Oral anticoagulation reversal: The missing PCC’s of the puzzle

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. Patient Case • 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

5. Patient Case • Labs 14.7 142 104 26 4.4 30 1.5 36.9 3.3 8.5 165 170 44 44.7

6. Patient Case • Labs • Vitals 94 bpm 146/104 O2 Sat 96% (16 bpm) 109 kg 14.7 142 104 26 4.4 30 1.5 36.9 3.3 8.5 165 170 44 44.7

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. Phytonadione (Vitamin K) • 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 • Recommendation • AHA – Class I; LOE: C • Chest – Grade 2C (against use of plasma) Morganstern et al. Stroke 2010 Holbrook et al. Chest 2012

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, O2 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 • 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 J Thromb Hemost 2008; 6

25. 4 – Factor PCC • 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 J Thromb Hemost 2008; 6

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

27. Activated PCC • 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 FEIBA package insert 2013

28. Activated PCC • 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 FEIBA package insert 2013

29. Activated PCC • 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 Int J Emerg Med (2009) 2

30. Activated PCC • 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 Int J Emerg Med (2009) 2

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

33. Coagulation Review Apixaban Rivaroxaban Dabigatran

34. Target specific oral anticoagulation Miesbach Thromb Hemost 2012

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

36. Rates of Major Bleeding Complications Miesbach Thromb Hemost 2012

38. Eerenberg et al. (2011) • 12 healthy male volunteers • Age: 24+ 4; BMI: 23+3 kg/m2 • Laboratory Assessment • Prothrombin time (PT) • Endogenous thrombin potential (ETP) • Activated partial thromboplastin time (aPTT) • Thrombin clotting time (TT) • Ecarin clotting time (ECT)

39. Eerenberg et al. (2011) • Study Design

40. Eerenberg et al. (2011) • Rivaroxaban

41. Eerenberg et al. (2011) • Dabigatran

42. 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

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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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