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Update: What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors?

Introduction

In August 2018, the UIC Drug Information Group reviewed the literature related to the use of andexanet alfa for the reversal of factor Xa inhibitors.1 This review can be accessed here. Since the publication of this review, additional studies and recommendations for andexanet alfa use have been published. The purpose of this article is to describe the updated literature for andexanet alfa in the setting of factor Xa inhibitor reversal.

Background

Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban) are commonly used for anticoagulation.2 Like all anticoagulants, these medications carry a risk of bleeding. Before the approval of andexanet alfa, no specific reversal agents were available for factor Xa inhibitors; instead, inactivated prothrombin complex concentrates (PCCs) were used off-label as first-line agents for factor Xa inhibitor reversal. Andexanet alfa is a recombinant modified human coagulation factor Xa protein that binds and sequesters apixaban and rivaroxaban, exerting a procoagulant effect.3 It has also been shown to inhibit tissue factor pathway inhibitor activity, which increases thrombin generation and further promotes coagulation. It is currently approved for the reversal of anticoagulation in patients treated with rivaroxaban or apixaban when reversal is necessary due to life-threatening or uncontrolled bleeding.

Andexanet alfa was approved through an accelerated approval pathway based on its demonstrated ability to produce changes in anti-factor Xa activity in healthy volunteers.3 Preliminary results from a single-arm trial in factor Xa inhibitor-associated acute major bleeding (ANNEXA-4) showed that andexanet alfa decreases anti-factor Xa activity in this patient population.4 Most patients also achieved excellent or good hemostasis after receiving andexanet alfa. However, andexanet alfa’s ability to improve hemostasis remains to be established, according to the prescribing information.3

Summary of new evidence

Since the previous FAQ, the final results from ANNEXA-4 have been released (Table).5 These results largely echo the preliminary trial findings, demonstrating that andexanet alfa produces a significant reduction in anti-factor Xa activity. Excellent or good hemostasis was attained in 82% of evaluable patients within 12 hours of andexanet alfa administration. However, the trial remains limited by its open-label, single-arm design. Patients who received blood products (including PCCs, whole blood, or plasma) were excluded from the trial, which may limit generalizability; it is unknown how the use of these interventions may affect the efficacy or safety of andexanet alfa. Additionally, patients requiring surgery within 12 hours of enrollment were excluded from ANNEXA-4, so data in patients requiring emergency surgery are lacking.

Several institutions have additionally published observational data on andexanet alfa (Table).6-9 Some have found rates of hemostatic efficacy and in-hospital mortality similar to those observed in ANNEXA-4; however, others (namely Nederpelt et al and Culbreth et al) have observed lower rates of efficacy, potentially due to differences in patient selection. The study by Nederpelt et al included a substantial number of patients who underwent surgery after andexanet alfa administration; since these patients would have been excluded from ANNEXA-4, this may account for some of the observed differences in outcome.7 This study also focused only on extracranial bleeding, whereas the ANNEXA-4 trial primarily included patients with intracranial bleeding. The small series by Culbreth et al included a number of patients who would not have been eligible for enrollment in ANNEXA-4.9 In this 15-patient series, 7 patients received PCC prior to andexanet alfa, and 3 had surgery within 12 hours after andexanet alfa administration. Baseline differences in bleed severity or other factors could also account for the observed variability in results across studies.

Andexanet alfa is not currently approved for the reversal of edoxaban or betrixaban.3 Although patients on edoxaban were eligible for enrollment in ANNEXA-4, only 10 patients receiving this drug were included.5 A recently published phase 2 pharmacokinetic study in healthy volunteers found that andexanet alfa decreased anti-factor Xa activity of edoxaban by a maximum of approximately 82%.10 This was lower than the maximum observed decrease in anti-factor Xa activity for rivaroxaban-treated subjects (93%), but still significantly different from placebo. Additional clinical data are necessary to confirm the efficacy of andexanet alfa in patients with active bleeding on edoxaban. A pharmacokinetic study in healthy volunteers was planned to examine andexanet alfa for betrixaban reversal, but this study was terminated prematurely (NCT03330457).11 No clinical data are available for andexanet alfa in this setting.

No prospective studies have compared andexanet alfa to PCC for acute bleeding in patients receiving factor Xa inhibitors, but some retrospective comparisons have been published (Table).12,13 A multicenter retrospective study offered descriptive data on over 3000 patients who were hospitalized for major bleeding associated with factor Xa inhibitor use (n=342 receiving andexanet alfa).12 In this study, andexanet alfa was associated with the lowest in-hospital mortality rate among reversal agents. However, some patients in this study received more than 1 intervention for anticoagulant reversal, and selection bias may account for some of the outcome differences that were observed. No adjustments were made for between-group differences in baseline characteristics, and hemorrhage size/severity in each group was not reported. A small retrospective observational study in 29 patients with intracranial hemorrhage found higher rates of good or excellent hemostasis among patients who received andexanet alfa versus 4-factor PCC.13 However, higher rates of thrombosis were also observed with andexanet alfa. Given the retrospective nature of the data, selection bias may have influenced the observed outcomes. Patients who received PCC may have received it because they did not qualify for andexanet alfa, or because they had more severe hemorrhages. Several important between-group differences were present at baseline, including differences in baseline Glasgow Coma Scale scores, baseline anticoagulant agent, pre-reversal hemorrhage volume, and hemorrhage location. Larger, prospective trials are needed to compare the efficacy of andexanet alfa and PCC for factor Xa inhibitor reversal.

Table. Overview of studies examining andexanet alfa for factor Xa inhibitor reversal published since August 2018.5-9,12,13
Study design and durationSubjectsInterventions/ComparatorsResultsConclusions
Prospective studies
Connolly 20195

ANNEXA-4

Phase 3b/4, MC, prospective, OL, single-group study

Follow up to 30 days after andexanet alfa		N=352 adult patients reported to receive apixaban, rivaroxaban, edoxaban, or ≥ 1 mg/kg enoxaparin within the past 18 hours with acute major bleeding

Mean age 77 years

Acute major bleeding: GI (26%), intracranial (64%), other (10%)

Factor Xa inhibitor: rivaroxaban (36%), apixaban (55%), enoxaparin (6%), edoxaban (3%)		Andexanet alfa IV bolus (15 to 30 min) followed by 2-hour infusion

Andexanet alfa 400 mg IV bolus and 480 mg infusion for all patients who took apixaban and all patients who took rivaroxaban >7 hours before andexanet alfa administration

Andexanet alfa 800 mg IV bolus and 960 mg infusion for all patients who took enoxaparin or edoxaban and all patients who took rivaroxaban ≤7 hours before andexanet alfa administration or at an unknown time		After IV bolus, median anti-factor Xa activity decreased by 92% (95% CI, 91 to 93) from baseline in apixaban patients and 92% (95% CI, 88 to 94) from baseline in rivaroxaban patients

At 4, 8, and 12 hours after administration, median anti-factor Xa activity was decreased from baseline by 32%, 34%, and 38%, respectively, for apixaban and 42%, 48%, and 62%, respectively, for rivaroxaban

Excellent or good hemostatic efficacy at 12 hours was achieved in 204/249 patients evaluable for this outcome (82%; 95% CI, 77 to 87)

Excellent or good hemostatic efficacy at 12 hours was achieved in 85% of patients with GI bleeding (95% CI, 76 to 94) and 80% of patients with intracranial bleeding (95% CI, 74 to 86)

Thrombotic events occurred in 34 patients (10%) during the 30-day follow-up period; 11 of these patients had thrombotic events within 5 days of andexanet alfa administration

Infusion reactions were reported in 2 patients

30-day mortality rate was 14% (n=49)		Treatment with andexanet alfa markedly reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, and 82% of patients had excellent or good hemostatic efficacy at 12 hours.
Retrospective studies comparing andexanet alfa and PCC
Coleman 202012

Retrospective MC observational study

N=3030 patients with hospitalizations for major bleeding associated with factor Xa inhibitor use between 2016 and 2019

Mean age 67.6 years

Acute major bleeding: GI (48%), intracranial (17%), traumatic (26%), critical compartment (4%), other (6%)

Factor Xa inhibitor: rivaroxaban (49%), apixaban (45%), edoxaban (6%), or other (<1%)		Andexanet alfa (n=342)

4-factor PCC (n=733)

Fresh frozen plasma (n=925)

Other reversal agent, such as 3-factor PCC, activated 4-factor PCC, recombinant factor VIIa, tranexamic acid, and vitamin K (n=794)

No reversal agent (n=438)		In-hospital mortality rates were 4%, 10%, 11%, 8%, and 8% for patients receiving andexanet alfa, 4-factor PCC, fresh frozen plasma, other reversal agents, and no reversal agent, respectively

Median length of ICU stay and median length of overall hospital stay: 2 days and 5 days respectively with andexanet alfa, 3 days and 5 days respectively with 4-factor PCC, fresh frozen plasma, and other interventions, and 2 days and 3 days respectively with no reversal agent		Andexanet alfa was associated with the lowest rate of in-hospital mortality among the agents studied; however, further studies are necessary to confirm this finding, as severity of bleeding or other important baseline characteristics may have differed across groups.
Barra 202013

Retrospective single-center observational study		N=29 adults with rivaroxaban- or apixaban-associated intracranial hemorrhage who received andexanet alfa or 4-factor PCC for anticoagulant reversal between 2016 and 2019

Median age 73.2 years

Most common anticoagulant was apixaban (83.3%) in the andexanet alfa cohort and rivaroxaban (72.7%) in the PCC cohort

Median hemorrhage volume at presentation: 20.6 mL in the andexanet alfa cohort and 37.4 mL in the PCC cohort		Andexanet alfa; all patients received a low-dose regimen (400 mg IV bolus over 15 minutes followed by 480 mg IV over 2 hours) in accordance with prescribing information guidelines (n=18)

4-factor PCC 25 to 50 units/kg IV (max, 5000 units; median dose, 26.9 units/kg) (n=11)		Good or excellent hemostasis was achieved in 88.9% of andexanet alfa-treated patients and 60% of PCC-treated patients (statistical comparison not performed)

Median Glasgow outcome score at hospital discharge was higher with andexanet alfa (4; IQR, 3 to 4) vs PCC (1; IQR, 1 to 3)

Good functional outcome at hospital discharge was observed in 55.6% of andexanet alfa-treated patients and 9.1% of PCC-treated patients

In-hospital mortality was 22.2% for andexanet alfa-treated patients vs 63.6% for PCC-treated patients

Rates of thromboembolic complications within 30 days were higher with andexanet alfa (16.7% vs 9.1%)		Patients receiving andexanet alfa had higher rates of good or excellent hemostasis and higher rates of thrombosis compared to patients receiving PCC. However, differences between groups at baseline (ie, lower CGS and larger pre-reversal hemorrhage volume in the PCC group) make it difficult to draw firm conclusions regarding comparative efficacy. Prospective studies are needed.
Other retrospective studies
Giovino 20206

Retrospective single-center observational case series		N=39 adults treated with andexanet alfa for factor Xa inhibitor-associated intracranial hemorrhage between June 2018 and December 2019

Mean age 81.9 years

Factor Xa inhibitor: apixaban (69.2%), rivaroxaban (28.2%), edoxaban (2.6%)

Median hemorrhage volume at presentation: 7.1 mL		Andexanet alfa (84.6% low-dose)Good or excellent hemostatic efficacy was achieved in 82.9% (n=35; 4 patients were excluded from this analysis due to receipt of surgical intervention prior to repeat bleed imaging)

Inpatient mortality was 10.3%

Mean length of stay was 5.4 days

1 patient had bilateral pulmonary embolism during hospitalization, and 1 patient was readmitted 27 days post-discharge for possible thromboembolic stroke		In a real-world population of patients with intracranial hemorrhage, andexanet alfa was associated with hemostatic efficacy and inpatient mortality similar to what was observed in the ANNEXA-4 trial.
Nederpelt 20207

Retrospective single-center observational case series		N=21 adults treated with andexanet alfa for factor Xa inhibitor-associated extracranial hemorrhage between January 2018 and December 2019

Mean age 73 years

Factor Xa inhibitor: apixaban (n=14), rivaroxaban (n=7)

Bleeding site: intra-abdominal (23.8%), GI (23.8%), intra-thoracic (19%), retroperitoneal (9.5%), prevertebral (9.5%), thigh/groin hematoma (9.5%), cervical epidural (4.8%)		Andexanet alfa (85.7% low-dose)Hemostatic efficacy at 24 hours was excellent in 14.3% and good in 33.3% (total, 47.6%)

In-hospital mortality rate was 38.1%

Median length of stay was 9 days

Surgical intervention was required for 13 patients, with a median time of 64 minutes between andexanet alfa bolus and incision

6 ischemic complications were reported in 4 patients (2 instances of ischemic stroke, and 1 instance each of pulmonary embolism, deep vein thrombosis, bowel ischemia, and liver ischemia)		Andexanet alfa was associated with poor overall outcomes, a low rate of hemostatic effectiveness, and a high rate of ischemic complications and mortality in this retrospective analysis of patients with extracranial bleeds. Many patients in this series underwent surgery after andexanet alfa administration; since surgical patients were excluded from the ANNEXA-4 trial, this may account for some of the observed differences in outcome.
Brown 20208

Retrospective single-center observational case series		N=25 adults treated with andexanet alfa for factor Xa inhibitor reversal between July 2018 and April 2019

Median age 75 years

Factor Xa inhibitor: apixaban (80%), rivaroxaban (20%)

Bleeding site: intracranial (n=13), GI (n=4), other (n=5); 3 non-bleeding patients received andexanet alfa for reversal prior to a surgical procedure		Andexanet alfaAmong patients with intracranial hemorrhage, 11 patients were evaluable for hematoma expansion, and 90.9% of those patients did not demonstrate expansion; 2 patients were not evaluable due to death prior to repeat imaging (n=1) or hematoma evacuation prior to repeat imaging (n=1)

Hemostasis was achieved for all patients (n=3) who received reversal for a surgical procedure

All patients with GI bleeding also received fresh frozen plasma, and 3 required endoscopy within 48 hours of andexanet alfa; hemostasis was not evaluated in this population due to the possibility of confounding

Mortality rates at 7 days and 30 days were 12% and 24%, respectively

No thromboembolic events were reported among the patients who survived		Andexanet alfa was associated with good hemostatic efficacy among patients with intracranial hemorrhage.
Culbreth 20199

Retrospective single-center observational case series		N=15 adults treated with andexanet alfa

Mean age 82 years

Factor Xa inhibitor: apixaban (n=7), rivaroxaban (n=8)

Bleeding site: intracranial (n=15); 1 patient additionally had retroperitoneal bleeding secondary to trauma		Andexanet alfa

7 patients received PCC prior to andexanet alfa		Inpatient mortality was 40%

No thrombotic events were observed		A mortality rate of 40% was observed when andexanet alfa was used for factor Xa inhibitor-associated intracranial hemorrhage in a small series of 15 patients (many of whom would not have met inclusion criteria for the ANNEXA-4 trial).
Abbreviations: CI=confidence interval; GCS=Glasgow Coma Scale; GI=gastrointestinal; ICU=intensive care unit; IQR=interquartile range; IV=intravenous; MC=multicenter; OL=open label; PCC=prothrombin complex concentrate.

Guideline recommendations on place in therapy

Several organizations have published updated guidelines on oral anticoagulant reversal that include recommendations for andexanet alfa use. In a 2019 guidance from the Anticoagulation Forum, the authors suggest the use of andexanet alfa in patients with rivaroxaban- or apixaban-associated major bleeding for whom a reversal agent is warranted (ie, patients with life-threatening bleeding, critical organ bleeding, or major bleeding not responsive to maximal supportive measures).14 If andexanet alfa is not available, the guidance suggests the use of 4-factor PCC for reversal. In patients with edoxaban- or betrixaban-associated bleeding that requires reversal, the guidance recommends off-label treatment with either high-dose andexanet alfa or 4-factor PCC. The guidance also suggests that andexanet alfa may be used to reverse factor Xa inhibitor anticoagulation in patients requiring reversal for urgent procedures.

In 2020, the American College of Cardiology published an expert consensus decision pathway for the management of bleeding in patients on oral anticoagulants.15 In this pathway, reversal/hemostatic agents are suggested for use in patients with major bleeding at a critical site and patients with life-threatening major bleeding. Andexanet alfa is the recommended reversal agent for patients with rivaroxaban- or apixaban-associated bleeding; PCC is listed as an alternative if andexanet alfa is not available. For patients with betrixaban- or edoxaban-associated bleeding, high-dose andexanet alfa is recommended off-label, with PCC as an alternative. Similar recommendations are echoed in a 2019 consensus statement from the American College of Emergency Physicians.16 In this statement, reversal agents are recommended for patients with life-threatening bleeding or critical site bleeding, as well as patients who are not bleeding but need to undergo an urgent/emergent surgical procedure.

Conclusion and ongoing trials

Evidence to support andexanet alfa’s use is primarily derived from noncomparative, single-arm studies in patients with acute major bleeding. Several guidelines recommend andexanet alfa as a first-line reversal agent for patients with factor Xa inhibitor-associated major bleeding and patients who require factor Xa inhibitor reversal prior to an urgent surgical procedure.14-16 However, given the high cost of andexanet alfa, additional data are needed to better determine its clinical value in real-world patient populations, especially when compared to non-specific reversal strategies such as PCC.13,17,18 Retrospective reports have compared andexanet alfa and PCC in acute major bleeding, but these studies are highly prone to selection bias, and prospective trials are needed.12,13 A prospective, randomized study comparing andexanet alfa to usual standard care in patients with intracranial hemorrhage is currently recruiting, with an estimated study completion date of November 2023 (NCT03661528).19 Additional data are also needed to support the use of andexanet alfa as a reversal agent in patients who require urgent surgical procedures. A prospective study is planned to address this question, with an estimated study completion date of July 2022 (NCT04233073).20

References

  1. Coglianese N. What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors? UIC Drug Information Group. Published August 2018. Accessed August 18, 2020. https://dig.pharmacy.uic.edu/faqs/2018-2/august-2018-faqs/
  2. Farina N, Miller JT. Pharmacologic reversal of direct oral anticoagulants. Crit Care Nurs Q. 2018;41(2):121-128. doi:10.1097/cnq.0000000000000193
  3. Andexxa. Package insert. South San Francisco, CA: Portola Pharmaceuticals; 2020.
  4. Connolly SJ, Milling TJ, Jr., Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. doi:10.1056/NEJMoa1607887
  5. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335. doi:10.1056/NEJMoa1814051
  6. Giovino A, Shomo E, Busey KV, Case D, Brockhurst A, Concha M. An 18-month single-center observational study of real-world use of andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage. Clin Neurol Neurosurg. 2020;195:106070. doi:10.1016/j.clineuro.2020.106070
  7. Nederpelt CJ, Naar L, Sylvesterc KW, et al. Evaluation of oral factor Xa inhibitor-associated extracranial bleeding reversal with andexanet alfa. J Thromb Haemost. 2020. doi:10.1111/jth.15031
  8. Brown CS, Scott RA, Sridharan M, Rabinstein AA. Real-world utilization of andexanet alfa. Am J Emerg Med. 2020;38(4):810-814. doi:10.1016/j.ajem.2019.12.008
  9. Culbreth SE, Rimsans J, Sylvester K, Pallin DJ, Connors JM. Andexanet alfa-the first 150 days. Am J Hematol. 2019;94(1):E21-e24. doi:10.1002/ajh.25326
  10. Lu G, Conley PB, Leeds JM, et al. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv. 2020;4(4):728-739. doi:10.1182/bloodadvances.2019000885
  11. A healthy volunteer PK/PD, safety and tolerability study of andexanet after betrixaban dosing. clinicaltrials.gov. Updated August 19, 2020. Accessed August 23, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03330457?term=NCT03330457&draw=2&rank=1
  12. 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. 2020. doi:10.2217/fca-2020-0073
  13. 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
  14. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. Am J Hematol. 2019;94(6):697-709. doi:10.1002/ajh.25475
  15. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(5):594-622. doi:10.1016/j.jacc.2020.04.053
  16. Baugh CW, Levine M, Cornutt D, et al. Anticoagulant reversal strategies in the emergency department setting: recommendations of a multidisciplinary expert panel. Ann Emerg Med. 2019. doi:10.1016/j.annemergmed.2019.09.001
  17. Yin E, McConnell KJ. Request for an Andexxa value analysis. Ann Pharmacother. 2020;54(7):715-717. doi:10.1177/1060028020902280
  18. Owusu KA, Effendi MK, DeFilippo NA, Reardon DP, Ian Lee A. Andexanet alfa: considerations and practical applications. Crit Pathw Cardiol. 2019;18(4):200-206. doi:10.1097/hpc.0000000000000190
  19. Trial of andexanet in ICH patients receiving an oral FXa inhibitor. clinicaltrials.gov. Updated July 28, 2020. Accessed August 23, 2020. https://clinicaltrials.gov/ct2/show/NCT03661528?term=andexanet&draw=4&rank=8
  20. Trial of andexanet in patients receiving an oral FXa inhibitor who require urgent surgery (Annexa-S). clinicaltrials.gov. Updated March 25, 2020. Accessed August 23, 2020. https://clinicaltrials.gov/ct2/show/NCT04233073?term=andexanet&draw=4&rank=6

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2020

The information presented is current as of August 6, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.