kcentra 072913 final
TRANSCRIPT
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Kcentra:
A 4-Factor Prothrombin Concentrate
Sylvia Doyle, Pharm.D.
Elva Angelique Van Devender, Ph.D., Pharm.D., BCPS
Legacy Good Samaritan Emergency Department
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May 3, 2015 2
Background
Kcentra is the first four-factor prothrombin complex
concentrate approved for the urgent reversal of
vitamin K antagonist-related major bleeding.
Approved on April 29, 2013 and expected to be
available by third quarter 2013.
Kcentra contains the vitamin K-dependent
coagulation factors II, VII, IX, and X and the
antithrombotic proteins C and S.
Legacy currently uses three factor PCC (generic
names Prothrombin Complex Concentrate or Factor
IX Complex, brand name Profilnine) as its preferred
product.
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Comparing Profilnine and Kcentra
Characteristics Prothrombin Complex Concentrates
Brand name Profilnine 3-factor PCC Kcentra 4-factor PCC
Source material Pooled human plasma Pooled human plasma
Microbial
reduction
Solvent detergent (no preservative) Chromatographic, heat-treated (no
preservative)
Formulation Single-dose vials (multiple sizes) Single-dose 500 unit vials
Factor
composition
Factor IX
500 units
400-620 units
Factor II NMT 750 units 380-800 units
Factor VII NMT 175 units 200-500 units
Factor X NMT 500 units 500-1020 units
May 3, 2015 3
NOTE: Profilnine does NOT contain heparin, but Kcentra does!
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The Clotting Cascade
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FFP vs. PCC Fresh frozen plasma (FFP), in combination with vitamin
K, has long been the most widely used blood product for
urgent reversal of coagulopathies in warfarin patients.
A number of concerns exist with the use of FFP in these
situations:
> Potential for transfusion reactions
> Time required for cross-matching and thawing
> Potential for fluid overload (200-250 mL/unit FFP)
> 10-20 mL/kg of FFP results in a 20-30% increase in clotting
factors (800-1600 mL for an 80 kg patient)
The 9th edition of the American College of Chest
Physicians Practice Guidelines recommends rapid
reversal of vitamin K antagonists (VKA) with 4-factor
PCC, rather than plasma, in patients with major bleeding
due to warfarin therapy (grade 2C).
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Pharmacology
The administration of PCC temporarily increases
plasma levels of factor II, VII, IX and X, that are
depleted with warfarin use
> reverses the antithrombotic effects of vitamin K
antagonism.
Because of the long half-life of warfarin, vitamin K is
required to reverse its anticoagulant effect
> allows the synthesis of vitamin-K dependent clotting
factors necessary to avoid a rebound increase in the
INR following PCC administration.
Clinical data consistently shows a rapid reversal of
the INR (within 10-30 minutes) in warfarin patients
following administration of PCC.
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The Challenge of the Newer Target-
Specific Oral Anticoagulants
New anticoagulants directly inhibit both free and clot-
bound coagulation factors.
Unlike warfarin, (which can be reversed with vitamin K),
there is no antidote for these new agents
> Dabigatran (direct thrombin inhibitor)
Consider oral charcoal if last dose < 2 hours ago
HD will remove 60% of drug over 2-3 hours
> Apixaban and rivaroxaban (direct factor Xa inhibitors)
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The Challenge of the Newer Target-
Specific Oral Anticoagulants cont.
How to reverse them?
> Withhold the agent in patients with mild-moderate bleeding
> Use PCC, FEIBA, or rFVIIa in patients with life-threatening
bleeding (lack of evidence!!!)
PCC does NOT directly reverse the anticoagulant effect of the
newer anticoagulation agents, but may overwhelm inhibitory
effects on factor IIa or Xa
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Efficacy: Use of Kcentra for warfarin
reversal in acute bleeding
Study design: Non-inferiority, open label, randomized
controlled trial of 212 warfarin patients followed for 90
days post PCC administration.
Study population/intervention:
> Age 26-96, on warfarin with acute major bleed; baseline
INR of ≥2.0
> All patients were given intravenous vitamin K
Exclusion criteria: h/o of thrombotic event, myocardial
infarction, cerebral vascular accident, transient
ischemic attack, unstable angina, severe peripheral
vascular disease, or disseminated intravascular
coagulation w/in the previous three months.
Kcentra dose was 25, 35, or 50 units (factor IX) per
kilogram (kg) body weight
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Results
Outcome PCC
(n=98)
FFP
(n=104) 95% CI
“Effective” hemostasis 72.4%
(71)
65.4%
(68) -5.8, 19.9
INR reduction to ≤ 1.3 at 30 minutes
after end of infusion
62.2%
(61)
9.6%
(10) 39.4, 65.9
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Adverse
events
PCC (n=98) FFP (n=104) 95% CI
Deaths 9.7% (10) 4.6% (5) -2.7, 13.5
Fluid
overload
5.8% (6) unrelated to
study drug
12.8% (14) 7 related to
study drug
15.8, 1.8
Thrombo-
embolic
events
8.7% (9) 5 possibly
related to study drug
5.5% (6) 3 possibly
related to study drug
-4.7, 11.5
“Effective” hemostasis was defined as a rating of excellent or good by a
blinded adjudication board
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Efficacy: Use of 4-factor PCC for mgmt of
dabigatran-associated bleeding: Authors Study type N Manageme
nt
Results
Zhou et al.
2011
Murine model
induced ICH
and tail-vein
bleeding time
4F-PCC 25-
100U/kg vs.
FFP vs.
rFVIIa
8mg/kg
· PCC > FFP in preventing hematoma expansion, higher doses PCC
more effective
· rFVIIa ineffective in reducing hematoma expansion
· Mortality lowest in PCC group
Eerenberg
et al 2011
RCT healthy
adult males
(in vivo)
12 4F-PCC
50U/kg vs.
placebo
· PCC had no effect on aPTT, Thrombin Time, or Ecarin Clotting time.
VanRyn et
al 2011
Rat model
tail-vein
bleeding time
(RTBT) vs.
TT, aPTT,
ECT, PT
4F-PCC 35-
40 U/kg vs.
FEIBA
100U/kg vs.
rFVIIa
0.5mcg/kg
· Complete normalization of rat tail bleeding time w/ all coagulation factor
concentrates
· TT, aPTT, ECT not normalized, despite reversal of RTBT
· PT reversed regardless of RTBT reversal
Marlu et al.
2012
Cross-over
healthy adult
males (ex
vivo)
10 4F-PCC
25units/kg
vs. FEIBA
80units/kg
vs. rFVIIa
120mcg/kg
· PCC increased endogenous thrombin potential area under the curve
(ETP-AUC) and increased peak thrombin generation
· FEIBA increased peak thrombin generation and corrected thrombin
generation lag time
· rFVIIa corrected thrombin generation lag time
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Efficacy: Use of 4-factor PCC for mgmt
of rivaroxaban-associated bleeding Authors Study
type
N Management Results
Eerenberg
et al.
2011
RCT
healthy
adult
males (in
vivo)
12 4F-PCC
50U/kg vs.
placebo
· PCC immediately and completely normalized the PT and
endogenous thrombin potential tests
Godier et
al. 2012
Rabbit
model
Using
high dose
rivaroxab
an
4F-PCC 40
units/kg vs.
rFVIIa
150mcg/kg
· Both PCC and rFVIIa corrected aPTT, and only partially
improved PT, ROTEM and thrombin generation parameters
· Neither PCC nor rFVIIa were effective in stopping bleeding
Marlu et
al. 2012
Cross-
over
healthy
adult
males (ex
vivo)
10 4F-PCC
25units/kg vs.
FEIBA
80units/kg vs.
rFVIIa
120mcg/kg
· PCC strongly corrected ETP-AUC, and partially corrected
peak thrombin generation
· FEIBA corrected peak thrombin generation
· rFVIIa partial correction of peak thrombin generation
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Safety/Adverse Reactions:
Black box warning: Arterial and venous
thromboembolic complications
Kcentra was not studied in patients with a history of
TE, MI, DIC, CVA, TIA, UA, or severe PVD within the
prior 3 months.
The most common adverse reactions
> headache (7.8%)
> hypotension (4.9%)
> nausea and vomiting (3.9%)
> arthralgia (3.9%).
Kcentra is derived from pooled human plasma and
there may be risk for transmission of infectious
agents.
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Contraindications
Absolute
> Patients with known anaphylactic or severe systemic
reactions to Kcentra or its components
> Patients with DIC
> Patients with known heparin-induced
thrombocytopenia (HIT)
Relative
> Venous or arterial TE in the past three months
> Underlying conditions that increase the risk of
thrombosis (e.g. crush injury, sepsis, recent major
surgery)
> Liver disease
> Intracranial hemorrhage not felt to be survivable
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Monitoring
blood pressure
heart rate
respiratory rate
baseline INR (for warfarin)
aPTT (for dabigatran)
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Target Patient Population
Legacy guidelines recommend the use of PCC for
antithrombotic-related bleeding in adult patients for
the following P&T approved indications:
> Patients on warfarin therapy with an elevated INR
greater than 2.0, or
> Patients on fondaparinux, rivaroxaban, dabigatran
AND
Patients with life-threatening bleeding (traumatic bleeding,
bleeding into a critical organ, hemoglobin drop > 5g/dL,
requiring reversal in 2 hours) related to anticoagulation
Patients requiring emergent surgery in a critical organ
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Administration and Dosing of Kcentra
For warfarin reversal in patients with an INR greater
than 2 AND life-threatening bleeding related to
anticoagulation
> The recommended dosage of Kcentra is 25–50
units/kg of body weight (up to 100 kg), depending on
the patient’s pretreatment INR value. Do not exceed
maximum dose for patients weighing more than 100 kg.
> (Unlike Profilnine, we do NOT use adjusted body weight
in obese patients!)
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Baseline INR ≥2.0 to <4.0 ≥4.0 to ≤6.0 >6.0
Dose* of Kcentra (units of factor IX)
per kg total body weight 25 units/kg 35 units/kg 50 units/kg
Maximum dose (units of factor IX) Not to exceed 2500
units
Not to exceed
3500 units
Not to exceed
5000 units
*Dose based on actual potency stated on carton for factor IX units. Pharmacy to round dose to
nearest vial.
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Administration and Dosing of Kcentra
Only ONE course of treatment should be given to
stop the bleeding episode
> unlike Profilnine, where we can give multiple doses!
As with Profilnine, we STILL must administer with
Vitamin K 10mg IV to avoid a rebound increase in the
INR.
> But FFP is NOT needed since more Factor VII
included!
Infuse reconstituted Kcentra intravenously at a rate of
0.12 mL/kg/min (~3 units/kg/min) up to a maximum
rate of 8.4 mL/min (~210 units/min).
Recheck INR 30 minutes after PCC administration.
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Administration and Dosing of Kcentra
For management of life-threatening bleeding in
patients on dabigatran
> There is no antidote for dabigatran!
> Check baseline aPTT, if greater than 1.5 x control (50
seconds in Legacy) administer Kcentra
> Kcentra 50 units (factor IX)/kg [total body weight] IV
x 1, no maximum dose, round to nearest whole vial
For management of life-threatening bleeding in
patients on apixaban or rivaroxaban
> There is no antidote for apixaban or rivaroxaban!
> No qualitative lab test available
> Kcentra 50 units (factor IX)/kg [total body weight] IV
x 1, no maximum dose, round to nearest whole vial
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Cost
Kcentra is $635 per 500 unit vial purchased on
consignment ($3,810 for an 80 kg patient with INR >
4 to < 6))
Profilnine is $0.87 per unit purchased on
consignment ($3,480 for an 80 kg pt with INR > 4)
FFP = $93 per unit, plus $93 for blood typing ($465
for an 80 kg pt – approximately 4 units FFP)
NovoSeven (r FVIIa) $1430 (1000 mcg vial), $2860
(2000mcg vial), $7153 (5000 mcg vial) purchased on
consignment ($10,013 for an 80 kg patient)
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Key Tips to Remember About Kcentra Monitor When Why Comment
INR on
admit
and 30
minutes
after
kcentra
admin
To assess INR
reversal prior to
surgery/proced
ure
Only one course of treatment should be given to stop the
bleeding episode .
Vitamin
K dose
(10 mg
IV)
With
PCC
order
To avoid
rebound in INR
after PCC
wears off (6
hours)
Must be given IV to ensure more rapid correction; IM
administration is contraindicated due to risk of hematomas
Dose
(MDs
and
RPHs)
Order
Entry or
Verifica
tion
To ensure
efficacy and
safety
INR 2-4: 25 u/kg (NTE 2500 Units)
INR 4-6: 35 u/kg (NTE 3500 Units)
INR >6: 50 u/kg (NTE 5000 Units)
Use TBW for patients up to 100 kg. Do not exceed the
maximum recommended dose for patients >100 kg.
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References 1. Profilnine SD [package insert] Grifols Biologicals Inc., Los Angeles, CA; August 2010
2. Kcentra [package insert] CSL Behring, Marburg, Germany; April 2013.
3. Holbrook A, et al. Evidence-Based Management of Anticoagulant Therapy, 9th edition: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST
2012;141(suppl):e152s-e1842s.
4. Sarode R, et al. Randomized phase IIIb study comparing safety and efficacy of 4-factor prothrombin
complex concentrate with plasma in subjects receiving vitamin K antagonists with major bleeding
[abstract]. Presented at Thrombosis and Hemostasis Summit of North America; Chicago, IL; May 3-5,
2012.
5. Eerenberg ES, et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate.
A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation 2011; 124:1573-
1579.
6. Van Ryn J, et al. The Successful Reversal of Dabigatran-Induced Bleeding by Coagulation Factor
Concentrates in a Rat Tail Bleeding Model Do Not Correlate with Ex Vivo Markers of Anticoagulation.
Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2316
7. Marlu R, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and
rivaroxaban: A randomized crossover ex vivo study in healthy volunteers. Thrombosis and
Haemostasis. 2012;108(2):217-224.
8. Godier A, et al. Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor
VII to Reverse Rivaroxaban in a Rabbit Model. Anesthesiology 2012;116:94-102.
9. Levi M, et al. Safety of Recombinant Activated FVII in Randomized Clinical Trials. NEJM
2010;363:1791-1800.
10. Crowther MA, et al. Managing bleeding in anticoagulated patients with a focus on novel therapeutic
agents. J Thromb Haemost 2009;7:197-110.
11. Siegal DM, et al. Reversal of novel oral anticoagulants in patients with major bleeding. J Thrombosis
and Thrombolysis 2013;35(3):391-398.
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Thank you!