Human Prothrombin Complex (PCC) (Beriplex P/N) in the emergency reversal of anticoagulation BCSLS Congress 2012 Kamloops, BC

Transcription

1 Human Prothrombin Complex (PCC) (Beriplex P/N) in the emergency reversal of anticoagulation BCSLS Congress 2012 Kamloops, BC Ayman Kafal Medical Affairs, Leader CSL Behring Canada 1

2 Prothrombin Complex Concentrate in anticoagulant reversal

3 Contents Anticoagulant reversal Epidemiology Mode of action Guidelines Prothrombin complex concentrates Beriplex P/N History and differentiation Indications and clinical use Clinical studies in anticoagulant reversal Challenges of the new Oral Anticoagulants What do we know? 3

4 Epidemiology

5 Epidemiology of oral anticoagulation therapy France Netherlands USA Canada Population 60 million 16.3 million 280 million 34 million Oral anticoagulation 600,000 (1.0%) 325,072 (2.0%) 2,500,000 (0.9%) 306,000 (0.9%) Leading drug Phenindione Acenocoumarol Warfarin Warfarin 5 Pengo et al. J Thromb Thrombolysis 2006; 21: 73 7

6 Primary indications for warfarin in clinical practice in the USA Primary indication Percentage of use Atrial fibrillation 39% DVT or pulmonary embolism 27% Valve replacement 13% Cardiomyopathy 10% Stroke 6% Other venous thrombosis 1% Left ventricular thrombus 1% Peripheral vascular disease 1% Other arterial thrombosis 1% N=1020 patients taking warfarin; DVT, deep vein thrombosis 6 Wittkowsky and Devine. Pharmacotherapy 2004; 24:

7 Bleeding risk in oral anticoagulant therapy Major haemorrhage episodes per 100 patient-years (population cohort studies) % (clinical trials) Minor haemorrhage 2 24 episodes per 100 patient-years US: 26, ,000 major bleeds/year estimated Intracranial bleeding associated with oral anticoagulation Approximately 13,000 cases per year in US ~70% intracerebral bleeds ~30% subdural haematomas Mortality from intracranial bleeds ~60% Progression of bleeding in ~50% of patients within 24 hours 7 Flaherty et al. Neurology 2007; 68:116 21; Libby and Garcia. Arch Intern Med 2002; 162: ; McMahan et al. J Gen Intern Med 1998; 13: ; Schulman. N Engl J Med 2003; 349:

8 Mode of action of anticoagulant reversal

9 Mode of action of vitamin K antagonists Vitamin K Reductase Targets Factors II, VII, IX, X Proteins C and S Reductase Vitamin K H 2 Glutamic acid Vitamin K oxide -Carboxyglutamic acid Oral anticoagulation agents (warfarin, phenprocoumon, fluindione and acenocoumarol) block both reduction steps 9 Adapted from Hirsh J, et al. Chest 1995; 108:

10 10 Options available for reversal of oral anticoagulation Coagulation factor concentrates (e.g. Beriplex P/N) Contain all clotting factors required in a concentrated form Fast application possible Low volume (20ml) Predictable and measurable effect A demonstrated rapid decrease in INR to 1.3 within 30 min after administration of Beriplex P/N* *PM Beriplex P/N (human prothrombin complex),nov 5, Vitamin K Available orally or intravenous Readily available and inexpensive Response slow and unpredictable Not appropriate for emergencies Human plasma (e.g. FFP, 24-hour plasma) Contains factors that are required and some that are not required Risk of fluid overload and viral transmission Longer time required to thaw and transfuse the product Duration of infusion requires patient monitoring May fail to completely reverse anticoagulation FFP, Fresh Frozen Plasma; FVIIa, activated Factor VII Source: The Pharmacology and Management of Vitamin K Antagonists, CHEST, September 2004

11 Prothrombin complex concentrates in anticoagulant reversal

12 Emergency reversal of oral anticoagulation Human plasma PCC Volume High Low Availability Widespread Widespread Speed of administration Slow Rapid Preparation time Slow Rapid Virus inactivation procedure Pooled SD plasma: yes single donor plasma: no SD plasma: yes single donor plasma: no Yes Yes Blood group Group specific Not group specific 12 Balanced factor content Thrombogenicity SD, solvent-detergent inactivated Every factor present, high inter-individual variation SD plasma: yes Methylene blue: yes Concentrated factors and thromboinhibitors Variable between PCCs PCC, prothrombin complex concentrate Hanley. J Clin Pathol 2004; 57: ; Stanworth, et al. Br J Haematol 2004; 126: ; Makris et al. Br J Haematol 2001; 114: ; Kohler. Thromb Res 1999; 95: S13 7

13 Median clotting factor values (IU/dL) Median clotting factor values (IU/dL) Emergency reversal of oral anticoagulation: fresh frozen plasma vs PCCs Pre-treatment Post-treatment FFP (800 ml) PCC (25 50 IU FIX/kg) II VII IX X 0 II VII IX X Factor Factor patients were enrolled in the study. The objectify was to compare the efficacy of infusion of fresh frozen plasma (FFP) and clotting factor concentrates on correction of the coagulation FFP, fresh frozen plasma; PCC, prothrombin complex concentrate Makris et al. Thromb Haemost 1997; 77:

14 What is the ideal prothrombin complex concentrate? Rapid response time Balance of coagulation factors and thromboinhibitors Normalisation of INR Ideal PCC Virus inactivated 14 Fast coagulation correction Easy and fast to administer INR, International Normalised Ratio; PCC, prothrombin complex concentrate Spahn DR, Cerny V, Coats TJ, et al. Management of bleeding following major trauma: a European guideline. Crit Care 2007; 11: R17 doi: /cc5686 Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999; 95: S13 17

15 PCC : Coagulation factors One 20mL vial contains: Component octaplex Beriplex in vivo T1/2 Factor II IU IU ~60h Factor VII IU IU ~4h Factor IX IU IU ~17h Factor X IU IU ~31h Protein C IU IU ~47h Protein S IU IU ~49h Heparin IU 8-40 IU Sodium citrate mm 3 mm Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: Beriplex Product Monograph, November

16 Beriplex P/N(Human prothrombin complex)- history and differentiation

17 Product features of Beriplex P/N Beriplex P/N (Human Prothrombin Complex) is a balanced PCC, which contains all the components necessary to rapidly restore haemostasis in a bleeding emergency caused by vitamin K antagonists. Beriplex P/N contains all essential coagulation factors: Factor II, Factor VII, Factor IX and Factor X Beriplex P/N contains the thromboinhibitors: Protein C and Protein S Beriplex P/N comes in a 500 IU vial and 20 ml diluent vial Factors in Beriplex P/N are immediately bioavailable after administration Beriplex P/N is tested by PCR, nanofiltered and pasteurised with proven risk reduction for transmissable infectious agents Storage at room temperature (up to +25 C) The shelf life of Beriplex P/N is 36 months. Beriplex P/N comes with the Mix2Vial * application set Maximum infusion speed 8mL/min 17 * Mix2Vial is a registered trademark of West or one of its subsidiaries PCR, polymerase chain reaction Beriplex P/N Product Monograph, November 5, 2010

18 Indications for Beriplex P/N Beriplex P/N (Human prothrombin complex) is indicated in adults ( 18 years of age) for the treatment of bleeding and perioperative prophylaxis of bleeding in acquired deficiency of the prothrombin complex coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or in case of overdose of vitamin K antagonists, when rapid correction of the deficiency is required. No adequate study in subjects with congenital deficiency is available. Beriplex P/N can be used for the treatment of bleeding and perioperative prophylaxis of bleeding in congenital deficiency of any of the vitamin K dependent coagulation factors only if purified specific coagulation factor product is not available. 18 Beriplex P/N Product Monograph, November 5, 2010

19 Composition of Beriplex P/N Medical Ingredients Factor II Factor VII Factor IX Factor X Protein C Protein S Beriplex P/N 500 IU content per vial IU IU IU IU IU IU Beriplex P/N also contains heparin and human antithrombin III. 19 Beriplex P/N Product Monograph, November 5, 2010

20 Contraindications Known hypersensitivity to any of the components of the product Risk of thrombosis, angina pectoris, recent myocardial infarction (exception: lifethreatening haemorrhages following overdosage of oral anticoagulants, and before induction of a fibrinolytic therapy). In the case of disseminated intravascular coagulation, prothrombin complex-preparations may only be applied after termination of the consumptive state. Known history of heparin-induced thrombocytopenia 20

21 Beriplex P/N: dosing recommendations Guide for dosage: 1 IU FIX, FVII, FII, FX per kg body weight can be expected to raise FIX by 1.3%, FVII by 1.6%, FII, FX by 1.8% Required dosage: The dose will depend on the International Normalised Ratio (INR) before treatment and the targeted INR. In the following table approximate doses (ml/kg b.w.) of the reconstituted product and IU of Factor IX/kg b.w. required for normalisation of INR (e.g. 1.3) at different initial INR levels are given. Initial INR > 6.0 Approximate dose ml/kg b.w Approximate dose IU (Factor IX)/kg b.w Administered by i.v. injection Administration speed should not exceed 210 IU/min (~8 ml/min) Important for Beriplex P/N substitution: Determination of antithrombin activity in cases with suspected coagulation activation 21 i.v., intravenous Beriplex P/N Product Monograph, November 5, 2010

22 Key Features Summary Beriplex P/N Octaplex Infusion Speed 8.4ml/min Start: 1 ml/min Thereafter: 2-3 ml/min Maximum dose 5000 IU 3000 IU Double Virus Inactivation Safety Profile Nanofiltration and Pasteurisation Nanofiltration and Solvent/detergent Over 16 years UK Licence 2006 Ease and Convenience Room Temp. Storage Mix2Vial with tighter grip 3 years Mix2Vial 2 years 22

23 Beriplex P/N clinical trials in anticoagulant reversal

24 Beriplex P/N in healthy volunteers: Phase I pharmacokinetic (PK) study First study to evaluate the PK of coagulation factors and anticoagulant proteins after PCC administration 15 healthy volunteers (mean age 41 ± 13 years) Single 50 IU/kg dose of Beriplex P/N infused i.v. at a maximum rate of 210 IU/min Actual rate achieved = 7.9 ml/min Blood taken at 5, 10, 15 and 30 minutes then at frequent intervals up to 144 hours post-infusion Assess plasma levels of coagulation factors and thrombogenicity markers 24 i.v., intravenous; PCC, prothrombin complex concentrate Ostermann et al. Thromb Haemost 2007; 98: 790 7

25 Beriplex P/N Phase I PK Study: Demonstrated rapid and sustained increases in coagulation factors FX (%) FVII (%) FII (%) FIX (%) Mean PCC infusion 200IU/min; Mean PPC dose 150 ml (3750IU) Pre i.v. PCC Minutes: Post-Infusion Time Hours: Post-Infusion 25 i.v., intravenous; PCC, prothrombin complex concentrate Ostermann et al. Thromb Haemost 2007; 98: 790 7

26 Protein S (%) Protein C (%) i.v. PCC Beriplex P/N Phase I PK Study: Demonstrated rapid and sustained increases in thromboinhibitors Pre Minutes Hours Time 26 i.v., intravenous; PCC, prothrombin complex concentrate Ostermann et al. Thromb Haemost 2007; 98: 790 7

27 Beriplex P/N in anticoagulant reversal: prospective Phase III study Prospective, open, uncontrolled, multinational, Phase III study 43 patients from 25 centres in eight countries To determine the efficacy of prothrombin complex concentrates (Beriplex P/N) in the emergency reversal of oral anticoagulation when urgent surgical intervention is required in patients experiencing an acute bleed To document the safety and tolerability of Beriplex P/N Beriplex P/N dosing based on baseline INR: Baseline INR Dose of Beriplex P/N IU/kg IU/kg > IU/kg Rapid infusion: up to a maximum of 210 IU/min most patients simultaneously received i.v. vitamin K 27 INR, International Normalised Ratio; i.v., intravenous Pabinger et al. J Thromb Hemost, Volume 6, Number 4, April 2008

28 IU/mL Beriplex P/N Phase III study: coagulation factor and thromboinhibitor levels Patients receiving OAT were eligible for this prospective multinational study if their INR exceeded 2 and they required either emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Study endpoints included INR normalization (<1.3.) by 30 minutes after PCC infusion and haemostatic efficacy Before 30 mins 1 h 3 h 6 h 12 h 24 h 48 h Time Factor II Factor VII Factor IX Factor X Protein C Protein S 28 Pabinger et al. J Thromb Hemost, Volume 6, Number 4, April 2008

29 Mean INR ± SD Beriplex P/N Phase III study: INR response IU/kg (INR = ) 35 IU/kg (INR = ) 50 IU/kg (INR >6.0) 1 0 Pre- Inf Time after end of infusion (hours) INR, International Normalised Ratio Pabinger et al. J Thromb Hemost, Volume 6, Number 4, April 2008

30 Thank you Ayman Kafal CSL Behring Canada Medical Affairs, Leader Phone: Cell: