#Antidote for coumadin trial

It is an elegant reversal agent for FXa-Is. Recently, the Food and Drug Administration approved andexanet alfa, the second DOAC specific reversal agent. 46 Nevertheless, idarucizumab was shown to reverse the effect of dabigatran for approximately 93% of patients within minutes. Therefore it lacked objective measurement of clinical haemostasis in ICH. Unfortunately, the study was was not designed for patients with ICH.

#Antidote for coumadin trial

REVERSE-AD trial (Reversal Effects of Idarucizumab on Active Dabigatran) enrolled patients with active bleeding and patients that need reversal of anticoagulation prior to a procedure. Idarucizumab is a monoclonal antibody that binds dabigatran. There are anticoagulant reversal agents specific for different DOACs ( tables 1 and 2). 33 There are no studies comparing aPCC to PCC to date. aPCC (20вЂ‰IU/kg) is also found to be more efficacious than FFP without significant increase in thrombotic complications. 29вЂ“32 PCC (more than US$5000 for 20вЂ‰IU/kg dose in a 70вЂ‰kg patient) is more expensive when compared with FFP (less than US$2000 per unit), however it is more cost-effective given its advantages over FFP as outlined above. 28 The rate of thrombotic complications remains similar between PCC and FFP. 25 PCC had a higher rate of INR reversal to 24вЂ‰hours for FFP and haematoma expansion was less for PCC group at 3 and 24вЂ‰hours. 27 The INCH trial (International Normalised Ratio Normalisation in Coumadin-Associated Intracerebral Haemorrhage) compared 30вЂ‰IU/kg dose of PCC to 20вЂ‰mL/kg FFP in reversal of VKA associated ICH. PCC results in rapid INR reversal and is not associated with complications such as fluid overload as seen with FPP.

Activated PCC (aPCC) also contains factor VII in addition to II, IX and X. PCC is comprised of clotting factors II, IX and X at levels significantly higher than FFP. 23вЂ“25 It requires high volumes and can worsen fluid balance in patients with heart failure resulting in pulmonary oedema as well as transfusion reactions. FFP reversal of INR can take up to 30вЂ‰hours making it an ineffective treatment of early haematoma expansion. It corrects coagulopathy by replacing plasma proteins to replete clotting factors. As their use will continue to rise, it is imperative to understand the management of DOAC related ICH.ДЇFP is the liquid portion derived from whole blood. 19 There is limited data on the reversal protocol of DOACs. 17 18ДOACs are becoming the preferred agents for oral anticoagulation when compared with VKAs given their safety profile. 16 Other studies have shown similar functional outcomes in patients with ICH receiving VKA and DOACs and also mortality benefit in patients on DOACs. There were no significant differences between the two groups. CROMIS-2 (The Clinical Relevance of Microbleeds in Stroke Study) compared all-cause 90-day mortality, functional outcome, ICH volume and haematoma expansion between patients with ICH associated with VKA and ICH associated with DOAC. The outcome of ICH while on DOACs remains a topic for research. 12вЂ“14 This could be explained by inconsistent use of DOACs resulting in subtherapeutic levels given their short half-lives. The rate of ischaemic stroke in patients taking DOACs has been noted to be higher when compared with warfarin. Additionally, the rate of only ICH is lower for DOACs at 0.3% to 0.4%вЂ‰when compared with warfarin at 0.7% to 0.8%. The rate of bleeding (including major haemorrhage, fatal haemorrhage, haemorrhagic stroke or ICH) is also lower for DOACs at 3% to 4%вЂ‰when compared with warfarin at 5% to 6%. 6 Recent trials including ARISTOTLE (apixaban), 7 8 RE-LY (dabigatran), 9 ROCKET AF (rivaroxaban), 10 ENGAGE AF-TIMI 48 (edoxaban) 10 on stroke and systemic embolism have shown non-inferiority of DOACs when compared with warfarin. DOACs do not require frequent monitoring of the international normalised ratio (INR) and have shorter half-lives with fewer drug interactions, making them more favourable for use than warfarin. Dabigatran (Pradaxa, Boehringer Ingelheim Pharmaceuticals) is a direct thrombin inhibitor, whereas rivaroxaban (Xarelto, Janssen Pharmaceuticals), apixaban (Eliquis, Bristol-Myers Squibb Company), edoxaban (Savaysa and Lixiana, Daiichi Sankyo) and betrixaban (Bevyxxa, Portola Pharmaceuticals) fall in the category of FXa-Is. Comparison of efficacy and safety between DOACs and VKAsДirect thrombin inhibitors and factor Xa inhibitors (FXa-Is) constitute the two classes of DOACs ( table 1).