a b s t r a c t

Objective: to describe the clinical and Safety outcomes between andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban or rivaroxaban in the setting of an Intracranial Hemorrhage .

Methods: A retrospective, multicentered descriptive study was conducted in hospitalized patients 18 years of age or older from June 2018 to October 2019 who received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the insti- tution wide formulary. Other exclusion criteria were history or presence of Heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated Hematoma volume of >60 mL, Glasgow coma scores <7, or no repeat CT head scan. Information was collected from the electronic medical records. The primary outcome was the achievement of excellent or good hemostatic efficacy upon the repeat computer tomography (CT) scan per- formed after the infusion of study drugs. Secondary outcomes included disposition, survival to hospital discharge, 30-day readmission, length of hospital stay, length of ICU stay, incidence of Thromboembolic events.

Results: A total of 24 patients were included in the study, of which 9 received AA and 15 received 4F-PCC. The achievement of excellent or good hemostatic efficacy upon repeat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (93.3%) patients in the 4-F PCC group. All patients in the AA group survived to hospital discharge with no 30-day morality and 86.7% patients in the 4F-PCC group.

Conclusion: This study suggests that real-world clinical and safety outcomes between andexanet alfa and 4F-PCC for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.

(C) 2022

1. Introduction

Andexanet alfa (AA) is a modified recombinant coagulation factor Xa approved for the reversal of apixaban and rivaroxaban in life- threatening or uncontrolled bleeds. It binds to and sequesters factor Xa inhibitors to reverse their anticoagulant effect [1]. Before its intro- duction into the market, Neurocritical care Society recommended the

Abbreviations: ICH, Intracranial hemorrhage; 4F-PCC, 4-factor prothrombin complex concentrate; CT, Computer tomography.

* Corresponding author at: Morristown Medical Center, 100 Madison Ave, Morristown, NJ 07960, United States of America.

E-mail addresses: ellyoh119@gmail.com (E.S. Oh), paul.schulze@atlantichealth.org (P. Schulze), frank.diaz@atlantichealth.org (F. Diaz), kunal.shah@atlantichealth.org (K. Shah), jose.rios@atlantichealth.org (J. Rios), michael.silverman@atlantichealth.org (M.E. Silverman).

¹ Present Address: 65 White Tail Lane, Wallingford, CT 06492, United States of America.

administration of 4-factor prothrombin complex concentrate or activated prothrombin complex concentrate (PCC) for the reversal of factor Xa inhibitors in the setting of an intracranial hemorrhage [2]. Since its approval, the American Heart Association/ American College of Cardiology/ the Heart Rhythm Society have stated AA is a useful agent for the reversal of rivaroxaban and apixaban in the event of a life-threatening or uncontrolled bleed [3]. The updated American Heart Association/American Stroke Association have similar recom- mendations in which AA is reasonable to reverse for direct factor Xa inhibitor-associated Spontaneous intracranial hemorrhage (ICH) with 4F-PCC or activated PCC as an agent that may be considered [4]. Despite the shift in recommendation, there have not been prospective clinical trials comparing therapies.

ANNEXA-4, an open-label, single group phase 3 trial, found 80% of patients with ICH achieved excellent or good hemostatic efficacy at 12 h. Clinical trials comparing AA with other therapies are lacking [5].

https://doi.org/10.1016/j.ajem.2022.11.023

0735-6757/(C) 2022

A phase 4 study comparing AA to usual care in acute ICH in patients re- ceiving factor Xa inhibitors is underway but expected to be completed by 2024 [6]. There is limited evidence for AA usefulness in the commu- nity setting. The objective of this study is to describe clinical and safety outcomes of AA and 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of an ICH.

1. Methods
   1. Study design

A multi-centered, retrospective descriptive study was conducted at a hospital system located in New Jersey from June 2018 to October 2019. Both arms were for separate 6-month periods from June 2018 to November 2018 for the 4F-PCC group and May 2019 to October 2019 for the AA group. These time periods were chosen due to the introduc- tion of AA to the hospital-wide formulary on May 2019 and to match a similar timeframe the year prior for the 4F-PCC group. The hospital system consisted of five hospitals located in northern New Jersey. Of which, one study center was a primary stroke center and Level I regional trauma center, and another study center was designated as a compre- hensive stroke center. The Institutional Review Board of the affiliated healthcare system waived the need for consent.

• 1. Patient selection

Patients were included if they were 18 years of age or older, received a dose of apixaban or rivaroxaban within 18 h of reversal agent after the addition of AA on system formulary, and received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of an ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the institution wide formulary. Other exclusion criteria were history or presence of heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated hematoma volume of >60 mL, isolated intraventricular hemorrhages, Glasgow Coma Score <7, or no repeat CT head scan post study drug administration. Information was collected from the electronic medical records.

• 1. Study drugs

The 4F-PCC on formulary was KCentra(R) (CSL Behring, King of Prussia, PA). The institutional dosing recommendation was 4F-PCC 50 units/kg intravenous once for apixaban and rivaroxaban reversal, but the use and dose of 4F-PCC were up to the discretion of the attend- ing physician. After the addition of AA to the institution wide formulary in May 2019, the institution’s clinical guideline for antithrombotic re- versal recommended AA as the first-line agent for the reversal of apixaban and rivaroxaban in major and life-threatening bleeds if the last dose of the offending agent was within 18 h prior to the diagnosis of an ICH. The institution’s policy for AA required the approval from pharmacy with an optional further escalation for approval from the chief medical officer if initially denied. For patients who took their last dose of apixaban >5 mg or rivaroxaban >10 mg within 8 h of diagnosis, the recommended dose was AA 800 mg Intravenous bolus over 30 min followed by 960 mg intravenous over 2 h. Those who took apixaban

<=5 mg, rivaroxaban <=10 mg, or their last dose >=8 h but <18 h prior to the diagnosis of an ICH, the recommended dose was AA 400 mg intrave- nous bolus over 15 min followed by 480 mg intravenous over 2 h. The time of last dose was verified by the patient, family/caregiver, or docu- mentation on medication administration records from noncommunity dwelling facilities. For missing radiographic measurements, a radiolo- gist reviewed CT scans to measure dimensions and calculate intraparen- chymal hematoma volume with the ABC/2 method [7] while thickness was measured for subdural and Subarachnoid hemorrhages.

• 1. Outcomes

The clinical outcomes included the achievement of excellent or good hemostatic efficacy upon completion of the repeat computer tomogra- phy (CT) scan after the infusion of the study drugs. The definitions for excellent and good hemostatic efficacy were <=20% and >20% but <=35% increase in hematoma volume or thickness compared to baseline, respectively. Other outcomes included 30-day mortality, survival to hospital discharge, 30-day readmission, length of ICU stay, length of hospital stay, disposition, and incidence of thromboembolic events.

• 1. Statistical analysis

Percentage and 95% confidence intervals were obtained for categor- ical variables, while medians and interquartile ranges were calculated for continuous variables. Statistical analyses were performed using GraphPad Prism version 9.4.1 (GraphPad Software, LLC) and Microsoft Excel 2016 (Microsoft Corporation).

1. Results
   1. Patient characteristics

A total of 34 patients received either AA or 4-F PCC for the reversal of apixaban or rivaroxaban in the setting of an ICH within the study timeframe. Of these, a total of 24 patients were included of which 9 re- ceived AA, and 15 received 4F-PCC. Three patients were excluded as they were transitioned to comfort care thus a repeat CT scan was not performed after the administration of the study drug. Two patients were excluded for receiving 4F-PCC prior to AA. Additional excluded pa- tients are listed on Fig. 1. Twelve (50%) patients were on apixaban

<=5 mg and 12 (50%) patients were on rivaroxaban >10 mg. Baseline characteristics are listed in Table 1. Therapeutic and monitoring inter- ventions are listed in Table 2.

• 1. Outcomes

The achievement of excellent or good hemostatic efficacy upon re- peat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (91.7%) patients in the 4-F PCC group. All patients in the AA group sur- vived to hospital discharge with no 30-day mortality, and 13 (86.7%) pa- tients in the 4F-PCC group survived to hospital discharge with a 30-day mortality of 13.3%. Median ICU and hospital length of stay were 3 days and 8 days in the AA group and 2 days and 6 days in the 4F-PCC group, respectively. Additional outcomes are displayed in Table 3.

Of those who survived to hospital discharge, 77.8% in the AA group and 57.1% in the 4F-PCC group were discharged to a higher level of care. thrombotic events occurred in 2 patients who received 4-F PCC. Both patients were originally on factor Xa inhibitors for atrial fibrillation

24 Patients Included

34 Patients Reviewed

15 Received 4F-PCC

9 Received Andexanet Alfa

10 Patients Excluded

3 No repeat CT scan post study drug

2 Received 4F-PCC prior to Andexanet Alfa 2 Hematoma volume >60 mL

2 Intraventricular hemorrhages only 1 Glasgow Coma Score <7

Fig. 1. Flow diagram of patients included and excluded from study.

Table 1

Baseline characteristics of included patients by study drug.

Characteristic Andexanet Alfa Group (n = 9)

4F-PCC Group (n = 15)

Table 2

Therapeutic and monitoring interventions.

Characteristic Andexanet Alfa Group (n = 9)

4F-PCC Group (n = 15)

Age, years – median (IQR) 82 (71, 85) 85 (77, 90)

Andexanet alfa low dose 7 (77.8) N/A

Andexanet alfa high dose 2 (22.2) N/A

Male 4 (44.4, 18.8-73.4) 9 (60, 35.7-80.3)

BMI, kg/m² – median (IQR) 33.3 (22.3, 35) 26.9 (23.9, 30.2)

CrCl, mL/min – median (IQR) 65.7 (48.3, 128.9) 64 (42, 76.6)

Past medical/surgical history

Transient ischemic attack 4 (44.4, 18.8-73.4) 6 (40, 19.8-64.3)

Diabetes mellitus 5 (55.6, 26.6-81.2) 4 (26.7,10.5-52.4)

Prior ischemic stroke 3 (33.3, 11.7-64.9) 4 (26.7,10.5-52.4)

4F-PCC dose (units/kg) – median (IQR)

Time between initial CT scan to study drug administration – median⁺ (IQR)

Time between CT scans – median⁺ (IQR)

Heart disease	1 (11.1, 0-45.7)	7 (46.7, 24.8-69.9)	Administration of desmopressin if	3/3 (100, 38.25-100)	5/6 (83.3, 41.8-98.9)
Venous thromboembolism	3 (33.3, 11.7-64.9)	2 (13.3, 2.5-39.1)	on antiplatelet – n/total (%)
Surgery in prior year	2 (22.2, 53.4-55.7)	1 (6.7, 0-31.8)	Received platelets	1 (11.1, 0-45.7)	2 (13.3, 2.5-39.1)
COPD	1 (11.1, 0-45.7)	1 (6.7, 0-31.8)	IV antihypertensive use within first	8 (88.9, 54,3-99.9)	8 (53.3, 30.1-75.2)

N/A 48.4 (36.3, 51.1)

1:32 (1:09, 2:26) 2:31 (1:21, 3:29)

8:21 (7:22, 11:28) 17:58 (12:03, 18:16)

Prior ICH 1 (11.1, 0-45.7) 0 (0, 0-23.9)

Home medication

Apixaban<=5 mg 4 (44.4, 18.8-73.4) 8 (53.3, 30.1-75.2)

Rivaroxaban>10 mg 5 (55.6, 26.6-81.2) 7 (46.7, 24.8-69.9

Antihypertensives 8 (88.9, 54.3-99.9) 13 (86.7, 60.9-97.5)

Antiplatelet agent 3 (33.3, 11.7-64.9) 6 (40, 19.8-64.3) Patient source location

Home	7 (77.8, 44.3-94.7)	12 (80, 54.1-93.7)
Nursing home	2 (22.2, 5.3-64.9)	0 (00, 0-23.9)
Assisted living	0 (0, 0-34.4)	1 (6.7, 0-31.8)
Skilled nursing facility	0 (0, 0-34.4)	1 (6.7, 0-31.8)
Subacute rehab	0 (0, 0-34.4)	1 (6.7, 0-31.8)

24 h of admission

Underwent surgical procedure 0 (0, 0-34.4) 3 (20, 6.3-46.0)

Abbreviation: 4F-PCC, 4 factor-prothrombin complex concentrate; IQR, interquartile; CT, computer topography; IV intravenous.

Note: Data expressed as n (%, 95% confidence interval) unless otherwise noted. ⁺Expressed as hour: minute.

hemostatic efficacy in 77.8% (95% CI 44.3-94.7) of patients similar to that of previous studies.

A wider range of hemostatic efficacy with PCCs has been reported

Baseline systolic blood pressure – median (IQR)

Location of initial hematoma

160 (150, 168) 137 (122, 156)

ranging from 52.6 to 81.8% [8,10,11,14-16]. This present study showed 91.7% (95% CI 62.5-99.9) of patients in the 4F-PCC group achieved ex-

Intraparenchymal hemorrhage 4 (44.4, 18.8-73.4) 6 (40, 19.8-64.3)

Subdural hemorrhage 4 (44.4, 18.8-73.4) 7 (46.7, 24.8-69.9)

Intraventricular hemorrhage 1 (11.1, 0-45.7) 1 (6.7, 0-31.8)

Subarachnoid hemorrhage 4 (44.4, 18.8-73.4) 0 (0, 0, 0-23.9)

Extra-axial hemorrhage 1 (11.1, 0-45.7) 1 (6.7, 0-31.8)

Petechial hemorrhage 0 (0, 0-34.4) 1 (6.7, 0-31.8)

ICH Score – median (IQR) 1 (0,1) 1 (1,2)

baseline GCS – median (IQR) 15 (14, 15) 15 (14, 15)

cellent or good hemostatic efficacy. This may be due to differences in dosing across studies which ranged from fixed dosing to weight-based dosing of 25-50 units/kg. At the time of the study, the study locations used 50 units/kg dosing with only 4 patients who received 25 units/ kg. Higher dosing may have contributed to higher efficacy. Three pa- tients in the 4F-PCC group underwent surgical procedure which would affect the evaluation of hemostatic efficacy; thus, they were

NIHSS – median (IQR);

Andexanet alfa

n = 4; 4F-PCC n = 9

Initial ABC/2 method – median (IQR); Andexanet alfa n = 4; 4F-PCC n = 7

Initial SDH thickness – median (IQR); Andexanet alfa n = 5; 4F-PCC n =7

12 (6, 16) 2 (0, 7)

3.35 cm³ (2.9, 6) 8.6 cm³ (0.8, 11.2)

0.8 cm (0.8, 1.1) 1.4 cm (0.58, 1.6)

Table 3

Endpoints.

Clinical Outcomes	Andexanet Alfa Group (n = 9)	4F-PCC Group (n = 15)
Achievement of excellent or	7/9 (77.8, 44.3-94.7)	11/12 (91.7, 62.5-99.9)
good hemostatic efficacy upon repeat CT scan+
Excellent hemostatic	5 (55.6, 26.6-81.2)	11 (93.3, 68.2-99.9)
efficacy+ Good hemostatic efficacy+	2 (22.2, 5.3-64.9)	0 (0, 0-23.9)

Abbreviation: 4F-PCC, 4 factor-prothrombin complex concentrate; IQR, interquartile; BMI, body mass index; CrCl, creatinine clearance; COPD, chronic obstructive pulmonary dis- ease; ICH, intracranial hemorrhage; GCS, Glasgow Coma Score; NIHSS, National Institute of Health Stroke Score; SDH, subdural hemorrhage.

Note: Data expressed as n (%, 95% confidence interval) unless otherwise noted.

Survival to hospital discharge 9 (100, 65.5, 100) 13 (86.7, 60.9-97.5)

30-day mortality 0 (0, 0-34.4) 2 (13.3, 2.5-39.1)

30-day readmission 0 (0, 0-34.4) 2 (13.3, 2.5-39.1)

prior to reversal, and both thrombotic events were deep vein thrombo- ses. No thromboembolic events were documented in the AA group.

1. Discussion

Currently, the comparison between AA and PCC are limited to retro- spective studies or case series [8-12]. Semon et al., reported no signifi- cant difference between treatments when comparing the achievement of hemostatic efficacy or mortality [8]. Ammar et al., also found no dif- ference in mortality when comparing both groups [9]. An ongoing Phase IV prospective trial comparing AA and usual care is projected to be completed in 2024 and will provide further insight in the differences

between treatment options [6].

Length of ICU stay – median (IQR)

Length of hospital stay –

median (IQR) Disposition

Home or assisted living	2 (22.2, 5.3-64.9)	6 (42.9, 21.3-67.5)
Acute rehab	4 (44.4, 18.8-73.4)	1 (7.1, 0-33.5)
Subacute rehab	3 (33.3, 11.7-64.9)	2 (14.3, 2.8-41.2)
Skilled nursing facility	0 (0, 0-34.4)	3 (21.4, 6.8-48.3)
Hospice	0 (0, 0-34.4)	1 (7.1, 0-33.5)
Inpatient rehab	0 (0, 0-34.4)	1 (7.1, 0-33.5)
Increased level of care upon	7/9 (77.8, 26.6-81.2)	8/14 (57.1)
discharge – n/total (%)

Safety endpoints Total incidence of

thromboembolic events

3 (3, 7) 2 (2, 4)

8 (5, 10) 6 (5, 8)

0 (0, 0-34.4) 2 (13.3, 2.5-39.1)

The ANNEXA-4 trial showed 80% of patients with the indication of reversal of factor Xa inhibitors in the setting of ICH have achieved excel- lent or good hemostatic efficacy upon repeat imaging [5]. Other retro- spective studies have found comparable results ranging from 64.7 to 88.9% with AA [8,10-13]. The AA group in this present study achieved

Deep vein thrombosis 0 (0, 0-34.4) 2 (13.3, 2.5-39.1)

Abbreviation: 4F-PCC, 4 factor-prothrombin complex concentrate; CT, computer topogra- phy; ICU, intensive care unit; IQR, interquartile.

Note: Data expressed as n (%, 95% confidence interval) unless otherwise noted.

⁺Individuals who underwent surgical intervention were excluded from the hemostatic ef-

ficacy analysis.

excluded in the hemostatic efficacy calculations. In addition, after the addition of AA onto the systemwide formulary, the treatment of AA was limited to patients with known time of ingestion of apixaban or rivaroxaban within the previous 18 h of treatment. A confounding factor may be that the timeframe to reverse with 4F-PCC during that study arm was not limited to only 18 h prior to diagnosis which could be cor- related to lower factor Xa inhibitor plasma levels. Without laboratory evaluation of anti-Xa activity or time limitation for treatment, the 4F-PCC group may have had patients who had less factor Xa inhibitor activity leading to higher hemostatic efficacy and thrombotic events.

An approval process was implemented to restrict the use of AA to patients with major bleeds who ingested their last dose of apixaban or rivaroxaban within 18 h of diagnosis. This did not show to have delayed therapy but may have introduced selection bias. Perhaps the involve- ment of pharmacists in the emergency departments in the institutions with the highest usage prevented a delay in therapy. Their presence may have reduced the time to drug administration with the use of satellite pharmacies. The approval process mimicked ANNEXA-4 by ex- cluding patients with larger hematoma volumes and lower GCS scores, which may explain no mortality in this group. The mortality in the 4F-PCC group from this study was comparable to those previously re- ported. A multi-centered survey reported 8.9% mortality with the used of AA and 25.3% with the use of 4F-PCC in ICH [17]. Other studies that have found mortality of 10.3-47.4% for AA in ICH and 12.2-63.6% for PCCs [8-10,12,14-16,18].

In terms of safety, there have been variable reports of thromboem- bolic events with AA and 4F-PCC in the reversal of factor Xa inhibitors. ANNEXA-4 reported 10% thrombotic events with AA [5]. Other case se- ries and retrospective studies reported 5.3-16.7% with AA [8-11,13]. Case series and cohort studies of PCC have found 0-31.4% thrombotic events in the setting of ICH [8-11,14,15]. Aside from the previously men- tioned bias, the occurrence of thrombotic events only in the 4F-PCC group may be explained by the mechanism of action of AA. AA inhibits the action of the offending anticoagulants with some procoagulant ef- fect, but 4F-PCC acts solely as a procoagulant [1,19]. Further evaluation in the risk of thrombosis between treatment options requires larger studies.

Additional limitations were a small sample size, as well as, the retro-

spective and observational nature of this study. This includes residual confounding and limited information from medical records such as pre- cise time of the bleed onset. Variation in treatment and monitoring pro- tocols between study periods may be a confounding factor. The timing of repeat CT imaging ranged from 2 to 48 h between initial and repeat scans which could be also confounding factor. Longer duration between CT scans may result in lower hemostatic efficacy.

1. Conclusion

This multicentered descriptive study suggests real-world clinical and safety outcomes between AA and 4F-PCCs for the reversal of factor Xa in- hibitors in the setting of ICH are similar to ones reported in clinical trials.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors contributions

ESO, FD, KS, and MES conceived and designed the study. SC acted as an advisor to the study. ESO, PS, FD, KS, JR, and MES supervised the con- duct of the study and data collection. ESO and PS managed the data. ESO, FD, KS, and MES provided the statistical advice on study design and an- alyzed the data. ESO drafted the manuscript, and all authors contributed to its revision. ESO takes responsibility for the paper as a whole.

CRediT authorship contribution statement

Elly S. Oh: Writing – original draft, Methodology, Investigation, For- mal analysis, Conceptualization. Paul Schulze: Writing – review & editing, Methodology, Investigation. Frank Diaz: Writing – review & editing, Supervision, Project administration, Methodology, Formal anal- ysis, Conceptualization. Kunal Shah: Writing – review & editing, Super- vision, Project administration, Methodology, Formal analysis, Conceptualization. Jose Rios: Writing – review & editing, Supervision, Methodology. Michael E. Silverman: Writing – review & editing, Super- vision, Methodology, Formal analysis.

Declaration of Competing Interest

The authors received no financial support for the research, author- ship, and/or publication of this article.

Acknowledgements

We thank Stephanie Chiu, MS and Teodoro Jerves Serrano, MD for statistical advice on this study.

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1. KCentra(R) [Package Insert]. CSL Behring LLC, Kankakee, IL; 2020.