Efficacy and safety of factor Xa inhibitor antidote after acute intracerebral bleeding


In the phase 4 ANNEXA-I trial among patients with acute intracerebral hemorrhage who were taking a factor Xa inhibitor, andexanet alfa resulted in a higher rate of hemostatic efficacy compared with usual care. However, this benefit was accompanied by an increased thrombotic event rate.

This summary is based on the publication of Connolly SJ, Sharma M, Cohen AT, et al. - Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040

Introduction and methods


Patients with an acute intracerebral hemorrhage who are taking factor Xa inhibitors have a risk of hematoma expansion, which is a predictor of poor outcomes [1,2]. Andexanet alfa is a modified recombinant inactive form of human factor Xa that rapidly reverses the anticoagulant effects of factor Xa inhibitors [3,4].

Previously, the ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial, a phase 3b/4 single-group cohort study among patients with acute major bleeding at any site, showed that almost 80% of the patients treated with andexanet alfa achieved hemostatic efficacy and 10% had a thrombotic event [5,6].

Aim of the study

The authors assessed the efficacy and safety of andexanet alfa compared with usual care in patients who had been treated with a factor Xa inhibitor shorty before having an intracerebral hemorrhage.


The ANNEXA-I (A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor) trial was a multicenter phase 4 RCT in which 530 patients with an acute intracerebral hemorrhage who had taken a factor Xa inhibitor ≤15 hours before were randomized to andexanet alfa or usual care. The trial ran from June 6, 2019, through May 27, 2023. Inclusion criteria included an estimated hematoma volume of 0.5–60 mL and a National Institutes of Health Stroke Scale (NIHSS) score ≤35 (NIHSS score ranges from 0 to 42, with higher scores indicating worse neurologic deficit). Patients with a subdural or subarachnoid hemorrhage as the main bleeding event were excluded.

On May 31, 2023, the prespecified interim efficacy analysis (n=452) met the criterion for efficacy, after which the Data and Safety Monitoring Board recommended that the trial be terminated. The safety analysis included all 530 patients, i.e., the first 452 patients plus 78 patients who were enrolled during the period from the database lock for the interim analysis to the time of the stopping recommendation.


The primary endpoint was hemostatic efficacy, defined as: (1) change in hematoma volume ≤35% at 12 hours after baseline; (2) increase in the NIHSS score <7 points at 12 hours; and (3) no receipt of rescue therapy 3–12 hours after randomization. The secondary endpoint was the percent change from baseline to nadir in anti–factor Xa activity during the first 2 hours after randomization. Safety endpoints included thrombotic events and mortality at 30 days.

Main results


  • In the primary efficacy population (n=452), hemostatic efficacy (primary endpoint) was achieved in 150 of 224 patients (67.0%) receiving andexanet alfa and 121 of 228 patients (53.1%) assigned to usual care (adjusted difference per 100 patients: 13.4 percentage points; 95%CI: 4.6–22.2; P=0.003).
  • This significant between-group difference appeared to be driven by a higher proportion of patients in the andexanet alfa group showing a hematoma volume change ≤35% (which was defined as good hemostatic efficacy) than in the usual-care group (76.7% vs. 64.6%; adjusted difference per 100 patients: 12.1 percentage points; 95%CI: 3.6–20.5).
  • For most of the patients who met the primary endpoint, the hematoma volume change was ≤20% (i.e., excellent hemostatic efficacy).
  • The median percent change from baseline to the 1-to-2-hour nadir in anti–factor Xa activity (secondary endpoint) was –94.5% (IQR: –96.6% to –88.9%) in the andexanet alfa group and –26.9% (IQR: –54.2% to –9.5%) in the usual-care group (P<0.001).


  • In the safety population (n=530), thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet alfa and 15 of 267 (5.6%) assigned to usual care (difference per 100 patients: 4.6 percentage points; 95%CI: 0.1–9.2; P=0.048).
  • The frequency of ischemic stroke was 6.5% in the andexanet alfa group and 1.5% in the usual-care group (difference per 100 patients: 5.0 percentage points; 95%CI: 1.5–8.8).
  • The 30-day mortality rate was 27.8% in the andexanet alfa group and 25.5% in the usual-care group (difference per 100 patients: 2.5 percentage points; 95%CI: −5.0 to 10.0; P=0.51). However, the trial was not designed to have sufficient power to draw a conclusion about the effect of the treatment (andexanet alfa or usual-care treatment) on death.


In the phase 4 ANNEXA-I trial among patients with acute intracerebral hemorrhage who were taking a factor Xa inhibitor, a larger proportion of patients receiving andexanet alfa achieved hemostatic efficacy compared with those assigned to usual care. However, andexanet alfa treatment was associated with a higher rate of thrombotic events, including ischemic stroke.

Find this article online at N Engl J Med.


  1. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:175-81.
  2. Delcourt C, Huang Y, Arima H, et al. Hematoma growth and outcomes in intracerebral hemorrhage: the INTERACT1 study. Neurology 2012;79:314-9.
  3. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413-24.
  4. Lu G, Hollenbach SJ, Baker DC, et al. Preclinical safety and efficacy of andexanet alfa in animal models. J Thromb Haemost 2017;1:1747-56.
  5. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016;375:1131-41.
  6. Milling TJ Jr, Middeldorp S, Xu L, et al. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation 2023;147:1026-38.

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