Efficacy and Safety of Four Factor Prothrombin Complex Concentrates As a Reversal Agent for Oral Xa Inhibitors
Authors: Gundabolu Krishna , Trevarrow Brian , Koepsell Scott A 
Published: October 2019

Abstract
INTRODUCTION: FDA had approved three oral Xa inhibitors (OXI) Rivaroxaban (R), Apixaban (A) and Edoxaban for the treatment of venous thromboembolism (VTE) and cardiac thromboembolism prophylaxis in patients with non-valvular atrial fibrillation (NV A fib). The incidence of major bleeding and intracranial hemorrhage (ICH) is lesser with OXI's compared to warfarin but due to lack of appropriate reversal agents, management of such situations are very difficult. In the healthy human volunteer studies Andexanet alfa, Activated or non-activated prothrombin complex concentrates (PCC) and recombinant factor VIIa have been studied but there is lack of good real time data due to which practices are diverse. KCentra (K) was FDA approved in 2013 for urgent reversal of warfarin in cases of acute major bleeding or emergent surgery and consists of inactive factors II, VII, IX, X, Protein C and Protein S. Our institution uses Kcentra to reverse OXIs starting in November 2014.
METHODS: After IRB approval, all requests for KCentra from November 2014 to June 2015 were reviewed. For patients who were on an OXI and had acute life threatening bleeding or needed urgent surgery, the following variables were analyzed: demographics, clotting assays, dose and type of OXI, length of hospital stay, mortality, thrombotic events and medications.
RESULTS: 12 requests for Kcentra were placed and at physicians discretion ten patients ultimately received it of which none died during that hospitalization. One of the two patients who didn't receive rapidly died (hepatic bleeding). Results include: Median age of 74 years (65-86 y), 6 were male (50%). Indications for OXI therapy- NV A fib (n=6), unprovoked VTE (n=2), provoked VTE (n=1), cancer associated VTE (n=1). The OXIs used were R (n=5) and A (n=5). Median time of administration of K from the last intake of the drug was 10 hours (8-15 h) and median length of hospital stay was 8 days (4-26). In 9 patients with available data, the pre-K median INR and PT was 1.4 (1.1-2.5)/20.6 s (11.8- 21.8s) and the median post-K INR and PT was 1.1 (1-1.8), 16.9 s (13.4-30.2 s), median activated partial thromboplastin time (aPTT) before K is 30.6 s (27.5-40.2 s). Anti Xa activity was tested in only 3 patients before K administration with a median of 0.66 IU/mL (0.54-1.48) and In 2 patients after K with a mean of 0.51 (0.32-0.71). Indications included emergent surgery in two (20%), ICH (20%)-1 spontaneous subdural hemorrhage (SDH) and 1 SDH after fall, 1 patient each on A and R, gastrointestinal bleeding (30%)- 1 gastric ulcer, 1 diverticular bleeding and 1 spontaneous with 2 of these 3 patients on R, Trauma (30%) causing spinal fractures (n=2) and hepatic bleeding (n=1). Median estimated glomerular filtration rate (eGFR), AST and ALT at the time of bleeding were 62 ml/min, 24 U/L and 17 U/L respectively. Median number of packed red blood cells (PRBC) transfused was 3 U with median hemoglobin at admission of 8.9 gm/dL (7-13.3) and median platelet count of 195 x10E3/cmm (163-356). The median K dose was 25 U/kg once (25-50) and one patient (10%) had acute VTE 14 days after administration (Lower extremity femoral DVT. 6 patients were on Aspirin (60%), 7 on p-glycoprotein (p-gp) inhibitors (70%), 3 (30%) on p-gp substrates & 2 (20%) on Selective Serotonin Reuptake Inhibitors.
CONCLUSION: Kcentra use was observed to be safe as a reversal agent with acceptable risk of thrombosis. Advanced age, concurrent use of P-glycoprotein inhibitors, antiplatelet agents appear to be risk factors for bleeding and use of OXI's with such risk factors should be cautioned.
Table. Age Sex Indication of A/C Drug Hospital days Indication for Kcentra # of PRBC ASA P-gp-X P-gp used 64 M NV Afib Rivaroxaban 20 mg QD 7 Spontaneous SDH 0 Yes Yes Atorvastatin 65 M UnprovokedVTE/PE Rivaroxaban 20 mg QD 9 Trauma-Liver cyst rupture 1 No No No 76 F ProvokedVTE Rivaroxaban 20 mg QD 4 Spontaneous GI bleeding Diverticular 7 No No No 70 M Cancer AssociatedVTE Rivaroxaban 20 mg QD 9 Bleeding penile cancer-surgery 4 Yes Yes EsomeprazolePravastatin 74 M UnprovokedVTE Rivaroxaban 20 mg QD 5 GI bleeding-gastric ulcer 3 No No No 84 F NV Afib Apixaban5 mg BID 4 Fall-SDH 0 Yes Yes Propafenone 73 F NV Afib Apixaban5 mg BID 26 Fall-Spinal trauma 2 No Yes Omeprazole 68 M NV Afib Apixaban5 mg BID 13 Surgery-Type A Aortic aneurysm 6 Yes Yes AmiodoroneSimvastatin 84 F NV Afib Apixaban5 mg BID 23 Trauma-Facial/spine fracture 3 Yes Yes Pravastatin 86 M NV Afib Apixaban5 mg BID 5 Spontaneous GI bleeding 6 Yes Yes Amiodorone

Disclosures
Off Label Use: Kcentra is not FDA approved as a reversal agent for oral direct Xa inhibitors.