Aprotnin Issues and Answers: An Interview by David A. Palanzo with James Tripp, Trasylol Scientific Affairs Liason

Trasylol is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CPB in the course of CABG. The effects of aprotinin use in CPB involve a reduction in systemic inflammatory response, which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal reexploration for bleeding.

Can aprotinin be used with aminocaproic acid?

No clinical studies have documented the safety and efficacy of Trasylol®(aprotinin injection, Bayer Corporation, West Haven, CT) when administered concomitantly with aminocaproic acid. Bayer can not recommend the use of Trasylol® in this manner. The addition of aprotinin therapy to patients previously treated with aminocaproic acid or other lysine analog antifibrinolytic agents (ie tranexamic acid) may pose deleterious clinical consequences.

Aprotinin, a serine protease inhibitor, inhibits circulating plasmin, systemic plasminogen activation, and the contact phase activation of coagulation through effects on kallikrein and Factor XII.1 Through inhibitory effects on thrombin formation and on inappropriate systemic plasmin activity, which occurs during cardiopulmonary bypass (CPB) and coronary artery bypass graft surgery (CABG), aprotinin serves to maintain hemostatic balance. Aprotinin does not inhibit tissue plasminogen activator-mediated fibrinolysis and therefore has minimal effect on physiologic fibrinolysis.

Lysine analog antifibrinolytic agents affect only tissue plasminogen activator-mediated fibrinolysis by blocking clot bound fibrin-plasminogen interactions. These agents do not affect the formation of thrombin or systemic plasmin.

A recent investigation using a swine model of bypass demonstrated that the combination of aminocaproic acid and aprotinin completely inhibited all biochemical markers of fibrinolysis without balanced effects on thrombin formation.2 Examination of medium-sized vessels revealed thrombus formation in the heart, lungs, and kidneys of the treated animals (n=8). In humans, clinical study centers have reported problems with thrombosis associated with aprotinin therapy when administered concomitantly with aminocaproic acid.3 While not confirmed in clinical investigations of CABG surgery, the balance of coagulation and fibrinolysis necessary to maintain hemostasis in the perioperative period may be greatly affected by the sequential administration of antifibrinolytic agents and aprotinin. This combination may promote unabated clot formation by blunting both clot bound fibrin- plasminogen mediated plasmin generation and systemic plasmin activity.

Is data available to guide aprotinin use in patient’s undergoing emergent CABG surgery
who had received platelet aggregation inhibiting drugs until surgery?

Aprotinin reduces platelet activation and loss of glycoproteins GIb and GpIIb/IIIa in the cardiopulmonary-bypass environment.1,4,5 Trasylol® (aprotinin injection, Bayer Corporation, West Haven CT) is recommended for CABG surgery patients at high risk for impaired hemostasis secondary to aspirin treatment or other coagulopathies.4,6-8 However, few experiences are published describing the efficacy or safety of aprotinin when used following treatment with newer oral platelet aggregation inhibiting drugs or with parenteral glycoprotein IIb/IIIa receptor antagonists.

Clopidogrel, a ticlopidine analogue, is a platelet aggregation inhibiting drug. In an animal model, Herbert et al. demonstrated that aprotinin reduced the prolongation of bleeding times associated with clopidogrel treatment.9 While controlled trials in humans have not been conducted, safe use of aprotinin with various platelet inhibiting agents, such as aspirin and ticlopidine, has been reported.10 These results suggest that aprotinin might constitute a useful intervention to reduce the hemorrhagic risk associated with either ticlopidine or clopidogrel treatment.

In clinical trials evaluating the efficacy of Abciximab, a glycoprotein IIb/IIIa receptor antagonist, no emergent CABG surgery patients received aprotinin. Case reports11 of aprotinin use after pretreatment with aspirin 325 mg and abciximab 0.25 mg/kg bolus followed by 9 mg / 500 ml infusion have been published. In one case report, a patient who had developed AMI with cardiogenic shock following PTCA was administered 5 X106 KIU aprotinin followed by 10 units of platelets after initiation of CPB. The author suggested that aprotinin therapy “appeared necessary and effective” in reducing mediastinal blood loss.

Eptifibatid and Tirofiban, antagonists of the GpIIb/IIIa receptor, inhibit platelet aggregation. No reports have appeared in the literature regarding patients who had received either eptifibatide or tirofiban and who later received aprotinin for emergent CABG surgery. This is consistent with the observation that these agents have not caused higher incidences of major bleeding in patients undergoing emergent CABG when compared to placebo in pivotal trials.12,13

Thus, preclinical evidence and anecdotal reports suggests that aprotinin may be beneficial to maintain balanced hemostasis in patients who have received these agents preoperatively. However, further studies on this issue are warranted.

Is aprotinin removed by hemofiltration?

Plasma constituents are removed by hemofiltration based on their size, charge and degree of binding to other proteins. Although aprotinin is not of sufficient size (6,512 daltons)4 to be retained by hemofiltration membranes which typically retain molecules that range from 15,000 – 55,000 daltons, it bears a net negative electrical charge which may hinder its passage through the negatively charged filter surface of the hemofiltration membrane.14,15

The precise contribution of filtration to overall aprotinin clearance has not been studied in controlled clinical trials. However, plasma aprotinin levels in fourteen (14) patients who underwent prolonged bypass surgery with ultrafiltration and a membrane oxygenator did not markedly differ from the range of levels previously demonstrated as effective in the absence of ultrafiltration.16,17 Plasma aprotinin concentrations dropped from 234 + 30 KIU/ml pre-CPB, to 179 + 22 KIU/ml at the end of CPB. The target kallikrein inhibiting dose of aprotinin is 200 KIU/ml.

Van Norman recently investigated the effects of hemofiltration on aprotinin levels during CABG surgery.18 The authors noted a slight augmentation in drug elimination (5-10%) above normal body clearance that had no significant clinical consequence in terms of either efficacy or safety.

In summary, while it is possible that aprotinin may be partially removed by hemoconcentration, there is neither anecdotal nor clinical evidence to date that suggests that the clinical efficacy of aprotinin is affected by the augmentation of clearance resulting from hemoconcentration during CPB.

Are aprotinin and heparin incompatible?

Bayer Corporation has recently received reports of Trasylol® (aprotinin injection) incompatibility with heparin when added to the pump prime solution of bypass circuits. Analysis of these reports suggests that the noted incompatibilities were the result of high concentrations of Trasylol® and heparin being added to non-recirculating reservoirs containing limited priming volumes.

The compatibility of Trasylol®, heparin, mannitol and corticosteroids have been demonstrated by Bayer Corporation in a pump prime solution of two liters total volume consisting of Plasma-Lyte® A Injection, heparin 10,000 units, mannitol up to 30 g, Solu-Medrol® up to 2 g, and Trasylol® 2,000,000 KIU. While Trasylol® is compatible with the above additives at 2 liters total volume and resulting concentrations, compatibility at lesser pump prime volumes has not been evaluated.

To avoid incompatibility when adding Trasylol® and heparin to the CPB pump prime, each agent must be added to the pump reservoir during recirculation of the pump prime volume to assure adequate dilution prior to admixture with the other component. The ratio of pump prime volume to admixture concentration must be maintained with continuous pump recirculation. Bayer Corporation recommends that parenteral drug products be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit.

In response to these reports and resulting clinical requests for admixture compatibility data with reduced priming volumes, Bayer Corporation has initiated studies of Trasylol® and heparin to determine compatibility at priming volumes of 1200 ml. Bayer Corporation emphasizes that the recirculating pump should be in operation continuously while admixtures are made. Additionally, until the current studies are completed, increasing the admixture concentrations is not recommended.

Safety Considerations

Trasylol is generally well tolerated. Graft patency, MI, renal or hepatic dysfunction, and mortality were comparable to placebo. In clinical studies, hypersensitivity and anaphylactic reactions were rare (<0.1%) in patients with no prior exposure to Trasylol. Upon reexposure, the overall reaction rate was 2.7% (reexposure within 6 months, 5%; after 6 months, 0.9%). For more information, please contact your local Trasylol Scientific Affairs Liaison or Clinical Communications at 1-800-288-8371. References

1. Mojcik et al. Ann Thorac Surg 2001; 71: 745-54.

2. Vang et al. J Extra-Corpor Technol 2000; 32: 196-206.

3. Royston. J Cardiothorac Vasc Anesth 1994; 8: 137-41.

4. Trasylol® , Aprotinin Injection, Prescribing Information, Bayer Corporation (West Haven, CT).

5. van Oeveren et al. J Thorac Cardiovasc Surg 1990; 99: 788-96.

6. Murkin et al. J Thorac Cardiovasc Surg 1994; 107: 554-61.

7. Bidstrup et al. Perfusion 1990; 5: 77-81.

8. Bidstrup et al. Ann Thorac Surg 2000; 69: 541-7.

9. Herbert et al. Thromb Res 1993; 71: 433-41.

10. Szefner. Int J Artif Organs 1995; 18: 633-48.

11. Alvarez. J Thorac Cardiovasc Surg 1998; 115: 472-3.

12. Integrilin, Eptifibatide, Prescribing Information. Cor Ther. (5/1998).

13. Aggrastat, Tirofiban, Prescribing Information. Merck (2/1998).

14. Brodie et al. in The Manual of Perfusion (eds. Haligan, M., Moore, P., Richards, K. & Brodie, J.) 61-65 (Glendale Medical Corporation, Augusta, GA, 1997).

15. Clar et al. J Extra-Corpor Technol 1995; 27: 158-63.

16. Bennett-Guerrero et al. Anesth Analg 1996; 83: 1189-92.

17. Dietrich et al. Anesthesiology 1990; 73: 1119-26.

18. Van Norman et al. J Cardiothorac Vasc Anesth 2000; 14: 253-6.