Aprotinin

CLASS

• antifibrinolytic

MECHANISM OF ACTION

• single chain polypeptide which occurs naturally in bovine lung and other tissues
• inhibits fibrionlysis via inactivation of free plasmin
• also inhibits trypsin and kallikrein
  -> when given prior to bypass: prevents clotting activation, factor consumption, platelet dysfunction -> reduced blood loss and transfusion

PHARMACEUTICS

• clear, colourless solution
• 1.4mg/mL in 0.9% saline = 10,000 kallikrein inactivator units

DOSE

• IV dose = 500,000 -> 1,000,000 KIU -> 200,000 KIU/hr until bleeding stops

INDICATIONS

1. life-threatening haemorrhage from hyperplasminaemia
2. acute pancreatitis
3. reduction of blood loss during bypass surgery, prostatectomy & liver transplantation
4. prevention of DVT

ADVERSE EFFECTS

• increased mortality -> moratorium
• renal failure
• can have hypersensitivity on repeat exposure
• can produce thrombophlebitis

PHARMACOKINETICS

• Absorption – IV only
• Distribution – highly protein bound
• Metabolism – lysosomes of kidneys
• Elimination – t1/2 = 1 hr

EVIDENCE

Positive

• shown to decrease bleeding and transfusion requirements with regard to patient with platelet dysfunction post cardiac bypass (inhibition of platelet aggregation -> prevention of microaggregate formation) in multiple previous trials (Cochrane review 2001 & JTCVD 2004)
• used to help with haemostasis and shown to decrease transfusion requirements in multiple studies including in trials recently
• transfusion and bleeding in cardiac surgical patients produces increased morbidity and therapies to decrease this are therefore important

Negative

• recent published meta-analysis and FDA inquiry has revealed a significant increase in morbidity associated with its use (in particular a significant increase in acute renal dysfunction) but not increase in CVA, MI or mortality. (Circulation 2007;115:2801–13)
• NEJM January 2006 – observational study with >4000 patients -> increased risks of CVA, MI, renal failure and CCF
• increased risk of renal dysfunction (decreased GFR) but does not increase risk for renal failure requiring dialysis
• BART trial in (Blood conservation using antifibrinolytics; a randominsed trial) – a trial comparing Aprotinin, Tranexamic and Epsilon-aminocaproic acid in preliminary data found that aprotinin produced a trend towards increased mortality -> moratorium on aprotinin use pending BART data -> significant increase in mortality and morbidity and recommended not using aprotinin in high risk cardiac surgery (May 2008 – NEJM)

There currently needs to be more information gathered to make a final decision on whether or not aprotinin should be disallowed in cardiac surgery.