Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors | Clinical Trial - ANNEXA-A
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.
Andexanet alfa would be safe and efficacious compared with placebo in reversing the anticoagulant effect of apixaban.
- Subjects on apixaban
Number of enrollees: 33
Duration of follow-up: 12 hours
Mean patient age: 59 years
Percentage female: 40%
- 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)
- 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)
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)
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.
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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