Is there a benefit to andexanet alfa over 4-factor prothrombin complex concentrate (4F-PCC) for traumatic head bleed (subdural/subarachnoid) in a patient on apixaban?

Comment by InpharmD Researcher

Specific data for reversal of apixaban in patients that experience traumatic head bleed is limited. Comparative clinical studies typically include a range of hemorrhages that can be spontaneous or traumatic. Based on retrospective, observational studies, the trends support andexanet alfa over 4F-PCC in clinical-related outcomes; however, higher-quality, prospective studies are needed to confirm these findings.

Background

A 2016 guidance statement from the Neurocritical Care Society and the Society of Critical Care Medicine suggest activated charcoal 50 g to intubated intracranial hemorrhage patients presenting within 2 hours of ingestion of an oral factor Xa inhibitor. If the intracranial hemorrhage occurred within 3-4 half-lives of ingestion, then Kcentra® (4-factor prothrombin complex concentrate [4F-PCC]) 50 units/kg or activated PCC (aPCC) 50 units/kg is recommended. However, since Andexxa® (andexanet alfa) was not approved at time of the statement's publication, it was not mentioned in this guideline. [1]

A 2019 guidance document from the Anticoagulation Forum suggests treatment with andexanet alfa in patients with rivaroxaban-associated or apixaban-associated major bleeding in whom a reversal agent is warranted. If andexanet alfa is not available, treatment with 4F-PCC 2,000 units is suggested. Similarly, Praxbind (idarucizumab) 5 g IV is recommended for dabigatran-associated major bleeding and aPCC 50 units/kg IV is suggested if idarucizumab is unavailable. In patients with edoxaban-associated or betrixaban-associated major bleeding in whom a reversal agent is warranted, off-label treatment with either high dose andexanet alfa (800 mg bolus given at 30 mg/min followed by a continuous infusion of 8 mg/min for up to 120 min) or 4F-PCC 2,000 units is suggested. These recommendations come from clinical trials involving andexanet alfa and prospective, cohort studies involving 4F-PCC for reversal of factor Xa-associated major bleeding. While some authors recommend weight‐based dosing of 4F-PCC (50 units/kg) for factor Xa inhibitor reversal, the Anticoagulation Forum prefers a fixed dose of 2000 units because it has been studied in patients with factor Xa inhibitor‐associated bleeding. Additional advantages of fixed dosing include greater simplicity for the ordering provider and pharmacy and reduced cost. [2]

A 2020 cost comparative study predicted the cost of andexanet alfa would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over USD $7,500 per hospitalization. The authors concluded 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of hemostasis compared to published data for andexanet alfa. [3]

References:

[1] Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med. 2016;44(12):2251-2257.
[2] Cuker A, Burnett A, Triller D, et al. Reversal of Direct Oral Anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019;94(6):679-709.
[3] Frontera JA, Bhatt P, Lalchan R, et al. Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage. J Thromb Thrombolysis. 2020;49(1):121-131. doi:10.1007/s11239-019-01973-z
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there a benefit to andexanet alfa over 4-factor prothrombin complex concentrate (4F-PCC) for traumatic head bleed (subdural/subarachnoid) in a patient on apixaban?

Please see Tables 1-4 for your response.

 

Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages

Design

Retrospective, single-center, observational study

N= 29

Objective

To evaluate the clinical and hemostatic outcomes of patients with oral FXa inhibitor-associated intracranial hemorrhage (ICH) treated with andexanet alfa or 4F-PCC and describe the operational procedures associated with each therapeutic agent

Study Groups

Andexanet alfa (n= 18)

4F-PCC (n= 11)

Inclusion Criteria

Age ≥ 18 years; on rivaroxaban or apixaban therapy at baseline; received andexanet alfa (Andexxa) or 4F-PCC (Kcentra) for reversal of ICH

Exclusion Criteria

Received andexanet alfa or 4F-PCC antithrombotic reversal for any reason other than reversal for ICH

Methods

Consecutive patients, using a medication dispense report, who received andexanet alfa or 4F-PCC for rivaroxaban- and apixaban-associated traumatic or spontaneous ICH admitted to a Level 1 trauma center. Andexanet alfa was administered to patients meeting eligibility criteria for ANNEXA-4 clinical trial enrollment or to patients presenting with an acute ICH with last known administration of apixaban or rivaroxaban within 18 hours.

4F-PCC was dosed 25 to 50 units/kg, dosed per treating clinician discretion, with a maximum dose of 5000 units. The low-dose andexanet alfa regimen was 400 mg intravenous bolus administered over 15 minutes followed by 480 mg infused over 2 hours while the high-dose andexanet alfa regimen was 800 mg intravenous bolus over 30 minutes followed by 960 mg infused over two hours. Re-treatment with andexanet alfa was not recommended.

Duration

April 1, 2016 to April 30, 2019

Outcome Measures

Primary: percentage of patients with good or excellent hemostasis on repeat imaging within 24 hours of antithrombotic

Secondary: incidence of good functional outcome at hospital discharge (defined as a Glasgow Outcome Score [GOS]> 3); the incidence of thromboembolic events within 30 days

Baseline Characteristics

  

4F-PCC (n= 11)

Andexanet alfa (n= 18)

Age (range), years

 71.0 (68.6 to 73.2) 83.4 (70.3 to 88.8)

Female

 2 (18.2%) 8 (44.4%)

Creatine clearance (range), ml/min

 56.7 (37.8 to 72.3) 52.8 (30.7 to 77.5)

Liver disease

 1 (9.1%) 2 (11.1%)

Apixaban use at baseline

Dose (range), mg/day

Time since last dose, hours

< 8 

8-18 

> 18 

3 (27.3%)

10 (5 to 10)

 

1 (33.3%)

1 (33.3%)

1 (33.3%)

15 (83.3%)

5 (5 to 10)

 

5 (33.3%)

4 (26.7%)

0 

Rivaroxaban use at baseline

Dose (range), mg/day

Time since last dose, hours

< 8 

8-18 

> 18 

8 (72.7%)

20 (20 to 20)

 

1 (12.5%)

0

3 (37.5%)

3 (16.7%)

15 (10 to 20)

 

1 (33.3%)

0

0

Concurrent antiplatelet therapy

Aspirin

P2Y12 inhibitor

Dual antiplatelet therapy

 

4 (36.4%)

0

0

 

3 (16.7%)

2 (11.1%)

0

Coagulation parameters on presentation

PT, seconds

PTT, seconds

INR

Platelets, K/μL

 

16.5 (15 to 18.8)

30.3 (26.5 to 32.3)

1.4 (1.2 to 1.6)

197 (180 to 262)

 

14.8 (14 to 16.3)

33.2 (27.3 to 38.9)

1.2 (1.1 to 1.3)

175 (127 to 222) 

Prothrombin complex concentrate

Dose, units/kg

Dose, units

11 (100%)

26.9 (21.8 to 43.7)

2,500 (2,364 to 3,231)

1 (5.6%)

9.4

500

Andexaanet alfa

High dose regimen

Low dose regimen

 

-

-

 

0

18 (100%)

Results

Endpoint

4F-PCC (n= 11)

Andexanet alfa (n= 18)

Hemostatic effectiveness

Excellent

Good

Poor

 

6 (60.0%)

0

4 (40.0%)

 

14 (77.8%)

2 (11.1%)

2 (11.1%)

Discharge functional status

Glasgow Outcome Score (range)

 

1 (1 to 3)

 

4 (3 to 4)

Incidence of new thrombosis

1 (9.1%)

3 (16.7%)

Adverse Events

N/A

Study Author Conclusions

Higher rates of occurrence of good or excellent hemostasis and GOS > 3 were observed on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS) scores and larger pre-reversal ICH volume.

InpharmD Researcher Critique

Since this study was limited based on the retrospective nature, single-center design and a small heterogenous patient population of both traumatic and spontaneous hemorrhage, a direct comparison of treatments was not possible. Additionally, patients who received 4F-PCC at an outside hospital and then transferred to the institution were not taken into consideration. 

 

References:

Barra ME, Das AS, Hayes BD, et al. Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages. J Thromb Haemost. 2020;18(7):1637-1647. doi:10.1111/jth.14838

 

Andexanet alfa and four‐factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage

Design

Retrospective, single-center, observational study

N= 56

Objective

To evaluate clinical outcomes of four‐factor prothrombin complex concentrate (4F-PCC) and andexanet alfa for the reversal of intracranial hemorrhage (ICH) associated with oral factor Xa inhibitors

Study Groups

Andexanet alfa (n= 21)

4F-PCC (n= 35)

Inclusion Criteria

Age ≥ 18 years; diagnosed with ICH; anticoagulated with apixaban or rivaroxaban prior to presentation; received either andexanet alfa or 4F-PCC 

Exclusion Criteria

Received either andexanet alfa or 4F-PCC for non-ICH indication; reversal of anticoagulants other than apixaban or rivaroxaban; received both andexanet alfa and 4F-PCC; or received alternative dosing of 4F-PCC

Methods

Eligible patients received either andexanet alfa or 4F-PCC in either the Emergency Department or Neuroscience Intensive Care Unit (ICU). Based on provider consensus (when the factor Xa inhibitor drug, dose, and/or timing of the last dose is unknown), if rivaroxaban level returns as > 0.15 ug/mL or an apixaban level > 200 ng/mL, then an additional low dose bolus is ordered, and infusion rate is increased to match the high-dose regimen of andexanet alfa.

Duration

Andexanet alfa: July 1, 2018 to September 1, 2019

4F-PCC: July 1, 2013 to September 1, 2019

Outcome Measures

Hematoma expansion, 30-day all-cause mortality, time from presentation to the administration of reversal agent, ICU length of stay, hospital length of stay, and 30-day readmission rate

Baseline Characteristics

  

Andexanet alfa (n= 21)

 4F-PCC (n= 35)

Age, years

 73.29 ± 11.97 74.51 ± 13.37

Male

 15 (71.4%) 14 (40.0%)

White

 17 (80.9%) 28 (80.0%)

DOAC

Apixaban

Rivaroxaban

 

14 (66.7%)

7 (33.3%)

 

20 (57.1%)

15 (42.9%)

Timing of last DOAC dose

< 8 h

≥ 8 h to < 18 h

≥ 18 h

 

4 (19.0%)

6 (28.6%)

6 (28.6%)

 

1 (2.9%)

6 (17.1%)

1 (2.9%)

Apixaban dosing

2.5 mg BID

5 mg BID

10 mg BID

 

4 (19.0%)

10 (47.6%)

0 

 

8 (22.9%)

11 (31.4%)

1 (2.9%)

Rivaroxaban dosing

15 mg once daily

15 mg BID

20 mg once daily

 

1 (4.8%)

0 

6 (28.6%)

 

2 (5.7%)

1 (2.9%)

11 (31.4%)

Admission laboratory results (interquartile range [IQR])

Apixaban assay level, ng/mL

Rivaroxaban assay level, μg/mL

Prothrombin time, seconds

INR

Activated partial thromboplastin time, seconds

Platelets (×109/L)

 

104 (88.5 to 149.5)

0.16 (0.10 to 0.24)

14.4 (13.0 to 15.7)

1.2 (1.1 to 1.3)

30.2 (27.5 to 34.2)

213 (151 to 272)

 

 43 (41.5 to 44.5)

0.21 (0.16 to 0.26)

14.3 (13.4 to 17.0)

1.2 (1.2 to 1.5)

29.2 (26.6 to 32.0)

226 (200 to 268)

Hemorrhage location

Intracerebral

Subdural

Subarachnoid

Multicompartmental

 

17 (81.0%)

2 (9.5%)

2 (9.5%)

0 

 

18 (51.4%)

1 (2.9%)

6 (17.1%)

10 (28.6%)

Dosing

Andexanet alfa

400 mg IV bolus + 480 mg infusion

800 mg IV bolus + 960 mg infusion

4F-PCC

Units

Units/kg

 

 

20 (95.2%)

1 (4.8%)

 

--

--

 

 

--

--

 

3,920.34 ± 940.48

48.25 ± 4.41

Results

Endpoint

Andexanet alfa (n= 21)

4F-PCC (n= 35)

Hematoma expansion

Yes

No

 

6 (35.3%)

11 (64.7%)

 

14 (45.2%)

17 (54.8%)

30-day all-cause mortality

 6 (30.0%)  14 (45.2%)

Time from presentation to the administration of reversal agent, hours (IQR)

2.67 (1.75 to 4.13)

1.73 (1.21 to 3.55)

Length of stay, days (IQR)

ICU 

Hospital

 

3.78 (2.54 to 6.69)

7.75 (4.64 to 15.87)

 

2.29 (1.37 to 5.83)

5.02 (2.72 to 8.56)

30-day readmission

  2/18 (11.1%) 2/22 (9.1%)

Study Author Conclusions

In this cohort, patients with ICH anticoagulated with apixaban or rivaroxaban, hemostatic efficacy rates differed between andexanet alfa and 4F-PCC. Additionally, 4F-PCC was found to have a higher rate of thrombotic events and mortality compared to andexanet alfa in this cohort of patients.

InpharmD Researcher Critique

This study is subject to limitations inherent to retrospective analysis, single-center, observational nature and historical bias. Additionally, patients receiving 4F-PCC were noted to have a lower GCS on admission and a high ICH score, thus limiting the ability to perform a direct comparison of the two reversal agents.

 

References:

Vestal ML, Hodulik K, Mando-Vandrick J, et al. Andexanet alfa and four-factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage [published online ahead of print, 2021 Jun 8]. J Thromb Thrombolysis. 2021;10.1007/s11239-021-02495-3. doi:10.1007/s11239-021-02495-3

 

Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study

Design

Retrospective, multi-center study

N= 1,075

Objective

 To describe the real-world utilization and outcomes associated with managing oral factor Xa inhibitor (FXai)-related major bleeds

Study Groups

Andexanet alfa (n= 342)

4F-PCC (n= 733)

Inclusion Criteria

 Hospitalized adult patients for FXai-related bleeding, indicative of bleeding due to extrinsic factors at the time of inpatient admission or during the hospital stay

Exclusion Criteria

 N/A

Methods

Patient data from electronic health records from 45 U.S. hospitals were collected for analysis. The study included different agents used to reverse FXai. For the purpose of the table, only the results from andexanet alfa and 4F-PCC were included.

Duration

 Data collection period: January 2016 to September 2019

Outcome Measures

In-hospital mortality due to all bleed types and stratified by gastrointestinal bleed, intracranial hemorrhage, critical compartment, trauma, and other bleeds; median length of stay in the hospital and intensive care unit (ICU)

Baseline Characteristics

  

Andexanet alfa (n= 342)

4F-PCC (n= 733)

Age, years

 69.1 70.1

Female

 154 (45%) 364 (50%)

FXa inhibitor

Apixaban

Edoxaban

Rivaroxaban

Other

 

47%

3%

50%

0

 

51%

8%

41%

0

Bleed type

Gastrointestinal

Intracranial hemorrhage

Critical compartment

Traumatic

Other

 

40%

20%

3%

31%

6%

 

41%

23%

29%

4%

3%

Results

Endpoint

Andexanet alfa (n= 342)

4F-PCC (n= 733)

In-hospital mortality due to all bleed types

GI bleed

Intracranial hemorrhage

Critical compartment

Trauma

Other bleeds

12 (4%)

2/137 (1%)

6/67 (9%)

0/11

4/105 (4%)

0/22

74 (10%)

12/303 (4%)

43/170 (25%)

1/26 (4%)

16/214 (7%)

2/20 (10%)

Median length of stay, days

 5 5

ICU length of stay, days

 2 3

Adverse Events

Not disclosed

Study Author Conclusions

 In-hospital mortality differed by bleed type and agents administered. Andexanet alfa was associated with the lowest rate of in-hospital mortality across all bleed types.

InpharmD Researcher Critique

 The baseline characteristics were sparse and did not capture the previous medical/prescription history nor longitudinal outcomes of the patients after discharge. There could be confounders that influenced the results. Andexanet alpha was approved in May 2018 which limited the data collection period compared to 4F-PCC.

 

 

References:

Coleman CI, Dobesh PP, Danese S, Ulloa J, Lovelace B. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study. Future Cardiol. 2021;17(1):127-135. doi:10.2217/fca-2020-0073

 

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage

Design

Retrospective, single-center, observational study

N= 44

Objective

To describe the experience with andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) in patients with oral reverse factor Xa inhibitors (FXi)-related traumatic and spontaneous intracranial hemorrhage (ICH)

Study Groups

Andexanet alfa (n= 28)

4F-PCC (n= 16)

Inclusion Criteria

Patients with life-threatening traumatic or spontaneous intraparenchymal, subarachnoid, subdural hemorrhages, and other intracranial bleeds after receiving apixaban or rivaroxaban; treated with at least one dose of AA or 4F-PCC

Exclusion Criteria

 Received both AA and 4F-PCC

Methods

Patients that required reversal of FXi received either AA dosed according to the product labeling for life-threatening bleeding associated with factor Xa inhibitors or 4F-PCC dosed with 25 units/kg up to 2,500 units per dose.

Duration

 Data collection period: July 2018 to April 2019

Outcome Measures

 Primary: ICH stability based on head computer tomography scans (CT) were defined as similar amount of blood from the initial scan at the onset of ICH to subsequent scans at 6 and 24 hours of treatment

Baseline Characteristics

  

Andexanet alfa (n= 28)

4F-PCC (n= 16)

 p-value

Age, years

 78 80 0.88

Female

 11 (39%) 5 (31%) 0.84

White

 24 (86%) 13 (81%) 0.84

Past medical history

Atrial fibrillation

Myocardial infarction

Stroke

 

20 (71%)

8 (29%)

8 (29%)

 

10 (62%)

1 (6%)

1 (6%)

 

0.74

0.12

0.12

Anticoagulant received

Apixaban

Rivaroxaban

 

19 (68%)

9 (32%)

 

12 (75%)

4 (25%)

 

0.74

0.74

Hemorrhage type

Spontaneous intracranial hemorrhage

Traumatic intracranial hemorrhage

Multicompartmental

Subdural hemorrhage

Contusions

 

20 (71%)

8 (29%)

7 (25%)

0

1 (4%)

 

8 (50%)

8 (50%)

5 (31%)

3 (19%)

0

0.20

Results

Endpoint

Andexanet alfa (n= 28)

4F-PCC (n= 16)

p-value

ICH stability based on CT scan

6 hours

24 hours

 

78%

88%

 

71%

60%

 

0.71

0.15

Incidence of thromboembolic events

 7% 0 0.53

Study Author Conclusions

In this limited sample of patients, no difference was found in neuroimaging stability, functional outcome, and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since the analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

InpharmD Researcher Critique

 As mentioned, the small sample size likely leads to an underpowered result which remains speculatory at best. The p-value may be reporting false negatives despite the potential for andexanet alfa to be more beneficial to 4F-PCC as seen in the results.

 

References:

Ammar AA, Ammar MA, Owusu KA, et al. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocrit Care. 2021;35(1):255-261. doi:10.1007/s12028-020-01161-5