Reviewed by Shannon Hextrum, MD
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Ammar AA, Ammar MA, Owusu KA, et al. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage [published online ahead of print, 2021 Jan 6]. Neurocrit Care. 2021;10.1007/s12028-020-01161-5. doi:10.1007/s12028-020-01161-5
Background: Andexanet alfa is FDA-approved for reversal of life-threatening bleeding related to oral factor Xa inhibitors (FXi). Trial data from ANNEXA-4 has shown that andexanet administration in life-threatening bleeds is associated with decreased anti-factor Xa activity and a high rate of good or excellent hemostasis. ANNEXA-4 is relevant to neurocritical care, as the majority of patients were enrolled with intracranial hemorrhage (ICH).1 Such evidence supporting the approval of andexanet, however, does not include a direct comparison between andexanet and four-factor prothrombin complex concentrate (4F-PCC). This retrospective review evaluates ICH stability and outcomes in patients who received andexanet or 4F-PCC for FXi-related ICH.
Methods:bThis was a single center, retrospective study that included all consecutive adults presenting during a one-year period with life-threatening spontaneous or traumatic ICH (i.e. intraparenchymal, subarachnoid, subdural) taking factor-X inhibitors (apixaban, rivaroxaban). All patients were reversed with either andexanet alpha or 4F-PCC (25units/kg up to 2,500 units). The primary outcome was ICH stability on computer tomography (CT) brain imaging at 6 and 24 hours from anticoagulant reversal, as determined by three providers independently reviewing scans and blinded to both reversal agent and outcome. Stability for intraparenchymal hemorrhage was defined by no more than 6 ml or 33% increase in ICH volume. A number of secondary outcomes were analyzed, including favorable discharge outcome defined as Modified Rankin Score (mRS) of 0-3, thrombotic events, discharge disposition, length of stay, and in-hospital mortality.
44 patients were included in analysis, 28 patients in the andexanet group and 16 patients in the 4F-PCC group. With regards to type of ICH, 19 of the 28 spontaneous ICH cases (68%) were intraparenchymal (IPH) and 12 of 16 traumatic ICHs (75%) had multicompartment involvement. There was no significant difference between treatment groups in age, admission Glasgow Coma Scale (GCS), IPH hematoma volume at baseline, and indication for anticoagulation. However, more patients receiving andexanet reversal were concurrently taking aspirin at baseline compared to those patients who received 4F-PCC (11 [39%] vs. 1 [6%], p=0.03). There were also more patients taking clopidogrel in the andexanet treatment group (2 vs. 0), although this difference was not statistically significant (p=0.53).
No significant differences were observed in the primary outcome; stability of imaging at 6 hours occurred in 21 patients receiving andexanet (78%) vs. 10 patients who received 4F-PCC (71%), p=0.71. While there was a trend towards increased stability at 24 hours in the andexanet treatment group, this was not statistically significant (88% stability vs. 60%, p=0.15). Favorable mRS was similar between treatment groups (36% vs 38%, p=0.81). There was no significant difference between the two groups in thrombotic events, length of stay, nor mortality.
No difference in hemorrhage stability at 6 and 24 hours was observed in this retrospective study of ICH patients on apixaban or rivaroxaban who received andexanet vs. 4F-PCC for ICH reversal and there was no difference in favorable outcome at discharge. This study is limited by a small sample size, lack of randomization and heterogeneity of conditions, i.e. spontaneous as well as traumatic ICH, although such variety does reflect the pragmatic use of anticoagulant reversal agents. There was a higher percentage of spontaneous ICH in the andexanet group (71% vs. 50%), though this difference did not reach statistical significance. While the baseline characteristics were largely similar between patients receiving either reversal agent, an important difference in baseline features did reach statistical significance; 11 patients in the andexanet group were taking aspirin, while only 1 patient was on aspirin in the 4F-PCC group, p=0.03. This difference alone is enough to suggest confounding; furthermore, the study did not address any antiplatelet reversal strategies that may have occurred within the two groups. Another important feature of the sample was that the median GCS on admission was 14 in each treatment arm, which may suggest a sample with less severe neurologic impairment on presentation. However, the proportion of inpatient mortality or hospice on discharge was 39% and 38% in the andexanet and 4F-PCC groups, respectively. Since the sample includes both traumatic and spontaneous ICH, it would be interesting to know if other complications related to trauma affected the mortality rates.
This study is limited by a small sample size and retrospective nature, however this important topic deserves close attention and further investigation due to implications regarding appropriate reversal of factor Xa inhibitor related hemorrhages and availability of andexanet across healthcare systems.
- 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;380(14):1326-1335. doi:10.1056/NEJMoa1814051