Transcript Kcentra In-Service – Full

Kcentra In-service
Adam M. Spaulding
Emergency Medicine Pharmacist
Waterbury Hospital
Prothrombin Complex Concentrates
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Contain Vitamin K-dependent clotting factors
Made from pooled human plasma
Activated: Novoseven, FEIBA
Inactivated: Profilnine, Bebulin, Kcentra
4-F PCC (Kcentra)
 Contains clotting factors: II, VII, IX, X
– All non-activated factors
– Contains heparin and ATIII to keep non-activated
 Contains proteins C and S and human albumin
– Mimics natural milieu
– Confers less risk of thrombosis
 Inactive ingredients: sodium citrate, sodium chloride
Kcentra [package insert]. 2013
Clinical Use
 FDA indication:
– Emergent reversal of bleeding due to Vitamin K
Antagonists
– Emergent reversal of anticoagulation prior to
emergent procedures
 Un-labeled indications:
– Emergent reversal of direct Xa inhibitors (+/- DTIs)
– Bloodless surgery
Kcentra [package insert]. 2013
USA
Guyatt, et al. CHEST 2012. PMID: 22315257
Spahn et al. Critical Care 2013. PMID: 23601765
Europe
Dosing
 VKA reversal: Based on INR and weight (kg)
– INR 2-4: 25units/kg
– INR 4.1-6: 35units/kg
– INR >6: 50units/kg
 Direct Xa inhibitors: Empirically weight-based
– Clinical presentation/history: 25-50units/kg
 >1 dose not studied, not recommended and not
approved at WH
Kcentra [package insert]. 2013
Spahn et al. Critical Care 2013. PMID: 23601765
Administration
 Europe: given bedside via syringe (each vial
pushed slowly over 2-3 minutes)
 USA (and WH): Contents pooled in a bag and
infused at 8.4mL/min (500mL/hr)
 Follow by 50-100mL NS at same rate
 MUST BE GIVEN WITH VITAMIN K
UK transfusion guidelines: Beriplex. JPAC. 2009
Kcentra [package insert]. 2013
“Advantages” over FFP:
Practical and Theoretical
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No checking blood
groups or cross-matching
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No waiting for blood to
thaw
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Less risk for viral
transmission
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No risk of TRALI
Babilonia, et al. Thrombosis Journal 2014. PMID: 24742134
• Less complications from volume
overload
• ≤200mL vs 800-1000mL
• Reduce transfusion reactions?
• Much quicker reversal of INR
PMID: 23935011
PMID: 23935011
PMID: 23935011
Safety
Hanke, et al. Br J Anaest. 2013. PMID: 23335567
PCC FOR NOACS (HUMAN STUDIES)
Author, Year
N
Study Design
Findings
Erenberg, 2011
12
• Dabigatran or rivaroxaban po x 2.5 d
• Treated with 3F-PCC bolus iv
• Measured PT and ETP over 24 hours
Findings
• PCC reversed PT, ETP in rivaroxaban
treated patients
• PCC did not reverse dabigatran
Marlu, 2012
10 Men
Dabigatran or rivaroxaban po x1
• Collected blood samples
• Treated blood (3-F PCC, rFVIIa, aPCC)
Findings
• Dabigatran – rFVIIa most effective
• Rivaroxaban - PCC most effective
Khoo, 2013
8
• Dabigatran+aPCC (FEIBA)
• Blood treated with aPCC
Findings
• aPCC reversed dabigatran
Dinklaar, 2013
9
• Rivaroxaban+ 3F-PCC
• PCC added to rivaroxaban-treated
samples
• Coagulation assays performed
Findings
• PCC normalized thrombin generation
• Did not normalize PT w/ initial dose
• Dose of PCC required depended on
type of assay
Korber, 2013
10
• Rivaroxaban + PCC/rFVIIa
• Blood samples treated with
rivaroxaban
• Added PCC and rVIIa
• Performed clotting assays
Findings
• PCC had no effect on clotting tests
• rVIIa reversed PT and clotting factor
time
Dabigatran
• Reversed with aPCC in 2/2 studies
Lazo-Langner, et al. Critical Care 2013. PMID: 23806169
Rivaroxaban
• Reversed with PCC in 3/4 studies
PCC for NOACs:
Limitations in the literature
 Many more animal studies than human studies
 Human clotting factors behave differently in non-humans
 Small “N”
 Wide variability in study design
 Different doses
 Different species
 Different outcomes (coagulation assays, bleeding time, blood loss)
 Healthy volunteers
 Reversal agents merely added to blood samples
 Extrapolation to bleeding patients?
 Outcomes include normalization of clotting tests as proxy for
bleeding cessation**
Our protocol
 Restrictions for use at Waterbury Hospital
Kcentra Restrictions
Inclusion Criteria:
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Treatment of life-threatening bleeding or major bleeding associated with
hemodynamic instability in patients taking warfarin, rivaroxaban or apixaban
(including those who present with intracranial hemorrhage and declining
neurologic status)
Rapid correction of INR in patients receiving warfarin and who required immediate
reversal for life-sustaining procedures (anticipated need within 8 hours)
Exclusion Criteria:
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Known history of heparin-induced thrombocytopenia
Disseminated intravascular coagulation is suspected
Able to tolerate FFP volume and slower time of onset
Bleeding due to dabigatran (advise the physician over the phone)
Bleeding in the absence of an anticoagulant
Our Protocol
Ordering and dosing
Preparation
Administration
Ordering/Dosing
 Limited to ER, Neurology, Trauma surgery and ICU
– STAT call to ED Pharmacist/Pharmacy
 Doses will be rounded to the nearest 500 factor
IX units by the verifying pharmacist
– Use the rounding cheat sheet
– Order must be re-entered
 Pharmacist verifies appropriate indication, dose
and that a concurrent order for Vitamin K exists
 Only one dose of Kcentra can be ordered/patient
Dosing Cheat Sheet
Storage and Preparation
Kcentra Kit Contents
(1) Contents list sheet
(10) Kcentra 500unit vials
(10) Manufacturer supplied 20mL diluents (SWFI)
(10) Mix2Vial transfer devices
(5) alcohol swabs
(4) 60mL syringes
(1) Intravia 250mL empty bag
(1) Premade label
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Nominal potency will be used to calculate # of vials
Vials will be reconstituted with Mix2Vial transfer set provided
Multiple syringes will be pooled into a 250mL Intravia container
LOT numbers will need to be documented in the medical record*
Administration
 Administer within 4 hours of reconstitution
 Dedicated line required for administration
– 2 separate lines preferable (one for Vitamin K)
 Administered as an infusion @ 500ml/hr
 After infusion, the line needs to be flushed with
NS
– Replace Kcentra with 50-100cc bag NS and run at
same rate
 Need f/u INR 30 minutes after infusion
Cost
 $1.34 per unit
 ~$670 per vial (~500 units)
 $6700 for 5,000 unit dose (max dose)
 Unlike Genentech for alteplase, Kcentra is not
reimbursed/replaced if the product is mixed, but not
used
 CMS offers NTAP program for Kcentra
 If total costs of inpatient stay exceed the MS-DRG payment
amount, NTAP attempts to pay the difference
 Payment is NOT based on the dosage of Kcentra administered
 Additional payments through NTAP are capped at $1,587.50
References
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Kcentra [package insert]. King of Prussia, PA: CSL Behring; 2013.
Guyatt GH, Aki EA, Crowther M, et al. Executive Summary: Antithrombotic therapy and prevention of
thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012; 141: 7S-47S. PMID: 22315257
Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major trauma:
an updated European guidelines. Crit Care 2013; 17(2):R76. PMID: 23601765
Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory
Committee (JPAC). UK Transfusion Guidelines: Beriplex. 2009. URL:
http://www.transfusionguidelines.org.uk/document-library/documents/prothrombin-complexconcentrate-beriplex-oxford-radcliffe-hospitals-2009
Babilonia K, Trujillo T. The role of prothrombin complex concentrates in reversal of target specific
anticoagulants. Thrombosis Journal 2014;12:8. PMID: 24742134
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in
patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase
IIIb study. Circulation 2013; 128:1234-1243. PMID: 23935011
Hanke AA, Joch C, and Gorlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated
prothrombin complex concentrate (Beriplex® P/N): a pharmacovigilance study. Br J Anaest. 2013; 1-9.
PMID: 23335567
Lazo-Langner A, Lang ES, Douketis J. Clinical review: clinical management of new oral anticoagulants: a
structured review with emphasis on the reversal of bleeding complications. Critical Care 2013; 17:230.
PMID: 23806169
Questions?