of aprotinin 280mg added to the priming fluid of the CPB circuit.

Aprotinin prolongs the results of coagulation assays which depend on contact activation, such as the activated partial thromboplastin time (APTT) and celite activated contact time (ACT). Consequently, in patients who are receiving aprotinin, the standard method for monitoring heparinisation during CPB, i.e. maintaining the celite ACT above 400 to 450 seconds, may not provide adequate anticoagulation. Although this issue remains unresolved, the current recommendation appears to be to maintain celite ACT values at >750 seconds during CPB, to administer heparin in a fixed-dose regimen based on patient weight or to utilise other monitoring tests (e.g. kaolin ACT or assays which measure plasma heparin concentrations) which are not affected by aprotinin.

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    Rick Davis & Ruth Whittington

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Various sections of the manuscript reviewed by: P.L. Baele, Department of Anesthesiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; C.R. Bailey, Department of Anaesthetics, Guy’s Hospital, London, England; B.P. Bidstrup, Director of Cardiothoracic Surgery, North Queensland Clinical School, University of Queensland, Townsville, Queensland, Australia; W. Dietrich, German Heart Center Munich, Institute for Anesthesiology, Munich, Germany; L.H. Edmunds, Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; M. Kawasuji, Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan; J.H. Lemmer, Cardiothoracic Surgeon, Northwest Surgical Associates, Good Samaritan Hospital, Portland, Oregon, USA; J.H. Levy, Associate Professor of Anesthesiology, Division of Cardiothoracic Anesthesiology and Critical Care, Emory University School of Medicine, Atlanta, Georgia/USA; B. Liu, Department of Thoracic and Cardiovascular Surgery, University of Göteborg, Göteborg, Sweden; A.D. Michelson, Department of Pediatrics and Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA; J.M. Murkin, Department of Anaesthesia, University Hospital, University of Western Ontario, London, Ontario, Canada; D. Roberts, Department of Thoracic and Cardiovascular Surgery, University of Göteborg, Göteborg, Sweden; K.M. Taylor, Cardiothoracic Surgery Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England; J.P.A.M. Schönberger, Department of Cardiopulmonary Surgery, Catharina Hospital, Eindhoven, The Netherlands; D.S. Watermeyer, Staff Anesthesiologist, St. Joseph Medical Center, Tacoma, Washington, USA.

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Davis, R., Whittington, R. Aprotinin. Drugs 49, 954–983 (1995). https://doi.org/10.2165/00003495-199549060-00008

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