Transcript Here - SMSHP

Jason
Williamson,
PharmD, BCPS
Clinical
Pharmacy
Specialist –
Drug Use
Policy and
Education
THROUGH THICK AND THIN:
APPROACHES TO
ANTICOAGULANT REVERSAL
The speaker has no actual or potential Conflict of Interest in relation to
this presentation.
Genesys
Regional
Medical
Center
OBJECTIVES - PHARMACIST
 Given a patient case, identify the appropriate dosing regimen
of a reversal agent or factor product utilized to reverse the
ef fects of a direct-acting oral anticoagulant (DOAC).
 Given a patient case, select appropriate monitoring
parameters after the utilization of a reversal agent or factor
product for the reversal of a DOAC.
 Discuss the benefits of blood factor/anticoagulant reversal
agent stewardship programs on patient care and on health
care expenditures.
OBJECTIVES – PHARMACY TECHNICIAN
 Distinguish between reversal agents and factor products
utilized in DOAC reversal.
 Select appropriate steps in the administration of
idarucizumab for the reversal of dabigatran.
 Identify adverse ef fects associated with available reversal
agents and factor products.
AUDIENCE POLLING QUESTION
 Which of the following best describes your experience with
blood factor products and anticoagulant reversal agents?
A. I have extensive experience with blood factor products and
anticoagulant reversal agents (e.g., involved in everyday practice)
B. I have some experience with blood factor products and
anticoagulant reversal agents (e.g., involved with a case requiring a
blood factor or reversal agent every so often)
C. I have minimal to no experience with blood factor products and
anticoagulant reversal agents (e.g., very few cases in practice, I
usually hand off to another pharmacist)
D. I have some experience with these medications but have great
difficulty keeping up with the rapid changes in evidence -based
reversal strategies
STRATEGIES FOR REVERSAL
OF DIRECT-ACTING ORAL
ANTICOAGULANTS
DIRECT ACTING ORAL ANTICOAGULANTS
(DOAC’S)
 Includes four unique agents that were developed to improve
upon the shortcomings of warfarin




Apixaban (Eliquis)
Dabigatran (Pradaxa)
Edoxaban (Savaysa)
Rivaroxaban (Xarelto)
 Despite some improvements to these shortcomings (e.g., lack
of dietary concerns with use, relatively fewer drug
interactions, etc), an issue with the use of DOAC’s arose
 Lack of specific reversal agent/antidote (until recently)
 How do practitioners manage bleeding episodes associated with the
DOAC’s?
 How to practitioners manage patients treated with a DOAC who
require an emergency surgery/urgent procedure?
Direct-Acting Oral Anticoagulants as a Class – Indications and PK/PD
Characteristic
Indications
Renal
elimination of
unchanged
drug (%)
Half-life (hr)
Protein binding
(%)
Dialyzable?
Apixaban
 NVAF
 DVT/PE
treatment
 DVT/PE
prophylaxis
after
TKA/THA
Dabigatran
 NVAF
 DVT/PE
treatment
 DVT/PE
prophylaxis
after THA
Edoxaban
 NVAF
 DVT/PE
treatment
Rivaroxaban
 NVAF
 DVT/PE
treatment
 DVT/PE
prophylaxis
after
TKA/THA
27
80
50
36
8-15
12-14
10-14
5-9
87
35
55
92-95
Unlikely
Yes
Unlikely
Unlikely
Selected Direct-Acting Oral Anticoagulants–
Major Bleeding and GI Bleeding
Drug
Endpoint
Major Bleeding
GI Bleeding
Apixaban vs warfarin
Prevention of stroke
or systemic
embolism in patients
with NVAF
2.13% vs 3.09%
0.76% vs 0.86%
Dabigatran vs
warfarin
Prevention of stroke
or systemic
embolism with NVAF
3.11% vs 3.36%
1.51% vs 1.02%
Dabigatran vs
warfarin
Prevention of
recurrent VTE in
patients with acute
VTE
1.6% vs 1.9%
4.2% vs 2.8%
Rivaroxaban vs
warfarin
Prevention of stroke
and systemic
embolism in patients
with NVAF
3.6% vs 3.4%
No data
Rivaroxaban vs
warfarin
Prevention of
recurrent VTE in
patients with PE
1.1% vs 2.2%
No data
Selected Direct-Acting Oral Anticoagulants –
Intracranial Hemorrhage and Fatal Bleeding
Drug
Endpoint
Intracranial
Hemorrhage
Fatal Bleeding
Apixaban vs warfarin
Prevention of stroke
or systemic
embolism in patients
with NVAF
0.33% vs 0.8%
No data
Dabigatran vs
warfarin
Prevention of stroke
or systemic
embolism with NVAF
0.3% vs 0.74%
1.45% vs 1.8%
Dabigatran vs
warfarin
Prevention of
recurrent VTE in
patients with acute
VTE
0% vs 0.2%
0.08% vs 0.08%
Rivaroxaban vs
warfarin
Prevention of stroke
and systemic
embolism in patients
with NVAF
0.5% vs 0.7%
0.2% vs 0.5%
Rivaroxaban vs
warfarin
Prevention of
recurrent VTE in
patients with PE
<0.1% vs 0.4%
<0.1% vs 0.1%
COAGULATION ASSAYS AND DOAC’S
 Routine monitoring of coagulation assays is typically not
required for the DOAC’s
 Extenuating Circumstances




Major bleeding
Surgery
Reversal of anticoagulation
Suspicion of overdose
COAGULATION ASSAYS
 aPTT
 Intrinsic pathway
 Chromogenic Anti-factor Xa
 Functional test which assesses plasma factor Xa concentrations
 Ecarin clotting time (ECT)
 Specific assay for thrombin production
 Direct measure of direct thrombin inhibitor activity (e.g., dabigatran)
 PT-INR
 Extrinsic and common pathway
 Thrombin clotting time (TT)
 Directly assesses activity of thrombin
USEFULNESS OF COAGULATION ASSAYS
 Factor IIa inhibitors (e.g., dabigatran)
 ECT > TT > aPTT > PT/INR
 Factor Xa inhibitors (e.g., apixaban, edoxaban, rivaroxaban)
 Chromogenic anti-factor Xa > PT/INR > aPTT
 Despite these depictions of the optimal coagulation assays for
each type of DOAC, many health systems lack an ability to
utilize these tests or have to send out specimens for analysis
by another laboratory
NON-PHARMACOLOGIC
MANAGEMENT OF BLEEDING
 Discontinue the anticoagulant involved
 Target hemostasis at the bleeding site
 Fluid resuscitation/hemodynamic support
 Transfusion
 Further intervention with factor products/reversal agents is
often required
PHARMACOLOGIC
MANAGEMENT OF BLEEDING
 Activated charcoal
 May be effective if given within 1-2 hours of last DOAC dose
 Hemodialysis
 May be considered in patients treated with dabigatran due to low
plasma protein binding
 May decrease drug levels by at least 50% after a 4 hour session
 Multiple factor products may be used for DOAC reversal
 Hospital formulary restrictions typically play a factor in which factor
products are selected for use
Thromb Haemost. 2013;109:596-605.
SELECTED FACTOR PRODUCTS
3 Factor PCC
Brand Name
Bebulin VH
Dose based on
4 Factor PCC
Profilnine SD
Kcentra
Units of factor IX activity
Factor II
24-38 IU/mL
150IU/100 fIX IU
0.76 -1.6 units/unit
Factor VII
< 5 IU/mL*
< 35 IU/100 fIX IU*
0.4-1 unit/unit
Factor IX
24-38 IU/mL
100 IU
0.8-1.24 units/unit
Factor X
24-38 IU/mL
100 IU/100 fIX IU
1-2.04 units/unit
Unfractionated
heparin
0.15 IU per 1 IU fIX
None
0.016-0.08 unit/unit
Other components
-
-
Protein C, Protein S,
Anti-thrombin III
* denotes products with non-therapeutic levels of factor VII
SELECTED FACTOR PRODUCTS
aPCC
rFVIIa
Brand Name
Feiba NF
NovoSeven RT
Dose based on
Units of factor VIII inhibitor
bypassing activity
Units of recombinant factor
VIIa
Factor II
1.3 IU/IU
-
Factor VII
0.9 IU/IU X
1000-8000 mcg X
Factor IX
1.4 IU/IU
-
Factor X
1.1 IU/IU
-
Unfractionated heparin
None
None
Other components
-
-
X denotes
products with activated factor VII
THROMBOGENICIT Y ASSOCIATED WITH
FACTOR PRODUCT ADMINISTRATION
 Use of factor products as part of a patient -specific DOAC
reversal strategy may confer an increased risk of a pro thrombotic state
 Specific factor component involvement has not been clearly defined
 Products containing protein C, protein S, and other anticoagulants
may preclude excessive thrombin production
 Providers must carefully balance the benefits of anticoagulant
reversal with the risks of thrombosis after reversal or seek
alternate methods of reversal
 “Targeted anti-anticoagulants” or agent -specific antidotes
of fer less risk for thrombogenicity than factor product
counterparts
IDARUCIZUMAB (PRAXBIND)
 Approved in October 2015 for
the reversal of the
anticoagulant ef fects of
dabigatran for emergency
surgery/urgent procedures or in
life-threatening or uncontrolled
bleeding
 Mechanism of action:
humanized monoclonal antibody
fragment that binds to
dabigatran and its
acylglucuronide metabolites
with an af finity for dabigatran ~
350 times greater than
thrombin
IDARUCIZUMAB DOSING AND
ADMINISTRATION
 5 gm IV (given as 2 separate 2.5 gm doses no more than 15
minutes apart)
 May be given as IV push or as IV infusion
 Give within 1 hour of removing from the vial if IV push selected
 Infuse no longer than 5 to 10 minutes if IV infusion selected
 No reconstitution required
 If specific coagulation parameters are re -elevated and
clinically relevant bleeding occurs OR if a second emergency
surgery/urgent procedure is needed and the patient elevated
coagulation parameters, an additional 5 gm dose may be
considered (supported by limited data)
IDARUCIZUMAB PK/PD
 In general, this agent neutralizes the anticoagulant ef fects of
idarucizumab within minutes of administration
 Median time of hemostasis restoration = 11 .4 hours
 Duration of at least 24 hours
 Half-life elimination 47 minutes (initial); 10.3 hours (terminal)
 Metabolized to small peptides and amino acids; also excreted
in the urine
IDARUCIZUMAB STORAGE/STABILIT Y
 Store intact vials at 36 – 46 o F; do not freeze
 Do not shake; do not tube (monoclonal antibody)
 Can be stored in original packaging at room temperature
 Up to 48 hours if in original packaging (protected from light)
 Up to 6 hours if exposed to light
WARNINGS/PRECAUTIONS WITH
IDARUCIZUMAB
 Coagulation parameter re -elevation may occur in some
patients (limited number in clinical trials). If clinically
relevant bleeding occurs in conjunction with elevated
coagulation parameters, consider an additional dose of
idarucizumab.
 Hypersensitivity may occur from administration
 Due to the underlying risk of thromboembolism associated
with reversed the ef fects of dabigatran, labeled dosing
information recommends restarting dabigatran or an
alternative anticoagulant when appropriate.
 Hereditary fructose intolerance?
EVIDENCE FROM REVERSE-AD TRIAL
 Purpose: determine the safety of 5 gm IV idarucizumab and its
capacity to reverse the anticoagulant ef fects of dabigatran in
patients who had a serious bleed or required an urgent
procedure
 Primary endpoint: maximum percentage reversal of
dabigatran within 4 hours after administration of
idarucizumab
Pre-dose test result [s]–minimum post-dose test result [s])
(Pre-dose test result [s]–upper limit of the normal range [s])×100
 Secondary endpoint: restoration of hemostasis
N Engl J Med. 2015;373(6):511-20.
EVIDENCE FROM REVERSE-AD TRIAL
 Idarucizumab rapidly and completely reversed the
anticoagulant activity of dabigatran in 88% to 98% of patients
with elevated clotting times at baseline
 There were no safety concerns among the 90 patients
involved in this study
 Includes patients given idarucizumab on clinical grounds but were
later found to have had normal results on clotting tests at baseline
N Engl J Med. 2015;373(6):511-20.
IN THE PIPELINE: ANDEXANET ALFA
 Presently studied but not yet approved for factor Xa inhibitor
reversal (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux)
 Currently being studied in phase 4 trials (ANNEXA -4), and
phase 3 trials (ANNEXA - A and ANNEXA -R) were released in
2015
 Purported mechanism of action : recombinant modified human
factor Xa decoy protein that is catalytically inactive but
retains the ability to bind factor Xa inhibitors in the active
state at a high af finity, restoring the activity of endogenous
factor Xa
EVIDENCE FROM ANNEXA -A AND
ANNEXA-R TRIALS
 Phase III, randomized, double -blind, placebo-controlled
clinical trials from March 2014 – May 2015 involving 2
clinical sites
 Inclusion criteria – age 50 – 75 years
 Exclusion criteria – history of:
 Abnormal bleeding, active bleeding, or risk factors for bleeding
 Thrombosis or risk factors for thrombosis
 Adult asthma or use of inhaled medication
 Primary study endpoint: percent change in anti -factor Xa
activity (examined nadir associated with bolus and with
infusion)
N Engl J Med. 2015;373(25):2413-24.
EVIDENCE FROM ANNEXA -A AND
ANNEXA-R TRIALS
Percent change in anti-factor Xa activity (mean  SD)
Bolus
Bolus +
Infusion
Study
Andexanet
Placebo
P-value
ANNEXA-A
942%
219%
< 0.001
ANNEXA-R
9211%
1815%
< 0.001
ANNEXA-A
923%
336%
< 0.001
ANNEXA-R
972%
4512%
< 0.001
N Engl J Med. 2015;373(25):2413-24.
OTHER REVERSAL AGENTS
IN THE PIPELINE
 Aripazine (PER977; ciraparantag) – reversal of all DOAC’s
presently on the market
 May additionally work against heparin and LMWH
N Engl J Med. 2014;371(22):2141-2.
STRATEGIES FOR REVERSAL
OF WARFARIN
ADVANCES IN THE MANAGEMENT OF
WARFARIN REVERSAL
 Phytonadione (vitamin K) is the antidote to warfarin, but this
agent by itself may not be suf ficient for acute major bleeding
issues or where rapid reversal of anticoagulation prior to an
emergency surgery is required
 Four factor prothrombin complex concentrate (Kcentra) is now
approved for the reversal of warfarin in specific patients
PROTHROMBIN COMPLEX CONCENTRATE
(KCENTRA)
 Contains factors II, VII, IX, and
X as well as protein C and S
(a.k.a. 4 factor PCC)
 Indicated for the urgent reversal
of acquired coagulation factor
deficiency induced by vitamin K
antagonist (e.g., warfarin)
therapy in patients with acute
major bleeding or a need for an
urgent surgery/invasive
procedure
 Dose depends on pretreatment
INR and on patient weight
DOSING 4 FACTOR PCC
Pre-treatment
INR
2-<4
4–6
>6
Dose (units of
factor IX)/ kg
body weight
25
35
50
Maximum dose
(units of factor
IX)
Not to exceed
2500
Not to exceed
3500
Not to exceed
5000
Dose based on actual potency as stated on the car ton, which varies
from 20-31 factor IX units/mL af ter reconstitution. Nominal potency
is 500 units or 1000 units per vial (25 units/mL af ter reconstitution).
NOTABLE WARNINGS/PRECAUTIONS
WITH 4 FACTOR PCC
 Increased risk for thromboembolic events (Boxed Warning in
the US)
 As patients treated with vitamin K antagonists have an underlying
risk of or a diagnosed thromboembolic disease state, administration
of PCC may predispose the patient to a thromboembolic complication
 Formulations contain heparin and are products or human
plasma (may contain infectious agents)
 4 factor PCC products contain factor VII ad should not be
confused with other products that contain low or
nontherapeutic levels of factor VII (e.g., Profilnine)
 Hypersensitivity reactions may occur from administration
EVIDENCE FOR 4 FACTOR PCC PRODUCTS
 Numerous prospective interventional trials and retrospective
observational studies have been published supporting use
 Notable publications
 Sarode et al. Circulation. 2013;128(11):1234-43.
 Pabinger et al. Journal of Thrombosis and Haemostasis.
2008;6(4):622-31.
 Preston et al. British Journal of Haematology. 2002;116(3):619-24.
 Open-label, randomized, multicenter phase III soon to be
published comparing 4 factor PCC to plasma in patients
requiring urgent surgery (N = 176)
FACTOR PRODUCT/
REVERSAL AGENT
STEWARDSHIP PROGRAMS
STEWARDSHIP PROGRAM FOR FACTOR
PRODUCTS/REVERSAL AGENTS
 University of North Carolina Medical Center (UNCMC)
 Innovative pharmacist-led program to improve prescribing,
dosing, and monitoring of clotting factor therapy
 Pharmacist assigned to round with hematologists daily,
recommending treatment plan modifications and dose
adjustments as necessary
Am J Health Syst Pharm. 2015;72(18):1579-84.
STEPS TO PROGRAM
DEVELOPMENT/IMPLEMENTATION
Selection of one formulary product
within each clotting factor class
Establishment of guidelines on blood
factor prescribing, order review,
compounding, and administration
Initial and ongoing education of
pharmacy, nursing, and medical staff
Am J Health Syst Pharm. 2015;72(18):1579-84.
RESULTS OF UNCMC PROGRAM
 Contributed both to cost savings and improved outcomes
 Increase in patients receiving clotting factors by 22%, but reduction
of doses dispensed by 45% overall
 Reduction in readmissions associated with bleeding episodes for
patients with hemophilia A
 Cost-savings estimated to exceed $4 million annually (from 4 year
program period)
 Numerous opportunities for improvement contributed to
reduction of doses dispensed
 Conversion of patients with hemophilia A or B from intermittent
infusions of factors VIII and IX to continuous infusion therapy
 Change in product selection for patients with hemophilia A
 Review of factor concentrate doses ordered beyond initial dose by
designated pharmacist team member
Am J Health Syst Pharm. 2015;72(18):1579-84.
APPLYING THIS ARTICLE TO
ANTICOAGULATION REVERSAL
 Despite many specific roles with blood factor use with
inherited bleeding disorders, a designated team of
pharmacists could be formed to optimize the utilization of
blood factor and reversal agent products within a variety of
health systems
 Specific institutional guidelines should be developed and
utilized to guide factor product and reversal agent selection,
dosing, and subsequent monitoring
 An interdisciplinary approach would likely result in the
greatest improvements in patient care as well as cost savings
DESIGN FOR FACTOR PRODUCT/REVERSAL
AGENT STEWARDSHIP
Pharmacist Chair and
Physician Chair
Support Pharmacists
Drug Use Policy/
Formulary Management
Pharmacy and Health
System Administration
CONCLUSIONS
 A variety of factor products and reversal agents (e.g., agent
specific antidotes) are available or in the pipeline for the
reversal of anticoagulation
 Pharmacy staf f members can assist with vital roles
associated with the use, dosing, administration, and patient
monitoring of medications used in anticoagulant reversal
 Factor and reversal agent stewardship programs have the
potential to improve patient care as well as contain health
care costs
DISCUSSION/QUESTIONS
PATIENT CASE - PHARMACIST
 Patient LK presents to the MICU with a new onset GI bleed.
Upon reviewing the patient’s medication profile, you discover
that the home medication list includes multiple blood
thinners. Among these blood thinners, dabigatran 150 mg PO
BID was prescribed for this patient for their NVAF. The patient
weighs 89 kg, is 87 years old, and is presently receiving
hemodialysis for their end stage renal disease.
Hematology/oncology is consulted and decides to hold
anticoagulation and initiate idarucizumab for reversal. As the
pharmacist, hem/onc seeks your input for this patient’s care
about the overall reversal strategy.
QUESTION 1 - PHARMACIST
 What’s the most appropriate dosing regimen of idarucizumab
to utilize for this patient case?
A. 2.5 gm IV push X 2 doses (no more than 15 minutes apart)
B. 5 gm IV push X 1 dose
C. 2.5 gm as an IV infusion X 2 doses
D. A and C
QUESTION 2 - PHARMACIST
 During administration of the idarucizumab, the prescribing
physician wants your suggestions about further monitoring of
the patient. What information do you provide the physician?
A. There is no further monitoring required.
B. Monitor for re-elevation of coagulation parameters (e.g., aPTT)
along with signs and symptoms of clinically relevant bleeding or
thrombosis.
C. Monitor the aPTT but there’s no need to monitor for bleeding or
thrombosis signs and symptoms.
D. Check an INR 4 hours and 8 hours after idarucizumab has been
administered.
QUESTION 3 - PHARMACIST
 Patient RK is a 78 year old male weighing 114 kg who presents
to the ER after falling at home. The medication history indicates
that he was taking warfarin 10 mg PO daily at home, but RK
cannot recall his last “Coumadin level.” Upon checking the INR in
ER, you find it is supratherapeutic at 8.5. Additionally, after
examining the patient, the ER physician is concerned about
reversing the effects of the warfarin due to clinical evidence of a
subdural hematoma. The physician orders Kcentra and vitamin K
10 mg IV per your health system’s reversal protocol, but looks to
you as the pharmacist for Kcentra dosing recommendations.
What dose of Kcentra do you recommend for RK?
A. 3500 units
B. 3990 units
C. 5000 units
D. 5700 units
QUESTION 4 - PHARMACIST
 Considering the factor stewardship program implemented at
the University of North Carolina Medical Center, which of the
following best depicts the potential benefits of a factor
product/anticoagulant reversal agent stewardship program?
A. Optimization of factor product/reversal agent dosing
B. Evidence-based guideline approaches to care for bleeding patients
C. Reduced health care expenditures
D. All of the above
QUESTION 1 - TECHNICIAN
 Which of the following is best described as a factor product?
A. Idarucizumab (Praxbind)
B. Andexanet alfa
C. aPCC (Feiba NF)
D. Aripazine
QUESTION 2 - TECHNICIAN
 Which of the following is best described as a “targeted anti anticoagulant”, not a factor product?
 Kcentra
 Andexanet alfa
 NovoSeven
 Profilnine SD
QUESTION 3 - TECHNICIAN
 Concerning the administration of idarucizumab, which of the
following statements is true?
A. Appropriate administration may include IV push or IV infusion.
B. Light protection is a concern for this medication, and the
medication can be stored for up to 6 hours at room temperature if
exposed to light.
C. Idarucizumab should be administered over no longer than 5 to 10
minutes if IV infusion selected.
D. All of the above are true
QUESTION 4 - TECHNICIAN
 True or False: thromboembolic risk after drug administration
is perhaps the most concerning risk associated with Kcentra,
and this concern is described in a boxed warning for the
medication.