ANNEXA-4

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Connolly SJ, et al. "Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors". The New England Journal of Medicine. 2016. 375(12):1131-1141.
PubMedFull text

Clinical Question

In adults with potentially life-threatening acute major bleeding, what is the efficacy and safety of andexanet for reversing the anticoagulant effects of the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, or enoxaparin?

Bottom Line

In this interim analysis, andexanet demonstrated that it will decrease anti factor-Xa activity and achieve hemostasis in 79% of patients.

Major Points

Andexanet alfa is a recombinant, modified human factor Xa decoy protein created to reverse the effects of factor Xa inhibitors such as low molecular weight heparins (e.g. enoxaparin) or direct oral anticoagulants (DOAC) (e.g. apixaban, edoxaban, rivaroxaban). Its action is to bind the anticoagulant to allow factor Xa activity, not to increase breakdown or clearance. [1] There are several indications for anticoagulation including atrial fibrillation or systematic thromboembolism. Prior to the advent of the DOAC (factor Xa or IIa inhibitors) the mainstay of treatment was vitamin-K antagonists. If reversal of anticoagulation was necessary this could be rapidly achieved with replacement of the vitamin-K dependant clotting factors and a supplemental dose of vitamin-K. [2] However, prior to the development of idarucizumab [3] and andexanet there was no reversal agent available and blood products were the only available treatment.

This paper is the interim analysis of an ongoing open-label observational trial including n=67 for a safety analysis and n=47 for an efficacy analysis. Excellent or good hemostasis[2] in 79% of patients was achieved, breaking down further there was 84% and 80% when broken own into the gastrointestinal bleed and intracranial bleeds, respectively. Pharmacokinetically, the anti-factor Xa activity was decreased in most patients observed. In the Sub-set of patients that the anti-factor Xa did not decrease, hemostatic control was still achieved. Adversely there was a 15% mortality rate and thromboembolic events in 18%, a third of which occurred within 3 days of the andexanet exposure.

This open-label, ongoing, observational trial is the first to outline the real-world experience with andexanet. The final report with the planned population of n=162 will need to be reviewed but enrollment has been ongoing for three years.

Guidelines

As of September 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, prospective, open label, single-group trial
  • N=114 (planned sample of N=162)
    • Efficacy population: N=47
    • Safety population: N=67
  • Setting: 20 centers in the United States, 1 in the UK, and 1 in Canada
  • Follow-up: 30 days
  • Enrollment: 10 April 2015 and Ongoing
  • Analysis: Preliminary Analysis
  • Primary Outcome: Rate of excellent or good hemostatic efficacy within 12 hours after infusion

Population

Inclusion Criteria

  • ≥ 18 years of age
  • received one of four factor Xa inhibitors: apixaban, rivaroxaban, edoxaban, or enoxaparin within the past 18 hours
  • experienced acute major bleeding: potentially life-threatening acute overt bleeding with signs or symptoms of hemodynamic compromise
  • acute overt bleeding with:
    • a decrease in hemoglobin ≥ 20 g/mL deciliter, or
    • a hemoglobin level ≤ 80 g/mL if no baseline hemoglobin level was available
    • investigator’s opinion that the hemoglobin would fall to ≤ 80 g/mL
  • acute symptomatic bleeding in a critical area/organ
  • Efficacy analysis only: anti–factor Xa activity ≥ 75 ng/mL

Exclusion Criteria

  • surgery within <12 hours after presentation (except minimally invasive surgery or procedure)
  • intracranial hemorrhage with GCS <7
  • estimated intracerebral hematoma volume > 60 ml
  • expected survival < 1 month
  • major thrombotic event within 2 weeks before enrollment
  • one of the following within 7 days before screening: vitamin K antagonist, dabigatran, prothrombin complex concentrate, or whole blood or plasma.

Baseline Characteristics

‘’Safety Population displayed

  • Demographics: mean age 77 years, 48% female, 81% Caucasian
  • Time to administration: presentation to drug 4.8h, time from consent to drug 1.7h
  • Anthropomorphics: mean BMI 28.1
  • Estimated Creatinine clearance mL/min: <30 9%, 30-60 46%, ≥60 39%
  • Anticoagulation indication: Atrial Fibrillation 70%, Venous thromboembolism 22%, both 7%
  • Medical History: MI 19%, Stroke 25%, Deep-vein thrombosis 30%, Pulmonary embolism 9%, Atrial fibrillation 73%, Heart failure 34%, Diabetes mellitus 34%
  • Agent being reversed: apixaban 46%, edoxaban 0%, enoxaparin 6%, rivaroxaban 48%
  • Site of bleed: Gastrointestinal 49%, Intracerebral 21%, Subdural 16%, Subarachnoid 4%, other 9%

Interventions

  • Treatment was administered as an initial bolus over 15-30 min followed by a 2-hour infusion
  • Doses based on agent being reversed
    • apixaban or rivaroxaban > 7 hours before andexanet: bolus 400 mg and infusion 480 mg
    • enoxaparin, edoxaban, or rivaroxaban ≤ 7 hours before administration or at an unknown time: bolus 800 mg and infusion 960 mg

Outcomes

Primary Outcomes

Efficacy population n=47

Excellent or good hemostasis 12 hours after the andexanet infusion
79% (95% CI 64-89)

Secondary Outcomes

Median anti-factor Xa level
Apixaban (n=20)
Baseline - 149.7 ng/mL
Post-Bolus - 10.3 ng/mL
End of infusion - 12.5 ng/mL
4-hours post infusion - 103.0 ng/mL
Enoxaparin (n=1)
Baseline - 0.61 IU/mL
Post-Bolus - 0.15 IU/mL
End of infusion - 0.19 IU/mL
4-hours post infusion - 0.46 IU/mL
Rivaroxaban (n=26)
Baseline - 277.0 ng/mL
Post-Bolus - 16.8 ng/mL
End of infusion - 30.6 ng/mL
4-hours post infusion - 177.7 ng/mL
modified Rankin scale in patients with intracranial bleed (n=28)
Baseline 2.2±1.9 to 2.0±2.0 at 30 days

Subgroup Analysis

Excellent or good hemostasis for gastrointestinal bleed (n=47)
84%
Excellent or good hemostasis for intracranial bleed (n=47)
80%

Adverse Events

Safety population n=67

Thrombotic events
18% (1 MI, 5 stroke, 7 DVT, 1 PE)
Within 3 days of andexanet: 30% patients
Between 4-30 days of andexant: 70% patients
Mortality
15%

Criticisms

  • This is an interim analysis
  • no patient in the population had been exposed to edoxaban
  • single-group cohort so no comparison can be made
  • Severe bleeding was excluded from analysis

Funding

  • Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer

Further Reading

  1. Lu G et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat. Med. 2013. 19:446-51.
  2. 2.0 2.1 Sarode R et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013. 128:1234-43.
  3. Pollack CV et al. Idarucizumab for Dabigatran Reversal. N. Engl. J. Med. 2015. 373:511-20.