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  • 1. New Blood Products and Their Roles in Hemorrhagic Stroke Doug Morrison Medical Director of Transfusion Medicine Fraser Health
  • 2. New Blood Products in Hemorrhagic Stroke - Outline Recombinant factor VIIa in ICH Oral Anticoagulant Associated Intracerebral Hemorrhage Therapeutic options for reversal of Warfarin Prothrombin Complex Concentrates Review of CBS National Distribution Data for PCC Fraser Health Audit of PCCs Revised NAC guidelines 2011 (TMAG Perspective) Possible role for urgent reversal of new oral anticoagulants
  • 3. rFVIIa : Niastase Hemophilia with inhibitors congenital acquired Acquired von Willebrand’s disease Congenital Factor VII deficiency Congenital platelet dysfunction syndromes
  • 4. Coagulation pathway Bleeding - FVIIa
  • 5. Original Article Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage Stephan A. Mayer, M.D., Nikolai C. Brun, M.D., Ph.D., Kamilla Begtrup, M.Sc., Joseph Broderick, M.D., Stephen Davis, M.D., Michael N. Diringer, M.D., Brett E. Skolnick, Ph.D., Thorsten Steiner, M.D., for the FAST Trial Investigators N Engl J Med Volume 358(20):2127-2137 May 15, 2008
  • 6. Study Overview In a previous phase 2 placebo-controlled trial, recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcome in patients with intracerebral hemorrhage Those findings were not reproduced in this phase 3 trial, in which rFVIIa reduced hematoma growth but did not improve clinical outcomes
  • 7. Kaplan-Meier Survival Curves Mayer SA et al. N Engl J Med 2008;358:2127-2137
  • 8. Conclusion Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 μg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04).
  • 9. The Practical Management of Intracerebral Hemorrhage with Oral Anticoagulatn Therapy -Review Risk 0.2 % - 0.6 % per year of treatment - VKA 70% are intracerebral, 30% subararchnoid OAT-ICH represent 15% of all ICH Many have supratherapeutic INR; however most have a therapeutic INR 30 day mortality 12-60% & double that of nonanticoagulated patients Hematoma volume & GCS major determinants L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228240
  • 10. Oral Anticoagulation Therapy Associated Intracerebral Hemorrhage (OAT-ICH) Hematoma enlargement is a major determinant of the poor prognosis in OAT-ICH OAT-ICH is associated with greater baseline volume of ICH, more hemorrhage expansion & greater mortality than spontaneous ICH Approx 50% of OAT-ICH patients present a secondary volume expansion compared to 17% of non-OAT-ICH patients L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228-240
  • 11. (OAT-ICH) Urgent Reversal of Coagulopathy Based on the premise that this will reduce the risk hematoma expansion or re-bleeding and facilitate surgical intervention, if indicated. immediate IV administration of vitamin K Factor replacement – Prothrombin complex concentrates (PCC), or – FFP (15-30 ml/kg) L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228-240
  • 12. NIKE Principles in the Reversal of Oral Anticoagulation Therapy Associated Intracerebral Hemorrhage N – Normalize the INR I – Immediate reversal in all patients, regardless of the size of the hemorrhage K – vitamin K must be included to avoid rebound elevation of the INR E – all levels of INR Elevation require urgent correction L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228-240
  • 13. Therapeutic options for reversal of Warfarin Withhold VKA – Two to three days to reach INR < 1.5 Vitamin K – Oral: slow decrease in INR over 12-24 hr – I.V.: onset in 4-6 hr, INR < 1.5 in 12-16 hr Factor replacement – 30 IU/kg (70kg) – FFP 2000 ml – PCC 2000 IU (80ml)
  • 14. Target INR and coagulation factor concentration Minor bleeding or invasive procedures: – clotting factor levels of 20 – 40% or – an INR of 1.5 – 2.0 Severe injury/bleeding or major surgery: – factor levels of 50 – 60% or – INR of 1.0 – 1.5
  • 15. Dzik WH. Transfusion Therapy: Clinical Principles and Practice, 2nd edition, AABB Press 2005 % coagulation Factors 100 % INR and Coagulation Reversal zone of normal hemostasis 50 % 30 % zone of anticoagulation PT (sec) INR 12 13 15.5 19 21.8 1 1.7 1.3 2.0 24 2.2 30 32 3.0
  • 16. Frozen Plasma for Immediate reversal of Warfarin 15-30 ml/kg 1050 – 2100 ml (70 kg) Familiar and less expensive Slow correction due to infusion time Risks include – – – – Volume overload (TACO) Allergic reactions TRALI Disease transmission
  • 17. Prothrombin Complex Concentrates (PCCs) for immediate reversal 40 – 120 ml rapidly over 20 – 60 min Reconstitution required but no ABO or thawing Predictable effect Risks • Solvent detergent eliminates risk of enveloped virus • Low risk of thrombosis
  • 18. PCC – Octaplex® & Beriplex® Human plasma derived second generation PCCs Contain vitamin K dependent factors II, VII, IX, X, Protein C and Protein S Used in Europe for several years prior to August 2008 introduction of Octaplex® to Canada
  • 19. PCC Factor levels One 20mL vial contains: Component octaplex Beriplex in vivo T1/2 Factor II 220-760 IU 380-800 IU ~60h Factor VII 180-480 IU 200-500 IU ~4h Factor IX 400-620 IU 400-620 IU ~17h Factor X 360-600 IU 500-1020 IU ~31h Protein C 140-620 IU 420-820 IU ~47h Protein S 140-640 IU 240-680 IU ~49h Heparin 80-310 IU 8-40 IU Sodium citrate 17-27 mM 3 mM Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Beriplex Product Monograph, November 2010 Beriplex Product Monograph, November 2010
  • 20. Clinical indications for PCCs Reversal of warfarin therapy or vitamin K deficiency in patients exhibiting major bleeding Reversal of warfarin therapy or vitamin K deficiency in patients requiring urgent (< 6 hour) surgical procedure. National Advisory Committee on Blood and Blood products, September 2008
  • 21. Clinical use of PCCs Not recommended for: – Elective surgery reversal of oral anticoagulation – Treatment of elevated INRs without bleeding or need for surgical intervention – Massive transfusion – Coagulopathy associated with liver dysfunction – Patients with recent history of thrombosis, myocardial infarction, ischemic stroke, or Disseminated Intravascular Coagulation (DIC) National Advisory Committee on Blood and Blood products, September 2008
  • 22. Clinical use of PCCs Contraindicated: – Patients with a history of heparin induced thromobocytopenia (HIT) Insufficient evidence for use in pregnant women or pediatric patients.
  • 23. Octaplex® monograph dosing recommendations to normalize the INR (< 1.2) within 1 hr INR 2.0 – 2.5 2.5 – 3.0 3.0 – 3.5 > 3.5 ml/kg 0.9 – 1.3 1.3 – 1.6 1.6 – 1.9 > 1.9 IU/kg 22.5 – 32.5 32.5 – 40.0 40.0 – 47.5 > 47.5 70 kg patient 1500 – 2000 2000 – 3000 3000 – 4000 >4000 NAC recommendations are lower, due to the fact the package insert recommendations will correct factor levels to normal despite the fact that normal hemostasis does not require 100% factor levels.
  • 24. “Activated PCC” - FEIBA Activated PCCs are different products characterized by the presence of activated factors (especially VIIa) and used in treatment of patients with coagulation factor inhibitors. FEIBA is licensed and in use in Canada More thrombogenic than second generation PCCs – in the 1970’s post operative thrombotic complications occurred in 46% of Hemophilia B patients receiving perioperative PCC
  • 25. PCC Production All PCCs undergo at least 1 pathogen reduction step: Nanofiltration Solvent-detergent treatment Pasteurization However, theoretical concerns exist regarding: Non-lipid enveloped viruses (hepatitis A, parvovirus B19) Prions (vCJD) ?Emerging pathogens? Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789
  • 26. PCCs: Concerns Thrombogenicity Especially with high risk patients, repeated dosing Attempt to minimize by inclusion of proteins C & S, heparin, +/- antithrombin Meta-analysis of PCC use for rapid VKA reversal found thrombotic incidence was 1.8% (95% CI = 1.0-3.0%) for 4-factor PCCs (0.7% for 3-factor PCCs)1 Exacerbation of coagulopathy/DIC (esp. in liver disease) Heparin induced thrombocytopenia Allergic/anaphylactic reactions Pathogen transmission 1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438. 1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438.
  • 27. PCCs in Canada May 2007: Health Canada approves Octaplex® for rapid reversal of warfarin or VKD in patients exhibiting major bleeding or requiring urgent (<6hrs) surgery July 2008: CBS begins distributing Octaplex® Sept 2008: NAC Recommendations for the Use of Octaplex® Nov 2010: Health Canada approves Beriplex® P/N July 2011: Updated NAC Recommendations for the Use of PCCs Aug 2011: CBS begins distributing Beriplex® P/N
  • 28. National Advisory Committee on Blood and Blood Products NAC provides professional leadership and advice in matters directly affecting the practice of transfusion medicine in hospitals, including utilization of blood & blood products NAC reports to the provincial and territorial (PT) Ministries of Health and Canadian Blood Services (CBS) via the PT/CBS Blood Liaison Committee Two representatives are appointed by each P/T MoH + four CBS representatives.
  • 29. NAC 2008 PCC Recomendations Adult dose: 40mL (2 vials = 1000 IU FIX activity) and 10mg vit K IV Higher dose may be necessary for extremes of weight or INR Maximum total dose: 120mL (6 vials = 3000 IU FIX activity) Administered IV at rate not exceeding 23mL/min (2-3 vials/hr) Post-dose monitoring: INR @ 10-15min, clinical outcomes day 1 & 30 http://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdf http://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdf
  • 30. Fraser Health PCC audit PCC orders screened by on-call hematopathologist Generally following NAC recommendations with individualization of the dosage – Patients weight & INR – Nature of the bleeding & degree of urgency – Recommend PT (INR) 15 min after infusion & repeat if necessary – Emphasis on IV vitamin K
  • 31. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Feb-Dec 2010 Cases by Site 30 26 # of Cases 25 20 15 11 10 8 10 8 5 3 5 3 3 0 ARH BH CGH ERH LMH PAH RCH RMH SMH
  • 32. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Indications for the Use of Octaplex in FHA % of 71 cases Feb - Dec 2010 12.7% 1.4% 11.3% 40.8% Pre-procedural ICH 15.5% GIB 35.2% Trauma Medical/Surgical Hemorrhage Epistaxis
  • 33. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Distribution of Octaplex Doses Feb-Dec 2010 Number of Patients 25 20 15 10 5 0 500 1000 1500 2000 Dose of Octaplex Given 2500 3000+
  • 34. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Weight-based Dosing of Octaplex Feb-Dec 2010 Number of Patients 35 30 25 20 15 10 5 0 0 to 10 10 to 20 20 to 30 30 to 40 Dose given (units per kg) >40
  • 35. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Mean Dose of Octaplex Over Time 2000 1769 1600 1500 1500 1286 1454 1544 1385 1200 875 800 400 0 Before Feb-Apr MayFeb 09 09 July 09 AugOct 09 NovFebJulyOctFeb 09 June 10 Sept 10 Dec 10
  • 36. INR Results post infusion 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Patients < 1.5 1.5-1.7 1.8-2.0 >2.0 < 1 hr % 38 24 63% 9 87% 4 1 1-4 hr 26 1 64 3 85% 12 86% 3 Total < 4 hr 19 73% 43 67% 7 1
  • 37. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Clinical Effect of Octaplex in 46 Bleeding Patients Feb-Dec 2010 60% 50% 40% 30% 20% 10% 0% Stop Decrease Same Increase C an't tell
  • 38. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Outcome in 35 Surgical Patients After Octaplex Feb-Dec 2010 120% 100% 97.2% 80% 60% 40% 20% 2.8% 0% No excessive bleeding Excessive bleeding
  • 39. 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Thrombotic events & Deaths 71 patients Feb-Dec 2010 20 15 10 5 0 MI Stroke DVT/PE Death
  • 40. Thromboembolic Events 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Ischemic Stroke (4 patients) – 3 deceased (FH-81, 104, 109) – 1 survived (FH-139) Venous thrombosis (2 patients) – 1 died from cardiogenic shock with evidence of thrombosis of tricuspid valve (FH-127) – 1 survived pulmonary embolus (FH-76) Myocardial Infarction – Deceased patient FH-81 above
  • 41. Deaths 2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases) Associated with thromboembolic event (4) – Ischemic stroke (FH-104 & 109) – Ischemic stroke & MI (FH-81) – Thrombosis of tricuspid (FH-127) Not associated with thromboembolism and thought secondary to presenting illness (12)
  • 42. NAC 2011 Recommendations Octaplex® and Beriplex® to be used interchangeably Special patient populations: insufficient evidence to recommend use in patients on direct thrombin or FXa inhibitors (dabigatran, rivaroxaban) Major change = dosing recommendations: INR < 3.0 → 40mL (2 vials = 1000 IU) INR 3.0-5.0 → 80mL (4 vials = 2000 IU) INR >5.0 → 120mL (6 vials = 3000 IU) Stressed preference for IV vitamin K over PO (never IM/SC) Highlighted the lack of strong RCT evidence of clinical efficacy in this area warrants continued data collection http://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdf http://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdf
  • 43. BC TMAG’s view of revised 2011 NAC guidelines Endorse the NAC recommendations “for the treatment of critical bleeding” – INR < 3.0 → 40mL (2 vials = 1000 IU) – INR 3.0-5.0 → 80mL (4 vials = 2000 IU) – INR >5.0 → 120mL (6 vials = 3000 IU) However, in the absence of critical bleeding, dosing should reflect the patient’s weight, INR and urgency of the situation with titration of the dose whenever possible.
  • 44. Novel Oral Anticoagulants Reversible, direct inhibitors of common pathway coagulation factors: – Thrombin (FIIa) = dabigatran (Pradax®) – FXa = rivaroxaban (Xarelto®), apixaban 2008: dabigatran and rivaroxaban licensed by Health Canada for posthip and knee replacement thromboprophylaxis Oct 2010: dabigatran approved by Health Canada for stroke prevention in patients with atrial fibrillation All 3 agents have completed or are nearing completion of trials in atrial fibrillation, acute VTE treatment, and secondary VTE prevention
  • 45. Novel Oral Anticoagulants Unlike warfarin, these agents have a broad therapeutic index Routine laboratory monitoring is not required Both agents undergo mainly renal excretion with a T1/2 of approx 12 hrs – Dabigatran (35% protein bound) is amenable to dialysis, but not rivaroxaban – Can give activated charcoal for acute (<2hrs) overdose of either drug But, if a patient anticoagulated with these drugs presents with life threatening bleeding (i.e. ICH) or requires emergency surgery... – How do we assess their degree of anticoagulation? – Can we urgently reverse the anticoagulant effects of these drugs?
  • 46. Dabigatran
  • 47. Why Dabigatran in Atrial Fibrillation? standard dose no monitoring no drug interactions improved outcomes – Thromboembolism:150 mg bid RR 0.66 (0.52 – 0.82) vs warfarin decreased bleeding complications
  • 48. Dabigatran Bleeding Risk End Point Warfarin (%) Dabigatran 110mg (%) Dabigatran 150mg (%) Major Bleeding 3.36 2.71 3.11
  • 49. Dabigatran Bleeding Risk End Point Warfarin (%) Dabigatran 110mg(%) Dabigatran 150mg (%) Age >75 yrs 0.61 0.14 0.26 Age >75 yrs 1.0 0.37 0.41** Intracranial Bleeding **p = 0.28 ? Underestimation of real life bleeding risk, due to comorbidities & use in renal insufficiency and the need for lower dosing in elderly patients
  • 50. Laboratory tests for Novel Anticoagulants There is currently no single laboratory test routinely available that provides specific evaluation of the anticoagulation effect of Dabigatran or other novel anticoagulants. Dabigatran excretion is prolonged in patients with abnormal renal function. Creatinine/GFR measurement is essential in bleeding patients.
  • 51. Laboratory tests for Novel Anticoagulants A normal INR and PTT should exclude the presence of significant levels of Dabigatran or other novel anticoagulants in most, but not all, patients. The most sensitive test for the presence of Dabigatran is the Thrombin Time – a normal result excludes the presence of this drug, but not the other new oral anticoagulants.
  • 52. Laboratory tests for Novel Anticoagulants There are currently no locally available tests that accurately quantifies Dabigatran anticoagulant activity or that of the other novel anticoagulants. The most sensitive test for the presence of Direct Factor Xa inhibitors is the PT/INR.
  • 53. No Antidote for Dabigatran PCC (Octaplex/Beriplex) and recombinant Factor VIIa (rFVIIa) have not been evaluated in clinical settings, and have NOT been demonstrated to improve coagulation assays in experimental and volunteer studies. These agents have been shown to decrease bleeding in a rat tail vein model despite absence of reversal of coagulation parameters.
  • 54. FFP
  • 55. PCC
  • 56. rfVIIa
  • 57. CRYO
  • 58. Animal & in vitro Data Rivaroxaban – Rat tail model: bleeding time prolongation due to rivaroxaban corrected with 50 IU/kg Beriplex® (7 vial dose for 70kg adult) but not with 25 IU/kg dose1 Dabigatran – Rabbit kidney injury model: Beriplex® corrected bleeding time and amount of blood loss in dose-dependent fashion2 – Rat tail model: bleeding time prolongation due to dabigatran corrected with 50 and 100U/kg Feiba and 100ug/kg rFVIIa; PTT elevation partially corrected with rFVIIa but not with Feiba3 – Human plasma: Feiba corrected dabigatran-inhibited ETP4 1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC251 1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC251 2. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486 2. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486 3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 0370 3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 0370 4. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127 4. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127
  • 59. PCC = 50 IU/kg Cofact® (3500 IU = 7 vials for 70kg adult) CIRCULATIONAHA.111.029017. Published online before print September 6, 2011 CIRCULATIONAHA.111.029017. Published online before print September 6, 2011
  • 60. Study Methods (cont.) 12 healthy male paid volunteers PPP samples taken pre-drug, pre-reversal agent, and postreversal agent at 15 min, 30 min, 1 hr, 2 hrs, 4hrs, 6hrs, 24 hrs Lab measurements used: – Rivaroxaban: PT, endogenous thrombin potential (ETP) – Dabigatran: aPTT, TT, ecarin clotting time (ECT) CIRCULATIONAHA.111.029017. Published online before print September 6, 2011 CIRCULATIONAHA.111.029017. Published online before print September 6, 2011
  • 61. Rivaroxaban Results High-dose PCC completely overcame rivaroxaban inhibition of FXa in the PT and ETP laboratory assay systems CIRCULATIONAHA.111.029017. Published online before print September 6, 2011 CIRCULATIONAHA.111.029017. Published online before print September 6, 2011
  • 62. Dabigatran Results High-dose PCC had no detectable effect on dabigatran inhibition of thrombin in the PT and ETP laboratory assay systems Problem: these assays are merely surrogates for clinical bleeding tendency CIRCULATIONAHA.111.029017. Published online before print September 6, 2011 CIRCULATIONAHA.111.029017. Published online before print September 6, 2011
  • 63. Management of Bleeding Novel Anticoagulants oral charcoal if ingestion within 2 hours mechanical compression if possible and surgical intervention where indicated crystalloid replacement and hemodynamic support, ensure maintenance of urine output (aggressive diuresis)
  • 64. Management of Bleeding Novel Anticoagulants blood product transfusion as indicated for anemia, thrombocytopenia or coagulopathy unrelated to dabigatran hemodialysis, particularly in the setting of overdose or renal impairment Consult Hematology
  • 65. Management of Bleeding Novel Anticoagulants the use of FFP, PCC, activated PCC or rFVIIa on a routine basis cannot be recommended as part of an effective reversal protocol based on the current medical literature Nonetheless, there are case reports that describe the use of FEIBA, rFVIIa or PCCs (Octaplex or Beriplex) and these agents are being used off-label to treat ICH in many Canadian hospitals, without any published evidence of efficacy.
  • 66. Management of Bleeding Novel Anticoagulants There is slightly more evidence of efficacy in humans of the use of PCC when dealing with bleeding associated with Rivaroxaban, possibly by overwhelming the inhibitor with Factor X Anecdotal reports suggest that FEIBA may be more effective than Octaplex or Beriplex in the context of Dabigatran
  • 67. Factor VIIa for Dabigitran In a controlled trial on healthy subjects the Melagatran-induced effects on PTT, TGP & platelet aggregation were not affected Based on these results it appears that VIIa is not effective in reversing DTI FAST study in non-anticoagulated ICH
  • 68. …So What To Recommend? Supportive therapy, diuresis +/- dialysis Consider antifibrinolytic therapy Tranexamic acid (10 mg/kg IV or 25 mg/kg orally, rounded to the nearest 500 mg.) For acute life threatening bleeds or urgent (<6hrs) surgery: – Clinician to discuss case with on-call hematopathologist for possible administration of “reversal agent” – Current recommendation of VGH hematology / hematopathology groups is 3000 IU PCC IV infusion (6 vials = 120 mL) – Outcomes (bleeding, thrombosis, death) should be monitored Rationale: – Attempt to overcome inhibition by increasing IIa and Xa generation – Avoid higher thrombosis risk of rFVIIa and FEIBA
  • 69. Conclusions Factor VIIa not recommended for treatment of ICH For urgent warfarin reversal, NAC 2011 recommendations advocate PCC dosage according to INR: – INR < 3.0 → 40mL (2 vials = 1000 IU) – INR 3.0-5.0 → 80mL (4 vials = 2000 IU) – INR >5.0 → 120mL (6 vials = 3000 IU) Very little evidence to guide situations that warrant immediate reversal of new anticoagulants – Current VGH recommendation = 3000 IU PCC – This is likely to change as the literature evolves!
  • 70. The End
  • 71. Beriplex® vs Octaplex® Similar content of vitamin K dependent factors including protein C & S Plus anti-thrombin III (0.6 IU/ml) & albumin Protein Z (36 IU/ml - ?proteolysis of Xa) Less heparin (0.5 IU/ml vs 6.0 IU/ml) Pasteurization vs S/D (both nano-filtered)
  • 72. PCC Factor levels One 20mL vial contains: Component octaplex Beriplex in vivo T1/2 Factor II 220-760 IU 380-800 IU ~60h Factor VII 180-480 IU 200-500 IU ~4h Factor IX 400-620 IU 400-620 IU ~17h Factor X 360-600 IU 500-1020 IU ~31h Protein C 140-620 IU 420-820 IU ~47h Protein S 140-640 IU 240-680 IU ~49h Heparin 80-310 IU 8-40 IU Sodium citrate 17-27 mM 3 mM Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Beriplex Product Monograph, November 2010 Beriplex Product Monograph, November 2010
  • 73. REVNEWANTICO… Study in Healthy Volunteers of the Reversion by Haemostatic Drugs of the Anticoagulant Effect of New Anti-thrombotics (REVNEWANTICO) – 10 healthy male volunteers, open-label, no control arm – Each given single dose of 20mg dabigatran or 150 mg rivaroxaban – Reversal agents: • Dabigatran = PCC, rFVIIa, Feiba • Rivaroxaban = rivaroxaban decoy (FXa-GLAless) – Primary outcome = thrombin generation time normalization – Secondary outcomes: • Dabigatran = normalization of TT and aPTT • Rivaroxaban = normalization of PT and anti-Xa activity – Completion date: June 2011 http://clinicaltrials.gov/ct2/show/NCT01210755 http://clinicaltrials.gov/ct2/show/NCT01210755