Aprotinin

Class: Hemostatics
VA Class: BL300
Chemical Name: Pancreatic basic trypsin inhibitor
Molecular Formula: C₂₈₄H₄₃₂N₈₄O₇₉S₇
CAS Number: 9087-70-1
Brands: Trasylol

Special Alerts:

[UPDATE 05/14/2008] Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study in the May 14, 2008 online issue of The New England Journal of Medicine, Bayer Pharmaceuticals notified the FDA of their intent to remove all remaining supplies of aprotinin (Trasylol) from hospital pharmacies and warehouses. Under a limited use agreement, access to aprotinin is limited to investigational use of the drug according to the procedures described in a special treatment protocol. The protocol allows treatment for certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery and who have no acceptable alternative therapy. Physicians using aprotinin in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients. For more information visit the FDA website at: , and .

[Posted 11/05/2007] FDA announced that, at the agency's request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of aprotinin injection (Trasylol), a drug used to control bleeding during heart surgery, pending detailed review of preliminary results from a Canadian study that suggested an increased risk for death. FDA requested the suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data. FDA has not yet received full study data but expects to act quickly with Bayer, the study's researchers at the Ottawa Health Research Institute, and other regulatory agencies to undertake a thorough analysis of data to better understand the risks and benefits of aprotinin injection.

Until FDA can review the data from the terminated study it is not possible to determine and identify a population of patients undergoing cardiac surgery for which the benefits of aprotinin injection outweigh the risks. However, understanding that individual doctors may identify specific cases where benefit outweighs risk, FDA is committed to exploring ways for those doctors to have continued, limited access to aprotinin injection. There are not many treatment options for patients at risk for excessive bleeding during cardiac surgery. Thus, FDA is working with Bayer to phase aprotinin injection out of the marketplace in a way that does not cause shortages of other drugs used for this purpose. For more information visit the FDA website at: , and .

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  Hypersensitivity reactions, including fatal anaphylactic or anaphylactoid reactions, reported with aprotinin treatment during surgery.¹

  
  


• 
  

  Fatal reactions occurred with initial (test) dose and also in individuals who tolerated initial (test) dose.^{1 42}

  
  


• 
  

  Risk increased in patients with prior exposure to aprotinin.¹ Most cases of anaphylaxis occur within first 12 months after reexposure to aprotinin; also reported >12 months after reexposure.¹ (See Contraindications under Cautions.)

  
  


• 
  

  Weigh benefits of aprotinin use in patients undergoing initial CABG against risk of anaphylaxis following any subsequent exposure to drug.^{1 41 42}

  
  

Introduction

A naturally occurring protease inhibitor isolated from bovine lung tissue; attenuates systemic inflammatory response and bleeding associated with cardiopulmonary bypass during CABG.^{1 2 4 7 12}

Uses for Aprotinin

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Prevention of Bleeding Associated with Cardiopulmonary Bypass during CABG

Used prophylactically to reduce both perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass during CABG who are at an increased risk for blood loss and blood transfusion, including that related to thrombolytic agents.^{1 8 9 10 11 12 15 16 29 32 33 34 41 42} (See Sensitivity and Dermatologic Reactions under Cautions and see Boxed Warning.)

Increased risk of serious cardiovascular, cerebrovascular, hypersensitivity, and renal complications with use of aprotinin;^{1 35 36 37 42} consider limiting use to situations in which benefits of the drug in reducing blood loss are thought to outweigh potential risks.^{1 36 37 38 40}

ACC and AHA state that routine use of aprotinin in patients undergoing cardiopulmonary bypass during CABG not recommended³⁴ but may be considered in selected high-risk patients (e.g., geriatric patients ≥65 years of age, females, patients with more than one diseased coronary artery, poor left ventricular function, history of heart surgery, patients requiring urgent CABG).³⁴

Aprotinin Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  For reduction of perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass during CABG, high-dose^{1 8 9 10 13 16 17 29 30} and low-dose^{1 10} prophylactic regimens of aprotinin have been used. No clinically important differences in efficacy between the high-dose and low-dose regimens in low-risk patients undergoing CABG;¹ use either dosage at clinician’s discretion.¹

  
  

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administered by IV injection, IV infusion through a central venous line, or by addition to the recirculating priming fluid of the cardiopulmonary bypass circuit.¹

Because of the risk for hypersensitivity reactions, all patients should receive a test dose.¹ Administer test and loading doses when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present.¹ Standard emergency treatments for hypersensitivity or anaphylactic reactions (e.g., epinephrine, corticosteroids) should be readily available in the operating room.¹

If no adverse reactions occur within 10 minutes following test dose, administer loading dose IV slowly over 20–30 minutes with patient supine.¹ Avoid rapid IV administration of large (e.g., loading) doses of aprotinin because of the potential for hypotension¹ and/or anaphylactoid reactions.⁴ Administer the loading dose after induction of anesthesia but prior to sternotomy.¹ In patients with known previous exposure, administer the loading dose just prior to cannulation.¹

After the loading dose, administer by continuous IV infusion until the surgical procedure is completed and the patient is removed from the operating room.^{1 8 9 13 16 17 29 30}

Delay the addition of aprotinin into the recirculating fluid of the cardiopulmonary bypass circuit (pump-priming dose) until after the loading dose has been safely administered.¹ Before initiating cardiopulmonary bypass, add the pump-prime dose to the recirculating priming fluid by replacing an aliquot of the priming fluid with the drug.^{1 8 9 16 17 29 30}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage and potency of aprotinin usually are expressed in terms of kallikrein inhibitor (KI) units, although expression in mg also has been used.^{2 12 27} Each mg of the drug has a potency of approximately 7143 units.^{12 28}

Adults

Prevention of Bleeding Associated with CABG

Prophylactic regimens include a test dose, a loading dose, a dose added to the recirculating priming fluid of the cardiopulmonary bypass circuit (pump-priming dose), and a dose administered by continuous IV infusion.¹ Observe patients for manifestations of possible sensitivity reactions.¹

Test Dose

IV

Administer a test dose of 10,000 units (1.4 mg [1 mL]) by IV injection at least 10 minutes before the loading dose.¹

Loading Dose

IV

After successful administration of the test dose, administer an IV loading dose of 2 million units (280 mg [200 mL]) for the high-dose regimen or 1 million units (140 mg [100 mL]) for the low-dose regimen.¹ Administer loading dose over 20–30 minutes.¹

After the loading dose, administer 500,000 units/hour (70 mg/hour [50 mL/hour]) by continuous IV infusion for the high-dose regimen^{1 8 9 13 16 17 29 30} or 250,000 units/hour (35 mg/hour [25 mL/hour]) by continuous IV infusion for the low-dose regimen.¹

Pump-priming Dose

IV

For the pump-priming dose with the high-dose regimen, replace an aliquot of priming fluid with 2 million units (280 mg [200 mL]).¹ For the pump-priming with the low-dose regimen, replace an aliquot of priming fluid with 1 million units (140 mg [100 mL]).¹

Prescribing Limits

Adults

Total dosages exceeding 7 million units (980 mg) within a 24-hour period have not been studied in controlled trials.^{1 28} Dosages up to 17.5 million units (2.45 g) within a 24-hour period have been administered to patients without any apparent toxicity.¹ However, maximum doses and/or dosages that can be administered safely have not been established.¹

Special Populations

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hepatic Impairment

No dosage recommendations; no data are available.

Renal Impairment

The manufacturer states that dosage adjustment is not necessary in patients with renal impairment.¹ Some clinicians recommend reduced dosages of the drug in patients with renal failure.^{4 21} (See Special Populations under Pharmacokinetics and see Renal Effects under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.¹

Cautions for Aprotinin

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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  Known or suspected exposure to aprotinin-containing products within the previous 12 months.^{1 41 42}

  
  


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  Known hypersensitivity to the drug.¹ Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing an allergic reaction to aprotinin.¹

  
  

Warnings/Precautions

Sensitivity Reactions

Sensitivity and Dermatologic Reactions

Hypersensitivity reactions, including fatal anaphylactic or anaphylactoid reactions, reported during surgery.^{1 42} (See Boxed Warning.) Hypotension is most frequent sign of anaphylactic or anaphylactoid reactions and may progress to anaphylactic shock with circulatory failure.^{1 42} Other manifestations of hypersensitivity reactions include skin eruptions, pruritus, dyspnea, nausea, and tachycardia.¹

Because of the risk for hypersensitivity reactions, all patients should receive a test dose of aprotinin.¹ Obtain history of any prior aprotinin exposure, including use of fibrin sealant products (e.g., Tissucol, Tisseel) that may contain aprotinin.^{1 42} However, hypersensitivity reactions to subsequent therapeutic doses of drug (e.g., loading dose, pump-prime regimen) may occur despite tolerance of the test dose.¹ Discontinue aprotinin immediately if a hypersensitivity reaction occurs, and institute appropriate therapy (e.g., epinephrine, corticosteroids, antihistamines).¹

The incidence of hypersensitivity reactions and anaphylaxis is higher in patients reexposed to aprotinin.¹ Particular caution is necessary when administering aprotinin (even in test doses) to such patients.¹ Standard emergency treatments for hypersensitivity or anaphylactic reactions should be readily available in the operating room.¹ Administer the test dose and loading dose of aprotinin when the patient is intubated and when the conditions for rapid cannulation (if necessary) and initiation of CABG are present.¹ Delay pump priming dose of aprotinin until after the loading dose has been safely administered.¹

Renal Effects

Increased risk of renal dysfunction and need for dialysis in perioperative period.^{1 36} Generally, postoperative renal dysfunction observed was not severe and was reversible.¹ However, renal dysfunction may progress to renal failure.¹ Risk may be increased particularly in patients with preexisting renal impairment or in those receiving concomitant drugs that alter renal function (e.g., aminoglycosides).¹ (See Interactions.) Limited data suggest an increased risk of renal failure and/or death in patients undergoing deep hypothermic circulatory arrest during aortic arch surgery†; such findings were not confirmed in a second case-control study.^{1 31}

Careful monitoring for occurrence of ischemic toxicity to kidneys recommended in patients undergoing CABG and receiving aprotinin.^{38 40} Manufacturer recommends monitoring S_cr regularly.¹ Weigh carefully the clinical benefit of reduced blood loss against the potential risks in patients with preexisting renal dysfunction (Cl_cr <60 mL/minute) or other risk factors for renal dysfunction.^{38 40} Promptly report serious and unexpected adverse effects to manufacturer or to FDA Medwatch program at 1-800-FDA-1088 or .^{38 40 42}

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cardiovascular Effects

Increased risk of MI or heart failure during a postmarketing observational study in patients undergoing CABG and receiving aprotinin; such effects not observed in pooled analysis of premarketing clinical trials.^{36 38 40}

FDA recommends careful monitoring for the occurrence of ischemic toxicity to the heart in patients undergoing CABG and receiving aprotinin.^{38 40} Reserve use to situations when the clinical benefit of reduced blood loss outweighs the potential risks.^{38 40} Promptly report serious and unexpected adverse effects to the manufacturer or to the FDA Medwatch program at 1-800-FDA-1088 or .^{38 40}

Rapid IV administration can cause a transient fall in BP.¹ Administer the IV loading dose over a period of 20–30 minutes while the patient is supine.¹

Nervous System Effects

Increased risk for cerebrovascular adverse events such as stroke, encephalopathy, or coma observed in patients receiving aprotinin compared with no treatment or treatment with other antifibrinolytic agents (i.e., aminocaproic acid, tranexamic acid).^{36 38 39 40}

FDA recommends careful monitoring for the occurrence of ischemic toxicity to the CNS in patients undergoing CABG and receiving aprotinin.^{38 40} Reserve use to situations when the clinical benefit of reduced blood loss outweighs the potential risks.^{38 40} Promptly report serious and unexpected adverse effects to the manufacturer or to the FDA Medwatch program at 1-800-FDA-1088 or .^{38 40}

Specific Populations

Pregnancy

Category B.¹

No adequate and controlled studies in pregnant women.¹ Use during pregnancy only when clearly needed.¹

Pediatric Use

Safety and efficacy in children younger than 18 years of age not established.^{1 28}

Geriatric Use

No overall differences in efficacy or safety were observed between geriatric and younger patients.¹

Common Adverse Effects

Atrial fibrillation,¹ hypotension,¹ MI,^{1 10 29 30} atrial flutter,¹ ventricular extrasystoles,¹ tachycardia,¹ ventricular tachycardia,¹ heart failure,¹ pericarditis,¹ peripheral edema,¹ fever,¹ infection,¹ nausea,¹ lung disorder,¹ pleural effusion,¹ atelectasis.¹

Interactions for Aprotinin

Nephrotoxic Drugs

Potential for increased risk of nephrotoxicity.^{1 a} Consider risks versus benefits of concurrent perioperative use of aprotinin and other nephrotoxic drugs.^{1 a}

Specific Drugs and Laboratory Tests

Drug	Interaction	Comments
Aminoglycosides	Potential for increased risk of nephrotoxicity1 a	Consider risks versus benefits of concurrent perioperative use1
Captopril	Potential antagonism of hypotensive effects1	Potential clinical importance not determined28
Fibrinolytic agents	Potential inhibition of fibrinolytic activity1
Test, Activated Clotting Time (ACT)	Prolongs ACT and overestimates degree of anticoagulation with heparin1	Minimum celite or kaolin ACTs of 750 or 480 seconds, respectively, suggested to ensure adequate anticoagulation1 Alternatively, use additional heparin during extended extracorporeal circulation 1 Standard loading dose and dosage of heparin added to prime volume of cardiopulmonary bypass circuits should total ≥350 units/kg1 Administer additional heparin based on patient weight and duration of cardiopulmonary bypass1 Alternatively, use protamine titration (method not affected by aprotinin) to monitor heparin concentrations1

Aprotinin Pharmacokinetics

Distribution

Extent

Distributes rapidly into the total extracellular space.¹ In animals accumulates principally in the kidney and is stored in phagolysosomes.¹

Elimination

Metabolism

Slowly degraded by lysosomal enzymes in the kidneys.¹

Elimination Route

Excreted principally by the kidneys.^{1 21} Approximately 25–40% of a single, radiolabeled dose is excreted in urine over 48 hours.¹

Half-life

About 150 minutes (initial half-life).¹ About 10 hours (terminal elimination half-life) when determined >5 hours after dosing.¹

Special Populations

Effect of hepatic impairment on pharmacokinetics not established.¹

Pharmacokinetics not altered substantially by age or renal impairment.¹

Stability

Storage

Parenteral

Injection

Store between 2–25°C.¹ Protect from freezing.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not administer other drugs concomitantly with aprotinin in the same central IV line.¹

To avoid incompatibility of heparin and aprotinin in the pump prime solution, add one agent during recirculation of the priming fluid to ensure adequate dilution prior to admixture with the other agent.¹

ActionsActions

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  Inhibits contact activation of the intrinsic clotting system (i.e., contact phase of coagulation), a pathway that both initiates coagulation and promotes fibrinolysis.^{1 17 19 21}

  
  


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  Minimizes perioperative bleeding and need for blood transfusion associated with CABG through effects on platelet and granulocyte function, coagulation, and fibrinolysis.^{1 4 16 17 18 19 21 24 25} May improve hemostasis during and after cardiopulmonary bypass by preserving platelet membrane receptors that maintain the adhesive and aggregative capacity of platelets.^{4 16 25} Attenuates fibrinolysis, inflammatory responses, and thrombin generation through inhibition of plasmin and plasma and tissue kallikreins.^{1 2 6 13}

  
  

  Because of its effects on kallikrein,^{17 19 21} aprotinin inhibits activation of the intrinsic clotting system.^{1 17 19 21} (See Specific Drugs and Laboratory Tests under Interactions.) The relative contribution of these effects to the drug’s therapeutic action remains to be fully elucidated.^{1 4 6 16 17 18 19 20 21 23 24 25}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of informing clinician of prior exposure to aprotinin, including use of fibrin sealant products (e.g., Tissucol, Tisseel) that may contain aprotinin.^{1 40 42} (See Sensitivity and Dermatologic Reactions under Cautions.)

  
  


• 
  

  Importance of informing clinician of prior allergic drug reactions.³⁹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and any concomitant illnesses (e.g., kidney disease) or prior heart surgery.^{1 39 42}

  
  


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  Potential for fatal anaphylactic reaction or kidney dysfunction.⁴²

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.³⁹

  
  


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  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Aprotinin (Bovine)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	10,000 units/mL (1.4 mg/mL)	Trasylol	Bayer

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bayer Corporation. Trasylol (aprotinin) injection prescribing information. West Haven, CT; 2006 Dec.

2. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs. 1985; 29:236-61. [IDIS 198903] [PubMed 2580684]

3. Hemostasis and blood coagulation. In: Guyton AC. Textbook of medical physiology. 8th ed. Philadelphia: WB Saunders; 1991:390-9.

4. Westaby S. Aprotinin in perspective. Ann Thorac Surg. 1993; 55:1033-41. [IDIS 312574] [PubMed 7682054]

5. Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med. 1986; 314:1446-8. [PubMed 3702953]

6. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood. 1990; 76:1680-97. [PubMed 2224118]

7. Hardy JF, Desroches J. Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth. 1992; 39:353-65. [IDIS 294811] [PubMed 1373346]

8. Royston D, Bidstrup BP, Taylor KM et al. Effect of aprotinin on the need for blood transfusion after repeat open-heart surgery. Lancet. 1987; 2:1289- 91. [IDIS 236843] [PubMed 2446091]

9. Bidstrup BP, Royston D, Sapsford RN et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg. 1989; 97:364-72. [IDIS 305131] [PubMed 2465457]

10. Cosgrove DM III, Heric B, Lytle BW et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg. 1992; 54:1031-8. [IDIS 306242] [PubMed 1280411]

11. Hardy JF, Belisle S. Aprotinin therapy for reoperative myocardial revascularization: an opposing view. Ann Thorac Surg. 1993; 56:198. [IDIS 317350] [PubMed 7687124]

12. Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth. 1992; 6:76-100. [PubMed 1371939]

13. van Oeveren W, Jansen NJG, Bidstrup BP et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg. 1987; 44:640-5. [IDIS 236510] [PubMed 2446574]

14. Becker RC, Alpert JS. The impact of medical therapy on hemorrhagic complications following coronary artery bypass grafting. Arch Intern Med. 1990; 150:2016-21. [IDIS 272476] [PubMed 2222086]

15. Rossi CM, Bianchi W, Zaccarini P et al. The medical therapy of hemorrhagic complications following coronary artery bypass grafting. Arch Intern Med. 1991; 151:1458-9. [IDIS 285039] [PubMed 1712192]

16. Mohr R, Goor DA, Lusky A et al. Aprotinin prevents cardiopulmonary bypass- induced platelet dysfunction: a scanning electron microscope study. Circulation. 1992; 86(Suppl II):II405-9. [IDIS 304825] [PubMed 1385010]

17. Dietrich W, Spannagl M, Jochum M et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology. 1990; 73:1119-26. [IDIS 297661] [PubMed 1701072]

18. Allison PM, Whitten CW. What is the mechanism of action of aprotinin? Anesthesiology. 1991; 75:377-8. Letter. (IDIS 286282)

19. Dietrich W, Richter JA. What is the mechanism of action of aprotinin? Anesthesiology. 1991; 75:378-9. Reply. (IDIS 286283)

20. Merle JP, Lancon JP, Dutrillaux F et al. Effects of aprotinin on postoperative bleeding. Anesthesiology. 1991; 75:379-80. [IDIS 286284] [PubMed 1713429]

21. Hunt BJ, Yacoub M. Aprotinin and cardiac surgery: reduces perioperative blood loss. BMJ. 1991; 303:660-1. [IDIS 285811] [PubMed 1717088]

22. Bethune DW. Aprotinin and cardiac surgery. BMJ. 1991; 303:991.

23. John LCH, Rees GM, Kovacs IB. Aprotinin and cardiac surgery. BMJ. 1991; 303:991-2.

24. Hunt BJ, Yacoub M. Aprotinin and cardiac surgery. BMJ. 1991; 303:1401. [IDIS 289082] [PubMed 1722126]

25. van Oeveren W, Eijsman L, Roozendaal KJ et al. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet. 1988; I:644.

26. Food and Drug Adminstration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to December 31, 1993. Rockville, MD; 1994 January.

27. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung. 1983; 33:479-94. [PubMed 6191764]

28. Miles Inc, West Haven, CT: Personal communication.

29. ons: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg. 1994; 107:543-53. [IDIS 325391] [PubMed 7508070]

30. Murkin JM, Lux J, Shannon NA et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg. 1994; 107:554-61. [IDIS 325392] [PubMed 7508071]

31. Sundt TM III, Kouchoukos NT, Saffitz JE et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg. 1993; 55:1418-24. [IDIS 316156] [PubMed 7685587]

32. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardral infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From website.

33. Efstratiadis T, Munsch C, Crossman D et al. Aprotinin used in emergency coronary operation after streptokinase treatment. Ann Thorac Surg. 1991; 52:1320-1. [IDIS 291699] [PubMed 1721803]

34. Eagle KA, Guyton RA, Davidoff R et al. ACC/AHA guidelines for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol. 1999; 34:1262-346. [IDIS 440562] [PubMed 10520819]

35. Mangano DT and the Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality form coronary bypass surgery. N Engl J Med. 2002; 347:1309-17. [IDIS 488783] [PubMed 12397188]

36. Mangano DT, Tudor JC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006: 354:353-65.

37. Karkouti K, Beattie WS, Dattilo KM, et al. Blod conservation and transfusion alternatives: a propensity socre case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion [serial online]. January, 20, 2006. Available from website. Accessed 2006 Feb 09.

38. Anon. FDA Public Health Advisory: Aprotinin Injection (marketed as Trasylol). Rockville, MD: Food and Drug Administration; 2006 Sep 29. Available at FDA website. Accessed 2007 Jan 25.

39. Anon. FDA patient information sheet: Aprotinin injection (marketed as Trasylol). Rockville, MD: Food and Drug Administration; 2006 Feb 08. Available at the FDA website. Accessed 2006 Feb 09.

40. Anon. FDA Information for healthcare professionals: Aprotinin injection (marketed as Trasylol). Rockville, MD: Food and Drug Administration; 2006 Sep.Available at the FDA website. Accessed 2006 Sep.

41. Center for Drug Evaluation and Research, Food and Drug Administration. FDA Alert: Aprotinin injection (marketed as Trasylol) information. Rockville, MD; Food and Drug Administration; Dec 2006. Available at FDA website. Accessed 2006 Dec 15.

42. Food and Drug Administration. FDA Information for healthcare professionals: Aprotinin injection (marketed as Trasylol). Rockville, MD; Dec 2006. Available at the FDA website. Accessed 2006 Dec 15.

a. Mercieri M, Mercieri A, Tritapepe L et al. High-dose aprotinin with gentamicin-vancomycin antibiotic prophylaxis increases blood concentratiosn of creatinine and cystatin C in patients undergoing coronary artery bypass grafting. Br J Anaesth. 1999; 82:531-6. [PubMed 10472217]

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