ANNEXA

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Siegal DM, et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity". The New England Journal of Medicine. 2015. 373(25):2413-2424.
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Clinical Question

In healthy older adults, what is the efficacy and safety of andexanet for reversing the anticoagulant effects of the factor Xa inhibitors apixaban or rivaroxaban?

Bottom Line

Andexanet effectively reverses the anticoagulant effects of factor Xa inhibitors apixaban and rivaroxaban within minutes of administration.

Major Points

Apixaban, rivaroxaban, and edoxaban are factor Xa inhibitors approved in the US for the management of nonvalvular atrial fibrillation and venous thromboembolism. Like the low-molecular-weight heparins enoxaparin, dalteparin, and tinzaparin—but in contrast to dabigatran, heparin, and warfarin—factor Xa inhibitors lack an FDA approved reversal agent.

Andexanet is a recombinant modified factor Xa protein that lacks the enzymatic activity of factor Xa. As such, it acts as a decoy protein binding and inactivating factor Xa inhibitors with high affinity; in so doing, it reverses their anticoagulant effects. Phase 2 trials in healthy volunteers showed that andexanet reversed the anticoagulant effects of apixaban, rivaroxaban, edoxaban, and enoxaparin in a dose-dependent and rapid manner.[1]

Published in 2015, this paper reported on two trials of andexanet. ANNEXA-A studied the use of andexanet in healthy older adults taking apixaban, while ANNEXA-R studied the drug in a similar patient population receiving rivaroxaban. A total of 145 adults between the age of 50-75 were enrolled and randomized to andexanet or placebo. Patients were anticoagulated with apixaban for 3.5 days or rivaroxaban for 4 days. On day 4, patients received either andexanet or placebo. The drug was administered as an IV bolus in part 1, and as an IV bolus plus infusion in part 2. The primary outcome was percent change in anti-Xa level from baseline to the post-andexanet nadir. Among patients treated with apixaban in part 1, there was a greater reduction in anti-Xa activity with andexanet compared to placebo (94% vs. 21%); the same was true among patients treated with rivaroxaban (92% vs. 18%). In part 2, patients receiving apixaban achieved a greater decrement in anti-Xa activity with andexanet compared to placebo (92% vs. 33%); similar results were seen in patients receiving rivaroxaban (97% vs. 45%).

Andexanet currently lacks regulatory approval, and remains investigational. As part of the regulatory approval process, the manufacturer has requested a label that includes the reversal of apixaban, rivaroxaban, edoxaban, and enoxaparin. Although ANNEXA-A and ANNEXA-R study the reversal of apixaban and rivaroxaban by andexanet, they exclude edoxaban and enoxaparin. Consequently in August 2016, the FDA requested additional efficacy and safety data for the two additional drugs.[2] This additional data will be available in the ANNEXA-4 trial[3] which evaluates andexanet in the management of bleeding among patients receiving apixaban, rivaroxaban, edoxaban, and enoxaparin.

Guidelines

As of March 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Randomized, double-blind, placebo-controlled studies
  • N=145
    • Andexanet: n=101 (48 in the apixaban study; 53 in the rivaroxaban study)
    • Placebo: n=44
  • Setting: 2 clinical sites in Arizona (ANNEXA-A) and California (ANNEXA-R)
  • Enrollment: March 2014-May 2015
  • Analysis: Intention-to-treat
  • Primary outcome: Change in anti-Xa activity

Population

Inclusion Criteria

  • Age 50-75 years
  • In "reasonably good health"
  • BP <160/92 mmHg
  • PT, PTT, ACT, Hgb, HCT, and platelet count in normal range
  • AST, ALT, and bilirubin ≤2x ULN
  • Creatinine <1.5 mg/dL
  • BMI 19-32 kg/m2 and weight ≥60 kg
  • Abstinence from alcohol

Exclusion Criteria

  • History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for bleeding
  • Positive FOBT in prior 6 months
  • History of thrombosis, signs or symptoms of thrombosis, or recent events thought to increase risk of thrombosis
  • Contraindication to anticoagulation
  • Use of antiplatelets, fibrinolytics, or anticoagulants in prior 7 days
  • Use of HRT, hormonal contraception, or testosterone in prior 4 weeks
  • Family history of hypercoaguability, including hetero- or homozygous for factor V Leiden or protein C, S, or AT activity below normal range
  • COPD or regular use of inhalers
  • Inhibitors/inducers of CYP3A4 and P-gp in prior 7 days
  • Positive screen for drugs of abuse
  • Condition impairing study drug metabolism or allergic to the study drugs
  • Potential for pregnancy or breastfeeding

Baseline Characteristics

From the andexanet group in the ANNEXA-A bolus only arm.

  • Demographics: Age 60 years, female sex 46%, 100% white race, 42% Hispanic or Latino
  • BMI: 26.7
  • Creatinine: 0.8 mg/dL

Interventions

ANNEXA-A
  • All participants received apixaban 5 mg orally twice daily for 3.5 days to achieve steady-state plasma levels
  • Randomized 3:1 to andexanet or placebo
  • On day 4, at 3 hours after the last dose of apixaban, andexanet was administered as a 400-mg IV bolus (30 mg/min) for part 1 of the study. For part 2, the 400-mg IV bolus was followed by a continuous infusion of 4 mg/min for 2 hours (480 mg in total).
ANNEXA-R
  • All participants received rivaroxaban 20 mg orally once daily for 4 days
  • Randomized 2:1 to andexanet or placebo
  • On day 4, at 4 hours after the last dose of rivaroxaban, andexanet was administered as a 800-mg IV bolus (30 mg/minute) for part 1 of the study. For part 2, the 800-mg IV bolus was followed by a continuous infusion of 8 mg/minute for 2 hours (960 mg in total)
  • The dose for andexanet is higher that in ANNEXA-A because of the higher initial maximum plasma concentration and larger volume of distribution of rivaroxaban.

Outcomes

Comparisons are andenaxet vs. placebo

Primary Outcomes

ΔAnti-Xa activity
ANNEXA-A, Part 1: 94 vs. 21% (P<0.001)
ANNEXA-A, Part 2: 92 vs. 33% (P<0.001)
ANNEXA-R, Part 1: 92 vs. 18% (P<0.001)
ANNEXA-R, Part 2: 97 vs. 45% (P<0.001)

Secondary Outcomes

≥80% reversal of anti-Xa activity
100 vs. 0% (P<0.001)

Adverse Events

  • There were no severe adverse events, and no thrombotic events
  • Antibodies to factor X or factor Xa were not detected in any participants
  • Nonneutralizing antibodies against andexanet were detected in 2% of patients who received placebo and in 17% who received andexanet. Neutralizing antibodies were not detected.

Criticisms

  • Different doses of andexanet are required depending on the factor Xa inhibitor used. This may be challenging in clinical setting and could cause under- or over-dosing if obtained information is incorrect.[4]
  • Patients who require urgent reversal of factor Xa inhibition activity due to bleeding or for emergency surgery were excluded. Thus it is not clear if andexanet would improve outcomes in patients with major bleeding.[4] This question is being addressed in the ANNEXA-4 study.

Funding

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

Further Reading

  1. Crowther M, et al. "A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal of Edoxaban-Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors". Blood. 2014;124:4269.
  2. Larry Husten. "FDA Delays Approval Of First Agent To Reverse Effect Of New Anticoagulants." Cardio Brief. August 17, 2016.
  3. Connolly SJ, et al. "Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors." N Engl J Med. 2016;375:1131-1141.
  4. 4.0 4.1 Connors JM. "Antidote for Factor Xa Anticoagulants". N Engl J Med. 2015;373:2471-2472.