5/15/2017
INTEGRIS Baptist Medical Center
Four-Factor Prothrombin Complex
Concentrate Outcomes in Patients
Receiving Weight-based Dosing Versus
Fixed-dosing
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John Jacob Cannedy, Pharm.D.
Pharmacy Specialist Resident (PGY1)
INTEGRIS Baptist Medical Center
Oklahoma City, OK
May 19, 2017
Abstract # 02
IRB Approved
1
Oklahoma City, Oklahoma
Private not-for-profit tertiary care hospital
511-bed facility
Centers of Excellence include:
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Disclosure
INTEGRIS
INTEGRIS
INTEGRIS
INTEGRIS
INTEGRIS
INTEGRIS
INTEGRIS
INTEGRIS
Heart Hospital
Hough Ear Institute
Nazih Zuhdi Transplant Institute
Paul Silverstein Burn Center
James R. Daniel Cerebrovascular and Stroke Center
Cancer Institute
Jim Thorpe Rehabilitation
Children’s at Baptist Medical Center
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Pre-test Assessment Questions
Jacob Cannedy
Potential conflicts of interest: none
Sponsorship: none
Proprietary information or results of ongoing
research may be subject to different
interpretations
• Speaker’s presentation is educational in
nature and indicates agreement to abide by
the non-commercialism guidelines provided
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1. What were perceived limitations in early trials of fixed-dosing?
a.
b.
c.
d.
Low average units/kg in study patients
Inconsistent vitamin K administration
Different products used in different trials
All of the above
2. What were advantages of fixed-dosing compared to weightbased dosing?
a.
b.
c.
d.
Decreased waste
Decreased time to administration
Utilization of a dosing protocol
All of the above
2
Objectives
5
Prothrombin Complex Concentrate
• Replaces coagulation factors II, VII, IX, X in
concentrations 25 times greater than FFP
• Does not neutralize activity
• Vitamin K must be co-administered during
warfarin reversal
• Explain the literature addressing use of 4FPCC
fixed-dosing strategies for urgent reversal
• Compare fixed-dosing versus weight-based
4FPCC dosing strategies based on results of a
retrospective study
– Ensure hepatic production of clotting factors replace
those consumed and prevent rebound increases in
INR values
• Onset 5-15 minutes
• Duration 12-24 hours used with vitamin K
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Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; January 16, 2017
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5/15/2017
INR Reduction Time Frame
FDA Off-label Indications
• Life threatening bleeding associated with oral
anti-Xa inhibitors
– Rivaroxaban (Xarelto)
– Apixaban (Eliquis)
– Edoxaban (Savaysa)
• Also suggested for use if intracranial
hemorrhage (ICH) occurred within 3 to 5 halflives of drug exposure
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Am J Health Syst Pharm. 2016 May 15;73(10 Suppl 2):S5-S13
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Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; January 16, 2017
Prothrombin Complex Concentrate
• For anti – Xa inhibitors, there is a continued
inhibition of endogenous clotting factors
• This makes FFP of limited value
• 4FPCC is used to withstand the inhibitory
duration of the Xa inhibitors by providing an
increased quantity of factors
FDA Approved Dosing
• VKA reversal:
– Individualize dosing based on current pre-dose
INR
• Pretreatment INR 2 to < 4: 25 units/kg; max 2,500 units
• Pretreatment INR 4 to 6: 35 units/kg; max 3,500 units
• Pretreatment INR > 6: 50 units/kg; max 5,000 units
– Dosage is expressed in units of factor IX activity
– Administer with vitamin K concurrently
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Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; January 16, 2017
Am J Health Syst Pharm. 2016 May 15;73(10 Suppl 2):S5-S13
FDA Approved Indication
FDA Off-label Dosing
• Urgent reversal of acquired coagulation factor
deficiency induced by vitamin K antagonist
(VKA)
• In patients with:
• Life threatening hemorrhage associated with
non VKA anticoagulation
– 50 units/kg with additional 25 units/kg if clinically
necessary is recommended
• ICH according to Neurocritical Care Society
– Acute major bleeding
– Need for urgent surgery/invasive procedure
– Factor Xa inhibitors or direct thrombin inhibitors:
• 50 units/kg if ICH occurred within 3 to 5 half-lives of
drug exposure
Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; January 16, 2017
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Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; January 16, 2017
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5/15/2017
Support for Fixed-dosing Strategy –
Literature Review
Fixed-dose Study with Kcentra
• 11 brands of PCC:
– 3-Factor PCC used in 431 patients (6 studies)
– 4-Factor PCC used in 2,132 patients (22 studies)
• Indications: varied from major bleed,
emergency surgery, and other reasons for VKA
reversal
• Fixed-dose strategy results:
Study Design
Protocol
Results
• Retrospective
review
conducted in the
U.S. with Kcentra
• 39 patients
requiring
emergent VKA
reversal
• Initial fixed dose
of 1500 units
regardless of INR
or patient weight
• Treatment failure
was post INR
of > 2
• INR reversal rate
achieved 92.3% for
target < 2
• 36 received
concomitant IV vitamin
K and 11 patients
received plasma
• 2 treatment failures,
both had initial INR >
10
• No thrombotic events
reported
• 30 survived to
discharge
– INR target reached in the range of 43 to 92% of
patients within the individual studies
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Wozniak et al. Transfusion and Apheresis Science 2012
Institutional Fixed-dosing Protocol:
Warfarin Reversal
Fixed-dose Study with Cofact
Study Design
Protocol
Results
• Prospective,
randomized, open-label
• Cofact 4FPCC,
Netherlands
• N= 93 emergent VKA
reversal
• Group A: fixed 500 units
+ 10 mg vitamin K
• Group B: Variable dosing
based on body weight +
10 mg vitamin K
• Target INR < 2.1 reached
after 15 minutes
• Group A: 42.6%
• Average: 8.9
units/kg
• Group B: 89.1 %
• Average: 18 units/kg
• ADEs: none directly
after infusion
• One patient in each
group had nonbleeding CVA
INR Pretreatment
INR > 5
INR 3-5
INR < 3
4-Factor PCC
3,000 units
2,000 units
1,000 units
Must also administer Vitamin K 5-10 mg given by IV infusion over 30 minutes
If INR ≥ 2, 20 minutes after dose infused, repeat with another 500 unit dose
If INR still ≥ 2, 20 minutes after second dose, may continue repeating 500 unit doses
20 minutes after each dose has infused not to exceed a total of 5,000 units
If INR unknown prior to treatment, 1,500 units fixed 4FPCC will be given
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Van Aart et al. Throm Res 2006 (24)
Institutional Fixed-dosing Protocol:
Factor Xa Inhibitor Reversal
Fixed-dose Study with Octaplex
Factor Xa Inhibitors: Rivaroxaban, Apixaban, Edoxaban
Study Design
Protocol
Results
• Retrospective study
conducted in
Canada
• N= 150 VKA
reversals for
bleeding or invasive
procedures
• 1,000 units +
vitamin K at
discretion of
physician
• Target INR 1.5 or
less fifteen minutes
after infusion
• INR reversal: 76% of
patients corrected
to INR 1.5 or less
• Average dose of
Octaplex based on
patient weight:
15 units/kg
Initial 4-Factor PCC dose:
Administer fixed 1,500 units over 10
minutes
Repeat 4-Factor PCC dose:
If aPTT not improved 20 minutes after
initial dose, may repeat with 500 units
over 5 minutes
Note: INR not utilized for monitoring, do not administer vitamin K
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Wozniak et al. Transfusion and Apheresis Science 2012
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5/15/2017
Retrospective Evaluation: Fixed-dosing
Protocol
Inclusion
Exclusion
Received 4FPCC
Received other concentrated coagulation
factors within past 7 days
Urgent Reversal of Warfarin or Anti Xa Inhibitor
Pregnant Women
Results after 4FPCC Administration in
Warfarin Reversal Patients
Weight-based Fixed-dosing
Dosing (n= 27)
(n= 6)
Results
P value
Pre-dose INR, mean ± SD
4.79 ± 3.75
4.12 ± 3.52
0.69
INR after 1st dose, mean ± SD
1.4 ± 0.4
1.28 ± 0.2
0.24
Time to first post-dose INR, mean ±
SD (hours)
4.8 ± 5
21 ± 28
0.22
Purpose of this study is to evaluate:
Clinical effectiveness
Safety
Cost effectiveness
Degree of Prescriber Compliance
Time to first post-dose INR < 2, mean
± SD (hours)
4.8 ± 5
21 ± 28
0.22
Average 4FPCC dose per patient,
units/kg
31.4
23.6
0.18
Weight-based: June 1, 2013 to May 19, 2016 (35 months)
Fixed-dosing: May 20, 2016 to October 3, 2016 (4 months)
Average number of 4FPCC doses per
patient, count (range high to low)
1
1
-
Adults > 18 years of age
Children
Prisoners
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Retrospective Evaluation:
Demographics
Weight-Based
Dosing
(35 months)
Fixed-Dosing
(4 months)
Number of patients
42 patients
Age (y) mean ± SD
68.8 ± 13
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Results after 4FPCC Administration in
Warfarin Reversal Patients (Continued)
P value
Results
Weight-based
Dosing (n= 27)
Fixed-dosing
(n= 6)
P value
10 patients
-
70 ± 10
0.51
Plasma units after first
4FPCC dose, count
21
0
-
Cryoprecipitate after first
4FPCC dose, count
5
0
-
Platelet units after first
4FPCC dose, count
1
0
-
Length of stay (days),
mean ± SD
7.3 ± 6
12 ± 11.9
0.41
Male, n (%)
28 (67%)
7 (70%)
0.99
Weight (kg) mean ±
SD
88.29 ± 20
90 ± 29
0.68
ICU admission, n
(%)
39 patients (93%)
10 patients (100%)
0.25
Oral antiplatelet
therapy
26 patients (62%)
5 patients (50%)
0.48
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Retrospective Evaluation: Chronic
Anticoagulation Profile
Results after 4FPCC Administration in
Factor Xa Inhibitor Reversal Patients
35
30
25
Number
of Patients
20
Fixed-dosing
Weight-based Dosing
15
10
5
0
Warfarin
Apixaban
Rivaroxaban Dabigatran
Edoxaban
23
21
Results
Weight-based
Dosing (n= 15)
Fixed-dosing
(n= 4)
P value
Pre-dose PTT, mean ± SD
30.21 ± 14.24
25.15 ± 2.05
0.33
PTT after 1st dose, mean ± SD
26.4 ± 0
NA
-
Time to first post-dose PTT, mean ±
SD (hours)
40 ± 0
NA
-
Average 4FPCC dose per patient,
units/kg
39.8
22.6
0.01
Average number of 4FPCC doses per
patient, count (range low to high)
1.06, (1-2)
1.5, (1-3)
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5/15/2017
Results after 4FPCC Administration in
Factor Xa Inhibitor Reversal Patients
(Continued)
Summary
Results
Weightbased Dosing
(n= 15)
Fixed-dosing
(n= 4)
P value
Plasma units after first 4FPCC
dose, count
15
2
-
Cryoprecipitate after first 4FPCC
dose, count
3
0
-
Platelet units after first 4FPCC
dose, count
4
0
-
Length of stay (days), mean ± SD
8.85 ± 7.71
14 ± 11.5
0.44
• Approved for urgent reversal of VKA or offlabel for anti-Xa inhibitors
• Literature of fixed-dosing has shown it to be as
efficacious as weight-based dosing
• Preliminary results indicate that patients
previously on warfarin can receive fixeddosing and achieve an INR < 2
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Retrospective Evaluation: Thrombotic
Complications Within 7 Days
Weight-based Dosing
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Post-test Assessment Questions
1. What were perceived limitations in early trials of fixed-dosing?
Fixed-dosing
a. Low average units/kg in study patients
b. Inconsistent vitamin K administration
c. Different products used in different trials
d. All of the above
2. What were advantages of fixed-dosing compared to weightbased dosing?
No complications
96%
a. Decreased waste
No complications 100%
Upper Extremity
DVT 4%
b. Decreased time to administration
c. Utilization of a dosing protocol
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Potential Benefits
• Based on preliminary data, annual cost savings
could be $50,826
• Faster administration times
• Less waste
• Reduction in VTE risk
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d. All of the above
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Four-Factor Prothrombin Complex
Concentrate Outcomes in Patients
Receiving Weight-based Dosing Versus
Fixed-dosing
John Jacob Cannedy, Pharm.D.
Pharmacy Specialist Resident (PGY1)
INTEGRIS Baptist Medical Center
Oklahoma City, OK
May 19, 2017
Abstract # 02
IRB Approved
30
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