Anticoagulant Reversal Handbook - Page 21

Acute bleeding
four ( plus factor VII ) activated or non-activated coagulation factors , but some studies reported lower effectiveness in reversal of VKA anticoagulation for 3F-PCCs and increased risk of thromboembolic events for activated types . 7 Bypassing agents , such as Factor Eight Inhibitor Bypassing Agent ( FEIBA ), a plasma-derived activated PCC comprising factors II , VII , IX and X , with the factor VII partially activated , and recombinant activated factor VII ( NovoSeven ), have also been used for the treatment of acute haemorrhagic episodes in bleeding disorders , with highly variable clinical responses . Their mechanism of action does not involve restoring haemostasis per se – they promote thrombin generation instead 8 – but there is very little evidence supporting their use as antidotes to warfarin . 9 , 10 A retrospective study conducted at a specialised trauma centre in the US showed a decrease in time to restore the international normalised ratio ( INR ), but no difference in mortality rate , when NovoSeven was administered to patients presenting with traumatic ICH while using warfarin . 11
4F-PCC Beriplex ® ( KCentra ® in the US ; also known as Confidex ® or Coaplex ® in some
countries ) is the first non-activated 4F-PCC specifically designed to reverse acquired coagulation factor deficiency due to VKAs in emergency settings , including occurrence of major haemorrhage and need for an urgent surgical or invasive intervention . It is available in more than 25 countries , including Europe , South America and Canada , and it was approved in the US in 2013 . 12
This plasma-derived product contains similar relative concentrations of human coagulation factors II , VII , IX and X , as well as endogenous antithrombotic proteins C and S , the clotting cascade factors affected by VKAs , and acts by replenishing the levels of these proteins in plasma . It is administered intravenously as an infusion and supplied as a lyophilisate in a single-use vial with 250 , 500 or 1000IU , which has to be reconstituted to a final concentration of 20 – 31U / ml . 13
Key data In a pivotal Phase III trial in non-surgical patients with acute major bleeding while on VKAs , 4F-PCC showed non-inferiority to FFP in achieving haemostasis , and superiority in INR reduction . Significant differences in mean plasma levels of VKDFs were seen between the two treatment arms , with rapid and sustained
increase of factors II , VII , IX and X within 30 minutes of treatment with 4F-PCC . The infusion volume and time were also significantly reduced for patients receiving 4F-PCC . The safety profiles of both treatments were very similar , with 4F-PCC presenting a lower incidence of fluid overload or similar cardiac effects . 14 A second seminal study involving patients requiring VKA reversal before undergoing urgent surgical or invasive procedures showed that 4F-PPC was superior to FFP in both clinical haemostasis and INR reduction . Moreover , the median time from start of infusion to initiation of the surgical procedure was shorter for patients receiving 4F-PCC . 15 The most common adverse reactions associated with the product observed in these two trials were headache , nausea and vomiting , hypotension and anaemia . Serious adverse events included stroke , deep vein thrombosis and venous insufficiency . Overall , the proportion of patients with adverse events , deaths and thromboembolic events , was similar between treatment arms 16 ( see Table 1 ).
A post hoc analysis of patient-level data collected from these two noninferiority Phase III trials of 4F-PCC identified predictors of volume overload , which is particularly relevant in the context of cardiac and renal disease .
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