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A Study in Participants With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study)

Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02329327
Enrollment
479
Registered
2014-12-31
Start date
2015-04-10
Completion date
2020-09-24
Last updated
2022-02-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bleeding

Keywords

Factor Xa Inhibitors, Major, Bleeding, Anticoagulant, Major Bleeding, Andexanet Alfa, Reversal Agent

Brief summary

The purpose of this study was to evaluate the hemostatic efficacy of andexanet alfa (andexanet) in participants receiving a factor Xa (FXa) inhibitor (apixaban, rivaroxaban, edoxaban, enoxaparin) who were experiencing an acute major bleed. The safety of andexanet was also studied.

Interventions

BIOLOGICALAndexanet

There were 2 possible dosing regimens: Low dose = 400 milligram (mg) bolus plus 4 mg/minute continuous infusion for 120 minutes; High dose = 800 mg bolus plus 8 mg/minute continuous infusion for 120 minutes.

Sponsors

Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)
CollaboratorINDUSTRY
Population Health Research Institute
CollaboratorOTHER
Alexion Pharmaceuticals, Inc.
Lead SponsorINDUSTRY

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

Key Inclusion Criteria: 1. Acute major bleeding episode that required urgent reversal of anticoagulation; defined by at least one of the following: * Acute bleeding that was potentially life-threatening, or * Acute bleeding associated with a fall in hemoglobin level by ≥2 grams/deciliter (g/dL), or * Acute bleeding associated with a hemoglobin level of ≤8 g/dL if no baseline hemoglobin was available, or * Acute bleeding in a critical area or organ such as intraspinal, pericardial, or intracranial. 2. If bleeding was intracranial or intraspinal, the participant must have undergone a head computed tomography (CT) or magnetic resonance imaging (MRI) scan demonstrating the bleeding. 3. Participant received or was believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban, or enoxaparin. 4. For participants with intracranial bleeding, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation. Key

Exclusion criteria

1. The participant was scheduled to undergo surgery in less than 12 hours, with the exception of minimally invasive surgery/procedures. 2. Participant with an intracerebral hemorrhage that had any of the following: * Glasgow coma score \<7, or * Intracerebral hematoma \>60 cubic centimeters as assessed by CT or MRI 3. Participants with visible, musculoskeletal or intra-articular bleeding as their qualifying bleed. 4. Expected survival of less than 1 month. 5. Recent history (within 2 weeks) of a diagnosed thrombotic event as follows: venous thromboembolism, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization or severe peripheral vascular disease within 2 weeks prior to Screening. 6. Severe sepsis or septic shock at the time of Screening. 7. Pregnant or a lactating female. 8. Participant received any of the following drugs or blood products within 7 days of Screening: * Vitamin K antagonist * Dabigatran * Prothrombin Complex Concentrate (PCC) products or recombinant factor VIIa (rfVIIa) * Whole blood, plasma fractions 9. Treated with an investigational drug \<30 days prior to Screening. 10. Planned administration of PCC, fresh frozen plasma or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion.

Design outcomes

Primary

MeasureTime frameDescription
Percent Change From Baseline In Anti-fXa Activity By FXa InhibitorBaseline, 12 Hours (post infusion)Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. The change from baseline was calculated as the reduction in anti-fXa activity from baseline to the on-treatment nadir (that is, the minimum value between end of bolus and end of infusion). Percent reduction was calculated as the ratio between the maximum change from baseline and the baseline value, multiplied by 100.
Participants Achieving Hemostatic Efficacy12 Hours (post infusion)Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons. These ratings were based on pre-specified criteria that were included in the EAC Charter. The EAC was blinded to anti-fXa activity levels. Participant results were classified as either success or failure based on the hemostatic efficacy rating (success = excellent/good, failure = poor/none). Participants rated by the EAC as non-evaluable due to administrative reasons were excluded from the analysis of hemostatic efficacy.

Secondary

MeasureTime frameDescription
Percent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyBaseline, 12 Hours (post infusion)This outcome measure assessed the relationship between hemostatic efficacy and anti-fXa activity in participants receiving an FXa inhibitor who had acute major bleeding. Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons.

Countries

Belgium, Canada, France, Germany, Japan, Netherlands, Spain, United Kingdom, United States

Participant flow

Participants by arm

ArmCount
Andexanet
Participants received andexanet as an intravenous (IV) bolus administered over \ 15 to 30 minutes, followed immediately by a continuous infusion administered over \ 120 minutes.
477
Andexanet - Additional Participants
Two additional participants received andexanet as an IV bolus administered over \ 15 to 30 minutes, followed immediately by a continuous infusion administered over \ 120 minutes. Data from these 2 participants were obtained and evaluated after the data cutoff date of 30-June-2020 and, as such, are presented separately.
2
Total479

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyDeath780
Overall StudyLost to Follow-up40
Overall StudyWithdrawal by Subject30

Baseline characteristics

CharacteristicAndexanetTotalAndexanet - Additional Participants
Age, Continuous77.9 years
STANDARD_DEVIATION 10.66
77.9 years
STANDARD_DEVIATION 10.66
71.0 years
STANDARD_DEVIATION 11.31
Bleed Type
Gastrointestinal
109 Participants109 Participants0 Participants
Bleed Type
Intracranial Hemorrhage
329 Participants331 Participants2 Participants
Bleed Type
Other
39 Participants39 Participants0 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
16 Participants16 Participants0 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
449 Participants451 Participants2 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
12 Participants12 Participants0 Participants
FXa Inhibitor
Apixaban
245 Participants245 Participants0 Participants
FXa Inhibitor
Edoxaban
36 Participants36 Participants0 Participants
FXa Inhibitor
Enoxaparin
22 Participants22 Participants0 Participants
FXa Inhibitor
Rivaroxaban
174 Participants176 Participants2 Participants
Race/Ethnicity, Customized
Race : Black or African American
29 participants29 participants0 participants
Race/Ethnicity, Customized
Race : Missing
9 participants9 participants0 participants
Race/Ethnicity, Customized
Race : Other
25 participants27 participants2 participants
Race/Ethnicity, Customized
Race : White
414 participants414 participants0 participants
Region of Enrollment
Europe
248 participants248 participants0 participants
Region of Enrollment
Japan
17 participants19 participants2 participants
Region of Enrollment
North America
212 participants212 participants0 participants
Sex: Female, Male
Female
218 Participants219 Participants1 Participants
Sex: Female, Male
Male
259 Participants260 Participants1 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
66 / 38215 / 97
other
Total, other adverse events
40 / 3828 / 97
serious
Total, serious adverse events
157 / 38243 / 97

Outcome results

Primary

Participants Achieving Hemostatic Efficacy

Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons. These ratings were based on pre-specified criteria that were included in the EAC Charter. The EAC was blinded to anti-fXa activity levels. Participant results were classified as either success or failure based on the hemostatic efficacy rating (success = excellent/good, failure = poor/none). Participants rated by the EAC as non-evaluable due to administrative reasons were excluded from the analysis of hemostatic efficacy.

Time frame: 12 Hours (post infusion)

Population: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
FXa Inhibitor: ApixabanParticipants Achieving Hemostatic EfficacyExcellent/Good134 Participants
FXa Inhibitor: ApixabanParticipants Achieving Hemostatic EfficacyPoor/None35 Participants
FXa Inhibitor: RivaroxabanParticipants Achieving Hemostatic EfficacyExcellent/Good102 Participants
FXa Inhibitor: RivaroxabanParticipants Achieving Hemostatic EfficacyPoor/None25 Participants
FXa Inhibitor: EdoxabanParticipants Achieving Hemostatic EfficacyExcellent/Good22 Participants
FXa Inhibitor: EdoxabanParticipants Achieving Hemostatic EfficacyPoor/None6 Participants
FXa Inhibitor: EnoxaparinParticipants Achieving Hemostatic EfficacyExcellent/Good14 Participants
FXa Inhibitor: EnoxaparinParticipants Achieving Hemostatic EfficacyPoor/None2 Participants
FXa Inhibitor: Rivaroxaban - Additional ParticipantsParticipants Achieving Hemostatic EfficacyPoor/None13 Participants
FXa Inhibitor: Rivaroxaban - Additional ParticipantsParticipants Achieving Hemostatic EfficacyExcellent/Good61 Participants
Bleed Type: Intracranial HemorrhageParticipants Achieving Hemostatic EfficacyPoor/None51 Participants
Bleed Type: Intracranial HemorrhageParticipants Achieving Hemostatic EfficacyExcellent/Good193 Participants
Bleed Type: OtherParticipants Achieving Hemostatic EfficacyExcellent/Good18 Participants
Bleed Type: OtherParticipants Achieving Hemostatic EfficacyPoor/None4 Participants
Andexanet: Low DoseParticipants Achieving Hemostatic EfficacyExcellent/Good218 Participants
Andexanet: Low DoseParticipants Achieving Hemostatic EfficacyPoor/None51 Participants
Andexanet: High DoseParticipants Achieving Hemostatic EfficacyPoor/None17 Participants
Andexanet: High DoseParticipants Achieving Hemostatic EfficacyExcellent/Good54 Participants
OverallParticipants Achieving Hemostatic EfficacyPoor/None68 Participants
OverallParticipants Achieving Hemostatic EfficacyExcellent/Good272 Participants
FXa Inhibitor: Rivaroxaban - Additional ParticipantsParticipants Achieving Hemostatic EfficacyPoor/None0 Participants
FXa Inhibitor: Rivaroxaban - Additional ParticipantsParticipants Achieving Hemostatic EfficacyExcellent/Good2 Participants
Bleed Type: Intracranial Hemorrhage - Additional ParticipantsParticipants Achieving Hemostatic EfficacyPoor/None0 Participants
Bleed Type: Intracranial Hemorrhage - Additional ParticipantsParticipants Achieving Hemostatic EfficacyExcellent/Good2 Participants
Andexanet: Low Dose - Additional ParticipantParticipants Achieving Hemostatic EfficacyExcellent/Good1 Participants
Andexanet: Low Dose - Additional ParticipantParticipants Achieving Hemostatic EfficacyPoor/None0 Participants
Andexanet: High Dose - Additional ParticipantParticipants Achieving Hemostatic EfficacyPoor/None0 Participants
Andexanet: High Dose - Additional ParticipantParticipants Achieving Hemostatic EfficacyExcellent/Good1 Participants
Primary

Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor

Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. The change from baseline was calculated as the reduction in anti-fXa activity from baseline to the on-treatment nadir (that is, the minimum value between end of bolus and end of infusion). Percent reduction was calculated as the ratio between the maximum change from baseline and the baseline value, multiplied by 100.

Time frame: Baseline, 12 Hours (post infusion)

Population: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 nanograms/milliliter (ng/mL) for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 international units (IU)/mL for enoxaparin.

ArmMeasureValue (MEDIAN)
FXa Inhibitor: ApixabanPercent Change From Baseline In Anti-fXa Activity By FXa Inhibitor-93.3 Percent Change
FXa Inhibitor: RivaroxabanPercent Change From Baseline In Anti-fXa Activity By FXa Inhibitor-94.1 Percent Change
FXa Inhibitor: EdoxabanPercent Change From Baseline In Anti-fXa Activity By FXa Inhibitor-71.3 Percent Change
FXa Inhibitor: EnoxaparinPercent Change From Baseline In Anti-fXa Activity By FXa Inhibitor-75.41 Percent Change
FXa Inhibitor: Rivaroxaban - Additional ParticipantsPercent Change From Baseline In Anti-fXa Activity By FXa Inhibitor-96.3 Percent Change
Secondary

Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy

This outcome measure assessed the relationship between hemostatic efficacy and anti-fXa activity in participants receiving an FXa inhibitor who had acute major bleeding. Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons.

Time frame: Baseline, 12 Hours (post infusion)

Population: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin.

ArmMeasureGroupValue (MEDIAN)
FXa Inhibitor: ApixabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyExcellent/Good-93.4 Percent Change
FXa Inhibitor: ApixabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyPoor/None-93.3 Percent Change
FXa Inhibitor: RivaroxabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyPoor/None-92.4 Percent Change
FXa Inhibitor: RivaroxabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyExcellent/Good-94.6 Percent Change
FXa Inhibitor: EdoxabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyPoor/None-65.2 Percent Change
FXa Inhibitor: EdoxabanPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyExcellent/Good-75.8 Percent Change
FXa Inhibitor: EnoxaparinPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyPoor/None-78.44 Percent Change
FXa Inhibitor: EnoxaparinPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyExcellent/Good-75.20 Percent Change
FXa Inhibitor: Rivaroxaban - Additional ParticipantsPercent Change From Baseline In Anti-fXa Activity By Hemostatic EfficacyExcellent/Good-96.3 Percent Change

Source: ClinicalTrials.gov · Data processed: Mar 1, 2026