a b s t r a c t

Objective: In 2018, the FDA approved andexanet alfa for the reversal of Life-threatening hemorrhages in patients anticoagulated with apixaban or rivaroxaban. Yet, cost-effective factor Xa inhibitor reversal remains controver- sial. The objective of this study was to describe real world utilization of andexanet alfa.

Methods: This was a retrospective case series of patients receiving andexanet alfa between July 28, 2018 and April 29, 2019 at a large academic health system. Baseline demographics, anticoagulant type and reversal, as well as brain imaging were collected. Primary endpoints were stability of hematoma for Intracranial Hemorrhage , and hemostatic effectiveness for patients undergoing surgical procedures. Secondary endpoints were thromboembolism and 30 day mortality.

Results: Of the 25 patients evaluated, 13 received andexanet alfa for ICH. Eleven of the 13 had follow-up imaging available and stability was observed in 90.9%. Three patients received andexanet alfa for reversal prior to surgical procedures, and 100% hemostatic effectiveness was achieved. Nine patients received andexanet alfa for reversal of extracranial bleeding, including gastrointestinal bleed (n=4). There were no thrombotic events in our cohort, and 30 day mortality was 24%. Sixty-four percent of patients would have met exclusion criteria for the ANNEXA-4 trial.

Conclusion: This is the largest series to date describing real-world utilization of andexanet alfa. Our series showed hemostatic efficacy in 90.9% of patients with ICH, and 100% in patients undergoing surgical procedures. There were no thrombotic complications. Yet, larger and comparative studies are needed to clarify the optimal agent and patient selection for reversal of factor Xa inhibitors.

(C) 2019

Introduction

Andexanet alfa was approved by the Food and Drug Administra- tion (FDA) in 2018 for treatment of life-threatening hemorrhage re- lated to the use of the factor Xa inhibitors, apixaban and rivaroxaban. Andexanet alfa exerts its Therapeutic effect by acting as a decoy pro- tein that binds directly to factor Xa inhibitors, thus rendering them ineffective and allowing endogenous factor Xa to activate thrombin

? All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

* Corresponding author at: Mayo Clinic, 200 First Street SW, Rochester 55905, MN, United States of America.

E-mail address: [email protected] (C.S. Brown).

[1]. Administration of the drug rapidly reduces anti-factor Xa activ- ity, but its effect on clinical outcomes remains less clear.

Approval of andexanet alfa was based on the ANNEXA-A and ANNEXA-R trials, both conducted in healthy volunteers, as well as an in- terim analysis from the ANNEXA-4 multicenter, prospective, open-label, single-arm trial that evaluated patients with major bleeding [2,3]. The full results of ANNEXA-4 have been published; however, the generaliz- ability of these studies is severely limited by its exclusion criteria [4].

Intracranial hemorrhage carries the highest morbidity and mortality among all factor Xa inhibitor-associated bleeds with 30-40% mortality rate and poor functional outcomes [5,6]. ICH patients included in the ANNEXA-4 studies were limited to those with a Glasgow coma scale (GCS) greater than seven and an estimated Hematoma volume of b60 mL [3,4].

Additionally, patients were excluded from the study who had a planned procedure within 12 h, leaving limited data to guide reversal in these patients [4]. Despite the favorable results observed in the study, extrapolation and applicability of these data remain controversial

https://doi.org/10.1016/j.ajem.2019.12.008

0735-6757/(C) 2019

clinical efficacy of andexanet alfa”>due to the restricted study patient population, lack of a comparator group, and high cost of andexanet alfa.

The objective of this study is to describe the use of andexanet alfa and the associated clinical outcomes of effectiveness and tolerability in a population treated at large academic medical centers.

Methods

Study design

This was a retrospective observational case series of patients who re- ceived andexanet alfa (Portola, San Francisco, California) for reversal of a factor Xa inhibitor since its first utilization (July 28, 2018) until April 29, 2019 at Mayo Clinic, which includes 3 large academic medical cen- ters (Arizona, Florida, Minnesota). Patients were identified as having re- ceived the medication from electronic medical records. Patients were excluded if they had declined authorization for use of medical records for research purposes. Baseline demographics, past medical history (including, pulmonary embolism (PE), Deep vein thrombosis , stroke, coronary artery disease (CAD), diabetes mellitus , surgery in the previous year, chronic obstructive pulmonary disease (COPD)), history of bleed, route of admission (transfer, presented to emergency department, in hospital bleed), anticoagulation information, indication for reversal, concomitant blood products, surgical procedures, neuroim- aging for patients with ICH, thrombotic events, and mortality were col- lected. A neurointensivist reviewed all imaging for patients presenting with ICH.

Study definitions

Hemostatic efficacy was evaluated for ICH patients and patients undergoing surgical procedures. Hemostasis for other bleeds was not evaluated due to many confounders that could not be controlled for in a retrospective fashion. For ICH, clinical efficacy was defined as lack of Hematoma expansion. Consistent with the ANEXXA-4 trial, Intraparenchymal hemorrhage (IPH) expansion was defined as N20% increase from pre-treatment hematoma volume, and subdural hematoma expansion was defined as N20% increase in maxi- mal hematoma diameter [4]. For IPH, volume was determined by the ABC/2 method [7]. For patients undergoing surgical procedures hemostasis was defined as no evidence of uncontrolled bleed in the operating room per review of the medical records, and no need for blood products. Thrombotic events and death were col- lected up to 30 days after andexanet alfa administration. Thirty days was selected to be consistent with the ANEXXA-4 trial [4]. Thrombotic events were defined as a new DVT, PE, stroke and acute coronary syndrome (ACS) per review of the medical record. This study was reviewed and approved by the Mayo Clinic Institutional Review Board.

Statistical analysis

Data was evaluated with descriptive statistics utilizing Microsoft Excel (2010). Data is presented as median with interquartile range (IQR).

Results

Baseline demographics

Of 30 patients receiving andexanet alfa for factor Xa inhibitor rever- sal during the study period, five patients were excluded due to declining authorization for use of medical records for research purposes. Median age of the remaining 25 patients (Table 1) was 75 (IQR 71-83) years, and 15 (60%) were female. Twenty patients (80%) were anticoagulated with apixaban, and five (20%) with rivaroxaban. The most common

indication for anticoagulation was atrial fibrillation (60%). Twenty pa- tients (80%) presented directly to the respective emergency depart- ments, three were transferred from other facilities, and two patients had bleeds while in the hospital. Three patients had a documented his- tory of a bleed (two gastrointestinal and one ICH), and four patients had surgery in the previous year. The median length of hospital stay was four days (IQR 3-6). Eleven (44%) of patients received andexanet alfa at the Minnesota campus, 4 (16%) at the Florida campus, 3 (12%) at the Arizona campus, and 7 (28%) from the health system sites. Thirteen patients received andexanet alfa for ICH while nine patients received andexanet alfa for bleeding at other sites including gastrointestinal (n = 4). Three patients received andexanet alfa for reversal of anticoagulation prior to procedures.

Clinical efficacy of andexanet alfa for patients with ICH

Nine patients had an IPH, one had an isolated intraventricular hem- orrhage, one had non-traumatic subarachnoid hemorrhage , and two patients had SDH (Table 2). Median Glasgow Coma Scale (GCS) upon presentation was 13 (IQR 13-15). Among patients who had an IPH the median ICH Score at presentation was 2 (IQR 1-3), and the me- dian ICH volume was 40.3 cm³ (IQR 27.2-59.6). Median post-treatment hematoma volume was 40.5 cm³ (IQR 20.45-47.95). The one patient with SAH died before repeat imaging could be obtained, and one patient had a right craniotomy for Hematoma evacuation prior to repeat imag- ing leaving 11 patients evaluable for hematoma expansion. Of these 11 patients, 10 (90.9%) did not have hematoma expansion.

Andexanet alfa for surgical procedures

Three patients received andexanet alfa for reversal prior to surgical procedures. One patient underwent left Brachial artery pseudoaneurysm repair with Primary repair of left brachial artery. The second patient de- veloped a large Malignant pericardial effusion leading to possible cardiac tamponade and was reversed prior to pericardiocentesis with pericar- dial drain. Lastly, a third patient received reversal prior to surgical de- bridement and removal of deep brain stimulator lead, extension lead, and pulse generator that was concerning for infection. In all three pa- tients hemostasis was 100%, as there was no note of uncontrolled hemo- stasis in the operating room and no blood products were needed.

Use of andexanet alfa for non-ICH hemorrhage

Nine patients received andexanet alfa for extracranial bleeding. Four patients had gastrointestinal bleeds. Additional indications for reversal are shown Table 1. Of the patients with gastrointestinal bleeds all pa- tients received fresh frozen plasma and three patients required endoscopy within 48 h of andexanet alfa administration; however, one patient proceeded to comfort measures prior to the procedure.

Thrombotic events and mortality

Six of 25 (24%) patients died within 30 days after receiving andexanet alfa; three patients (12%) died within seven days and an ad- ditional three patients died within 30 days. Four of the six patients who died presented with an ICH, one with a gastrointestinal bleed, and one undergoing an emergent procedure (pericardiocentesis). Per review of the electronic medical record 83% of the deaths were likely attributable to the underlying bleeding event, and no deaths were noted to be attrib- utable to thrombotic events.

Of the remaining 19 patients, no patient had recorded new throm- botic events.

Table 1

Patient characteristics.

Patient

Age/sex

Weight (kg)

BMI

creatinine clearance (mL/min)

Past medical history

FXai & dose

Indication for FXai

Indication for reversal

Blood products within 24 h of reversal (units)

Andexanet alfa dose

Death within 30 days

1

82 F

82.7

30.4

30-59

DVT, PE

Apixaban 10 mg BID

DVT/PE

Intracranial

None

High

No

2

75 F

61

26.1

>=60

DVT, PE

Apixaban 2.5 mg BID

DVT/PE

Intracranial

None

Low

No

3

71 M

112

35.3

>=60

Stroke, HF, CAD

Apixaban 5 mg BID

AF

Intracranial

None

Low

No

4

44 M

132.9

41.9

>=60

Stroke, DVT, DM

Rivaroxaban 10 mg QD

DVT

Intracranial

None

Low

Yes

5

72 F

86.3

30.7

>=60

PE, Diabetes

Rivaroxaban 15 mg QD

DVT/PE

Intracranial

None

High

No

6

57 M

88.5

26.5

>=60

DVT

Apixaban 10 mg BID

DVT

Intracranial

None

Low

No

7

72 M

102

31.4

30-59

DVT

Apixaban 5 mg BID

DVT

Intracranial

None

Low

Yes

8

83 F

68.2

28.8

>=60

–

Apixaban 5 mg BID

AF

Intracranial

4F-PCC (1604 units)

Low

No

9

86 M

86.2

27.4

>=60

CAD, HF

Apixaban 2.5 mg BID

AF

Intracranial

None

Low

No

10

93 M

81.2

26.5

>=60

HF

Apixaban 5 mg BID

AF

Intracranial

None

Low

Yes

11

70 F

81.6

28.2

>=60

PE, DM

Apixaban 5 mg BID

DVT/PE

Intracranial

None

High

No

12

82 F

69.6

25.6

>=60

CAD

Apixaban 5 mg BID

AF

Intracranial

None

High

Yes

13

90 F

57.8

21.2

30-59

–

Rivaroxaban 15 mg QD

AF

Intracranial

None

High

No

14

94 F

68.6

27.7

b30

–

Rivaroxaban 15 mg QD

AF

Gastrointestinal

2 RBC, 2 FFP

Low

No

15

63 F

121

47.3

>=60

–

Apixaban 5 mg BID

AF

Gastrointestinal

2 RBC, 2 FFP

Low

No

16

74 M

75

25.4

>=60

DVT

Apixaban 5 mg BID

DVT

Gastrointestinal

1 RBC, 2 whole blood

Low

No

17

83 M

72.6

26

>=60

COPD

Apixaban 5 mg BID

AF

Gastrointestinal

3 RBC, 2 FFP, 1 Plt

Low

Yes

18

69 F

86

33.6

>=60

DM

Apixaban 5 mg BID

AF

Othera

2 RBC, 2 FFP, 1 Plt

Low

No

19

89 F

45.8

20.4

>=60

MI

Apixaban 2.5 mg BID

AF

Othera

4 RBC, 1 FFP

Low

No

20

74 F

80.8

35.9

30-59

–

Rivaroxaban 20 mg QD

AF

Othera

2 RBC, 1 FFP

High

No

21

79 M

83

27

>=60

CAD

Apixaban 5 mg BID

AF

Othera

1 RBC

Low

No

22

89 F

76.2

31.8

b30

Stroke

Apixaban 5 mg BID

AF

Othera

2 RBC

Low

No

23

75 F

50.6

17.5

>=60

CAD

Apixaban 2.5 mg BID

PAD

Surgical procedureb

None

Low

No

24

57 F

70

26.7

>=60

DVT, PE

Apixaban 5 mg BID

DVT/PE

Surgical procedureb

None

Low

Yes

25

82 M

81.6

24.4

>=60

–

Apixaban 5 mg BID

AF

Surgical procedureb

None

Low

No

Abbreviations: BMI = body mass index, FXai = factor Xa inhibitor, DVT = deep vein thrombosis, PE = pulmonary embolism, HF = heart failure, DM = diabetes mellitus, CAD = coronary artery disease, AF = atrial fibrillation, PAD = peripheral arterial disease, RBC = red blood cells, FFP = fresh frozen plasma, Plt = platelets, 4F-PCC = 4 factor prothrombin complex concentrate.

^a Large chest wall and right flank subcutaneous hematoma, acute atraumatic vaginal hemorrhage in the setting of recent gynecologic surgery, 11.5 x 4.6 hematoma of right flank region, right iliac vein injury after micropacemaker placement leading to Retroperitoneal hematoma, perinephric hematoma (underlying right renal mass).

^b Surgical procedures: Left brachial artery pseudoaneurysm repair with primary repair of left brachial artery, pericardiocentesis, Surgical debridement and removal of deep brain stimulator lead, extension lead, and pulse generator.

Concomitant blood products and surgical procedures to achieve hemostasis

None of the patients with ICH received red blood cell (RBCs), platelets, or FFP within 24 h of andexanet alfa administration (Table 1), while one patient received four factor prothrombin com- plex concentrate (4F-PCC) 17.5 h after andexanet alfa. Of patients presenting with extracranial bleeding, nine received RBCs, two re- ceived platelets, six received FFP, and one received whole blood within 24 h of andexanet alfa administration. No patients received an additional dose of andexanet alfa.

Three patients received andexanet alfa for reversal prior to surgical procedures. In addition to these three patients, as previously noted, one patient with an ICH required a right craniotomy. Additionally two patients required emergent procedures; one patient underwent exter- nal ventricular drain placement and one patient required surgery to achieve hemostasis.

Exclusion from ANEXXA-4 trial

For inclusion in the ANEXXA-4 trial patients had to receive their last dose of factor Xa inhibitor within the previous 18 h. Due to the

Table 2

Characteristics of patients with ICH

Patient	Age/sex	Type of ICH	Location	GCS on presentation	ICH score	Modified Fisher	Initial hematoma volume (cm3)	Intraventricular blood	Repeat hematoma volume (cm3)	Time between imaging (hours: minutes)	Hematoma expansion
1	82 F	IPH	Supratentorial	13-15	1		27.2	No	22.2	13:04	No
2	75 F	IPH	Supratentorial	13-15	1		59.6	No	59.5	19:01	No
3	71 M	IVH	Right lateral ventricle	15				Yes			No
4	44 M	SAH		3		4		Yes			NA
5	72 F	IPH	Supratentorial	6T	3		273.6	Yes	Interval surgeryb		NA
6	57 M	IPH	Supratentorial	15	0		14.1	No	15.2	6:00	No
7	72 M	IPH	Infratentorial (pontine)	6T	4		35	Yes	37	4:58	No
8	83 F	SDH		15			14a	No	14a	3:40	No
9	86 M	SDH		15			6a	No	10a	9:19	Yes
10	93 M	IPH	Supratentorial	13-15	3	13.2		Yes	13.4	18:50	No
11	70 F	IPH	Supratentorial	15	1	40.3		No	44	24:00	No
12	82 F	IPH	Supratentorial	13-15	2	40.6		No	44.1	6:57	No
13	90 F	IPH	Supratentorial	14	3	86.4		Yes	80.2	6:56	No

Abbreviations: ICH: intracranial hemorrhage, IPH = intraparenchymal hemorrhage, IVH = intraventricular hemorrhage, SAH = subarachnoid hemorrhage, SDH = subdural hematoma, GCS = Glasgow coma scale, NA = not available.

^a Diameter in millimeters (mm).

^b Patient received right craniotomy for evacuation.

retrospective nature of the study, time of last dose was not available for all patients. Nine patients in our cohort had a documented time of last dose of factor Xa inhibitor and two of these patients had their last dose N18 h prior to reversal. Additionally, 16 patients (64%) met ex- clusion criteria for the ANNEXA-4 trial (Table 3). The most common reason for exclusion was receiving FFP.

Discussion

This observational study reports real-world utilization of andexanet alfa since its FDA approval. Our study found a majority of pa- tients received andexanet alfa for ICH and achieved effective hemostasis (90.9%). Additionally our study is the first to report the successful use of andexanet alfa prior to surgical procedures. Our cohort had a mortality rate of 24% and there were no thrombotic complications in our cohort. Given the extensive exclusion criteria in the ANEXXA-4 trial, a majority of the patients in the current cohort would have been excluded from that study. Our study adds to the data by Culbreth and colleagues who reported their experience on 15 patients (14 of which had an ICH) who received andexanet alfa with no thrombotic events and a 40% mor- tality rate [8].

Prior to approval of andexanet alfa, prothrombin complex concen- trates (PCC) have been used for reversal of factor Xa inhibitors. Numer- ous small prospective observational studies and retrospective studies have evaluated the efficacy and safety of PCC for factor Xa inhibitor re- versal. These trials which have had variable patient populations and def- initions of hemostatic efficacy, and have demonstrated 65 to 95% of patients achieving hemostatic efficacy [9-15]. Our study showed similar hemostasis in ICH patients as compared to these trials. As with all rever- sal agents, Risk of thrombotic events should be considered. Studies eval- uating PCC have shown thrombotic events ranging from 0 to 8% [9- 12,14,15]. Thrombotic events in these studies were evaluated over var- ioUS time frames. Our study found a thrombotic event rate of 0% for thrombotic events up to 30 days.

With the availability of reversal agents for factor Xa inhibitors, an important persisting question is the identification of patients most likely to benefit from reversal. Some small studies have found no im- provement in outcomes in patients with ICH receiving PCC for reversal of factor Xa inhibitors [5,13]. Given the limitations of the ANEXXA-4 trial and considerations of cost-effectiveness (underscored by the

$25,000-$50,000 price per dose of andexanet alfa) controversy remains regarding the optimal reversal agent for factor Xa inhibitors.

This study also describes the use of andexanet alfa for factor Xa in- hibitor reversal for surgical procedures, a non-FDA approved indication. Three patients in our study received reversal prior to surgical proce- dures. Although all patients were able to undergo surgical procedures with adequate hemostasis, questions previously discussed regarding the optimal patient population for the use of andexanet alfa hold true when considering the optimal approach for reversal of factor Xa inhibi- tors prior to surgery.

There are limitations of our study that warrant discussion. This is a single health system retrospective study without a comparator arm. We also limited our hemostatic efficacy evaluation to intracranial

Table 3

Patients in study cohort who met exclusion from ANNEXA-4.

Reason for exclusion	Number of patientsa
Received FFP	6
Received whole blood	1
GCS b 7	3
Thrombosis in previous 2 weeks	2
Initial hematoma volume N 60 mL	2
Anticipated OR within 12 h	3

Abbreviations: FFP = fresh frozen plasma, GCS = Glasgow coma scale, OR = operating room.

^a Patients may have met N1 exclusion criteria.

hemorrhages and surgical procedures. We felt there were many cofounders which could not be controlled for in reviewing hemostatic efficacy retrospectively in the other populations who received andexanet alfa in our study. We evaluated thrombotic events up to 30 days after administration of andexanet alfa; however some patients may have been missing follow-up information. We are also unable to account for blood products administered prior to transfer to our hospi- tals. Given the retrospective nature, and utilization of the electronic medication record for data we were unable to access last dose of antico- agulants for a majority of patients. Despite the limitations, our study provides further information on the utilization of andexanet alfa since its FDA approval.

Conclusion

Our study is the largest to date describing the utilization of andexanet alfa since its FDA approval. We found andexanet alfa to have good hemostatic efficacy in our ICH population; however, given our small sample size and lack of comparator arm, larger studies are needed to determine the optimal role of andexanet alfa in clinical practice.

Author contributions

Caitlin Brown: Conceptualization, Methodology, Investigation, Writing – original draft. Rachael Scott: Conceptualization, Method- ology, Investigation, Writing – original draft. Meera Sridharan: Methodology, Investigation, Writing – review & editing. Alejandro Rabinstein: Conceptualization, Methodology, Investigation, Writing – review & editing.

Declaration of competing interest

AR participated in Advisory Board meeting for Portola.

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