Shock Syndromes II

viii.

Andexanet alfa dosing is complex (Table 7) and individualized according to the underlying

anticoagulant and time from last dose. For example, rivaroxaban achieves higher serum

concentrations, so andexanet doses are higher for rivaroxaban with recent administration than

for apixaban.

ix.

Although andexanet alfa may work for all direct and indirect anti-Xa inhibitors, it is only FDA

approved for apixaban and rivaroxaban reversal in life-threatening or uncontrolled bleeding.

evidence.

The antidotes for DOAC reversal were FDA reviewed under the Fast Track designation.

The FDA called for the inclusion of an andexanet alfa arm compared with a usual care arm for

anti-Xa reversal in patients experiencing intracranial hemorrhage. The ANNEXA-I study was

designed to compare the effectiveness of andexanet alfa with usual care in treating intracranial

hemorrhage. This trial was necessary because prior studies, such as ANNEXA-4, did not

randomize patients to a placebo group, and efficacy and safety data were based on single-

arm trials. The results of the trial indicate that ANNEXA-I met its prespecified criteria for

hemostatic efficacy when compared with standard care. These promising results prompted

the early termination of the study after a planned interim analysis. The data suggested an

NNT of 8, showing significant efficacy. However, this benefit was counterbalanced by a higher

incidence of adverse events, including thrombotic complications such as ischemic stroke and

myocardial infarction, with an NNH of 21. The increased risk of thrombotic events highlights

the need for careful consideration of the treatment’s safety profile.

ii.

Therefore, it remains unknown whether the novel antidotes will affect morbidity or mortality

associated with anticoagulants in life-threatening hemorrhage.

PCCs for DOAC reversal

PCCs and aPCCs have traditionally been used off-label as a nonspecific reversal agent for

DOAC reversal before the development of novel antidotes.

ii.

Supporting data are primarily based on laboratory reversal of factor Xa inhibitors from in

vitro animal models, ex vivo human samples, and healthy volunteer subjects. These trials have

important limitations and inconsistent results.

iii.

More recently, PCC was an effective reversal for anti-Xa inhibitors in bleeding patients, as

evaluated by hemostatic response at defined time intervals, but these trials are limited by

single-arm observational study design and lack of analysis of laboratory reversal.

iv.

PCC has not consistently been shown to reverse laboratory values associated with dabigatran.

Several guidelines recommended 4F-PCC or aPCC administration at 25–50 units/kg for anti-

Xa reversal before the availability of andexanet alfa. Guidelines may continue to evolve as

more robust data comparing andexanet alfa with usual care become available. Clinicians

should carefully consider the non-sustained duration of reversal of andexanet alfa and the lack

of data in emergency surgical procedures.

vi.

Use of PCCs and aPCCs carries a risk of thromboembolic events, particularly at higher doses,

necessitating a careful risk-benefit assessment.

vii.

Further studies comparing andexanet alfa with PCC-based regimens in real-world clinical

scenarios