by Antje Schmidt-Pogoda, Fachärztin für Neurologie, Klinik für Neurologie mit Institut für Translationale Neurologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster

In recent weeks, a phased launch of andexanet alfa (Ondexxyaâ) was started in Germany, Austria, the United Kingdom, the Netherlands, Sweden, Denmark and Finland.

For stroke physicians, the market release of Andexanet alfa is most interesting, because the factor Xa reversal agent is the first specific approach for the treatment of patients with intracranial haemorrhage associated with rivaroxaban or apixaban.

Andexanet alfa acts as a decoy for factor Xa inhibitors, which means that it binds to factor Xa inhibitors and prevents them from inhibiting the activity of factor Xa.

Prior to its approval in Europe, the use of andexanet alfa was evaluated in the ANNEXA-4 trial. In ANNEXA-4, 352 patients with major bleeding within 18 hours after the last administration of a Factor XA inhibitor received a bolus of andexanet alfa, followed by a 2-hour infusion.

Among patients who had received apixaban or rivaroxaban, the median anti-factor Xa activity decreased by 92%, and 82% of patients had excellent or good hemostatic efficacy at 12 hours.

The most important limitation of the ANNEXA-4 trial is that it did not include a control group. However, it was determined that a randomized control group would raise ethical concerns, with respect to the risks of placebo administration in a potentially life-threatening condition.

Another limitation is that the percentage of patients who had received edoxaban (3%) or enoxaparin (6%) was too small to draw meaningful conclusions on the reversal of these agents.1

How shall we apply andexanet alfa?

Based on the last dose of apixaban/rivaroxaban and the time since the last drug intake, the manufacturer’s instructions propose either a high dose regimen or a low dose regimen (table 1).

Table 1 Assignment of patients to either high dose or low dose regimen

Factor Xa inhibitor Last dose Timing of last dose
< 8 h or unknown ³ 8 h
Apixaban £ 5 mg Low dose Low dose
> 5 mg or unknown High dose
Rivaroxaban £ 10 mg Low dose Low dose
> 10 mg or unknown High dose

 

The high dose regimen involves an intravenous bolus at a target rate of approximately 30 mg/min over 30 minutes, followed by administration of a continuous infusion of 8 mg/min for 120 minutes. The low dose regimen consists of an intravenous bolus at a target rate of approximately 30 mg/min over 15 minutes, followed by administration of a continuous infusion of 4 mg/min for 120 minutes (table 2).

Table 2 Dosing regimens

  Initial bolus Continuous infusion
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg)
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg)

 

In ANNEXA-4, the percentage of patients who had received edoxaban (3%) or enoxaparin (6%) was too small to draw meaningful conclusions on the reversal of these agents. However, off-label use may still be considered in those patients.

In contrast to the Dabigatran reversal agent Idarucizumab (Praxbindâ), we have not yet any experiences with the use of andexanet alfa for the reversal of factor Xa inhibitors before intravenous thrombolysis. In this context, the long duration of the continuous infusion represents a limitation of andexanet alfa. However, individual patients with severe strokes, e.g. due to basilar artery occlusion, may still benefit from delayed thrombolysis after factor Xa reversal, if the occlusion site is not accessible or reperfusion cannot be achieved by thrombectomy We are looking forward to seeing more evidence in the area.

 

 Reference

  1. Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-35.