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Slide1
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
Slide2About These Slides
Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:
These slides may not be published, posted online, or used in commercial presentations without permission. Please contact info@ProCE.com for details
2
Slide credit: ProCE.com
Slide33
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 online at www.ProCE.com, and proof of completion will be posted in NABP CPE Monitor profiles.
Slide4CE 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 ObjectivesAt 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 casesEvaluate 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 developmentFundingThis activity is supported by an educational grant from Alexion, AstraZeneca Rare Disease.4
Slide55
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.
Slide6Disclosures
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.6
Slide77
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.
Slide88
Faculty
Tyree H. Kiser, PharmD, FCCM, FCCP, BCCCP, BCPS
Professor, Department of Clinical PharmacyUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Critical Care Pharmacy Specialist, Department of Pharmacy
University of Colorado HospitalAurora, ColoradoCharles E. “Kurt” Mahan, PharmD, PhC, FASHP, FCCPAdjunct Associate Professor, PharmacyUniversity of New Mexico Health Sciences CenterAlbuquerque, New Mexico
Slide9Learning 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 anticoagulantsDiscuss strategies to address formulary concerns, including access to reversal agents, streamlining administration, waste prevention, and institutional policy development9
Slide10Abbreviations
FXa: factor Xa
ED: emergency department
GI: gastrointestinalUGIB: upper gastrointestinal bleedLGIB: lower gastrointestinal bleedEGD: esophagogastroduodenoscopyGU: genitourinary CC: chief complaintMVR: mitral valve repairDVT: deep vein thrombosisVTE: venous thromboembolism PE: pulmonary embolismSVC: superior vena cavaMAP: mean arterial pressurePRBC: packed red blood cellsDOAC: direct oral anticoagulantICH: intracranial hemorrhage ICU: intensive care unitLOS: length of stayHA: headachePMH: past medical historyCOPD: chronic obstructive pulmonary disease
10
HFrEF: heart failure with reduced ejection fractions/p: status postPAD: peripheral artery diseaseL: left4F-PCC: four factor prothrombin complex concentrateFXAi: oral factor Xa inhibitor ISTH: International Society of Thrombosis and HemostasisBMI: body mass indexVd: volume of distribution DD-intx: drug into interactions
Slide11Individual 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.
Slide12Oral FXa Inhibitor Use Continues to GrowMore than 8 million patients are currently on FXa inhibitors in the US
Projected 26 million worldwide by 2025
Guideline endorsements
AHA/ACC/HRSCHESTESC12
January. J Am Coll Cardiol. 2019;74:104. Lip. Chest. 2018;154:1121. Steffel. Eur Heart J. 2018;39:1330.
Slide13Patient 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 graftMed history:Apixaban 5 mg twice daily (took dose in the AM with breakfast)Aspirin 81 mg dailyED course: patient began to develop L arm dysmetriaStroke team is activatedNIHSS score 1 (0-4, normal-impaired)GCS score 12
Pertinent Labs:
Treatment:CT head orderedConsults:NeurologyNeurosurgeryHematologyNeuro ICU for hospital admitTestReferenceResultHb13.5 - 18.0 g/dL10.2HCT40.0 - 54.0 %33.6Anti-Xa (UFH/LMWH)0 IU/mL1.7eGFR>59 mL/min/1.73 m277
13
Slide14Imaging 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
Slide15What would be the most appropriate recommendation regarding andexanet alfa?
Patient does not qualify for anticoagulant reversal
Patient is outside the effective treatment window
Administer high-dose andexanet alfaAdminister low-dose andexanet alfa
15
Slide16Oral 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
Slide17Which of the following meets major bleeding criteria per the ISTH?
Nosebleed requiring a visit to urgent care
GI bleed (Hb 1 g/dL drop) requiring ED visit
Retroperitoneal bleed (BP 80/45 mm Hg) requiring 2 units of PRBCLeg injury resulting in baseball sized hematoma
17
Slide18ISTH Definitions of BleedingMajor 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 bloodClinically relevant nonmajor bleedDoes not meet criteria for “major bleed,” but requires one of these:Leading to hospitalization or increased level of careRequiring medical intervention by a healthcare professionalPrompting a face to face (ie, not just a telephone or electronic communication) evaluation
18
Kaatz. J Thromb Haemost. 2015;13:2119.
Slide19Rates of Bleeding With Warfarin, Apixaban, and Rivaroxaban in NVAF Trials
19
(ARISTOTLE or ROCKET-AF)
Major Bleed
(%/yr)
Intracranial Hemorrhage(%/yr)Gastrointestinal Bleed*(%/yr)
Apixaban
1
Warfarin
2.13%
3.09%
0.33%
0.80%
0.76%
0.86%
Rivaroxaban
2
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 bleeds
1,2
1. Granger. NEJM. 2011;365:981.
2. Patel. NEJM. 2011;365:883.
Slide20Risk Factors for OAC-Associated Bleeding
Siegal. Eur Heart J. 2013;34:489.
20
Slide21Anticoagulation-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 anticoagulantsDOACS associated with a 50% reduction in the rate of ICH compared to VKAsHematoma expansion in patient not taking oral anticoagulants30%-40% within 3-6 hrData on hematoma expansion for patients on VKAs or DOACs variable and limited36%-54%
21
Steiner. Stroke. 2017;48:1432.
Slide22Impact 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 staysICH: average LOS 17 daysBleeding at critical site (intraocular, pericardial, intraspinal, intra-articular): average LOS 13 daysMajor trauma: average LOS 10 daysMajor 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.
Slide23Anticoagulant-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
Dabigatran, Rivaroxaban, Apixaban, or EdoxabanWarfarin
In-hospital Mortality
in Cohort Studies
30-day ICH-related Mortality
in NVAF Clinical Trials
ARISTOTLE
Trial
3
Rocket AF Trial
4
Apixaban
Rivaroxaban
Slide24Markers of Poor Prognosis for Intracranial Hemorrhage24
An. J Stroke. 2017;19:3. Aguilar. Mayo Clin Proc. 2007;82:82.
Slide25What Outcomes Are Important for Patients Hospitalized for Bleeding Events?Mortality
ICU and hospital LOS
Stroke center outcomes
Discharge dispositionReadmission within 30 daysRebleedingThromboembolic eventsCost25
What about hemostasis?
Slide26ISTH 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 productsInvasive interventions are either avoided or carried out with blood loss not exceeding the expected amount in a patient with normal hemostasis Visible bleedingThe above + cessation of visible bleeding within 4 hr after hemostatic agent administrationIntracranial 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 presentation26Khorsand. J Thromb Haemost. 2016;14:211.
Slide27Factors Influencing Outcomes With Anticoagulation Reversal in ICHLocation and cause
Intracerebral, intraventricular, etc
Trauma vs spontaneous
Baseline hematoma volume (>30 mL)>60 mL and GCS <8 = predicted mortality >90% at Day 30Hematoma expansionPredominant in first 1-3 hr; 33% of patients have >33% growth from baselineFor each 10% increase in volume, 5% increase in mortality HR27
Concha. Stroke. 2021;52:1520.
Slide28Time 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 treatment28
Symptom onset to door
Door to treatment initiationAnticoagulant dose to ED arrival
Door to CT scan
CT scan to treatment initiation
Concha. Stroke. 2021;52:1520.
Slide29Anticoagulant Intensity at Time of Bleed Impacts Outcomes
Warfarin
(INR)
Mortality Odds Ratio in ICH<21.5 (0.6-3.7)2-32.0 (1.0-4.1)
>33.7 (1.6-8.4)
29Concha. 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
Slide30DOAC 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
.
Slide31ACC Anticoagulant Bleeding Guidance
31
Gordon. J Am Coll Cardiol. 2020; 76:594.
The image on this slide has been removed intentionally due to Copyright
Slide32ACC Anticoagulant Bleeding Guidance
32
Gordon. J Am Coll Cardiol. 2020; 76:594.
The image on this slide has been removed intentionally due to Copyright
Slide33ACC Anticoagulant Bleeding Guidance
33
Gordon. J Am Coll Cardiol. 2020; 76:594.
The image on this slide has been removed intentionally due to Copyright
Slide34What is the FDA-approved agent available specifically for reversal of rivaroxaban or apixaban?
34
Kcentra
(4F-PCC)
Profilnine
(3F-PCC)Praxbind (idarucizumab)Andexxa (andexanet alfa)FEIBA (aPCC)
Slide35Company
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
Slide36Other Reversal Options for OACs36
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.
Slide37Imaging 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
Slide38ACC Anticoagulant Critical or Life-Threatening Bleed Reversal Guidance
38
Gordon. J Am Coll Cardiol. 2020; 76:594.
The image on this slide has been removed intentionally due to Copyright
Slide39What is the dose of andexanet alfa for this patient? (last dose of apixaban 5 mg ~10 hr prior
)
2000 units x1
50 units/kg x 1800 mg, then 960 mg inf.400 mg, then 480 mg inf.
39
Slide40ACC-recommended dose of 4F-PCC for life- threatening ICH associated with factor Xa inhibitor if you can’t access andexanet alfa is:
12.5 units/kg
2500 units
2000 units 50 units/kg
100 units/kg
40
Slide41Andexanet alfa: FDA-Approved Dosing41
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
Slide42Comparing 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
Slide43Quick Summary43
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
Slide44Dosing and Cost Controversies44
Frontera. Neurocrit Care. 2016;24:6. Majeed. Blood. 2017;130:1706. Shulman. Thromb Haemost. 2018;118:842. Connolly. NEJM. 2016;375:1131.
Andexxa [MP-AnXa-US-0160]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; Sept 2020. Courtesy of Jrimsans
*
With New Technology Add-On Payment
Slide45Prep/Administration Considerations, Thrombosis Risk?45
Frontera. Neurocrit Care. 2016;24:6. Majeed. Blood. 2017;130:1706. Shulman. Thromb Haemost. 2018;118:842. Connolly. NEJM. 2016;375:1131.
Andexxa [MP-AnXa-US-0160]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; Sept 2020. Courtesy of Jrimsans
*
With New Technology Add-On Payment
Slide46Optimizing Administration, Dosing, and Follow-upInitiate 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 formularyEvaluate underlying risk of thrombosisPresenting reason + patient + reversal agentEducation regarding timing of administration and duration of effectProspectively/retrospectively review cases Restart anticoagulation when hemostasis acceptable46
Slide47Monitoring the Reversal StrategyWas hemostasis achieved (refer back to ISTH criteria
)?
Hemoglobin/hematocrit
Hematoma stabilizationHemodynamic stabilityHepatic and renal functionDrug–drug interactions impacting responseThrombosis riskLevel of anticoagulation remaining?47
Slide48Conventional 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
Slide49What 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.
Slide50Case: 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 laterHe was discharged from rehab after 3 wk of careNo headache or dizziness and alert, conversant, with left greater than right weakness in the legsHis most recent clinic visit now living with his son, no major complaintsHe says his breathing feels fine, and he denies LE edema or orthopneaHe reports some residual dizziness
Hospital course:
He was originally awake and following commands but subsequently declined and had increased work of breathing, leading to intubationRepeat 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
Slide51Learning 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 anticoagulantsDiscuss strategies to address formulary concerns, including access to reversal agents, streamlining administration, waste prevention, and institutional policy development
51
Slide52During
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
Slide53Call 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 agentAmerican College of Emergency Physician Guidelines among other guidelines differentiated these approaches53
Chacko. Indian J Crit Care Med. 2019;23(suppl 4):S241. Salyer. Essential Emergency
Medicine. 2007:923.Baugh. Ann Emerg Med. 2020;76:470.
Slide54REVERSE-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
Slide55REVERSE 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 (su
rgery, 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
Slide56What is the FDA-approved agent available specifically for reversal of dabigatran?
56
Kcentra
(4F-PCC)
Profilnine (3F-PCC)
Praxbind (idarucizumab)Andexxa (andexanet alfa)FEIBA (aPCC)
Slide57Idarucizumab 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
Slide58Native 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 formation
2,3
Slide59ANNEXA-4 Study Design
Efficacy Measurements
Change in anti–
fXa activity
Clinical hemostatic efficacy through 12 hr
Safety MeasurementsThrombotic eventsAntibodies to fX, fXa, andexanet30-day mortalityDay 1Patient 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
*A
pixaban, rivaroxaban, enoxaparin, or edoxaban
Slide60Site of Initial Bleeding
Safety
vs Efficacy Population
352
254
Intracranial Bleeding227 (64%)171 (67%) Nontraumatic
128
99
Glasgow Coma Scale, mean
14
14
NIHSS, mean
5.7
5.2
mRS, mean
2.8
2.8
T
rauma 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
Slide61Main 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 HemostasisBinomial 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
Slide620
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
Connolly. NEJM. 2019;380:1326.
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
Slide63ICH Hematoma Expansion Between 1 and 12 Hr
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 scan54 of 55 had volume expansion ≤20% relative to 1 hr scan51 of 55 had volume expansion ≤10% relative to 1 hr scan63
Slide64Biomarker-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
Slide65Thrombotic
Events
Before
oral anticoagulation restart or never restarted
34 (9.7%)
After oralanticoagulation restart0Patients in Safety Analysis (n = 352)Total<6 days after bolus6-14 days after bolus15-30 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
Connolly. NEJM. 2019;380:1326.
65
Slide66Safety: Mortality
Patients in Safety Analysis (n = 352)
Total
<6 days after bolus
6-14 days after bolus
15-30 days after bolusDeaths within 30 days49(13.9%)82120 Cardiovascular Noncardiovascular Uncertain Cause3512271015511361
Mortality Rate by Bleed Type: ICH (15.0%); GI (11.1%)
Connolly. NEJM. 2019;380:1326.
66
Slide67Annexa-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 populationThrombotic events at 30 days had occurred in 9.7% of subjects and were less prevalent after restarting anticoagulation
67
Slide68ANNEXA-I Study DESIGN
1,2
.
Name
Phase
Protocol TitlePlannedANNEXA-I4A 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 Care
1
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.
Slide69ANNEXA-I Study Schematic (First 12 Hr)
Hr
Post Randomization69
-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
Connolly. NEJM. 2019;380:1326.
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.
Slide70Usual Care vs Andexanet alfa
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.
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 min70
Slide71To 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 randomizationTo evaluate the length of initial hospitalization for primary bleeding eventTo evaluate the rate of rehospitalizationTo evaluate adverse events and vital signsTo evaluate the immunogenicity of andexanet alfaTo evaluate the effect of andexanet alfa vs usual care on anti–FXa activityTo evaluate the effect of andexanet alfa vs usual care on neurologic functionTo evaluate the effect of andexanet alfa vs usual care on the rate of effective hemostasisANNEXA-I Objectives1,2SafetyPrimary efficacySecondary efficacyNCT03661528. 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
Slide72ANNEXA-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 EAC
1,2
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 randomizationEfficacy endpoints are assessed with blindingBlinded core lab for scans and blinded NIHSS score assessor at each site72
Slide73ANNEXA-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 baseline73
Slide74Annexa-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 9/202474
Slide75What 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
Slide76ANNEXA-S Study DESIGN
NCT04233073
Name
Phase
Protocol Title and DescriptionPlannedANNEXA-S2Single 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
1
00
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:
E
ffective 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
minut
e
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
Slide77What About Prothrombin Complex Concentrate?
Slide78Let’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 2003Whistleblowers (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 worldHigh 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.
Slide79Other 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.
Slide80Issues 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 levels4F-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 apixabanthe 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/mLWhy 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
Slide81Why 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.
Slide822021 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 treatmentOff-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 evidenceGlobal 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.
Slide83Andexanet vs Prothrombin Complex Concentrates: Differences in Reversal of Factor Xa Inhibitors in in vitro Thrombin Generation
Lu. Res Pract Thromb Haemost. 2020;4:1282
83
Slide84Lu 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)
Lu. Res Pract Thromb Haemost. 2020;4:1282
84
Slide85Effect of PCC vs Saline on Anti-FXa Levels in Steady State Rivaroxaban: 2014
Levi. J Thromb Haemost. 2014;12:1428.
85
Slide86Study 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% placeboP <.001 P <.001 86
Slide87FIX ICH Study –
Pre-planned analysis of PCC for Xa inhibitor reversal from the Neurocritical Care Society Pharmacy Study Group
Panos. Circulation. 2020;141:1681.
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
Slide88Potential 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 patientsHemostatic agent rescue was not considered a hemostatic efficacy failureLimited 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 rates19% mortality rate was likely underestimated because of excluded populations73 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.
Slide89Outcomes 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 bleedingOnly 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 includedReceived 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
HOSPITAL CHART AUDIT
METHODOLOGY
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
Slide90Real-World Effectiveness
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
RESULTS
HOSPITAL CHART AUDITReversal or Replacement Treatment by Bleed TypeTotal 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%
-
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.
90
Slide91Real-World Effectiveness
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.RESULTS
HOSPITAL CHART AUDIT
In-Hospital Mortality Shown by Bleed Type for Each Reversal or Replacement AgentAllBleeds
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%)
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.
91
Slide92Real-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 confoundersThis 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 subgroupsReversal 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 periodLimited data were available regarding patient baseline characteristics
LIMITATIONS
HOSPITAL CHART AUDITColmean. Future Cardiol. 2020;17:127. 92
Slide93Real-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 casesIn 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 agentAnalysis 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
FINDINGS
HOSPITAL CHART AUDITColmean. Future Cardiol. 2020;17:127. 93
Slide94Overlap in Study Populations
Data Source
Real-World Effectiveness
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 PCC
2
Patients are excluded if they:
Did not receive PCCs (ORANGE patients only)
Did not receive rivaroxaban, & apixaban
H
ad 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
ORANGE-ANNEXA-4 MATCHED ANALYSIS
METHODOLOGY
Outcomes and Analysis
NICE Decision Support Unit technical support document (TSD) 17 was used to inform the propensity score matching (PSM) framework
3
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
Slide95Real-World Effectiveness
Cohen. 30-day mortality following andexanet alfa. Presentation from ACC 2020.
ORANGE-ANNEXA-4 MATCHED ANALYSIS
METHODOLOGY
Refinement of Patient Populations
Total safety population
n = 2192
Patients receiving warfarin
(n = 1,771)
and dabigatran
(n = 46)
Total safety population
(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)
Total safety population
n = 352
Patients receiving enoxaparin
(n = 20)
and edoxaban
(n = 10)
Total safety population
(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
Slide96Real-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
RESULTS
ORANGE-ANNEXA-4 MATCHED ANALYSISPopulation
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
Slide9733 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 controlledConclusion: Our data require further validation with future randomized clinical trialsUpdated Systematic Review and Meta-analysis on PCC and DOACs
Milioglou. J Thromb Thrombolysis. 2021;[Epub].
97
Slide98Phase 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 criteriaSecondary outcomes: endogenous thrombin potential, 30-day mortality and TEEntry 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 levelsEstimated enrollment of 200 patients and completion by 2024 and recruiting in 2 US sites in California and Mississippi
98
NCT04867837.
Slide99Search 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 conductedCase series’ evaluation was performed using a validated tool* adapted for this topicThe 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 reportedDescriptive statistics used to summarize assessment of each item
Continuous data reported as medians with 25%, 75% ranges
Methodological and Reporting Quality Assessment
QUALITY EVALUATION OF CASE SERIES
METHODOLOGY
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:
D
escribed 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
Slide100Costa. 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 thrombosisInsufficient reporting on anticoagulant agent details, time from last dose, and time from presentation was present in identified case series
Conclusions on Limitations of 4f-pcc Case Series
FOUR Factor Prothrombin Complex ConcentrateQUALITY EVALUATION OF CASE SERIES100
Slide101Treatment 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
Slide102Performance 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 DOACsAforementioned limitations of PCC observational studiesExtensive 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 guidanceFrequency of patients presenting with life-threatening bleedingLow-volume vs high-volume centersTypes of patients presenting with bleedingTraumaNeurosurgeryGastrointestinal bleedingAbility to control and monitor useWill providers attempt to use high cost specific reversal agents for indications other than life-threatening bleedingHard stop or gatekeeper/committee approvalCost Comparisons, Payer Coverage, NTAP – do cost comparisons take into consideration outcomes during and after hospitalization?Formulary Management and Policy ConsiderationsPeled. Neurocrit Care. 2020;33:20. Mahan. Neurocrit Care. 2020;33:323.
102
Slide103Regardless 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?
ORNot bleeding and needs emergent surgery/urgent procedure?
Provide emergent
t
reatment/supportive
c
are
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
Administer
appropriate
reversal agent
Baugh. Ann Emerg Med. 2020;76:470.
103
ACEP Guidelines
Slide104ACEP 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
Slide105Guidelines 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 StewardshipMultidisciplinary discussion in conjunction with goals of care105
Slide106Several 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 approachesMultidisciplinary collaboration is key to positive patient outcomesConclusions
106
Slide107Question and Answer Session
Slide108Management 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
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