DOAC antidote vs. prothrombin complex in DOAC-related intracranial hemorrhage

Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis

Literature - Costa OS, Connolly SJ, Sharma M, et al. - Crit Care. 2022 Jun 16;26(1):180. doi: 10.1186/s13054-022-04043-8.

Introduction and methods


Annually, life-threatening bleeding occurs in approximately 0.7% of patients treated with a DOAC in RCTs [1]. Andexanet alfa is a modified form of human factor Xa [2]. This antidote is approved by the FDA (accelerated approval) and EMA (conditional approval) for adults treated with apixaban or rivaroxaban who require reversal of anticoagulation due to life-threatening or uncontrolled bleeding [3,4]. Four-factor prothrombin complex concentrate (4F-PCC) have been used as an alternative,off-label approach to stop severe bleeding [5,6]. However, no randomized trial comparing the effectiveness and safety of andexanet alfa with 4F-PCC has been conducted.

Aim of the study

This study indirectly compared the effectiveness and safety of andexanet alfa with 4F-PCC based on data from the ANNEXA-4 study and a synthetic control group in patients with apixaban- or rivaroxaban-related intracranial hemorrhage (ICH)


The investigators conducted an indirect comparative study of the effectiveness and safety of andexanet alfa and 4F-PCC in adults who were admitted to an US hospital for an acute ICH within 24 hours of taking apixaban or rivaroxaban. Data on apixaban were from 107 patients participating in the ANNEXA-4 trial, a multicenter, prospective open-label phase 3 study with no control group. Data on 4F-PCC were collected from the electronic health record of 95 patients admitted to 1 of 3 hospitals within Hartford HealthCare; together, these patients constituted the synthetic control group. Patients with an EMW score <7, hematoma volume >60 mL, or planned surgery within 12 hours of the index CT or MRI scan were excluded. To correct for confounding, a propensity score method was used, assigning weights to patients proportional to their likelihood of belonging to the other treatment group (i.e., overlap weighting).


The co-primary outcomes were hemostatic effectiveness (‘excellent or good’ vs. ‘poor or none’) and 30-day all-cause mortality. 'Excellent or good' hemostatic effectiveness was defined as ≤35% increase in hematoma size from index to repeat CT or MRI scan approximately 12 hours after administration of andexanet alfa or 4F-PCC. The secondary outcome measure was the occurrence of thrombotic events during the first 5 days after administration of the reversal agent.

Main results


  • The percentage of patients in whom hemostatic efficacy was excellent or good was 85.8% (95%-BI: 77.7-91.8) in the andexanet alfa group, compared with 68.1% (95%-BI: 57.7-77.3) in the 4F-PCC group (OR: 2.73; 95%BI: 1.16-6.42).
  • 30-day all-cause mortality was 7.9% (95%-BI: 3.6-13.8) in the andexanet alfa group, compared with 19.6% (95%-BI: 12.1-24.0) in the 4F-PCC group (OR: 0.36; 95%BI: 0.13-0.98).


  • In the andexanet alfa group, 2 thrombotic events occurred in the first 5 days after administration, whereas in the 4F-PCC group no patient developed a thrombotic event.


This indirect comparative study shows that in adult patients who develop acute intracranial hemorrhage within 24 hours of taking apixaban or rivaroxaban, treatment with andexanet alfa results in better hemostatic efficacy and lower 30-day all-cauase mortality than 4F-PCC.

Randomized controlled trials that investigate andexanet alfa compared to usual care in large populations are ongoing.


1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-62.

2. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-51.

3. ANDEXXA. ANDEXXA® (coagulation factor Xa (recombinant), inactivatedzhzo). Lyophilized powder for solution for intravenous injection [package insert]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2021. 2021.

4. ONDEXXYA. ONDEXXYA® 200 mg powder for solution for infusion [Summary of Product Characteristics]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2021. 2021.

5. Gerner ST, Kuramatsu JB, Sembill JA, et al. Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage. Ann Neurol. 2018;83(1):186-96.

6. Milling TJ Jr, Clark CL, Feronti C, et al. Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: a retrospective multi-center analysis. Am J Emerg Med. 2018;36(3):396-402.

Find this article online at Crit Care.

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