Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors | Clinical Trial - ANNEXA-A

Description:

One of the biggest drawbacks with novel oral anticoagulants (NOACs) such as rivaroxaban and apixaban is the availability of a reliable antidote in emergent situations, such as significant bleeding. The current trial sought to compare the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of apixaban.

Hypothesis:

Andexanet alfa would be safe and efficacious compared with placebo in reversing the anticoagulant effect of apixaban.

Study Design

Patient Populations

  • Subjects on apixaban

    Number of enrollees: 33
    Duration of follow-up: 12 hours
    Mean patient age: 59 years
    Percentage female: 40%

Exclusions

Primary Endpoints

  • Percent change in anti-fXa activity from baseline (measurement at peak concentration, before start of bolus) to nadir (smaller value of 2 or 5 minutes post end of bolus)

Secondary Endpoints

  • Occurrence of 80% or greater reduction in anti-fXa activity from baseline to nadir
  • Change in free apixaban concentration from baseline to nadir
  • Change in thrombin generation from baseline to peak (largest value of 2, 5, or 10 minutes post end of bolus)

Drugs/Procedures Used

Patients on apixaban were randomized in two parts:

- Part 1: Andexanet alfa bolus 400 mg IV bolus vs. placebo (current trial) 
- Part 2: Andexanet alfa bolus 400 mg IV bolus + infusion 4 mg/min vs. placebo (future trial) 

Principal Findings:

Part 1: A total of 33 patients were randomized, 24 to andexanet alfa and 9 to placebo. The median age was 59 years.

The primary endpoint of change in anti-factor Xa (fXa) levels from nadir to baseline was significantly greater in the adexanet arm (94% vs. 25%, p < 0.0001). Peak effect was observed a couple of minutes after completion of the bolus. In the absence of a maintenance infusion, anti-fXa levels gradually increased by 25% by 1 hour and were similar to placebo by 2 hours. Number of subjects with >80% reversal was greater in the andexanet arm (100% vs. 0%, p < 0.0001). Concordantly, free apixaban levels decreased rapidly following bolus administration, and were significantly lower in the andexanet arm. Thrombin generation appeared to increase following infusion, with a return to baseline in all patients in the andexanet arm.

There were no serious or severe adverse events reported, including thrombotic events. No antibodies to factor X or fXa were detected.

Interpretation:

The results of this small trial indicate that bolus administration of 400 mg andexanet alfa, a novel antidote for the NOACs, results in rapid normalization of fXa and thrombin levels in patients on apixaban. In the absence of a maintenance infusion, the effect appears to last for 1-2 hours. Other trials with rivaroxaban are ongoing.

Andexanet alfa is a recombinant engineered version of human fXa. It acts as a fXa decoy, and retains high affinity for all fXa inhibitors (such as NOACs and low molecular weight heparin). One of the biggest concerns about NOAC use is the lack of a reliable antidote (such as protamine for unfractionated heparin), especially in emergent situations such as major or life-threatening bleeding. This agent may help mitigate this concern, although further details regarding safety, efficacy, and logistic issues (such as cost and ease of storage) are awaited.

Keywords: AHA Annual Scientific Sessions


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