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Andexanet for Factor Xa Inhibitor-Associated Intracerebral Hemorrhage
Quick Takes
- The ANNEXA-I trial compared andexanet alfa with usual care in patients with factor Xa inhibitor-associated intracerebral hemorrhage.
- Andexanet alfa use reduced the risk of significant hematoma expansion as compared to usual care with prothrombin complex concentrate.
- However, use of andexanet alfa was associated with a higher risk of thrombotic events, notably ischemic stroke, as compared to usual care.
Study Questions:
What is the effect of andexanet alfa, a reversal agent for factor Xa inhibitors, on hematoma volume expansion in patients with intracerebral hemorrhage?
Methods:
The authors conducted a randomized clinical trial of patients who had taken a factor Xa inhibitor within 15 hours before presenting with an acute intracerebral hemorrhage. Patients were randomized to receive andexanet alfa or usual care (typically with a prothrombin complex concentrate). The primary endpoint was hemostatic efficacy, defined by all of the following occurring at 12 hours: 1) hematoma expansion of ≤35%; 2) an increase in the National Institutes of Health Stroke Severity score <7, and 3) receipt of no rescue therapies. The primary endpoint was adjudicated by a blinded panel. The secondary outcome was the reduction from baseline to the 1- to 2-hour nadir in anti-factor Xa activity. Post hoc analyses assessed the modified Rankin scale (mRS) at 30 days. Safety endpoints included thromboembolic events and death. The trial was stopped early by the Data Safety Monitoring Board (DSMB) after reviewing interim efficacy and safety data.
Results:
A total of 263 patients were randomized to receive andexanet alfa and 267 were randomized to usual care. Efficacy was assessed in 452 patients and safety assessed in 530 patients. In the usual care arm, 85.5% received prothrombin complex concentrate (median dose 3000 IU). Hemostatic efficacy was achieved in 150/224 (67.0%) patients receiving andexanet and 121/228 (53.1%) patients receiving usual care (adjusted difference, 13.4%; 95% confidence interval [CI], 4.6-22.2%; p = 0.003). The median reduction in anti-factor Xa activity was 94.5% with andexanet alfa and 26.9% with usual care (p < 0.001). Thrombotic events occurred in 27/263 (10.3%) patients who received andexanet alfa and 15/267 (5.6%) patients receiving usual care (risk difference, 4.6%; 95% CI, 0.1-9.2%; p = 0.048). Ischemic stroke occurred in 17 (6.5%) patients receiving andexanet alfa, and four (1.5%) patients receiving usual care. There was no difference in the mRS scale or death within 30 days between the two groups.
Conclusions:
The authors conclude that among patients with factor Xa inhibitor-associated intracerebral hemorrhage, receipt of andexanet alfa resulted in better control of hematoma expansion than usual care, but with an increased risk of thrombotic events (including ischemic stroke).
Perspective:
Ever since andexanet alfa was FDA approved for the reversal of factor Xa inhibitor-associated bleeding, clinicians have been waiting for head-to-head randomized trial evidence of efficacy and safety as compared to prothrombin complex concentrates. The ANNEXA-I trial was stopped early by the DSMB due to interim analysis data showing efficacy benefit with andexanet alfa. This interim finding was confirmed in the final analysis, with fewer patients experiencing significant hematoma expansion if they received andexanet alfa as compared to usual care. However, the signal of thrombotic risk seen in prior nonrandomized studies was again seen in the ANNEXA-I study, with a nearly 2x increased risk of thrombotic events, primarily from ischemic stroke.
Further studies will need to explore the reasons for this increase in thrombotic event rate, which may relate to the successful reversal of anti-factor Xa activity or through a direct procoagulant effect through the binding of tissue factor pathway inhibitor. Reassuringly, there was no difference in the rate of 30-day death between the two treatment arms (26-28%) and functional status, as assessed by the mRS.
This study clearly established the efficacy and benefit of andexanet alfa for patients with factor Xa inhibitor-associated intracerebral hemorrhage. Moving forward, clinicians will need to identify the patients at highest risk of hematoma expansion who likely would benefit from andexanet alfa therapy instead of usual care with prothrombin complex concentrate. At the same time, clinicians will need to identify ways to reduce thrombotic risk after administration of andexanet alfa, which may include judicious use of prophylactic heparin.
Clinical Topics: Anticoagulation Management, Vascular Medicine
Keywords: Cerebral Hemorrhage, Factor Xa Inhibitors
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