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