1. Oral anticoagulation reversal: The missing PCC’s of the puzzle Jason Makii, Pharm.D., BCPS Clinical Pharmacy Specialist, Neurosciences Critical Care Department of Pharmacy Services, University Hospitals Case Medical Center Clinical Assistant Professor, Department of Neurology Case Western Reserve University School of Medicine

2. Disclosures Off-label usage

3. Objectives Describe the pharmacology of prothrombin complex concentrates (PCC) Discuss the role of PCC in the reversal of oral anticoagulation Apply this presentation content to a patient case

4. JF 81 yom – PMH: HTN, CHF, DM, A.fib – Home Meds: ASA, coumadin, carvedilol, clonidine, furosemide, lisinopril, metformin, glipizide, aldactone, – HPI: Woke up with headache Progressively worsened → Left sided weakness GTC seizure in ED Patient Case

5. Labs 165 8.5 44.7 14.7 170 142 104 26 4.430 1.5 36.9 44 3.3

6. Patient Case Labs Vitals 94 bpm146/104O 2 Sat 96% (16 bpm) 109 kg 165 8.5 44.7 14.7 170 142 104 26 4.430 1.5 36.9 44 3.3

7. Imaging…

8. What do you do?!

9. Guidelines… ICH AHA/ASA 2010 “Correct INR as rapidly as possible” Vitamin K infusion plus Fresh frozen plasma (FFP) Prothrombin complex concentrate (PCC) Recombinant factor VIIa

10. Guidelines… Chest 2012 Rapid reversal desirable Vitamin K with one of the following: Prothrombin complex concentrate (PCC) Fresh frozen plasma (FFP) Recombinant factor VIIa

11. Coagulation Review

12. OAC reversal Phytonadione Blood Products PCC

13. Phytonadione (Vitamin K)

14. Necessary for hepatic synthesis of clotting factors II, VII, IX, X Adjunctive therapy for more rapidly acting agents Dosing: 10 mg IVPB over 10-20 min – Life-threatening bleeding (AHA-Class I, LOE: C; Chest Grade 2C) Morganstern et al. Stroke 2010 Holbrook et al. Chest 2012

15. Blood Products Platelets – ICH with history of anti-platelet use? – AHA – Class IIb; LOE: B Morganstern et al. Stroke 2010

16. Blood Products Fresh Frozen Plasma – Pro: Contains required clotting factors – II, VII, IX, X – Cons: Infection transmission Infusion reactions (TRALI) Preparation time Volume Morganstern et al. Stroke 2010 Holbrook et al. Chest 2012 – Recommendation AHA – Class I; LOE: C Chest – Grade 2C (against use of plasma)

17. Prothrombin Complex Concentrate (PCC) Plasma-derived factor concentrates – 3-factor (3F-PCC): Factors II, IX, X – 4-factor (4F-PCC): Factors II, VII, IX, X – Activated PCC (aPCC): Factors II, aVII, IX, X Kalus AJHP 2013

18. 3 – Factor PCC Pearls: Contains heparin (Bebulin®) Exact vial potency indicated on vial Infuse no faster than: 2 mL/ min (Bebulin®) or 10 mL/min (Profilnine®) Kalus AJHP 2013

19. 3F-PCC Dosing for OAC Factor based: Boulis et al. (1999) Correction speed and complications Dose: FIX units = weight (kg) x target factor correction* (* = 40 to 50) Results Time to correction: 2.95+0.46 hrs for FIX vs. 8.9+1.51 hr for std. treatment (P<0.01) FFP volume: 399+ 271 mL for FIX and 2712+346 mL for std. treatment (P<0.0007) Thrombosis & Hemostasis (1997) 71

20. 3F-PCC Dosing for OAC Factor based: Boulis et al. (1999) Adverse Reactions No complications observed in the FIX group 5/8 patients treated with FFP experienced complications of fluid overload MI, SVT, Intubation, O 2 desaturation No outcome difference attributed to FIX Thrombosis & Hemostasis (1997) 71

21. 3F-PCC Dosing for OAC INR Based van Aart et al. (2006) Effectiveness of: Standard 400 IU FIX Individualized dosing based on weight and INR 400 IU FIX (50 kg, INR 2.8  < 2.1) – 2000 IU FIX (100 kg/INR 7.5  < 1.5) Results – target INR 15 min. after dose 89% individualized vs. 43% standard dose (p < 0.001) Thrombosis Research (2006) 118

22. 3F-PCC Dosing for OAC INR Based van Aart et al. (2006) Adverse Reactions 4/93 patients 2 non-bleeding CVA from hypotension 2 sepsis No outcomes differences evaluated Thrombosis Research (2006) 118

23. 4 – Factor PCC KCentra® Indication: Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist therapy in adult patients with acute major bleeding KCentra® FDA approved April 2013 Indicated for acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in adult patients with acute major bleeding Kalus AJHP 2013 KCentra Package Insert 2013

24. 4 – Factor PCC J Thromb Hemost 2008; 6 Pabinger et al. 2008 – Efficacy and Safety of stratified Beriplex ® P/N Primary: Normalization of INR at 30 min following PCC Secondary: Hemostatic efficacy in acute bleed and preventing major bleeding during interventional procedures – Results INR < 1.3 @ 30 min in 40/43 patients Clinical hemostasis was very good in 40/43

25. 4 – Factor PCC J Thromb Hemost 2008; 6 Pabinger et al. 2008 – Adverse reactions 25/43 experienced ADE – 6 classified as serious (3 deaths) » Death: 1 PE related to PCC, 2 infection » Survivors: Gastric Ca, Duodenal ulcer, stroke while on UFH – No outcomes differences evaluated

26. 4 – Factor PCC Dosing Pearls: Contains heparin Exact vial potency indicated on vial Infuse @ 3 units/kg/min, up to 210 units/min Kcentra Package Insert 2013 Pre treatment INR 2 – <44 – 6>6 Dose of Kcentra (units of Factor IX) / kg body weight 253550 Maximum dose (units of Factor IX) 250035005000

27. Activated PCC FEIBA package insert 2013 Factor Eight Inhibitor Bypassing Agent (FEIBA) – Anti-inhibitor coagulant complex indicated for use in hemophilia A and B patients with inhibitors for: Control and prevention of bleeding episodes Peri-operative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes

28. Activated PCC FEIBA package insert 2013 Factor Eight Inhibitor Bypassing Agent (FEIBA) – Two formulations available Vapor heated Nanofiltration – Contains Non-activated factors II, IX, and X Activated factor VII Does not contain heparin

29. Activated PCC Int J Emerg Med (2009) 2 FEIBA for reversal of warfarin induced coagulopathy – Wojcik et al (2009) Retrospective review of FFP practices vs. FEIBA protocol – 500 units of FEIBA when INR < 5 – 1000 units of FEIBA when INR > 5 Primary Endpoint: INR normalization Secondary Endpoint: Survival of patients

30. Activated PCC Int J Emerg Med (2009) 2 FEIBA for reversal of warfarin induced coagulopathy – Wojcik et al (2009) Results – 36/72 FEIBA patients had 30 min. INR <1.4 vs. 23/69 FFP patients (P=0.017) – No difference in survival or length of hospital stay between the two cohorts Adverse Reactions – 5/72 FEIBA patients had ADE possibly related to FEIBA » MI, CR-DVT, 2-ACS, MVR  V fib arrest

31. Prothrombin Complex Concentrate (PCC) Pro – Less volume – Rapid INR reversal – No need for blood type and cross match Con – No large outcome studies – Thromboembolic complications – Recommendation AHA – Class IIa; LOE: B Chest – Grade 2C Morganstern et al. Stroke 2010 Holbrook et al. Chest 2012

32. Assessment Question PCC is short for: a)Protamine Complex Concentrate b)Protamine Coagulant Concentrate c)Pre-albumin Coagulation Complex d)Prothrombin Complex Concentrate e)Prothrombin Coagulant Concentrate

33. Assessment Question PCC does not contain: a)von Willebrand Factor b)Factor II c)Factor VII d)Factor IX e)Factor X

34. Target-specific oral anticoagulation Direct thrombin inhibitors Dabigatran (Pradaxa®) Factor Xa inhibitors Rivaroxaban (Xarelto®) Apixaban (Eliquis®)

35. Coagulation Review Apixaban Rivaroxaban Dabigatran

36. Target specific oral anticoagulation DabigatranApixabanRivaroxaban TargetThrombinFXa T 1/2 (h)12-179-149-13 Dosing75-150 mg BID2.5 – 5 mg BID10 – 30 mg Daily Peak Plasma conc.2 – 3 h1 – 3 h2 – 4 h Protein Binding~35%87%92 – 95 % Renal Elimination80%25%66% MetabolismPotent P-gp inducers/inhibitors CYP3A4 P-gp inducers/inhibitors CYP3A4 P-gp inducers/inhibitors MonitoringNot required Miesbach Thromb Hemost 2012

37. Dabigatran Annals of Pharmacotherapy September 2012 2.5 h HD session: TT decreased from 90.6 sec  60.2 sec (UL 19.9)

38. Rates of Major Bleeding Complications IndicationStudySever Bleeding Incidence VTE prevention after hip replacement RECORD 1Rivaroxaban 10 mg QD: 0.3 % Enoxaparin 40 mg QD: 0.1 % VTE prevention after hip replacement RECORD 3Rivaroxaban 10 mg QD: 0.6 % Enoxaparin 40 mg QD: 0.5 % VTE prevention after hip or knee replacement RE-NOVATE and RE-MODEL Dabigatran 150 mg QD 1.3% Enoxaparin 40 mg QD 1.3% Stroke prevention in atrial fibrillation RE-LYDabigatran 150 mg BID: 3.1% Warfarin QD: 3.4% Secondary prevention of ACS APPRAISE-2Apixaban 5 mg BID: 1.3% Placebo: 0.5% Stroke prevention in atrial fibrillation ARISTOTLEApixaban 5 mg BID: 2.13% Warfarin: 3.09% Miesbach Thromb Hemost 2012

40. Eerenberg et al. (2011) 12 healthy male volunteers Age: 24+ 4; BMI: 23+3 kg/m 2 Laboratory Assessment Prothrombin time (PT) Endogenous thrombin potential (ETP) Activated partial thromboplastin time (aPTT) Thrombin clotting time (TT) Ecarin clotting time (ECT)

41. Eerenberg et al. (2011) Study Design

42. Eerenberg et al. (2011) Rivaroxaban

43. Eerenberg et al. (2011) Dabigatran

44. Eerenberg et al. (2011) Conclusions PCC neutralized the surrogate markers of bleeding for rivaroxaban PCC has no effect on the surrogate markers of bleeding for dabigatran

45. Dabigatran / FEIBA – Case Reports J Emerg Med 2014 FEIBA = 40 units/kg FEIBA = 27.5units/kg FEIBA = 26 units/kg

46. Antidotes… aDabi-Fab (Dabigatran) 350 times greater affinity for Dabigatran than thrombin PRT4445, Portola Pharmaceuticals Andexanet alfa completed Phase 1 and 2 studies in 65 patients Expert Opin Investig Drugs 2013 Blood 2013

47. Dabigatran (PI information) No specific reversal agent available HD can remove dabigatran, but limited use as treatment for bleeding aPCC, rFVIIa, 3F-PCC may be considered, but no clinical trials data Protamine and Vitamin K are not expected to work Consider platelets if thrombocytopenic or have history of long term anti-platelet use

48. Apixaban (PI information) No specific reversal agent available Not expected to be dialyzable Protamine and Vitamin K are not expected to work No experience with antifibrinolytic agents No scientific rationale for desmopressin or aprotinin PCC, aPCC or rFVIIa may be considered, but lack clinical studies Charcoal reduces absorption of apixaban

49. Rivaroxaban (PI information) No specific reversal agent available High protein binding, not expected to be dialyzable Protamine and Vitamin K are not expected to work Partial PT reversal was seen with PCC in healthy volunteers aPCC or rFVIIa have not been evaluated

50. Patient Case Received 2500 units Kcentra Wt. 110 kg, INR 3.3 Mild neurological deficits Resumes ADL Occasionally disoriented Some short term memory loss Discharged to Rehab after 10d hospital stay

51. Summary PCC preferred agents for reversal of warfarin associated hemorrhage 4F-PCC may have a role in FXa inhibitor reversal aPCC may have a role in DTI reversal Specific antidotes for DTI and FXa inhibitors are currently in development

52. Oral anticoagulation reversal: The missing PCC’s of the puzzle Jason Makii, Pharm.D., BCPS Clinical Pharmacy Specialist, Neurosciences Critical Care Department of Pharmacy Services, University Hospitals Case Medical Center Clinical Assistant Professor, Department of Neurology Case Western Reserve University School of Medicine