Baby, Now We Got Bad Blood:
Andexxa® vs. Kcentra® for Reversal
of Factor Xa Inhibitor-Associated
Intracranial Hemorrhage
Ashley E. Lock, PharmD PGY2 Emergency Medicine Pharmacy Resident
Department of Pharmacotherapy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center, UT Health San Antonio September 13, 2019
Learning Objectives 1. Discuss the pathophysiology and clinical assessment of a patient with Factor Xa
inhibitor-associated intracranial hemorrhage (ICH)2. Review the pharmacology of Factor Xa inhibitors and reversal agents3. Compare evidence for andexanet alfa and 4-factor prothrombin complex
concentrate and apply to a patient with ICH
LOCK 2
Assessment Questions
1. What is the role of Factor Xa (FXa) in the coagulation cascade? a. Converts plasmin to plasminogen b. Binds to the FXa receptor on platelets c. Complexes with FVa to convert prothrombin to thrombin d. The initial step in the extrinsic pathway e. The initial step in the common pathway f. Both c and e
2. What systolic blood pressure (SBP) goal is associated with less hematoma expansion in patients with acute intracranial hemorrhage due to oral anticoagulants?
a. SBP <160 mmHg within 4 hours b. SBP <160 mmHg within 1 hour c. SBP between 140 – 179 mmHg within 24 hours d. SBP between 140 – 179 mmHg within 6 hours
3. True/False: Andexanet alfa for reversal of FXa inhibitor acute major bleeding has a higher rate of hemostatic efficacy compared to 4-factor prothrombin complex concentrate.
a. True b. False
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Faculty (Speaker) Disclosure: Ashley E. Lock has indicated she has no relevant financial
relationships to disclose relative to the content of her presentation.
LOCK 3
Background
I. Oral anticoagulation (OAC)
A. Direct oral anticoagulants
i. Factor Xa (FXa) inhibitors: rivaroxaban, apixaban, edoxaban, betrixaban
ii. Direct thrombin inhibitor (DTI): dabigatran
B. FXa inhibitor mechanism of action: directly inhibits free and clot-bound factor Xa,
decreasing thrombin generation and subsequent fibrin production, thereby preventing
platelet aggregation1,2
i. See Appendix A for Factor Xa inhibitors
C. Epidemiology
i. Predominant indications for OAC: atrial fibrillation (AF), venous
thromboembolism (VTE)
ii. Use of direct oral anticoagulants (DOACs) has increased compared to warfarin
1. Decrease in major bleeding3,4
2. Fewer drug and food interactions
3. Absence of required coagulation monitoring with DOACs5
iii. OACs account for 17.6% of emergency department visits due to adverse effects,
the highest rate of all drug classes6,7
D. Risk factors for major bleeding on anticoagulation therapy1
i. Age >65 years old
ii. Recent surgery or trauma
iii. History of stroke
iv. Uncontrolled hypertension
v. Renal or hepatic failure
vi. Concomitant medications: antiplatelets, nonsteroidal anti-inflammatory drugs
vii. Anticoagulation intensity (especially at initiation of therapy)
II. Intracranial hemorrhage (ICH)
A. Epidemiology
i. Primary ICH (without anticoagulation) mortality: 30 – 55%8,9
ii. Every 1-mL increase in hematoma volume increases death and disability by 7%10
iii. ICH occurs 8 times more frequently in patients on OAC9
iv. OAC-ICH is associated with higher mortality than primary ICH (67%)8,9
v. Incidence of OAC-ICH: 0.25 – 1.1% annually9
vi. Mean age of patients with OAC-ICH: 60 – 70 years old9
B. Prognosis
i. Predictors of poor prognosis: elderly, large hematoma volume (≥40 mL),
intraventricular involvement, depressed mental status, hematoma
expansion8,9,11
LOCK 4
III. Pathophysiology of clot formation12
A. Vessel injury
B. Vessel spasm
C. Platelet activation
i. Purpose: form platelet plug at
injury site
ii. Occurs through exposed
collagen and thrombin
generation
iii. Result: activated platelets
express receptors (GPIIb/IIIa),
allowing platelet aggregation
via cross-linked fibrinogen
D. Coagulation cascade
i. Purpose: reinforce platelet
plug
ii. Intrinsic and extrinsic
pathways lead to the common
pathway
iii. In vivo: vessel injury exposes tissue factor (TF) to circulating Factor VII (FVII),
activating it to FVIIa (Figure 1)
1. FVIIa/TF complex initiates the common pathway
a. Directly: activates Factor X to Factor Xa (FXa)
b. Indirectly: activates Factor IX (FIXa), which complexes with
FVIIIa to activate Factor X
2. FXa/FVa complex converts prothrombin to thrombin
3. Thrombin converts fibrinogen to fibrin
iv. Result: fibrin strands strengthen platelet plug
FXa
Key component of common pathway
prothrombin
↓
thrombin
fibrin
↓
fibrinogen
Clot formation
Figure 1. Coagulation cascade in vivo12
Figure 2. Coagulation cascade common pathway12
LOCK 5
Management of Oral Anticoagulant Intracranial Hemorrhage (OAC-ICH)
Figure 3. OAC-ICH management pathway13
I. Assessment of bleed severity13
A. Primary assessment (i.e. airway, breathing, circulation, disability, exposure)
B. Bleeding at a critical site (i.e. intracranial, intraocular, spinal, pericardial tamponade,
hemothorax, intra-abdominal, retroperitoneal)
C. Decrease in hemoglobin ≥2 g/dL or receipt of ≥2 units packed red blood cells (PRBCs)
D. Signs and symptoms13
i. Active hemorrhage at critical site
ii. Altered mental status with or without neurologic deficit
iii. Hemodynamic instability
iv. Respiratory failure
v. Pallor, skin mottling, cool extremities, or paresthesias
E. History of present illness
i. Determine time of last dose of oral FXa inhibitor13
1. Drug is eliminated within 3 – 5 half-lives
2. Consider renal and hepatic impairment – increases elimination half-life
F. Imaging
i. Computed tomography (CT) scan of head, chest x-ray, and ultrasound
G. Coagulation monitoring13,14
i. Coagulation assays, such as: prothrombin time (PT), international normalized
ratio (INR), activated partial prothromboplastin time (aPTT), and thrombin time
(TT), are poor indicators of bleed severity14
ii. INR does not correlate with degree of anticoagulation with oral FXa inhibitors
iii. Do not delay treatment of major bleed while awaiting coagulation results in
patients with suspected OAC-ICH
iv. Anti-FXa activity levels are used to monitor FXa inhibitors and enoxaparin
1. ISTH recommends reversal of serious bleed with DOAC levels >50 ng/mL
or >30 ng/mL in patients undergoing high bleed risk procedures13
2. Not widely available15
Assess • Identify bleed severity
Control
• Blood pressure control
• Consider reversal and/or surgical intervention
Restart • Weigh risks and benefits of continued anticoagulation
LOCK 6
II. Control
A. Discontinue the anticoagulant
B. Supportive measures10
i. Endotracheal intubation
ii. Resuscitation with intravenous fluids and/or blood products
iii. Intracranial pressure management to achieve ICP <22 mmHg
1. Neurosurgical hematoma evacuation
iv. Hypertonic intravenous fluids (e.g. 3% sodium chloride, mannitol)
C. Decontamination
i. Consider activated charcoal if anticoagulant dose taken within 2 hours of oral
FXa inhibitor ingestion16
1. Dose: 1 g/kg (maximum: 50 g) oral or enteral once
2. Not recommended in patients with aspiration risk
3. Intubated patients: do not administer activated charcoal if the patient
has an un-cuffed endotracheal tube or during gastric suctioning
ii. Hemodialysis: not indicated, FXa inhibitors are highly protein bound and
minimally dialyzable16
D. Blood pressure management
i. SBP threshold should be maintained ≥100 mmHg for age 50 – 69 years, and
≥110 mmHg for age 15 – 49 or >70 years10
ii. Most ICHs present with acutely elevated SBP, which is associated with increased
risk of hematoma expansion and mortality10
1. INTERACT-I: intensive BP control (SBP <140 mmHg) within 6 hours of
spontaneous ICH (sICH) onset reduces incidence of hematoma
expansion10
2. ATACH-II: BP control to SBP <140 mmHg is safe in sICH9,10
iii. Fast-acting antihypertensive agents are recommended to acutely lower blood
pressure (e.g. nicardipine, clevidipine, labetalol)10
Table 1. Gerner ST, et al. Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage (RETRACE-II). Ann Neurol. 2018;83(1):186-96.11
Design Multi-center, observational cohort study
Patient Population N = 146 patients with spontaneous ICH; rivaroxaban 110 (75.3%), apixaban
21 (14.4%), dabigatran 15 (10.3%)
SBP reduction at 4 hours SBP <160 mmHg at 4 hours after admission was associated with lower risk
of HE
Hematoma expansion No significant association between 4F-PCC administration and HE
(RR = 1.057, 95% CI 0.565 – 1.977)
Baseline anti-FXa activity Strong positive association between anti-FXa level >118 ng/mL and HE
N = 40/131; AUC 0.711 (95% CI 0.645-0.777; p <0.001) Median (IQR) 4F-PCC dose 2,000 (1,500 – 3,000) units
In-hospital mortality 29/146 (19.9%) HE = hematoma expansion; ICH = intracranial hemorrhage; IQR = interquartile range; SBP = systolic blood pressure
LOCK 7
E. Hemostatic efficacy
i. Definitions of hemostatic efficacy vary widely among OAC reversal studies
ii. International Society of Thrombosis and Hemostasis (ISTH) provides
standardized criteria for major bleeding (Appendix B)
F. Factor Xa inhibitor reversal
Reversal Agents
I. 4-factor prothrombin complex concentrate (4F-PCC) (Kcentra®)
A. Contains factors II, VII, IX, X, Proteins C and S, and heparin17
B. FDA-approved for reversal of vitamin K antagonist-induced coagulation factor deficiency
in the setting of urgent surgery, invasive procedure, or acute major bleeding17
i. Current standard of care for FXa inhibitor reversal (off-label indication)
C. Mechanism of action
i. Provides a high concentration of non-activated clotting factors, which are
activated during hemorrhage, to indirectly overcome anticoagulant effects of
FXa inhibitors14
D. Dosing for FXa inhibitor reversal
i. 50 units/kg (FIX component) IV if OAC-ICH occurred within 3-5 half-lives of drug
exposure or in patients with liver failure (low-quality evidence)13,16
E. Pharmacokinetics and pharmacodynamics
i. In the setting of VKA reversal, 4F-PCC decreases INR rapidly to ≤1.3 within 30 minutes of initiation18
ii. Clotting factor half-lives18
Table 2. Clotting factor half-lives Clotting factor/protein Half-life (hours)
Factor II 60
Factor VII 4 – 6
Factor IX 24
Factor X 48 – 72
Protein C 8
Protein S 30
F. Clinical efficacy and safety of 4F-PCC in OAC-ICH i. 4F-PCC corrects INR faster than plasma for warfarin reversal19,20
Table 3. Sarode, et al. 2013: Efficacy and safety of a 4F-PCC in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013 Sep 10; 128(11): 1234–43.20
Design Multi-center, open-label, noninferiority trial (N = 202)
INR reduction to ≤1.3 at 0.5 hours
62.2% vs. 9.6% (difference 52.6%, 95% CI 39.4 – 65.9)
Effective hemostasis 72.4% vs. 65.4% (difference 7.1%, 95% CI -5.8 – 19.9)
Thrombotic events 7.8% vs. 6.4%
Mortality at 30 days 5.8% vs. 4.6%
LOCK 8
ii. Thrombotic event risk with 4F-PCC for warfarin reversal: ~1.8 – 9.1%21 iii. Literature for 4F-PCC in FXa inhibitor-associated ICH limited by several factors:
1. Small sample size 2. Heterogeneity in outcomes 3. Varying criteria for hemostatic efficacy 4. Thrombotic event follow-up time 5. Lack of control groups
Table 4. 4F-PCC and FXa inhibitor reversal: summary of trial outcomes22-28
Study (na) % ICHb 4F-PCC dose
Hemostatic efficacy
Thrombotic events
Mortality Functional outcomes
Berger, et al. 2019 (n = 22)
100% ICH
25 units/kg 94.7% 9.1%
(14 days) 18.2%
(in-hospital) -
Majeed, et al. 2017 (n = 84)
70.2% ICH 26.7
units/kg 72.9%
2.4% (30 days)
32% (30-day)
-
Dybdahl, et al.c 2019 (n = 62)
100% tICH 50 units/kg - 1.6%
(in-hospital) 11/38 (29%) (in-hospital)
AM-PAC: ~50%
Harrison, et al.c 2018 (n = 14)
14.2% tICH 85.7% sICH
25 – 50 units/kg
- 0%
(30 days) 14.2%
(in-hospital) -
Sheikh-Taha, et al. 2019 (n = 29)
72.4% ICH 50 units/kg 72.4% 3.4%
(30 days) 20.7%
(in-hospital) -
Gerner, et al. 2017 (n = 146)
100% sICH ≤25 – ≥50 units/kg
- - 19.9%
(in-hospital)
mRS 0 – 3 at 90 days:
31.1%
Grandhi, et al. 2015 (n = 18)
44.4% tICH 55.5% sICH
3,177 units mean dose
94.4% 5.6%
(90 days) 33.3%
(in-hospital)
mRS ≤2 at 90 days: 33.3%
aNumber of patients on non-vitamin K antagonists
bType of ICH not reported in all studies
cStudy design included a comparator group
AM-PAC = activity measure for post acute care; ICH = intracranial hemorrhage; mRS = modified Rankin scale (Appendix C); sICH = spontaneous ICH; tICH = traumatic ICH
II. Andexanet alfa (Andexxa®) (ADX)
A. Mechanism of action
i. Recombinant modified human FXa decoy protein that binds with direct FXa
inhibitors, low molecular weight heparin, and activated antithrombin III15,29
ii. ADX also binds to the endogenous anticoagulant tissue factor pathway inhibitor,
which could contribute to procoagulant effects13,29
1. Thrombin levels remain elevated 22 hours after ADX administration29
LOCK 9
B. FDA-approved in May 2018, under accelerated approval given the lack of a standard of
care agent for FXa inhibitor reversal30
i. FDA Accelerated Approval Program (AAP) expedites approval for drugs treating
serious diseases in which there is an unmet medical need30
1. Approval is based on surrogate endpoints (e.g. laboratory values,
radiographic imaging, or physical signs) rather than clinical outcomes
2. AAP requires drug companies to perform Phase 4 trials to confirm
clinical benefit
C. Indication: apixaban or rivaroxaban reversal due to life-threatening or uncontrolled
bleeding29
D. Black box warning: VTE, myocardial infarction, ischemic stroke, cardiac arrest, or sudden
death29
E. Dosing
i. Considerations: specific FXa inhibitor ingested, FXa inhibitor dose, time of last
FXa inhibitor dose
Table 5. Andexanet alfa dosing regimens29
Dose Initial Bolus Continuous Infusion Total number 200 mg vials
Low dose 400 mg at 30 mg/min 4 mg/min for up to 120 min 5
High dose 800 mg at 30 mg/min 8 mg/min for up to 120 min 9
Table 6. Andexanet alfa dose based on rivaroxaban or apixaban dose29
FXa inhibitor FXa inhibitor last dose
<8 hours or unknown
≥8 hours
Rivaroxaban ≤10 mg Low dose
Low dose >10 mg or unknown High dose
Apixaban ≤5 mg Low dose
>5 mg or unknown High dose
ii. Safety and efficacy of repeat doses have not been determined F. Pharmacokinetics and pharmacodynamics
i. Onset of action: rapid decrease in anti-FXa activity within 2 minutes29
ii. Elimination half-life: 3 – 4 hours
iii. Pharmacodynamic half-life: 1 hour31
1. Infusion following the bolus is necessary to extend duration of action
III. Pharmacoeconomics
Table 7: Cost comparison with 4F-PCC32-34
Reversal agent ADX 4F-PCC
Price per unit dose $33.00/mg $2.90/unit
Total cost per treatment Low Dose: $33,000 High Dose: $59,400
Max dose (5,000 units): $14,500
LOCK 10
IV. Guidelines
Table 8. Guidelines on FXa inhibitor reversal13,16,35,36
Neurocritical Care Society (2016)
4F-PCC 50 units/kg if ICH occurred within 3-5 half-lives or in the context of liver failure
American College of Cardiology (2017)
4F-PCC 50 units/kg is reasonable for emergency reversal in life-threatening bleed
CHEST (2018) Use a specific reversal agent when available
AHA/ACC/HRS (2019) ADX can be useful for reversal of rivaroxaban and apixaban for life-
threatening or uncontrolled bleeding AHA/ACC/HRS = American Heart Association/American College of Cardiology/Heart Rhythm Society
Clinical Question
Is andexanet alfa as safe and efficacious as 4 factor prothrombin complex concentrate for reversal of
Factor Xa inhibitor-associated intracranial hemorrhage?
Table 9. Connolly SJ, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-35. (ANNEXA-4)37-38
Objective
Evaluate efficacy and safety of andexanet alfa in patients with acute major bleeding occurring while taking a factor Xa inhibitor
Methods
Multi-center, prospective, open-label cohort study conducted at 63 sites in North America and Europe from April 2015 – May 2018
Only patients with ICH were enrolled from July 2016 – August 2017
Patient Population
Inclusion:
Age ≥18 years old
Acute major bleeding: bleeding with hemodynamic instability or in a critical area, decrease in Hgb ≥2 g/dL or Hgb ≤8 g/dL
Received apixaban, rivaroxaban, or edoxaban at any dose or enoxaparin ≥1 mg/kg/day in the last 18 hours
Exclusion:
Planned surgery within 12 hours after ADX (except minimally invasive procedures)
ICH with GCS <7 or hematoma >60 mL
Expected survival <1 month
Thrombotic event 2 weeks before enrollment
Use of VKA, dabigatran, PCC, rFVIIa, whole blood, or plasma in the previous 7 days
Andexanet alfa
4F-PCC
LOCK 11
Intervention
Dosing: ADX bolus over 15-30 minutes followed by a 2-hour infusion o Low dose regimen: bolus 400 mg over 15 minutes, infusion 480 mg o High dose regimen: bolus 800 mg over 30 minutes, infusion 960 mg o See Table 6. Andexanet alfa dose based on rivaroxaban or apixaban dose
Anti-FXa activity and unbound fraction of FXa inhibitor measured before and during ADX treatment and at 4, 8, and 12 hours after the end of treatment
Patients were followed for ≥30 days or until death
Outcomes
Efficacy:
Co-primary outcomes: o Percent change in anti-FXa activity after ADX o Percentage of patients with excellent or good
hemostatic control 12 hours after completion of ADX infusion (Appendix D)
Safety:
Mortality
Thrombotic events
Antibody development to ADX, native FX, or FXa
Statistical Analysis
Effective hemostasis presented with 95% confidence interval calculated with the binomial test
Association between hemostatic efficacy and change in anti-FXa activity evaluated with ROC curves
Continuous variables reported as mean and standard deviation or median and IQR
Categorical variables reported as frequencies
Results
Safety population (all patients who received ADX): ICH 227 (64%), GIB 90 (26%)
Mean age 77 years
Indications for anticoagulation: AF 481 (79.4%), VTE 107 (17.7%)
Most patients were on rivaroxaban (n = 228, 37.6%) and apixaban (n = 328, 54.1%)
N = 606
Primary Outcomes Efficacy Population (n = 254)
% Reduction in anti-FXa activity Apixaban (n = 134) 92% (95% CI, 91 – 93)
Rivaroxaban (n = 100) 92% (95% CI, 88 – 94)
Hemostatic efficacy at 12 hours Overall (n = 249): 82% (95% CI, 77 – 87) Excellent: 171 (68.7%)
Good: 33 (13.3%) Poor: 45 (18.1%)
Safety Outcomes Safety Population (n = 352)
Thrombotic events within 30 days Time of event n = 34 (10%)
<5 days 11
6 – 14 days 11
15 – 30 days 12
Mortality within 30 days Cause of death n = 49 (14%)
Cardiovascular 35
Non-cardiovascular 12
Unknown 2
Antibody development No patients developed antibodies to FX, FXa, or ADX
No significant correlation seen between hemostatic efficacy and reduction in anti-FXa activity during ADX treatment
LOCK 12
Author’s Conclusions
In patients with FXa inhibitor-associated acute major bleed, andexanet alfa significantly decreased anti-FXa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours
Reviewer’s Critique
Strengths:
Multi-center, prospective study
Adjudication committee verified major bleed criteria and outcomes
Independent committee reviewed safety data – important for a manufacturer-driven study
Limitations:
Single-arm, open-label study design
Excluded patients with GCS < 7
Anti-FXa activity not patient-centered
BP control not reported in ICH patients
Time to ADX not reported
Reviewer’s Conclusion
Though anti-FXa activity decreased with ADX treatment, it did not correlate with hemostatic efficacy
Risk of thromboembolism cannot be fully described without a control group
Rate of thromboembolism is relatively higher than what is reported in studies with 4F-PCC
Future randomized controlled trials are necessary to elucidate the efficacy and safety of ADX in reversal of oral FXa inhibitors
ADX = andexanet alfa; AF = atrial fibrillation; FX = factor X; FXa = activated factor X; GCS = Glasgow coma score; GIB = gastrointestinal bleed; Hgb = hemoglobin; ICH = intracranial hemorrhage; IQR = interquartile range; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated factor VII; ROC = receiver-operating-characteristic; VKA = vitamin K antagonist
Table 10. Dybdahl D, et al. Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage. Am J Emerg Med. 2019 Jan 9. pii: S0735-6757(19)30008-7.25
Objective
Determine efficacy and safety of 4F-PCC for reversal of FXa inhibitors in traumatic ICH
Methods
Retrospective cohort study conducted at two trauma centers in Ohio
Data collected from the institutional trauma database and EMR from March 2015 – August 2017
Institutional protocol utilized by trauma surgeons and neurosurgeons to determine need for FXa inhibitor reversal of traumatic ICH with 4F-PCC
Patient Population
Inclusion:
Trauma patients with ICH diagnosis and taking oral FXa inhibitor prior to admission
ICH confirmed by head CT
Exclusion:
None listed
Intervention
Patients who received 4F-PCC for FXa inhibitor reversal compared to those who did not receive 4F-PCC for FXa inhibitor reversal
Institutional protocol: o INR ≥ 1.5: 4F-PCC 50 units/kg, max dose 5,000 units o INR ≤ 1.4: 4F-PCC not recommended
Outcomes
LOCK 13
Efficacy:
Primary outcome: in-hospital mortality
Secondary outcomes: o Functional recovery using AM-PAC daily activity score o Hospital LOS o ICU LOS
Safety:
In-hospital events: o VTE o Ischemic stroke or TIA o MI
Statistical Analysis
Demographic and clinical data evaluated using descriptive statistics, mean ± standard deviation for continuous variables and frequencies and percentages for categorical variables
Means compared between independent groups using two-sample t-test or Wilcoxon tests
ANCOVA used to compare continuous outcomes between groups while controlling for ISS
Chi-square test used to compare percentages between groups
Logistic regression used to compare percentages while controlling for ISS
Results
Mean age 79.1 yrs, predominantly female (64.5%)
Patients similar at baseline except those who received 4F-PCC had significantly higher baseline ISS than those who did not receive 4F-PCC (17.6 ± 8.9 vs. 12.1 ± 6.4; p = 0.019)
Provider adherence to reversal protocol: 62.3% o In-hospital mortality higher in protocol compliant patients with 4F-PCC: 29% vs. 5%; p =0.038
Patients on apixaban 31 (50%), rivaroxaban 31 (50%)
N = 62 4F-PCC (n = 35) No Reversal (n = 27) p value
Primary Outcome In-hospital mortality 22.9% 3.7% 0.034a
Secondary Outcomes
AM-PAC scoreb 17.1 ± 3.27 16.2 ± 4.48 0.46
ICU LOS (days) 2.5 ± 3.19 1.4 ± 3.77 0.0024c
Hospital LOS (days) 6.4 ± 5.58 5.2 ± 5.61 0.40
Safety Outcomes
VTE 1 (2.9%) 0 (0) 0.38 Ischemic stroke/TIA 0 (0) 4 (14.8%) 0.019d
MI 0 (0) 0 (0) N/A
aDifference not statistically significant after controlling for ISS in logistic regression model (p = 0.20)
bScores correlate with 50.11% and 53.32% functional impairment at hospital discharge, respectively
cDifference not statistically significant after controlling for ISS in ANOVA (p = 0.64)
dDifference not statistically significant after controlling for ISS in logistic regression model (p = 0.94)
Subgroup analysis: o No difference in mortality between groups by neurosurgical intervention, gender, antiplatelet
use, or site of injury o Higher mortality in the 4F-PCC group among patients 65 – 79 years old (31% vs. 0%; p = 0.036)
Discharge disposition not significantly different between groups (p = 0.70)
Author’s Conclusions
Clinical effectiveness of 4F-PCC for oral FXa inhibitor reversal remains unknown
Thrombotic events are uncommon with 4F-PCC
Larger, multi-center, RCTs are necessary to determine safety and efficacy of 4F-PCC for reversal of oral FXa inhibitors
Reviewer’s Critique
LOCK 14
Strengths:
First study to include a comparator group to 4F-PCC in traumatic ICH patients
Assessed patient functional outcomes – patient-centered outcome
Confirmed ICH with head CT – internal validity
Performed subgroup analysis and controlled for ISS with logistic regression
Limitations:
Retrospective study with small sample size
Institutional protocol utilized INR cutoff to determine need for 4F-PCC
Follow-up time limited to hospital stay
Time of last dose FXa inhibitor not reported
Hematoma expansion on CT and BP control not reported
Did not study hemostatic efficacy
Reviewer’s Conclusion
4F-PCC for reversal of FXa inhibitor-associated traumatic ICH may not provide a mortality benefit over no reversal with 4F-PCC, though type II error should be considered
Rate of thrombotic events is low with 4F-PCC, though events may not have been detected due to lack of follow-up past hospital discharge
Multi-center, randomized controlled trials are necessary to determine safety and efficacy of 4F-PCC AM-PAC = activity measure for post acute care; CT = computed tomography; EMR = electronic medical record; FX = factor X; FXa = activated factor X; GCS = Glasgow coma score; GIB = gastrointestinal bleed; ICH = intracranial hemorrhage; ISS = injury severity score; LOS = length of stay; MI = myocardial infarction; RCT = randomized controlled trial; TIA = transient ischemic attack; VTE = venous thromboembolism; 4F-PCC = four factor prothrombin complex concentrate
Table 11. Sheikh-Taha, M. Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. Intern Emerg Med. 2019 Mar;14(2):265-269.27
Objective
Assess achievement of effective clinical hemostasis using 4F-PCC in patients on chronic apixaban and rivaroxaban with major bleeding
Methods
Retrospective chart review conducted at a tertiary teaching center in Huntsville, Alabama
Data collected from electronic medical records from June 2016 – June 2018
Patient Population
Inclusion:
Major bleeding while on apixaban or rivaroxaban who received 4F-PCC o Major bleeding defined using ISTH criteria
Exclusion:
Patients needing reversal for emergency surgery or procedure
Intervention
Patients received a single dose of 4F-PCC 50 units/kg (max dose 5,000 units)
Patients followed until death or discharge
Outcomes
Efficacy:
Primary outcome: clinical hemostasis
Secondary outcomes: o In-hospital mortality o Hospital LOS o Patients on concomitant drugs interacting with
apixaban or rivaroxaban (i.e. aspirin, SSRI, NSAIDs, prasugrel, clopidogrel, omega 3)
Safety:
Thrombotic events: o VTE o Stroke or TIA o Myocardial infarction
LOCK 15
Statistical Analysis
Data evaluated using descriptive statistics, mean and standard deviation for continuous variables and frequencies and percentages for categorical variables
Results
Mean age 73.8 yrs, predominantly female (55.2%)
Patients on apixaban 13 (44.8%), rivaroxaban 16 (55.2%)
Indications for anticoagulation: AF 23 (79.3%), VTE 5 (17.2%), hip replacement 1 (3.4%)
Bleeding site: ICH 21 (72.4%), GIB 4 (13.8%)
Majority of patients (96.6%) received last dose of FXa inhibitor on the day of hospital admission
Received additional hemostatic treatment (i.e. PRBCs, FFP, platelets): 9 (31%)
N = 29
Primary Outcome
Clinical hemostasis ICH GIB
Overall: 21 (72.4%) 13/21 (61.1%)
4/4 (100%)
Secondary Outcomes
In-hospital mortality 6/29 (20.7%)
Hospital LOS (mean [range]) 5.9 (2 – 15) days
Patients on concomitant drugs interacting with apixaban or rivaroxaban
16 (55.2%)
Safety Outcome
Thrombotic events 1 (3.4%) (ischemic stroke)
Author’s Conclusions
Use of 4F-PCC appears to be effective in attaining clinical hemostasis in patients on apixaban or rivaroxaban with major bleeding
4F-PCC may be an alternative for patients with major bleeding if andexanet alfa is not available
Reviewer’s Critique
Strengths:
Guideline-recommended 4F-PCC dose
Standardized criteria for hemostasis
Recorded concomitant drugs affecting clinical hemostasis
Verified time of last dose within 3-5 half-lives to assess need for FXa inhibitor reversal
Limitations:
Small sample size
Retrospective study with no comparator group
Follow-up time limited to hospital stay
Time of 4F-PCC administration not reported
ICH type and severity not reported
Hematoma expansion on CT not reported
Reviewer’s Conclusion
4F-PCC may achieve hemostatic efficacy for FXa inhibitor-associated major bleeding
Future, comparative studies are necessary to further define efficacy and safety of 4F-PCC
Presence of concomitant agents affecting hemostasis should be considered when managing patients on apixaban or rivaroxaban with major bleeding
Conclusions cannot be drawn about the rate of thromboembolism with 4F-PCC given the small sample size and limited follow-up duration
AF = atrial fibrillation; CT = computed tomography; DVT = deep vein thrombosis; FXa = activated factor X; GIB = gastrointestinal bleed; ICH = intracranial hemorrhage; ISTH = International Society of Thrombosis and Hemostasis; LOS = length of stay; NSAID = nonsteroidal anti-inflammatory drug; PE = pulmonary embolism; SSRI = selective serotonin reuptake inhibitor; TIA = transient ischemic attack; VTE = venous thromboembolism; 4F-PCC = four factor prothrombin complex concentrate
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Summary
1. There is insufficient evidence to recommend ADX over 4F-PCC in FXa inhibitor-associated ICH,
based on the following patient-centered outcomes:
Table 12. Summary of patient-centered outcomes19-28
Outcomes ADX versus 4F-PCCa
Hemostatic efficacy 82% vs. 78.4% ± 13.6
No clinically significant difference in hemostatic efficacyb
Thrombotic risk 10% vs. 3.06% ± 0.3
Clinically significant higher thrombotic risk with ADX
Mortality 14% vs. 24.2% ± 3.2
Clinical significance unclearb,c
Functional outcomes Unable to assess, not evaluated by ANNEXA-4 and most 4F-PCC studies
Cost ADX significantly more expensive than 4F-PCC
Cost-difference ~$45,000 a4F-PCC values listed as mean ± standard deviation of the study outcomes summarized in Table 4
bNote that ANNEXA-4 and the majority of 4F-PCC trials lacked comparator groups. It is unknown whether
the rates of these outcomes would be higher or lower compared to placebo. cThe studies driving high mortality rate in the 4F-PCC group included ICH patients, regardless of GCS,
whereas ANNEXA-4 excluded ICH patients with GCS <7.11,24,25
2. Management of traumatic and spontaneous ICH is not well-characterized
a. Blood pressure control may be more important than 4F-PCC administration in reducing
risk of hematoma expansion in spontaneous ICH
b. Studies on traumatic ICH have shown low rates of in-hospital thrombotic risk and similar
mortality and hemostatic efficacy rates compared to ADX7,25
c. It is unknown the effect that blood pressure control may have on traumatic ICH and risk
of hematoma enlargement
3. Anti-FXa activity monitoring does not correlate with hemostatic efficacy and is not widely
available among health systems
4. Future, comparative studies with larger sample sizes are necessary to be able to measure
incidence of thrombotic events and mortality
5. Data is lacking on the use of concomitant adjunctive therapies (i.e. 4F-PCC, tranexamic acid,
DDAVP, whole blood, FFP, platelets, rVIIa) with ADX
Recommendations
1. In patients with FXa inhibitor-associated ICH, 4F-PCC is recommended over ADX at this time
2. Weight-based dose 4F-PCC 50 units/kg should be utilized
3. Coagulation monitoring of INR and/or anti-FXa level activity is not recommended
a. Decisions to reverse FXa inhibitor-associated ICH should be made based on clinical
assessment of bleed severity
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4. Goal systolic blood pressure <160 mmHg within 4 hours of admission to reduce hematoma
expansion in spontaneous FXa inhibitor-associated ICH8,11
Future Directions
1. ANNEXA-4 trial to be extended in sites in Germany and Japan to include more edoxaban
patients10
2. Phase 4 randomized, multi-center trial of andexanet alfa compared to usual care, including 4F-
PCC, in patients with acute ICH, conducted by Portola Pharmaceuticals10,38
a. Status: recruiting 440 patients
b. Study period: January 18, 2019 – November 1, 2023
c. Inclusion: ICH presenting within 12 hours of onset and 15 hours of FXa inhibitor
3. Ciraparantag (PER977)14,39
a. Synthetic, water-soluble molecule, reverses all DOACs, UFH, LMWH, and fondaparinux
b. Currently in Phase II trials, not FDA-approved
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Appendices
Appendix A.* Factor Xa inhibitors1,41-43
Apixaban Rivaroxaban Edoxaban
Dosing: NVAF prophylaxis
5 mg PO BID 20 mg PO daily with evening meal
60 mg PO daily
Dosing: DVT/PE treatment
10 mg PO BID x 7 days, then 5 mg PO BID
15 mg PO BID x 21 days, then 20 mg PO daily with evening meal
60 mg PO daily after 5-10 days of parenteral anticoagulant
Renal dose adjustment
Yesa Yes Yesb
Hepatic dose adjustment
Not recommended in Child-Pugh class C
Avoid in Child-Pugh class B or C
Not recommended in Child-Pugh class B or C
Protein binding 87% 92-95% 55%
Dialyzable No No No
Half-life 9-14 hrs 7-11 hrs 10-14 hrs *Betrixaban not included for the purposes of this presentation aDose adjust to 2.5 mg BID in NVAF patients meeting 2 of 3 criteria: age ≥80 years, weight ≤60 kg, SCr ≥1.5 mg/dL
bAvoid edoxaban in patients with creatinine clearance <15 mL/min or >95 mL/min
BID = twice daily; DVT = deep vein thrombosis; NVAF = nonvalvular atrial fibrillation; PE = pulmonary embolism; PO = oral; SCr = serum creatinine
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Appendix B. International Society of Thrombosis and Hemostasis (ISTH) criteria44
Definitions of effective hemostasis
Non-visible bleeding Visible bleeding Musculoskeletal bleeding
Intracranial bleeding
Hgb stable at 48 hr after PRBCs and
hemostatic agent
Bleeding cessation within 4 hr after
hemostatic agent
Pain and swelling improved within 24 hr
Hematoma volume stable or ↑<35% of
baseline, assessed by CT 6-24 hr from initial CT
No need for additional treatment at 48 hr
Invasive procedures are avoided or
performed with a normal amount of
blood loss
Invasive procedures are avoided or
performed with a normal amount of
blood loss
Fasciotomy is avoided or performed with a normal amount of
blood loss
No deterioration of GOS-E at 24 hr
compared to baseline
No neurologic dysfunction or limb
loss at discharge or at 30 days
No neurologic dysfunction at discharge or at 30 days as assessed
with any validated scoring system
CT = computed tomography; GOS-E = extended Glasgow outcome scale; Hgb = hemoglobin; PRBC = packed red blood cells
Appendix C. Modified Rankin Scale (mRS)
Score Degree of disability Description
0 No symptoms at all N/A
1 No significant disability despite symptoms
Able to carry out all usual duties and activities
2 Slight disability Unable to carry out all previous activities but able to look after
own affairs without assistance
3 Moderate disability Requiring some help but able to walk without assistance
4 Moderately severe disability
Unable to walk without assistance and unable to attend to own bodily needs without assistance
5 Severe disability Bedridden, incontinent and requiring constant nursing care
and attention
6 Dead N/A
Appendix D. Hemostatic efficacy criteria20,38
Type of major bleed ANNEXA-4* Sarode, et al.
ICH: Excellent ≤20% increase in hematoma volume vs baseline on repeat CT
at 1 and 12 hrs post-infusion
≤20% increase in hematoma volume vs baseline on repeat CT at 3 and 24 hrs
ICH: Good ≤35% increase in hematoma volume vs baseline on repeat CT
at 12 hrs post-infusion
>20% but ≤35% increase in hematoma volume vs baseline on repeat CT at 24
hrs
*Adapted from criteria used by Sarode, et al. 2013