Frequently asked questions

Q1. What does aprotinin do?

A.

Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (CABG).1

Aprotinin has demonstrated reduced incidence of massive post-operative bleeding and reduced need for transfusion of blood products for patients undergoing isolated coronary artery bypass graft surgery.2 Additionally, aprotinin has been shown to be superior to both TXA and EACA with respect to avoiding re-operation for bleeding and significant peri-operative bleeding from chest tubes in CABG surgery.2

References: 

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
  2. European Medicines Agency. Assessment report. Antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid. 18 September 2013. Available from: https://www.ema.europa.eu/en/documents/referral/assessment-report-antifibrinolytic-medicines-aprotinin_en.pdf. Accessed July 2020.
Q2. Which patients should receive aprotinin?

A.

Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (CABG).

The decision to use aprotinin would be based on a patient assessment made by the cardiothoracic surgeon and/or anaesthetist. Patients who are undergoing isolated coronary artery bypass graft surgery (on pump) and who are considered at high risk of major blood loss and transfusion may benefit from receiving aprotinin.

Please refer to the section on our website: Which patients undergoing isolated CABG are at higher risk of transfusion?

Reference:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q3. Which patients should not receive aprotinin?

A.

Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (CABG).

Aprotinin is contraindicated in the following patients:

  • Those who are hypersensitive to the active substance.
  • Those with a positive aprotinin-specific IgG antibody test.
  • Those with a suspected previous exposure including in fibrin sealant products during the last 12 months (if no aprotinin specific IgG antibody test is possible prior to treatment).

Aprotinin should also not be used when CABG surgery is combined with another cardiovascular surgery because the benefit risk balance of aprotinin in other cardiovascular procedures has not been established.

Reference: 

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q4. What is the safety profile of aprotinin?

A.

Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (CABG). 1

Aprotinin has a well-established safety profile based on decades of research. A meta-analysis demonstrated no increase in the risk of in-hospital mortality for patients treated with aprotinin vs. placebo or other antifibrinolytic agents.2

These findings are in line with other leading reviews of aprotinin:

– Cochrane review (2011) – which also showed no increased risk of myocardial infarction, stroke or renal dysfunction/failure vs. placebo3

– Health Canada guidance (2011) – which concluded the benefit of aprotinin outweighs its risk in appropriate patients4

– European regulatory assessment (2013) – which recommended lifting the licence suspension 5

Additionally, The EACTS/EACTA 2017 Guidelines recommend using aprotinin: Antifibrinolytic therapy (TXA, aprotinin and EACA) is recommended to reduce bleeding and transfusions of blood products and reoperations for bleeding (TXA and aprotinin).6

Adverse drug reactions (ADRs) based on all placebo-controlled clinical studies with aprotinin sorted by CIOMS III categories of frequency (aprotinin n=3817 and placebo n=2682; status: April 2005) are listed as follows:1

Uncommon: may affect up to 1 in 100 patients
  • Myocardial ischaemia
  • Coronary occlusion/thrombosis
  • Myocardial infarction
  • Pericardial effusion
  • Thrombosis
  • Oliguria
  • Acute renal failure
  • Renal tubular necrosis
Rare: may affect up to 1 in 1,000 patients
  • Allergic reaction Anaphylactic /anaphylactoid reaction
  • Arterial thrombosis (and its organ specific manifestations that might occur in vital organs such as kidney, lung or brain)
Very rare: may affect up to 1 in 10,000 patients
  • Anaphylactic shock (potentially life threatening)
  • Disseminated intravascular coagulation
  • Coagulopathy
  • Pulmonary embolism

 

If you have any concerns over the safety of aprotinin please use our contact form to make an enquiry to our team who would be happy to discuss any particular concerns you may have. Alternatively, if you have an adverse event you wish to report please contact Nordic Pharma Ltd. on 0800 121 8924 or email at NordicGB@eu.propharmagroup.com. Adverse events can also be reported by using the reporting forms and information found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

References:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
  2. Howell N et al. J Thorac Cardiovasc Surg. 2013;145:234–40.
  3. Henry DA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011;(1):CD001886.
  4. Health Canada. Final report—expert advisory panel on Trasylol (aprotinin) 2011: Available from: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2011/13544a-eng.php
  5. European Medicines Agency. Assessment report. Antifibrinolytics containing aprotinin,aminocaproic acid and tranexamic acid. 18 September 2013. Available from: https://www.ema.europa.eu/en/documents/referral/assessment-report-antifibrinolytic-medicines-aprotinin_en.pdf. Accessed December 2020.
  6. Boer C et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J Cardiothor Vasc Anesth. 2018;32:88–120.
Q5. What about aprotinin and kidney function?

A.

Results from recent observational studies indicate that renal dysfunction could be triggered by aprotinin, particularly in patients with pre-existing renal dysfunction. An analysis of all pooled placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) has found elevations of serum creatinine values >0.5 mg/dL above baseline in patients with aprotinin therapy. Careful consideration of the balance of risks and benefits is therefore advised before administration of aprotinin to patients with pre-existing impaired renal function or those with risk factors (such as concomitant treatment with aminoglycosides).1

An increase in renal failure and mortality compared to age-matched historical controls has been reported for aprotinin treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation of the thoracic aorta. Adequate anticoagulation with heparin must be assured (see also above).

A multicentre observational study suggests that aprotinin use does not independently increase the risk of renal failure in cardiac surgery patients.2 A transient rise in creatinine among patients receiving aprotinin normalised at post-operative day 3, and no difference between the study arms was found.2

References:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
  2. Deloge E et al. Aprotinin vs. tranexamic acid in isolated coronary artery bypass surgery. Eur J Anaesthesiol 2017;34:1–8.
Q6. Why should you use aprotinin when you can use tranexamic acid (TXA)?

A.

In a study of patients at high risk of bleeding and transfusion, aprotinin offered the following advantages over TXA:

  • Lower post-operative blood loss
  • Lower need for transfusions
    • 32% aprotinin vs 46% TXA
  • Shorter stays in ICU (61 hours [24-72h] for aprotinin vs. 87 hours [48-96h] for TXA; p<0.001)

In this study, patients in the TXA group received an intravenous bolus infusion of 10 to 30mgkg_1 for 10 to 20 min as a loading dose after induction of anaesthesia. Subsequently, a continuous intravenous infusion ranging from 0.5 to 15mgkg_1 h_1, depending on the centre and the patient’s renal function, was administered until the end of surgery. This is outside the indicated dosing for TXA in the UK SPC.

For further information on how the mode of action of aprotinin differs from that of TXA please refer to our section About aprotinin.

Reference:

  1. Deloge E et al. Aprotinin vs. tranexamic acid in isolated coronary artery bypass surgery. Eur J Anaesthesiol 2017;34:1–8.
Q7. Can you combine TXA and aprotinin?

A.

In the SmPCs of both aprotinin and tranexamic acid, there is no mention of possible pharmacological interactions between these two products. However, Nordic Pharma Ltd. does not recommend combining different antifibrinolytics during a surgical procedure.

Please refer to our section About aprotinin for further information regarding the differences between aprotinin and TXA.

Reference:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q8. Is a test dose needed?

A.

Owing to the risk of allergic/anaphylactic reactions, a 1 ml (10,000 KIU) test dose should be administered to all patients at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the 1 ml test dose, the therapeutic dose may be given. A H1-antagonist and a H2-antagonist may be administered 15 minutes prior to the test dose of aprotinin. In any case, standard emergency treatments for anaphylactic and allergic reactions should be readily available.

Reference:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q9. What is the difference between the half and full Hammersmith dose? What do you recommend?

A.

Aprotinin can be administered in 2 dose-regimens: full-dose (full-Hammersmith) and half-dose (half-Hammersmith).

No clinical study was conducted to compare efficacy and safety of these 2 dose regimens.

Nevertheless, a dose-response effect has been demonstrated in a pooled analysis of US trials. In this analysis, the relative reduction in transfusion rate compared to placebo was:

Full dose Half-dose
Primary CABG -31.2% -30.7%
Repeat CABG -38.5% -36.2%

 

Full-Dose aprotinin

N = 361

Half-Dose aprotinin

N = 366

Placebo

N = 365

n % n % n %
Deaths 12 3.3 18 4.9 12 3.3
Any adverse event 292 80.9 300 82.0 304 83.3
Any drug-related adverse event 50 13.9 42 11.5 45 12.3

 

The events that appear to have a dose-response relationship (with rates in the full-dose aprotinin group exceeding those in the half-dose aprotinin group that exceeds those in the placebo group) were myocardial infarction, diarrhoea, dyspnoea and lung disorder.

The choice of dose regimen should be made based on the bleeding risk related to the procedure and the patient (comorbidities, medications, etc.).

Please click here to find more information on the dosing and administration of aprotinin.

Reference:

  1. Data on file
Q10. Is aprotinin suitable for children?

A.

The safety and efficacy in children below 18 years of age have not been established. Therefore, aprotinin should not be used in children.

The indication of aprotinin is prophylactic use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (i.e. CABG that is not combined with other cardiovascular surgery).

Reference:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q11. Can my centre order aprotinin if we do not perform cardiac surgery?

A.

Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery. Aprotinin should only be used after careful consideration of the benefits and risks, and alternative treatments.

Nordic Pharma Ltd. are therefore unable to supply any centre which does not perform cardiac surgery.

Reference:

  1. Aprotinin 10,000 KIU/ml Injection BP Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2472/smpc. Accessed December 2020.
Q12. Where can you purchase aprotinin from in the UK?

A.

Aprotinin is available for cardiac centres to purchase from Mawdsleys Pre Wholesaler. If you have previously not ordered aprotinin, you will be asked to supply further information before your order will be processed.

Q13. What is the cost of aprotinin?

A.

The price of aprotinin is £79 per vial. Please see aprotinin Prescribing Information for more information