Full Study Report Of Andexanet Alfa For Bleeding Associated With Factor Xa Inhibitors
Connolly S.J. et al, N Engl J Med. 2019 Apr 4;380(14):1326-1335
Andexanet alfa is a modified recombinant inactive form of human factor Xa and is the second antidote for a direct oral anticoagulant to become available in the US, (Praxbind in 2015).
Here we have the full results of ANNEXA-4, a prospective, open-label, single-group study conducted at 63 centers in North America and Europe including adults (age >18) with acute major bleeding that had received at least one dose of a FXa inhibitor within the previous 18 hours.
Enrolled 352 patients from April 2015 -May 2018, including the 67 patients reported previously with a mean age of 77 years; 55% of which were on apixaban and 36% were on rivaroxaban; primary site of bleeding was intracranial in 227 patients (64%) and gastrointestinal in 90 (26%).
In the lab based efficacy analysis, patients had 92% reduction in anti FXa activity regardless of if they were taking apixaban or rivaroxaban – worked the same for both.
In the “clinical” primary outcome 82% were adjudicated as having excellent or good hemostatic efficacy at 12 hours (vast majority excellent) – broken down by disease was true for 85% of patients with ICH and 80% of patients with GIB.
In terms of safety, 10% of patients had a thrombotic event in the 30 day follow-up period, with about a 1/3 of these in the first week, 1/3 in the second week, and 1/3 in weeks 3-4.
Big trial on an important topic, but several limitations worth noting including the lack of a control group (not a trial), convenience sample of patients, no real patient oriented outcomes, assessors unblinded to treatment with an outcome of hemostatic efficacy that is highly subjective and subject to bias, and sponsored by the drug manufacturer (not necessarily bad, but worth knowing).
EDITOR’S COMMENTARY: In this single arm trial excluding the sickest of the sick, andexanet alpha use resulted in significantly lower laboratory measured anti FXa activity at 12 hours and subjective improvements in hemostasis, but it is not clear if these translate to improved clinical outcomes as there was no comparison arm. It is expensive at 50K per dose, but if you have access to it and your patient is circling the drain, I think it is worth a try. Although the mechanism makes me believe it will work, we need to wait for results of the ongoing RCT before using routinely.
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