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Management of Anticoagulant-Related Major
Bleeding: Clinical Updates and Best Practices for
Health-System Pharmacists
Provided by ProCE, LLC and supported by an educational grant from
Alexion, AstraZeneca Rare Disease

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CE Activity Information and Accreditation
ProCE, LLC is accredited by the Accreditation Council for Pharmacy Education
as a provider of continuing pharmacy education. ACPE Universal Activity
Number 0221-9999-21-279-L01-P has been assigned to this live knowledge-
based activity (initial release date 12-8-2021). This activity is approved for
1.5 contact hr (0.15 CEU) in states that recognize ACPE providers. The activity
is provided at no cost to learners. Learners must complete the online posttest
and activity evaluation within 30 days of the activity to receive pharmacy CE
credit. No partial credit will be given. Statements of completion will be issued
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Monitor profiles.

CE Activity Information and Accreditation
Target Audience
The target audience for this activity includes pharmacists, including clinical and health-system, ambulatory care,
and community pharmacists, who care for patients with anticoagulant-related major bleeding. In addition, the
target audience includes pharmacy directors, chief pharmacy officers, and other stakeholders in health-system
pharmacy.
Learning Objectives
At the conclusion of this activity, learners should be able to:
 Discuss key guideline recommendations regarding the management of anticoagulant-related bleeding
 Select appropriate reversal agents and dosing strategies in the context of patient cases
 Evaluate recent clinical data regarding the efficacy and safety outcomes of reversal agents for oral
anticoagulants
 Discuss strategies to address formulary concerns, including access to reversal agents, streamlining
administration, waste prevention, and institutional policy development
Funding
This activity is supported by an educational grant from Alexion, AstraZeneca Rare Disease.
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Disclosure of Conflicts of Interest
ProCE requires instructors, planners, managers, and other individuals
who are in a position to control the content of this activity to disclose any
relevant conflict of interest (COI) they may have as related to the content
of this activity. All identified COI are thoroughly vetted and resolved
according to ProCE policy.
ProCE is committed to providing its learners with high-quality CME/CE
activities and related materials that promote improvements or quality in
healthcare and not a specific proprietary business interest of a
commercial interest.

Disclosures
The faculty reported the following relevant financial relationships or relationships to
products or devices they have with ineligible companies related to the content of this
CME/CE activity:
Tyree H. Kiser, PharmD, FCCM, FCCP, BCCCP, BCPS, has disclosed that he has no conflicts of
interest to report.
Charles E. “Kurt” Mahan, PharmD, PhC, FASHP, FCCP, has disclosed that he has received
funds for research support, consulting fees, and fees for non-CME/CE services from
Portola/Alexion/AstraZeneca; received consulting fees and fees for non-CME/CE services from
Janssen; received fees for non-CME/CE services from BMS/Pfizer; received consulting fees
from Western Sky Community Care Healthplan Pharmacy and Therapeutics Committee.
The planners/managers reported the following relationships:
ProCE staff members have no relevant conflicts of interest to report.
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Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that
are not indicated by the FDA. The planners of this activity do not recommend the use of any agent
outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily
represent the views of the planners. Please refer to the official prescribing information for each
product for discussion of approved indications, contraindications, and warnings.
Disclaimer
Learners have an implied responsibility to use the newly acquired information to enhance patient
outcomes and their own professional development. The information presented in this activity is not
meant to serve as a guideline for patient management. Any procedures, medications, or other courses
of diagnosis or treatment discussed or suggested in this activity should not be used by healthcare
professionals without evaluation of their patient’s conditions and possible contraindications and/or
dangers in use, review of any applicable manufacturer’s product information, and comparison with
recommendations of other authorities.

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Faculty
Tyree H. Kiser, PharmD, FCCM, FCCP, BCCCP, BCPS
Professor, Department of Clinical Pharmacy
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Critical Care Pharmacy Specialist, Department of Pharmacy
University of Colorado Hospital
Aurora, Colorado
Charles E. “Kurt” Mahan, PharmD, PhC, FASHP, FCCP
Adjunct Associate Professor, Pharmacy
University of New Mexico Health Sciences Center
Albuquerque, New Mexico

Learning Objectives
 Discuss key guideline recommendations regarding the management
of anticoagulant-related bleeding
 Select appropriate reversal agents and dosing strategies in the
context of patient cases
 Evaluate recent clinical data regarding the efficacy and safety outcomes
of reversal agents for oral anticoagulants
 Discuss strategies to address formulary concerns, including access to
reversal agents, streamlining administration, waste prevention, and
institutional policy development
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Abbreviations
 FXa: factor Xa
 ED: emergency department
 GI: gastrointestinal
 UGIB: upper gastrointestinal bleed
 LGIB: lower gastrointestinal bleed
 EGD:
esophagogastroduodenoscopy
 GU: genitourinary
 CC: chief complaint
 MVR: mitral valve repair
 DVT: deep vein thrombosis
 VTE: venous thromboembolism
 PE: pulmonary embolism
 SVC: superior vena cava
 MAP: mean arterial pressure
 PRBC: packed red blood cells
 DOAC: direct oral anticoagulant
 ICH: intracranial hemorrhage
 ICU: intensive care unit
 LOS: length of stay
 HA: headache
 PMH: past medical history
 COPD: chronic obstructive
pulmonary disease
10
 HFrEF: heart failure with reduced
ejection fraction
 s/p: status post
 PAD: peripheral artery disease
 L: left
 4F-PCC: four factor prothrombin
complex concentrate
 FXAi: oral factor Xa inhibitor
 ISTH: International Society of
Thrombosis and Hemostasis
 BMI: body mass index
 Vd: volume of distribution
 DD-intx: drug into interactions

Individual Oral Anticoagulant Prescription Claims as a Proportion of Total Oral
Anticoagulant Prescription Claims Among Medicaid Beneficiaries Over Time
11
Clara. J Am Coll Cardiol. 2019;73:526.

Oral FXa Inhibitor Use Continues to Grow
 More than 8 million patients
are currently on FXa inhibitors
in the US
 Projected 26 million worldwide
by 2025
 Guideline endorsements
‒ AHA/ACC/HRS
‒ CHEST
‒ ESC
12
January. J Am Coll Cardiol. 2019;74:104. Lip. Chest. 2018;154:1121. Steffel. Eur Heart J. 2018;39:1330.
3
4
5
6.5
8
0
1
2
3
4
5
6
7
8
9
2016 2017 2018 2019 2020
Million
Patients

Patient Case: ICH
 Case: 58-yr-old male presents to the ED at 10 PM
 CC: new onset HA, nausea, vomiting, and dizziness
 PMH: COPD, lung cancer in remission (s/p
resection in 2012), HFrEF (EF 30%), CAD, atrial
fibrillation, PAD s/p bypass graft
 Med history:
‒ Apixaban 5 mg twice daily (took dose in the
AM with breakfast)
‒ Aspirin 81 mg daily
 ED course: patient began to develop L arm
dysmetria
‒ Stroke team is activated
‒ NIHSS score 1 (0-4, normal-impaired)
‒ GCS score 12
 Pertinent Labs:
 Treatment:
‒ CT head ordered
‒ Consults:
‒ Neurology
‒ Neurosurgery
‒ Hematology
‒ Neuro ICU for hospital admit
Test Reference Result
Hb 13.5 - 18.0 g/dL 10.2
HCT 40.0 - 54.0 % 33.6
Anti-Xa
(UFH/LMWH)
0 IU/mL 1.7
eGFR >59 mL/min/1.73 m2
77
13

Imaging Results:
• Hemorrhage in the left
cerebellum measuring 2.7
x 1.7 cm, with
intraventricular extension.
• No midline shift, mass
effect or evidence of acute
territorial infarct
Treatment:
• Stroke team asks
pharmacist for anticoag
reversal recommendation

Audience
Response
What would be the most appropriate
recommendation regarding andexanet alfa?
A. Patient does not qualify for anticoagulant reversal
B. Patient is outside the effective treatment window
C. Administer high-dose andexanet alfa
D. Administer low-dose andexanet alfa
15

Oral Anticoagulant–Associated Bleeding
 Major bleeding on warfarin and DOACs, including ICH, does
happen
 Anticoagulant-associated bleeding is associated with significant
morbidity, mortality, and use of healthcare resources
 There is a need to have effective strategies to manage OAC
associated bleeding to mitigate clinical and economic effects
Hankey. Stroke. 2014;45:1304. Schulman. J Thromb Haemost. 2010;8:202.
Palmer. Annu Proc Assoc Adv Automot Med. 2007; 51:13. Desai. Thromb Haemost. 2013;110:205. 16

Audience
Response
Which of the following meets major bleeding
criteria per the ISTH?
A. Nosebleed requiring a visit to urgent care
B. GI bleed (Hb 1 g/dL drop) requiring ED visit
C. Retroperitoneal bleed (BP 80/45 mm Hg) requiring 2 units of PRBC
D. Leg injury resulting in baseball sized hematoma
17

ISTH Definitions of Bleeding
 Major bleeding in nonsurgical patients (any of the following)
‒ Fatal bleeding
‒ Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal,
intra‐articular or pericardial, or intramuscular with compartment syndrome
‒ Bleeding causing ≥2 g/dL Hb fall or leading to transfusion of ≥2 units PRBC or whole blood
 Clinically relevant nonmajor bleed
‒ Does not meet criteria for “major bleed,” but requires one of these:
‒ Leading to hospitalization or increased level of care
‒ Requiring medical intervention by a healthcare professional
‒ Prompting a face to face (ie, not just a telephone or electronic communication) evaluation
18
Kaatz. J Thromb Haemost. 2015;13:2119.

Rates of Bleeding With Warfarin, Apixaban, and
Rivaroxaban in NVAF Trials
19
(ARISTOTLE or
ROCKET-AF)
Major Bleed
(%/yr)
Intracranial
Hemorrhage
(%/yr)
Gastrointestinal Bleed*
(%/yr)
Apixaban1
Warfarin
2.13%
3.09%
0.33%
0.80%
0.76%
0.86%
Rivaroxaban2
Warfarin
3.6%
3.4%
0.5%
0.7%
3.2%
2.2%
Rivaroxaban and apixaban were compared with warfarin across NVAF trials. Due to differences in trial designs and patient populations, no direct
comparisons between agents can be made.
*Investigators defined gastrointestinal bleeds as major bleeds1,2
1. Granger. NEJM. 2011;365:981. 2. Patel. NEJM. 2011;365:883.

Risk Factors for OAC-Associated Bleeding
Advanced age
• Subgroup analyses of RE-LY, ROCKET-AF, and ARISTOTLE have shown a
numerically increased risk
• DOAC dose reductions have been recommended in advanced elderly for some
agents/indications
Renal dysfunction
• Increases risk regardless of impact on PK (eg, warfarin and DOACs)
• Patients with at least moderate renal dysfunction have increased risk of bleeding
with DOACs
• Dose reductions have been recommended in moderate and/or severe renal
dysfunction
Concurrent use of antiplatelet drugs
• In RE-LY, aspirin use increased the risk of intracranial hemorrhage
(RR: 1.6)
Siegal. Eur Heart J. 2013;34:489. 20

Anticoagulation-Associated Intracranial Hemorrhage
 ICH rates for specific anticoagulants
‒ 0.3%-0.6% per yr for vitamin K antagonists like warfarin
‒ 0.1%-0.2% per yr for direct oral anticoagulants
‒ DOACS associated with a 50% reduction in the rate of ICH compared to VKAs
 Hematoma expansion in patient not taking oral anticoagulants
‒ 30%-40% within 3-6 hr
 Data on hematoma expansion for patients on VKAs or DOACs variable and
limited
‒ 36%-54%
21
Steiner. Stroke. 2017;48:1432.

Impact and Consequences of Anticoagulant-Associated
Bleeding
 FXa inhibitor bleeding events
‒ ~200,000 hospitalizations and ~30,000 deaths annually
‒ FXa-related major bleeding associated with long hospital stays
‒ ICH: average LOS 17 days
‒ Bleeding at critical site (intraocular, pericardial, intraspinal, intra-
articular): average LOS 13 days
‒ Major trauma: average LOS 10 days
‒ Major bleed with hemodynamic instability: average LOS 10 days
22
Hankey. Stroke. 2014;45:1304. Schulman. J Thromb Haemost. 2010;8:202. Palmer. Annu Proc Assoc Adv
Automot Med. 2007;51:13. Desai. Thromb Haemost. 2013;110:205.

Anticoagulant-Related Mortality With Intracerebral or
Intracranial Hemorrhage
23
Inohara. JAMA. 2018;319:463. Milling. Am J Emerg Med. 2018;36:396.
Held. Eur Heart J. 2015;36:1264. Hankey. Stroke. 2014;45:1304.
No anti-
coagulation
26.5%
33%
23%
0%
10%
20%
30%
40%
45%
48%
0%
10%
20%
30%
40%
50%
60%
Dabigatran,
Rivaroxaban,
Apixaban, or
Edoxaban
Warfarin
In-hospital Mortality
in Cohort Studies
30-day ICH-related Mortality
in NVAF Clinical Trials
ARISTOTLE
Trial3
Rocket AF
Trial4
Apixaban Rivaroxaban

Markers of Poor Prognosis for Intracranial Hemorrhage
24
Failure to lower anticoagulation rapidly
Large volume of blood
Intraventricular extension
Midline shift
Severe neurological deficits
An. J Stroke. 2017;19:3. Aguilar. Mayo Clin Proc. 2007;82:82.

What Outcomes Are Important for Patients Hospitalized
for Bleeding Events?
 Mortality
 ICU and hospital LOS
 Stroke center outcomes
 Discharge disposition
 Readmission within 30 days
 Rebleeding
 Thromboembolic events
 Cost
25
 What about hemostasis?

ISTH Recommendations for Assessment of
Major Bleeding Management
 Nonvisible bleeding
‒ Effective hemostasis is achieved when:
‒ Hemoglobin level is stable at 48 hr after initial treatment with packed red cells and hemostatic agent
‒ By 48 hr after the start of the initial management, there is no need for further infusion of hemostatic agents or coagulation
factors, or transfusion of other blood products
‒ Invasive interventions are either avoided or carried out with blood loss not exceeding the expected amount in a patient
with normal hemostasis
 Visible bleeding
‒ The above + cessation of visible bleeding within 4 hr after hemostatic agent administration
 Intracranial bleeding
‒ Nonvisible bleeding criteria plus:
‒ Hematoma volume is stable, or increased by <35% as compared with baseline volume), as assessed by a CT scan within
12 hr (time window of 6-24 hr after the index CT)
‒ No deterioration of the Extended Glasgow Outcome Scale (GOS-E) as assessed at 24 hr in comparison with that at
presentation.
‒ No neurologic deterioration/dysfunction is present at discharge (at discharge can be replaced by “at Day 30,” whenever
applicable) as assessed with any validated scoring system (eg, GOS-E) as compared with that at presentation
26
Khorsand. J Thromb Haemost. 2016;14:211.

Factors Influencing Outcomes With Anticoagulation
Reversal in ICH
 Location and cause
‒ Intracerebral, intraventricular, etc
‒ Trauma vs spontaneous
 Baseline hematoma volume (>30 mL)
‒ >60 mL and GCS <8 = predicted mortality >90% at Day 30
 Hematoma expansion
‒ Predominant in first 1-3 hr; 33% of patients have >33% growth from
baseline
‒ For each 10% increase in volume, 5% increase in mortality HR
27
Concha. Stroke. 2021;52:1520.

Time from Event and Last Anticoagulant Dose Is a Key Factor for
Reversal Strategy and Clinical Trial Data Interpretation in ICH
 Hematoma expansion is one modifiable variable commonly evaluated
 Time from symptom onset to treatment initiation
 Time from last anticoagulant dose to treatment
28
Symptom onset to door Door to treatment initiation
Anticoagulant dose to
ED arrival
Door to CT scan CT scan to treatment initiation
Concha. Stroke. 2021;52:1520.

Anticoagulant Intensity at Time of Bleed Impacts
Outcomes
Warfarin (INR) Mortality Odds
Ratio in ICH
<2 1.5 (0.6-3.7)
2-3 2.0 (1.0-4.1)
>3 3.7 (1.6-8.4)
29
Concha. Stroke. 2021;52:1520. Rosand. Arch Intern Med. 2004;164:880.
 72% of ANNEXA-4 study patients
had anti-Xa >75 ng/mL
 Longer time between dose and
reversal was independently
associated with excellent or good
hemostatic efficacy in ICH subgroup

DOAC Pharmacology: Factors to Consider in Reversal
30
Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban
Mechanism of action
Direct Thrombin
Inhibitor
Factor Xa Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor
Clearance 80% renal 36% renal 27% renal 50% renal 11% renal
Peak action 1-3 hr 2-4 hr 3-4 hr 1-2 hr 3-4 hr
Half-life
12-17 hr
(18 to ≥24 hr
if GFR <50)
5-9 hr 12 hr 10-14 hr 19-27 hr
Drug interaction
pathways
PgP substrate
Major
(CYP3A4/5,
CYP2J2, PgP
substrate)
Major
(CYP3A4 and PgP
substrate)
Minor
(CYP3A4)
No
Dosing Twice daily Once daily Twice daily Once daily Once daily
Dosing intensity and indication is also an important factor to consider with reversal strategy.

ACC Anticoagulant Bleeding Guidance
31
Gordon. J Am Coll Cardiol. 2020; 76:594.
The image on this slide has been removed
intentionally due to Copyright

32

33

Audience
Response
What is the FDA-approved agent available
specifically for reversal of rivaroxaban or apixaban?
34
A. Kcentra (4F-PCC)
B. Profilnine (3F-PCC)
C. Praxbind (idarucizumab)
D. Andexxa (andexanet alfa)
E. FEIBA (aPCC)

Company Agents Target Phase
CSL Behring
Kcentra Prothrombin Complex
Concentrate + Vitamin K
Factors II, VII, IX, X
(Warfarin)
FDA approved
Boehringer Ingelheim
Idarucizumab
Fully humanized monoclonal Fab
Dabigatran only FDA approved
Portola Pharmaceuticals, Inc.
Alexion Pharmaceuticals, Inc.
AstraZeneca
Andexanet alfa
Recombinant, modified human Factor
Xa
Factor Xa Inhibitors
(Riva, Apix, Edox, Betrix)
LMWH, fondaparinux
FDA approved
Perosphere, Inc.
Ciraparantag
Di-arginine piperazine
All DOACs
(Dabi, Riva, Apix, Edox)
UFH, LMWH, fondaparinux
II
OAC Specific Reversal Options
35

Other Reversal Options for OACs
36
Drug Vitamin K FFP
3 or 4-
Factor PCC
aPCC
(FEIBA)
rFVIIa Dialysis
Warfarin + + + + + -
Dabigatran - - +/- + - +
Rivaroxaban - - + + - -
Apixaban - - + + +/- -
Edoxaban - - + + +/- -
Betrixaban - - + + - -
Siegal. Eur Heart J. 2013;34:489.
Siegal. J Thromb Thrombolysis. 2015.

ACC Anticoagulant Critical or Life-Threatening Bleed
Reversal Guidance
38

Audience
Response
What is the dose of andexanet alfa for this
patient? (last dose of apixaban 5 mg ~10 hr
prior)
A. 2000 units x1
B. 50 units/kg x 1
C. 800 mg, then 960 mg inf.
D. 400 mg, then 480 mg inf.
39

Audience
Response
ACC-recommended dose of 4F-PCC for life-
threatening ICH associated with factor Xa
inhibitor if you can’t access andexanet alfa is:
A. 12.5 units/kg
B. 2500 units
C. 2000 units
D. 50 units/kg
E. 100 units/kg
40

Andexanet alfa: FDA-Approved Dosing
41
Andexxa [MP-AnXa-US-0160]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; Feb 2021. Courtesy of Jrimsans
Safety watch: Remove “<“
or “>” as may cause dosing
errors during high stress
clinical scenarios.
Brigham and Women’s: 73
low-dose administrations
versus 7 high-dose
Most patients are on
Apixaban 5 mg BID and
Rivaroxaban 15-20 mg daily
BID: twice daily
Majority of the time will be giving Low dose for Apixaban use, unless the patient is in the loading period for VTE
Flush line with 50-mL normal saline

Comparing Guidelines for Reversal of Oral
Anticoagulants in Major Bleeding
42
2020 ACC Expert Consensus
Pathway
AC Forum Guidance Document
2019
AHA/ACC/HRS AF Guidelines
2019
American College of Emergency
Physicians 2019
Administer andexanet alfa*
If andexanet alfa is not available, it is
reasonable to administer 4F-PCC (2000
units) or aPCC (50units/kg)
Consider activated charcoal for known
recent ingestion (within 2-4 h)
*ANNEXA-4 full report excluded patients with DOAC
levels <75 ng/ml because those patients were
considered to have clinically insufficient levels for
reversal agent. If drug effect/ level can be assessed
without compromising urgent clinical care decisions,
then assessment should be performed before
andexanet alfa is administered
Rivaroxaban and apixaban major
bleeding  Suggest andexanet alfa; if
not available, suggest 4F-PCC 2000
units
Edoxaban or betrixaban-associated major
bleeding  suggest high dose
andexanet alfa or 4F-PCC 2000 units
Andexanet alfa can be useful for the
reversal of rivaroxaban and apixaban in
the event of life-threatening or
uncontrolled bleeding (COR IIa, B-NR)
Tier 1: andexanet alfa if <18 hr from last
dose
Tier 2: suggest 4F-PCC 10-25 units/kg
only if first-line reversal agents (andexanet
alfa) unavailable
Define which patients benefit from reversal or replacement
strategies. Examples:
- A small traumatic SAH w/
normal neuro exam with DOAC received more than 2 half-
lives ago, may not require a reversal agent
- A large ICH with midline shift and NIHSS score greater
than 22 is catastrophic
January. Heart Rhythm. 2019;16:e66. Cuker. Am J Hematol. 2019;94:697. Frontera. Crit Care Med. 2016; 44:2251. Tomaselli. J Am Coll Cardiol.
2017;70:3042. Baugh. Ann Emerg Med. 2020;76:470. Tomaselli. J Am Coll Cardiol. 2020;76:594. Courtesy of Jrimsans

Quick Summary
43
aPCC
• Activated PCC
• Optimal dose unclear: 50 u/kg
to fixed dose 2000 units
• Risk of thromboembolic
events unclear
• 50 units/kg ~$5300
• Fast administration
4F-PCC
• Inactivated PCC
• Risk of thromboembolic events
unclear
• 50 units/kg ~$4800
Andexanet alfa
• Decoy protein
• Two set dosing schemes
• 10% thromboembolic
events
• $13,000* to $50,000
• Semifast administration
(2.5 hr)
Frontera. Neurocrit Care. 2016;24:6. Majeed. Blood. 2017;130:1706. Shulman. Thromb Haemost. 2018;118:842.
Connolly. NEJM. 2016;375:1131. Andexanet alfa PI.; Sept 2020. Courtesy of Jrimsans
* With New Technology Add-On Payment

Dosing and Cost Controversies
44
aPCC
• Activated PCC
• Risk of thromboembolic
events up to 10%
• 50 units/kg ~$5300
4F-PCC
• Inactivated PCC
up to 10%
• 50 units/kg ~$4800
Andexanet alfa
• Decoy protein
events
• $13,000* to $50,000
• Semifast administration
(2.5 hr)
Connolly. NEJM. 2016;375:1131. Andexxa [MP-AnXa-US-0160]. South San Francisco, CA: Portola
Pharmaceuticals, Inc.; Sept 2020. Courtesy of Jrimsans

Prep/Administration Considerations, Thrombosis Risk?
45
aPCC
• Activated PCC
unclear
• 50 units/kg ~$6300
4F-PCC
• Inactivated PCC
unclear
• 50 units/kg ~$5800
Andexanet alfa
• Decoy protein
events
• $13,000* to $50,000
• Bolus = Fast
• Semifast bolus + infusion
(2.5 hr)
Connolly. NEJM. 2016;375:1131. Andexxa [MP-AnXa-US-0160]. South San Francisco, CA: Portola
Pharmaceuticals, Inc.; Sept 2020. Courtesy of Jrimsans

Optimizing Administration, Dosing, and Follow-up
 Initiate early discussion (if able)
 Get the full picture
‒ Surgery versus medical therapy only vs transfer
‒ Drip and ship? 4F-PCC allowed prior? Know ahead!
 Which agents are available on formulary
 Evaluate underlying risk of thrombosis
‒ Presenting reason + patient + reversal agent
 Education regarding timing of administration and duration of effect
 Prospectively/retrospectively review cases
 Restart anticoagulation when hemostasis acceptable
46

Monitoring the Reversal Strategy
 Was hemostasis achieved (refer back to ISTH criteria)?
‒ Hemoglobin/hematocrit
‒ Hematoma stabilization
 Hemodynamic stability
 Hepatic and renal function
 Drug–drug interactions impacting response
 Thrombosis risk
 Level of anticoagulation remaining?
47

Conventional and Available Laboratory Assays
48
Dabigatran Rivaroxaban/Apixaban/Edoxaban/Betrixaban
Drug
Present
Thrombin time
(TT)
Anti-factor Xa (calibrated to LMWH/UFH)
*Other possible labs: chromogenic anti–factor
Xa calibrated to each drug
Quantitative
Test
N/A
*lab of choice
would be dTT
N/A
*Other possible labs: chromogenic anti–factor
Xa calibrated to each drug
Sensitivity:
PT vs APTT
aPTT >PT/INR PT>APTT
Anti-factor Xa calibrated to LMWH/UFH – not
as predictable/accurate
No/Limited
Effect
Anti–factor Xa TT
• Standard coagulation assays cannot
differentiate between below-therapy,
on-therapy, or above-therapy ranges
• Anti–factor Xa (Heparin/LMWH) will
tell presence of agent
• Anti–factor Xa assays have numerous
kits and reagents
• Not recommended to extrapolate and use
observed values in the literature without
knowing your laboratory methods
• Know your kit and reagents!
*TEG / ROTEM are utilized at our institution – may be useful to guide other product replacements

What Is Current Practice for Bleeding Patients?
49
Patients Andexanet alfa 4F-PCC FFP Other No reversal
All bleeds 3030 342 (11%) 733 (24%) 925 (31%) 794 (26%) 438 (14%)
GI bleed 1453 137 (9%) 303 (21%) 466 (32%) 423 (29%) 228 (16%)
Intracranial
hemorrhage
507 67 (13%) 170 (34%) 146 (29%) 111 (22%) 47 (9%)
Critical
compartment
113 11 (10%) 26 (23%) 36 (32%) 34 (30% 14 (12%)
Trauma 781 105 (13%) 214 (27%) 250 (32%) 180 (23%) 82 (10%)
Other bleed 176 22 (13%) 20 (11%) 27 (15%) 46 (26%) 67 (38%)
Single agent 64% 83% 72% 47% 86% 64%
1075 (35.5%) of major bleeds treated with andexanet alfa or 4F-PCC
Coleman. Future Cardiol. 2020;17:127.

Case: ICH (continued)
 Hospital course:
‒ He was discharged to rehab after 3 wk of
hospitalization
‒ He was cleared by neurosurgery to start aspirin by
discharge with a preliminary plan to transition to
apixaban monotherapy 2 wk later
‒ He was discharged from rehab after 3 wk of care
‒ No headache or dizziness and alert, conversant, with
left greater than right weakness in the legs
‒ His most recent clinic visit now living with his son, no
major complaints
‒ He says his breathing feels fine, and he denies LE
edema or orthopnea
‒ He reports some residual dizziness
 Hospital course:
– He was originally awake and following commands
but subsequently declined and had increased
work of breathing, leading to intubation
– Repeat scan at that time was unchanged
– Neurosurgery consulted who took him urgently
for suboccipital craniectomy
– They evacuated blood from the 4th ventricle, but
left the intraparenchymal component due to
proximity to deep nuclei
– He returned to ICU for further management
– Over the next 2 wk showed significant clinical
improvement with mild left arm and leg
weakness
50

Learning Objectives
 Discuss key guideline recommendations regarding the management of
anticoagulant-related bleeding
 Select appropriate reversal agents and dosing strategies in the context
of patient cases
 Evaluate recent clinical data regarding the efficacy and safety
outcomes of reversal agents for oral anticoagulants
 Discuss strategies to address formulary concerns, including access to
reversal agents, streamlining administration, waste prevention, and
institutional policy development
51

During the Last Decade, New Agents Have Emerged for
Anticoagulation and Reversal of Anticoagulation
NVAF
DVT/STEMI
Warfarin
Era
Dabigatran
2010
Enoxaparin
1993-2010
Hip/knee/NVAF
Rivaroxaban
2011
DVT/PE
Rivaroxaban
2012
Hip/knee/DVT/PE
Apixaban
2014
Hip
Dabigatran
2015
CAD/PAD
Rivaroxaban
2018
NVAF
Apixaban
2014
DVT/PE
Dabigatran
2014
VTE
Rivaroxaban
2017
Acutely Ill Medical
Rivaroxaban
2019
Prophylaxis of stroke and
systemic embolism in
patients with atrial fibrillation
Prophylaxis of DVT in
patients undergoing
hip/knee replacement
surgery; prophylaxis
of stroke in patients
with abnormal heart
rhythm
Reduce continued risk
of VTE
Reduce risk of major
cardiovascular events
in CAD/PAD
Prophylaxis of clots in
acutely ill patients
Treat/reduce recurrence
of clots for patients with
DVT/PE
Reduce risk of stroke
and systemic embolism
in patients with NVAF
Prophylaxis and
treatment of DVT;
prophylaxis and
treatment of STEMI
Reduce risk of clots
following hip/knee
replacement surgery;
treatment of DVT/PE
Prophylaxis of
DVT/PE following hip
replacement surgery
Treatment of DVT/PE
Low Molecular Weight Heparin
Direct Thrombin Inhibitor
Direct FXa Inhibitor
1. Crowther. Blood. 2008;111:4871- 2. Lovenox PI. 3. Pradaxa PI. 4. Eliquis PI. 5. Xarelto PI.
52
Factor Replacement
Reversal / Antidote
NovoSeven
1999
KCENTRA
FEIBA
2013
IDARU-
CIZUMAB
2015
ANDEXANET
2018

Call to Action to Differentiate “Reversal Agent” and
“Antidote” from “Factor Replacement Strategy”
 “Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either
by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its
end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote
administration may not only result in the reduction of free or active toxin level, but also in the
mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition,
receptor blockade or direct antagonism of the toxin.”
 For PCC use in oral FXa Inhibitor patients such as apixaban and rivaroxaban who require bleeding
control, insufficient evidence exists to label PCC as an ”Antidote” or “Reversal Agent” and it is a
“Factor Replacement Strategy” in this population
 Idarucizumab for dabigatran and andexanet for rivaroxaban and apixaban do meet this definition as
an antidote or reversal agent
 American College of Emergency Physician Guidelines among other guidelines differentiated these
approaches
53
Chacko. Indian J Crit Care Med. 2019;23(suppl 4):S241. Salyer. Essential Emergency
Medicine. 2007:923.Baugh. Ann Emerg Med. 2020;76:470.

REVERSE-AD: Trial Design
0-15 min 90 days follow-up
Hospital
arrival
5 g idarucizumab
(2 x2.5 g IV)
Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 d
Pre-1st vial 1 h
Blood
samples
Primary endpoint: Maximum reversal within 4 hr
based on dTT, ECT
Pollack. Thromb Haemost. 2015;114:198.
Group A (n = 298)
Patients taking
dabigatran with
uncontrolled
bleeding
Group B (n = 196)
Patients taking
dabigatran requiring
emergency surgery
54

REVERSE AD Full Cohort Study Overview
Reverse AD: Idarucizumab Reverses Anticoagulant
Effect of Dabigatran
Idarucizumab was 100% effective in reversing the anticoagulant effect of
dabigatran among 300 patients with uncontrolled bleeding (median time to
bleeding cessation, 2.5 hr) and among 200 patients who required an urgent
procedure (median time to procedure initiation, 1.6 hr)
Pollack. NEJM. 2017;377:431.
REVERSE AD Full Cohort Conclusions
• In emergency situations, idarucizumab rapidly, durably, and safely reversed
the anticoagulant effect of dabigatran
• Deaths Group A (bleeding, n = 298): 12.3% (30 days) and 18.7% (90 days)
• Deaths Group B (surgery, n = 196): 12.4% (30 days) and 18.5% (90 days)
• Idarucizumab has been available in the US since 2015 and was approved
based off of the early interim analysis by the FDA
55

Audience
Response
What is the FDA-approved agent available
specifically for reversal of dabigatran?
56
A. Kcentra (4F-PCC)
B. Profilnine (3F-PCC)
C. Praxbind (idarucizumab)
D. Andexxa (andexanet alfa)
E. FEIBA (aPCC)

Idarucizumab Availability
With similar data as
andexanet and FDA approval,
why is there much less
availability of andexanet with
oral factor Xa use being much
higher than dabigatran?
Praxbind idarucizumab. Find praxbind 57

58
Native Factor Xa
Active site
Siegal. NEJM. 2015;373:2413. Data on file. 2.5 Clinical Overview. South San Francisco, CA: Portola Pharmaceuticals Inc.; 2017.
Prevents anticoagulant effect by
removing GLA domain, which
eliminates the ability of the protein to
assemble into the prothrombinase
complex
Native FXa
Cannot form a
prothrombinase complex
ANDEXXA
decoy molecule
Active site
Binds with high affinity
Binds to and sequesters the
FXa inhibitors apixaban and
rivaroxaban
Andexanet alfa Acts as a FXa Decoy and Reverses Fxa
Inhibitor Activity
Andexanet binds to FXa inhibitors apixaban or rivaroxaban with high affinity
Andexanet binds and sequesters the FXa inhibitors, apixaban and rivaroxaban. This allows
native FXa to restore thrombin generation, which is necessary for fibrin and clot formation2,3

59
ANNEXA-4 Study Design
Efficacy Measurements
◆ Change in anti–fXa activity
◆ Clinical hemostatic efficacy
through 12 hr
Safety Measurements
◆ Thrombotic events
◆ Antibodies to fX, fXa, andexanet
◆ 30-day mortality
Day 1
Patient with acute
major bleed, meeting
inclusion criteria
Patient Screening
IV
Bolus
2-hr
IV Infusion
Safety
follow-up visit
Day 30
Day 3
If last dose of fXa
inhibitor* was within
18 hr
Andexanet Treatment
Bleeding and Laboratory Assessment
Assessments:
After end of infusion
1 hr 4 hr 8 hr 12 hr
*Apixaban, rivaroxaban, enoxaparin, or edoxaban

Site of Initial Bleeding
Safety vs Efficacy Population 352 254
Intracranial Bleeding 227 (64%) 171 (67%)
Nontraumatic 128 99
Glasgow Coma Scale, mean 14 14
NIHSS, mean 5.7 5.2
mRS, mean 2.8 2.8
Trauma related 99 72
Intracerebral site 137 104
Hematoma Volume ≤10cc 84 66
Hematoma Volume 11-60 cc 53 38
Sub-dural site 75 58
Subarachnoid site 57 43
Time from baseline scan to drug admin, hr (SD) 2.4 (1.6) 2.4 (1.6)
Gastrointestinal Bleeding 90 (26%) 62 (24%)
Upper 27 21
Lower 21 14
Unknown 42 27
Other Bleeding site 35 (10%) 21 (8%)
Connolly. NEJM. 2019;380:1326.
60

Main Results:
Effective Hemostasis at 12 Hr Post Andexanet
Number of Major
Bleeds Adjudicated
Number of Patients
Who Achieved
Excellent or Good
Hemostasis
Percent of Patients
Who Achieved
Excellent or Good
Hemostasis
Binomial Exact 95%
Confidence Interval
249 204* 82% 77%-87%
• Of 204 patients, 171 (84%) were “excellent” and 33 (16%) were “good”
• Study was also enriched to recruit more ICH
Connolly. NEJM. 2019;380:1326. 61

0
200
400
600
800
Anti–fXa
Level
(ng/mL)
Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr
Median 149.7 11.1 11.5 97.2 104.6 91.3
Percent Change -92% -92% -32% -34% -38%
(95% CI) (-93 to -91) (-93 to -91) (-38 to -29) (-36 to -27) (-41 to -34)
Anti–fXa Activity in Efficacy Population (N = 254)
Example here is apixaban
• Apixaban-treated patients (n = 134): median anti–fXa decreased from of 149.7 ng/mL at baseline to 9.8 ng/mL (93.4%; 95% CI 92%-94%)
• Rivaroxaban-treated patients (n = 100) : median anti–fXa decreased from 211.7 ng/mL at baseline to 11.4 ng/mL (92.5%; 95% CI 90%-94%)
62

ICH Hematoma Expansion Between 1 and 12 Hr
12 Hr Scan
(vs baseline)
1 Hr Scan
(vs baseline)
Non-traumatic, single-
compartment, efficacy
evaluable IPH
N =
71
Volume expansion ≤35%
N = 56
Volume expansion ≤35%
N = 55
Volume expansion >35%
N = 1
Volume expansion >35%
N = 15
 71 efficacy evaluable patients had nontraumatic, single-compartment,
intraparenchymal hemorrhages
 Of these, 56 had volume expansion ≤35% from baseline at 1 hr
 Of these, 55 of 56 (98%) remained <35% from baseline at 12 hr *
Of the 55 patients at 12 hr with volume expansion≤35% relative to baseline:
• 55 of 55 had volume expansion ≤35% relative to 1 hr scan
63

Biomarker-Efficacy Correlation
 Whole treated population: no significant relationship between hemostatic
efficacy and reduction in anti–factor Xa activity
 ICH patients: anti–factor Xa activity reduction magnitude was a moderate
predictor of hemostatic efficacy
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
1-specificity
Sensitivity
AUC (95% CI): 0.53
(0.44 - 0.62)
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
1-specificity
Sensitivity
AUC (95% CI): 0.64
(0.53 - 0.74)
All Patients on
Oral FXa Inhibitor
ICH Patients on
Oral FXa Inhibitor
Connolly. NEJM. 2019;380:1326. 64

Thrombotic
Events Before oral anticoagulation
restart or never restarted
34 (9.7%)
After oral
anticoagulation restart
0
Patients in Safety Analysis
(n = 352)
Total
<6 days
after bolus
6-14 days
after bolus
15-30 days
after bolus
Restart of any anticoagulation
(includes prophylactic dose
heparins)
220
(62%)
145 46 29
Restart of oral anticoagulation 100
(28%)
31 37 32
Safety: Restarting Anticoagulation
65

Safety: Mortality
Patients in Safety Analysis (n = 352) Total
<6 days
after
bolus
6-14 days
after bolus
15-30 days
after bolus
Deaths within 30 days
49
(13.9%)
8 21 20
Cardiovascular
Noncardiovascular
Uncertain Cause
35
12
2
7
1
0
15
5
1
13
6
1
Mortality Rate by Bleed Type: ICH (15.0%); GI (11.1%)
Connolly. NEJM. 2019;380:1326. 66

Annexa-4 Takeaway Points
 Andexanet infusion rapidly reversed anti–fXa activity with an
onset within 2-3 min
 Effective hemostasis adjudicated to occur in 82% of patients
 ICH 30-day mortality was 15%
 Hemostatic efficacy correlated with anti–fXa reduction in ICH
patients but not the general study population
 Thrombotic events at 30 days had occurred in 9.7% of subjects
and were less prevalent after restarting anticoagulation
67

ANNEXA-I Study DESIGN1,2
.
Name Phase Protocol Title Planned
ANNEXA-I 4
A phase IV randomized clinical trial of andexanet alfa [andexanet alfa for injection] in acute
intracranial hemorrhage in patients receiving an oral factor Xa inhibitor
440
900*
* Interim analysis planned at 50% enrollment (N=450).
†Clinical + radiographical + durability of response
900 patients
presenting with
acute ICH within 6
hr of symptom
onset and within
15 hr of taking
apixaban,
rivaroxaban or
edoxaban
Andexanet alfa
(IV bolus + Infusion)
Usual Care1
30-Day Follow-up
Primary Efficacy Endpoint:
Proportion of patients achieving
effective hemostasis†
Safety Endpoints:
Occurrence of thrombotic events
All-cause mortality
1:1 Randomization
Primary endpoint based on achievement of
hemostasis (excellent/good) determined by
blinded EAC; must meet all criteria:
• Clinical: <7-point increase in NIHSS (NIH
Stroke Scale) at 12 hr
• Imaging: ≤35% increase in hematoma volume
between baseline and 12 hr
• Durability of response: no hemostatic rescue
therapy within 12 hr post randomization
68
NCT03661528. Protocol for: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in
Patients Receiving an Oral Factor Xa Inhibitor. Data on File, Alexion Pharmaceuticals, 2021.

ANNEXA-I Study Schematic (First 12 Hr)
Hr Post Randomization
69
-2h 0h 1h 2h 3h 6h 12h
CT/MRI
Labs
Anti-FXa,
TG,
Antibodies
Anti-FXa,
TG,
Antibodies
Anti-FXa TG
± 1 hr
Clinical
GCS,
NIHSS,
mRS
GCS,
NIHSS
GCS,
NIHSS
GCS,
NIHSS
GCS,
NIHSS
Treatment
andexanet or usual care
Randomization
Protocol for: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in

Usual Care vs Andexanet alfa
Protocol for: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in
 Usual care
‒ Will consist of any treatment(s) (including no treatment) other than andexanet
alfa administered within 3 hr after randomization that the investigator and/or
other treating physicians consider to be appropriate
 Andexanet alfa
‒ Patients will receive one of 2 dosing regimens of andexanet alfa based on which
FXa inhibitor they received and the amount and timing of the most recent dose
‒ Andexanet alfa will be given as an IV bolus administered over ~15-30 min,
followed immediately by continuous infusion administered over ~120 min
70

 To evaluate the occurrence of thrombotic events at 30
days
 To evaluate in-hospital and 30-day mortality (all-cause,
cardiovascular, and bleeding)
 To evaluate the occurrence of invasive intracranial
procedures post randomization
 To evaluate the length of initial hospitalization for primary
bleeding event
 To evaluate the rate of rehospitalization
 To evaluate adverse events and vital signs
 To evaluate the immunogenicity of andexanet alfa
 To evaluate the effect of
andexanet alfa vs usual care
on anti–FXa activity
on neurologic function
on the rate of effective
hemostasis
ANNEXA-I Objectives1,2
S A F E T Y
P R I M A R Y
E F F I C A C Y
S E C O N D A R Y
E F F I C A C Y
NCT03661528. Protocol for: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial
Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor. Data on File, Alexion
Pharmaceuticals, 2021.
As measured by:
• Clinical evaluation: NIHSS
• Imaging: CT/MRI scans
• Durability of response
71

ANNEXA-I Primary Efficacy Endpoint
NCT03661528. Protocol for: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial
Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor. Data on File, Alexion Pharmaceuticals, 2021.
 Achievement of effective hemostasis, as determined by the blinded EAC1,2
‒ For a patient to have excellent or good hemostasis efficacy, he or she must meet all of
the following criteria:
‒ NIHSS score of less than +7-point change from the baseline score at 12 hr post
randomization
‒ No greater than 35% increase from baseline in hematoma volume/thickness at 12 hr post
randomization
‒ Have not received rescue therapy within 12 hr post randomization
‒ Efficacy endpoints are assessed with blinding
‒ Blinded core lab for scans and blinded NIHSS score assessor at each site
72

ANNEXA-I Secondary Efficacy Endpoints
NCT03661528.
 Percent change from baseline to nadir in anti-FXa activity during the first 3 hr
post randomization
 Change from baseline in NIHSS at 24 hr post randomization
 Change from baseline in GCS score at 24 hr post randomization
 Proportion of neurologic deterioration, as defined by NIHSS increase ≥4 or
GCS score decrease ≥2 at 24 hr post randomization vs baseline
73

Annexa-I Status as of 11/9/2021
▸294 patients enrolled of a planned 900 patients
▸An interim analysis of 450 patients is planned in 6/2022 with information
being made available to the public likely in 10/2022
▸Planned completion date is 9/2024
74

What About Andexanet in Surgical Patients?
ANNEXA S
A Phase 2 Randomized Clinical Trial of Andexanet alfa in
Surgical Patients Receiving an Oral Factor Xa Inhibitor

ANNEXA-S Study DESIGN
NCT04233073
Name Phase Protocol Title and Description Planned
ANNEXA-S 2
Single arm, prospective, open-label clinical trial to evaluate the efficacy and safety of
andexanet alfa patients who require urgent surgery that have been anticoagulated
with the FXa (activated factor X) inhibitors.
100
Study Population
100 patients
receiving a factor
Xa inhibitor who
require urgent
surgery
Andexanet alfa
(IV Bolus + Infusion)
Surgery up to 6 hr
30-Day Follow-up
Primary Efficacy Endpoint:
• Effective hemostasis.
• Change in anti-FXa activity
• Blood Loss
• Post-op bleeding
Safety Endpoints:
Occurrence of thrombotic events.
All-cause mortality.
Key Eligibility criteria:
• <15 hr since the last FXa inhibitor dose
• Need for surgery in <12 hr
• No life threatening bleeding
• Procedures using heparin excluded
76
Andexanet alfa Dosing
• (15 minute IV Bolus to begin prior to start of surgery + Infusion)
• Initial infusion for at least 2 hr and from start to end of surgery
• Extended infusion for up to 4 hr
Annexa-S Status as of 11/9/2021
Recruiting on track and set to report out
second quarter of 2022

77
ProCE.com
What About Prothrombin Complex Concentrate?

Let’s Backup to the Yr 2000 to 2012
 Recombinant factor VIIa (NovoSeven®) began to gain widespread use for non-hemophiliac patients
including battlefield trauma and off-label use driven by physicians in the US Army with combat guidelines
including off-label NovoSeven suggested use as early as January 2003
 Whistleblowers (US Army Physician and Novo Medical Science Liason) - Claimed “Novo illegally funded
medical experiments on injured soldiers in Iraq in a bid to widen the use of NovoSeven. The research
eventually indicated that NovoSeven was not more useful than older alternatives for controlling bleeding
in injured patients, and it carried the risk of excessive clotting in wounded patients. Yet Novo's
unapproved, ‘off-label’ promotion eventually made NovoSeven the standard treatment for wounded
soldiers in Iraq and Afghanistan, according to the suit.”
 “Studies and presentations made by Army physicians and researchers led to NovoSeven's use in combat
wounded, and influenced civilian doctors to administer the drug as well”
‒ Use was for anticoagulated and non-anticoagulated patients in the civilian world
‒ High rates of arterial and venous thromboembolism with no clear benefit
 Multiple analyses later demonstrated more harm than benefit with its use at a cost of roughly “$10,000
per vial” at that time and off-label use halted abruptly in 2011/2012 as risks outweighed benefits in non-
hemophiliac patients (eg, trauma, cardiac surgery)
 Novo Nordisk settled for approximately $25 million
78
ReliasMedia. Drug Criteria & Outcomes. Fareed. Clin Appl Thromb Hemost. 2007;13:121.
CBS News. Drug company illegally experimented on wounded soldiers in Iraq, suit says. MySanAntonio. Army again probing
Fort Sam payments. The United States Department of Justice. Danish pharmaceutical Novo Nordisk to pay $25 million to
resolve allegations of off-label promotion of Novoseven.

Other Treatment and “Factor Replacement” Options for
OACS
79
Drug Vitamin K FFP
3 or 4-
Factor PCC
aPCC
(FEIBA)
rFVIIa Dialysis
Warfarin + + + + + -
Dabigatran - - +/- + - +
Rivaroxaban - - + + - -
Apixaban - - + + +/- -
Edoxaban - - + + +/- -
Betrixaban - - + + - -
Siegal. Eur Heart J. 2013;34:489.
Siegal. J Thromb Thrombolysis. 2015.

Issues With the Use of a Factor Replacement Strategy
for Oral FXa Bleeds
 KCentra and FEIBA were approved in 2013 with no FDA approval/ indication for use in FXa inhibitor bleed treatment  yet
there has been plenty of time for the companies to have studied and supported research/RCTs in this area as compared to
leaving the question to clinicians to study in the real world
 PCC’s were studied in phase 2 for their effect on anti-FXa levels in oral FXa inhibitor patients – then development was
abandoned by the companies as there was no effect on anti-Fxa levels
 4F-PCCs are unable to overcome FXa inhibition by direct binding and neutralization of FXa inhibitors.
‒ Since 4F-PCCs provide FX (not FXa), and FXa inhibitors do not bind FX, treatment with 4F-PCCs has no direct effect on the
anti-FXa activity of rivaroxaban or apixaban
‒ the 4F-PCC dose required to overcome the FXa inhibitor via this mechanism would be around 20 fold higher than the
highest approved dose (ie, ~1000 IU/kg or 150 vials each containing 500 units).
‒ 4F-PCC PCCs did not normalize thrombin generation in vitro at inhibitor levels ≥75 ng/mL and only begins to have any
effect on hemostasis at the point that apixaban/rivaroxaban levels below 75 ng/mL and more around 18.75 ng/mL
‒ Why is that important? In Annexa-4, 75% of bleeding patients had levels well above 75 ng/mL (medians 149.7 and 211.8
ng/mL for apixaban and rivaroxaban respectively)
 4F-PCC contains multiple other factors that are not depleted such as Factor II, VII/VIIA and IX as well as Protein C and S. It also
contains therapeutic levels of factor VII/VIIa
 In bleeding patients taking DOACs, PCC dosing ranges from ~ 10 to 160 units/kg with little standardization
80
Lu. Res Pract Thromb Haemost. 2020;4:1282

Why Is the Effect of PCC on Anti-Fxa Levels Important?
 The FDA Division Director, who oversaw the andexanet review process believed
that andexanet alfa’s effect on the surrogate outcome of anti-FXa levels was
reasonably likely to predict a clinical benefit due to its >90% decrease in anti-FXa
activity, and the strong biological plausibility that this decrease could lead to
hemostasis and improve morbidity and mortality in bleeding patients receiving
apixaban and rivaroxaban who require reversal
 None of the studies that measured anti-FXa activity showed any effect of 4F-PCCs
in reversing anti-FXa levels – yet we have continued to utilize it for FXa inhibitor
bleeds
 Are we repeating history?
 PCC use for fXa inhibitors may be due to anchoring bias, confirmation bias,
framing effects, and other biases that justify its use based off of very low
quality of evidence.
 Increased weight should be given to regulatory (eg, FDA) approvals and ongoing
pursuit of research in collaboration with the FDA
81
Food and Drug Administration. Summary basis for regulatory action—Andexxa 2019. Levi. J Thromb Haemost. 2014;12:1428.
Cheung. J Thromb Haemost. 2015;13:1799. Barco. Br J Haematol. 2016;172:255. Nagalla. Clin Transl Sci. 2016;9:176. Song. J Thromb
Haemost. 2017;15:2125. Levy. J Thromb Haemost. 2018;16:54. Saposnik BMC Med Inform Decis Mak. 2016;16:138.

2021 Congressional Research Service: Off-Label Use of
Prescription Drugs
 “A worst-case scenario for the nation’s health would be the widespread acceptance of a drug for
an off-label use that sufficient research would have revealed to be ineffective, unsafe, or both.
Aside from the drug’s direct harm, the time spent waiting to see whether it worked would have
been time not spent exploring other treatment options”
 “Unchecked off-label prescribing may also threaten the FDA gold standard of drug approval. If
clinicians had already accepted a new use into practice through off-label prescribing, a
manufacturer may choose to not invest resources to go through clinical trials and the FDA
process to win approval”
 Off-label use of 4F-PCC specifically for Xa inhibitor reversal appears fall into both of these above
concerns with at least 40% - 60% of its use being off label and much of that for Xa inhibitor
bleed treatment
 Off-label use of 4F-PCC has critically slowed higher quality level research of FDA approved
agents despite 4F-PCC having very low quality of evidence, very limited comparative data, and
many health-systems have perpetuated its use rationalizing and justifying the use of PCC despite
poor evidence
 Global annual market of the anticoagulant reversal and factor replacement products is expected
to reach $2.2 billion by 2028
82
Congressional Research Service. Off-label use of prescription drugs. Scharman. Eur J Haematol. 2018;101:349.
Polaris Market research. Anticoagulant reversal drugs market size is projected to reach $2.20 billion by 2028.

Andexanet vs Prothrombin Complex Concentrates: Differences in Reversal of
Factor Xa Inhibitors in in vitro Thrombin Generation
83

Lu and Colleagues Conclusions
• Andexanet normalized tissue factor-initiated thrombin generation (TF-
TG) over a wide range of apixaban and rivaroxaban concentrations
tested (19-2000 ng/mL)
• However, 4F-PCC (or individual factors) was unable to normalize
endogenous thrombin potential (ETP) or peak thrombin (Peak) in the
presence of apixaban or rivaroxaban (75-500 ng/mL). TF-TG was only
normalized by 4F-PCC at inhibitor concentrations <75 ng/mL (ETP) or
<37.5 ng/mL (Peak)
• Both the theoretical calculations and experimental data demonstrated
that 4F-PCCs are only able to normalize TG over a low and narrow range
of FXa inhibitor concentrations (<75 ng/mL)
84

Effect of PCC vs Saline on Anti-FXa Levels in Steady State
Rivaroxaban: 2014
Levi. J Thromb Haemost. 2014;12:1428. 85

Study Results: Primary Efficacy Endpoint
Siegal. NEJM. 2015;373:2413.
ANNEXA - A ANNEXA - R
92.3 + 3% andexanet vs 33 + 6% placebo 97 + 2% andexanet vs 45 + 12% placebo
P <.001 P <.001
86

FIX ICH Study –
Pre-planned analysis of PCC for Xa inhibitor reversal from the Neurocritical Care
Society Pharmacy Study Group
Panos. Circulation. 2020;141:1681.
26 study sites
submitted data
on patients
treated from
January 2015
to March 2019
Apixaban or
rivaroxaban
associated ICH
who received
PCC for
management
Retrospective,
multicenter,
observational
cohort
Patient Characteristics
Numbers based off of efficacy analysis population (n = 433)
Primary intracranial
site
Intracerebral 39.7%
Subarachnoid 15.7%
Subdural 44.6%
Multiple 23.8%
Anticoagulant
Apixaban 54%
Rivaroxaban 46%
Anticoagulation
indication
Atrial fibrillation 77.8%
VTE Treatment 15.9%
Other 6.2%
Renal Function
<30 ml/min 8.5%
30-60 ml/min 33.7%
>60 ml/min 45.5%
PCC Administered
Activated PCC (FEIBA) 27.3%
Four Factor PCC (Kcentra) 72.7%
Primary Endpoints
Hemostatic Efficacy (n = 433)
Overall 81.8%
Intracerebral 73.3%
Subarachnoid 85.3%
Subdural 88.1%
aPCC 88.1%
4PCC 79.4%
Thrombotic Events (n = 663)
Overall (n = 25pts) 3.8%
Definition of Hemostasis:
modified Sarode criteria
• “Unable to record the exact timing of the last
dose of apixaban or rivaroxaban due to lack of
uniform documentation…”
• Xa levels prior to PCC in only 98 (14.8%) of
patients with only 8 of those being calibrated to
the anticoagulant
• 73 more deaths in the safety arm vs hemostatic
efficacy arm. (126 vs 53) so if patients died they
were often likely were NOT considered in the
hemostatic efficacy results falsely elevating
results
• Competing risk of death affects hemostatic
efficacy results
87

Potential Limitations of FIX-ICH Study
 Retrospective, observational cohort study that lacks rigor of a prospective study or randomized controlled trial and has no
comparator.
 Lower acuity of ICH population is likely elevating hemostatic efficacy results
‒ 44.6% SDH (88.1% hemostatic efficacy)
‒ 15.7% SAH (85.3% hemostatic efficacy)
‒ 39.7% Intracerebral hemorrhage (73.3% hemostatic efficacy)
‒ Excluded patients with intraventricular hemorrhage expansion and patients undergoing surgery which was approximately 1/3 of patients
‒ Hemostatic agent rescue was not considered a hemostatic efficacy failure
 Limited observation window up until discharge only – not followed out to 30 days out of hospital. This falsely lowers
thromboembolism rates (4%) and also lowers mortality rates.
 The data suggest a high level of unknown or low-level of anticoagulation because anti-Fxa levels were only measured in 14.8% of
patients and only 8 of those were with calibrated assays. In addition, with the lack of recording of the last dose of Xa inhibitor, it is
quite possible a majority of patients may not have been anticoagulated at therapeutic levels or may have been at levels that would
not require a reversal agent or a factor replacement strategy.
‒ Patients who are not anticoagulated at a significant level would obviously have higher hemostatic efficacy rates
 19% mortality rate was likely underestimated because of excluded populations
 73 more deaths in the safety arm suggesting the competing risk of death also falsely elevates hemostatic efficacy results since these
were likely failures of PCC to control the bleeding or due to other reasons such as death before follow up imaging could occur
88
Panos. Circulation. 2020;141:1681.

Outcomes and Analysis
Search Strategy
Real-World Effectiveness
• Patients hospitalized for oral FXa inhibitor-related bleeding between Jan 2016 and Sept 2019
were identified through electronic medical records (EMR) from 45 hospitals in the U.S.
Patients were included in the analysis if they:
• Were an adult patient hospitalized for anticoagulation-related bleeding
− Only hospitalizations with ICD-10 indicative of bleeding due to extrinsic factors
(i.e., anticoagulant and antithrombotic) at the time of inpatient admission or during
the hospital stay were included
• Received an oral FXa inhibitor prior to admission and were managed with reversal or
replacement agents (andexanet alfa, 4F-PCC, fresh frozen plasma and other agents)
Patient Selection Criteria
Outcomes evaluated included:
• Patient demographics
• Bleed type (GI bleed, ICH, critical compartment
bleed, traumatic not otherwise specified or other)
• Length of hospital say (LOS)
• Level of care (inpatient vs ICU)
• Anticoagulant administered prior to the bleed
• Reversal or replenishing agent
• In-hospital mortality status
Descriptive analyses were conducted
H O S P I TA L C H A RT A U D I T
M E T H O D O L O G Y
This information is not intended to support any off-label uses of
FDA approved products nor of products that are not approved for
use or available in the United States.
Colmean. Future Cardiol. 2020;17:127. 89

Note: andexanet alfa patient data only collected from 2018-2019. *Used as a single agent, with no other concomitant reversal or replacement agents administered. †All other: 3-factor
PCCs, recombinant Factor VIIa, activated 4F-PCC, tranexamic acid and vitamin K.
 11% of bleeds were treated with andexanet alfa, 24% with 4F-PCC, 31% with FFP, 26% with other agents (3F-PCCs, activated 4F-PCC,
recombinant Factor VIIa, tranexamic acid, vitamin K, protamine sulfate) and in 14% no reversal or replacement agents were
administered (%’s add to >100% due to concomitant therapy)
 Bleeds were typically managed with a single agent
R E S U L T S H O S P I TA L C H A RT A U D I T
Reversal or Replacement Treatment by Bleed Type
Total sample Andexanet alfa 4F-PCC
Fresh frozen
plasma
All
other†
No reversal
administered
All Bleeds 3,030 342 (11%) 733 (24%) 925 (31%) 794 (26%) 438 (14%)
GI Bleed 1,453 137 (9%) 303 (21%) 466 (32%) 423 (29%) 228 (16%)
Intracranial Hemorrhage 507 67 (13%) 170 (34%) 146 (29%) 111 (22%) 47 (9%)
Critical Compartment 113 11 (10%) 26 (23%) 36 (32%) 34 (30%) 14 (12%)
Trauma 781 105 (13%) 214 (27%) 250 (32%) 180 (23%) 82 (10%)
Other Bleed 176 22 (13%) 20 (11%) 27 (15%) 46 (26%) 67 (38%)
Single agent* 1,940 83% 72% 47% 86% -
Colmean. Future Cardiol. 2020;17:127. 90

Note: andexanet alfa patients only collected from 2018-2019. †All other: 3-factor PCCs, recombination factor VIIa, activated 4F-PCC, tranexamic acid, and vitamin K.
R E S U L T S H O S P I TA L C H A RT A U D I T
In-Hospital Mortality Shown by Bleed Type for Each Reversal or Replacement Agent
All
Bleeds
GI
Bleed
Intracranial
Hemorrhage
Critical
compartment
Trauma
Other
Bleed
Mortalities / Total Hospitalizations
Total 271 / 3,030 (9%) 57 / 1,453 (4%) 115 / 507 (23%) 13 / 113 (12%) 78 / 781 (10%) 8 / 176 (5%)
Andexanet alfa 12 / 342 (4%) 2 / 137 (1%) 6 / 67 (9%) 0 / 11 (0%) 4 / 105 (4%) 0 / 22 (0%)
4-Factor PCC 74 / 733 (10%) 12 / 303 (4%) 43 / 170 (25%) 1 / 26 (4%) 16 / 214 (7%) 2 / 20 (10%)
Fresh frozen plasma 105 / 925 (11%) 20 / 466 (4%) 40 / 146 (27%) 4 / 36 (11%) 40 / 250 (16%) 1 / 27 (4%)
All other† 67 / 794 (8%) 15 / 423 (4%) 25 / 111 (23%) 7 / 34 (21%) 18 / 180 (10%) 2 / 46 (4%)
No reversal or replacement
Administered
34 /438 (8%) 12 / 228 (5%) 11 / 47 (23%) 2 / 14 (14%) 6 / 82 (7%) 3 / 67 (4%)
Colmean. Future Cardiol. 2020;17:127.
91

Real-World Effectiveness: Limitations
 This study is subject to limitations related to the observational nature of the study and data collection using EMR and
hospitalization events as identified by ICD10 codes; thus, there is the possibility for missed, inaccurate, or incomplete
medical records
 Hospitalization records provide detail limited to the current admission and do not capture previous medical or
prescription history, longitudinal outcomes or patient management after discharge
 Unable to account for baseline characteristics, bleed size and severity, and other potential confounders
 This study was not designed to provide comparative efficacy and safety data and should not be interpreted as providing
evidence of either superiority or non-inferiority of ANDEXXA or supportive care therapies. Further study is warranted to
confirm clinically and statistically relevant differences in in-hospital mortality. Due to the descriptive nature of this
study, no inferential comparisons should be made across subgroups
 Reversal or replacement agents could have been used concomitantly
 Since andexanet alfa was approved by the FDA in May 2018, data collection was limited to May 2018 onwards rather
than the entire study period
 Limited data were available regarding patient baseline characteristics
L I M I T A T I O N S H O S P I TA L C H A RT A U D I T
92

Real-World Effectiveness: Conclusions
 In-hospital mortality differed by type of bleed and the reversal or replacement agent used
 Andexanet alfa had the lowest mortality rate across bleed types as well as a shorter ICU stay than the other
agents
 In 342 bleeds treated with andexanet alfa, it was the sole agent in 82.7% of cases
 In 733 bleeds treated with four-factor prothrombin complex concentrate, it was the sole agent in
72.4%.
 Of 3030 oral FXa inhibitor bleeds, 14% (438) were not administered any bleeding management
reversal agent
 Analysis suggests that mortality rates may differ across treatments used in management of oral FXa
inhibitor-associated bleeds, with andexanet alfa showing the lowest rate of inpatient mortality across
all bleed types
F I N D I N G S H O S P I TA L C H A RT A U D I T
93

Overlap in Study Populations
Data Source
Connolly. NEJM. 2019;380:1326. Green. Haematologica. 2018;103: 738.
The Decision Support Unit. NICE DSU technical supporting document 17
Cohenl. 30-day mortality following andexanet alfa. Presentation from ACC 2020.
Two single-arm patient-level datasets were used:
• ANNEXA-4: prospective, open-label, global, single-arm, phase 3b/4
study of patients taking apixaban / rivaroxaban who received
andexanet alfa1
• ORANGE: 3-yr prospective registry of anticoagulated patients
admitted to UK hospitals with major bleeding who received PCC2
Patients are excluded if they:
• Did not receive PCCs (ORANGE patients only)
• Did not receive rivaroxaban, & apixaban
• Had missing data for relevant variables (mortality and age)
Patient Selection Criteria
Clinical experts agreed study populations overlapped substantially based
on inclusion/exclusion criteria
Key differences noted:
• ORANGE did not have exclusion criteria while ANNEXA-4 did
• Volume of blood products received was sufficient for inclusion in
ORANGE
• Hemodynamic compromise was sufficient for inclusion in ANNEXA-4
O R A N G E - A N N E X A - 4 M AT C H E D A N A LY S I S
Outcomes and Analysis
• NICE Decision Support Unit technical support document (TSD) 17 was
used to inform the propensity score matching (PSM) framework3
• After PSM, the baseline characteristics were similar across the whole
population and ICH and GI subgroups, whereas the matching process
was more varied in the other bleeds subgroup
94

Cohen. 30-day mortality following andexanet alfa. Presentation from ACC 2020.
O R A N G E - A N N E X A - 4 M AT C H E D A N A LY S I S
Refinement of Patient Populations
Total safety population
n = 2192
Patients receiving
warfarin (n = 1,771) and
dabigatran (n = 46)
(apixaban and
rivaroxaban only)
n = 372
Patients with observed
mortality
n = 365
Patients observations
for all relevant
covariates
n = 363
Patients
From
ORANGE
Patients without
observed mortality (n =
7)
Patients without
observed age
(n = 2)
n = 352
Patients receiving
enoxaparin (n = 20) and
edoxaban (n = 10)
(apixaban and
rivaroxaban only)
n = 322
Patients with observed
mortality
n = 322
Patients observations
for
all relevant covariates
n = 322
Patients
From
ANNEXA-4
95

Real-world Effectiveness
Cohen. 30-day mortality following andexanet alfa. Presentation from ACC 2020.
 PSM-adjusted 30-day mortality for patients treated with andexanet alfa was lower than for patients receiving PCCs
30-Day Mortality After Propensity Score Matching
R E S U L T S O R A N G E - A N N E X A - 4 M AT C H E D A N A LY S I S
Population Number of matches
30-day mortality
andexanet alfa (%)
30-day mortality
PCC (%)
Relative reduction
(PCC to andexanet alfa) (%)
Whole cohort
Andexanet alfa = 322
PCC = 88
14.60 34.09 -57.17
ICH subgroup
Andexanet alfa = 209
PCC = 47
15.31 48.94 -68.72
GI subgroup
Andexanet alfa = 82
PCC = 28
12.20 25.00 -51.20
Other bleeds subgroup
Andexanet alfa = 31
PCC = 8
16.13 12.50 29.04
96

 33 studies of 2568 patients; the majority of studies being uncontrolled
retrospective cohort studies and 62% of patients presented with intracranial
hemorrhage
 Pooled proportion outcomes for hemostasis 80%, mortality 15%, and
thromboembolic adverse events 3%. High- vs low-dose PCC did not affect
hemostasis or thrombosis
 Patients with ICH had higher mortality rates at 22%
 Heterogeneity was significant (Ι2 >50% with P <.05) for all pooled proportional
outcomes. The quality of evidence was low given that included studies were
not randomized or controlled
 Conclusion: Our data require further validation with future randomized clinical
trials
Updated Systematic Review and Meta-analysis on PCC
and DOACs
Milioglou. J Thromb Thrombolysis. 2021;[Epub]. 97

Phase III Study of OCTAPLEX in Patients With Acute Major Bleeding on
DOAC Therapy With Factor Xa Inhibitor
 Multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive
design, phase III study to demonstrate the hemostatic efficacy and safety of four-factor
prothrombin complex concentrate, OCTAPLEX, in patients with acute major bleeding on DOAC
therapy with factor Xa inhibitor. Patients will be randomized 1:1 to either of two study groups of
bleeding patients: low-dose vs high-dose OCTAPLEX. (Similar components as Kcentra)
 Primary outcome: Hemostatic efficacy [time frame: within 24 hr after the start of initial
management] Binary outcome of effective (rating of excellent or good) or noneffective (rating of
poor/none) in management of major bleeding events as assessed by the Independent Data
Monitoring and Endpoint Adjudication Committee (IDMEAC) according to predefined criteria
 Secondary outcomes: endogenous thrombin potential, 30-day mortality and TE
 Entry criteria includes requirement for baseline anti–factor Xa activity equivalent to at least 100
ng/mL according to the available test (eg, chromogenic assay)
‒ Interestingly anti-FXa levels are not a secondary outcome likely because there is now knowledge that PCC
does not affect anti-FXa levels
 Estimated enrollment of 200 patients and completion by 2024 and recruiting in 2 US sites in
California and Mississippi
98
NCT04867837.

Search Strategy
FOUR Factor Prothrombin Complex Concentrate
*Modified from original developed by Murad et al. Uses exploratory questions/items to assess a case series’ methodological and reporting quality in respect to its selection,
exposure, and outcome.
Costa. BMJ Open. 2020;10:e040499.
• A bibliographic literature search of Medline and EMBASE
augmented with backwards citation tracking and review
of conference proceedings of major cardiology,
neurology, and thrombosis and hemostasis meetings
over the past 2 yr from Jan 1, 2011, through May 31,
2020, was conducted
• Case series’ evaluation was performed using a validated tool* adapted for this topic
− The tool included items addressing patient selection (S1-5), bleed/outcome
ascertainment (A1-8), causal/temporal association (C1-6), and reporting (R1-15)
• Percentage of series meeting each criterion (yes/+) is reported
• Descriptive statistics used to summarize assessment of each item
• Continuous data reported as medians with 25%, 75% ranges
Methodological and Reporting Quality Assessment
Q U A L I T Y E VA L U AT I O N O F C A S E S E R I E S
Case series were included if they:
• Described the use of 4F-PCC in ≥10 patients for
management of major, severe, or life-threatening bleeding
while taking oral FXa inhibitor
Case series were excluded if they:
• Described the use of andexanet alfa, three-factor PCC,
activated PCC, unspecified PCC, or recombinant factor VIIa
as the primary reversal agent
• Described the reversal of dabigatran or warfarin, reversal of
non-bleeding surgical patients, non-major bleeds, or healthy
volunteers
This analysis systematically identified existing case series
describing 4F-PCC use in the reversal of oral
FXa inhibitor–relating bleeds and evaluated methodological and
reporting quality
99

Costa. BMJ Open. 2020;10:e040499
 Unclear definitions, and lack of adjudication of, the index bleed (especially
extracranial), hemostatic effectiveness and thrombosis
 Failure to impose and/or describe a maximum time since last anticoagulation dose
(part of inclusion in 14%, reported in 29%) and/or the need for sufficiently elevated
anticoagulation activity/levels for inclusion
 Failure to follow patients for sufficient duration of time to assess important
outcomes including mortality and thrombosis
 Insufficient reporting on anticoagulant agent details, time from last dose, and time
from presentation was present in identified case series
C O N C L U S I O N S O N L I M I T A T I O N S O F 4 F - P C C C A S E S E R I E S
FOUR Factor Prothrombin Complex Concentrate
Q U A L I T Y E VA L U AT I O N O F C A S E S E R I E S
100

Treatment of Anticoagulation-Associated Hemorrhage Is
Agent Specific
In response to an increase in adverse events
related to these widely prescribed medications,
this alert provides guidance on the safe use and
management of DOACs to all medical practitioners
and health care organization leaders, particularly
chief medical officers, pharmacists, emergency
department clinicians, and quality and
safety officers
A reversal mechanism that works for
one DOAC may not work for another
DOACs present different risks than heparin and
warfarin and have different reversal mechanisms
A DOAC-specific reversal agent may not be effective in
treating another kind of DOAC. For each anticoagulation medication
used by patients coming to their organization, providers must be
aware of variations in presentation severity (eg, location and severity
of bleeding, indication for reversal) and appropriate reversal agents
(eg, drug discontinuation, use of concentrated clotting therapy)
Hospitals and critical access hospitals should
stock blood products and any antidotes appropriate
for use with each type of anticoagulant
The Joint Commission. Sentinel Event Alert. 2019;61:1-5.
101

 Performance of current reversal agents or factor replacement strategies
‒ FDA approved or off label use? – Review process comments for FDA approved agents
‒ Some organizations prefer to stay with existing blood factor product strategy
 Pharmacology/Mechanism of Action for targeted, rationally designed reversal agents versus factor
replacement strategies for DOACs
‒ Aforementioned limitations of PCC observational studies
 Extensive data and evidence that PCC is not “Standard of Care” for DOAC patients that are bleeding and
require intervention
 Do surrogate endpoints of anti-Fxa / ECT/ dTT correlate with clinical efficacy?
 Societal recommendations, guidelines and guidance
 Frequency of patients presenting with life-threatening bleeding
‒ Low-volume vs high-volume centers
 Types of patients presenting with bleeding
‒ Trauma
‒ Neurosurgery
‒ Gastrointestinal bleeding
 Ability to control and monitor use
‒ Will providers attempt to use high cost specific reversal agents for indications other than life-threatening bleeding
‒ Hard stop or gatekeeper/committee approval
 Cost Comparisons, Payer Coverage, NTAP – do cost comparisons take into consideration outcomes during
and after hospitalization?
Formulary Management and Policy Considerations
Peled. Neurocrit Care. 2020;33:20. Mahan. Neurocrit Care. 2020;33:323.
102

Regardless of Site, Bleeding Is the Most Common Complication of
Anticoagulant Use That Requires Careful Evaluation and Management
REASSESS: Clinical | Labs | Imaging
Anticoagulated Patient Enters ED
Is the patient bleeding?
OR
Not bleeding and needs emergent surgery/urgent procedure?
Provide emergent treatment/supportive care
Clinical | Labs | Imaging
Routine Care
and
Reassessment
YES
AND
YES
NO
NO
Class
Direct thrombin
inhibitor
Direct Xa inhibitor
AT-mediated
inhibition of Xa
Inhibition of thrombin; indirectly
inactivates Xa
Vitamin K
antagonist
Agent Dabigatran
Rivaroxaban/
Apixaban
Edoxaban Betrixaban Fondaparinux
Unfractionated
Heparin
Enoxaparin/
Dalteparin
Warfarin
Last Dose (<8-12 hr) (<18 hr) (10-14 hr) (19-24 hr) (17-21 hr)
(PTT Based)
(1-2 hr)
(3-5 hr)
(INR Based)
(20-60 hr)
IS THE PATIENT IMPROVING?
Consider Redosing and Admit to Hospital Admit to Hospital
YES
NO
Consider Discharge
IS THE PATIENT IMPROVING?
NO YES
OR
Does the nonbleeding patient need emergent surgery/urgent procedure?
Is the bleed life-threatening at a critical site?
or
A d m i n i s t e r a p p r o p r i a t e r e v e r s a l a g e n t
Baugh. Ann Emerg Med. 2020;76:470.
103
ACEP
Guidelines

ACEP Guidelines Note That Immediate Supportive Care Is Critical for All Patients
Whether or Not a Replacement or Reversal Agent Is Used
Consider topical/nebulized for ear, nose, or
throat bleeding; intravenous for traumatic
or gynecologic bleeding
Consider for antiplatelet therapy
Consider in overdose within 1-2 hr
of ingestion of an oral anticoagulant
Tranexamic
acid
Desmopressin
Charcoal
Hold
anticoagulation/
antiplatelet
agents
Optimize
comorbidities*
Blood
products
Intravenous
fluids
Send labs†
Establish
intravenous
access
Source
control‡
Airway,
breathing, and
circulation
assessment
Emergency
Treatment and
Supportive Care
Interventions
Initial Emergency Care =
Supportive Care =
Additional Considerations =
*Comorbidities, including renal or hepatic dysfunction, must be recognized and considered. †Do not delay treatment for results. ‡Manual, surgery, interventional radiology, or endoscopy.
Baugh. Ann Emerg Med. 2020;76:470.
104

Guidelines and Stewardship programs should address the following:
‒ Which patients should receive these reversal agents?
‒ Which agents does your institution carry on formulary?
‒ Do you limit to life-threatening bleeding?
‒ How do you define that?
‒ Should you treat the abnormal coagulation tests?
‒ What about urgent surgery? Elective surgery?
‒ When should labs be drawn to assess effect?
‒ When should anticoagulation be restarted?
Guidelines and Stewardship
Multidisciplinary discussion in conjunction with goals of care
105

 Several updated guideline recommendations have emerged regarding the
management of anticoagulant-related bleeding
 The specific reversal agents idarucizumab and andexanet are often
recommended as first line over factor replacement strategies primarily
because of regulatory approval and more demanding research
 PCC has been available since 2013, yet not undergone rigorous clinical
testing nor regulatory review for Xa inhibitor reversal with recent
systematic reviews suggesting RCTs are needed with PCC
 Prospectively or retrospectively measure adherence and performance and
adapt approaches
 Multidisciplinary collaboration is key to positive patient outcomes
Conclusions
106

107
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