Safety Concerns Arise Amid Andexanet’s Superior Performance in Hematoma Expansion Resolution
Overall, a significantly greater amount of patients on Andexanet had hematoma volume expansion of 35% or less; however, these patients had greater risk of thrombolytic events and lower modified Rankin scale scores at 30 days.
Stuart J. Connolly, MD
Published data from the ANNEXA-I clinical trial (NCT03661528) of patients with intracerebral hemorrhage (ICH) on a factor Xa inhibitor showed that andexanet rapidly reduced anti-factor Xa activity and resulted in better control of hematoma expansion than usual care. Despite this, the reduction in hematoma expansion was accompanied by an increase in thrombotic events, including stroke, and that the benefit of the drug still remains in somewhat question.1
In the study, patients who had taken factor Xa inhibitors within 15 hours before having an ICH were randomly assigned 1:1 to either Andexanet (n = 263) or usual care (n = 267). Efficacy, assessed in an interim analysis featuring 452 patients, showed that hemostatic efficacy was achieved in 67% (150 of 224) of patients receiving andexanet and in 53.1% (121 of 228) of patients on usual care (adjusted difference, 13.4 percentage points; 95% CI, 4.6-22.2; P = .003).
Published in the New England Journal of Medicine, hemostatic efficacy, the primary end point, was defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale (NIHSS) of less than 7 points at 12 hours, and no receipt of rescue therapy between 3 and 12 hours. Coming into the study, 85.5% of those on usual care received prothrombin complex concentrate.
Led by Stuart J. Connolly, MD, a professor of medicine at McMaster University in Ontario, Canada, a change of less than 7 points in NIHSS score was observed in 87.9% of those on Andexanet vs 83.0% of those on usual care. Rescue therapy was used in 97.3% and 93.4% of patients in each respective group as well. The median percent change in anti-factor Xa activity between baseline and the 1-to-2-hour nadir, otherwise considered a secondary end point, was –94.5% (IQR, –96.6 to –88.9) with andexanet vs –26.9% (IQR, –54.2 to –9.5) with usual care (P <.001).
The authors noted that, "A rapid reduction in anti–factor Xa activity was observed with andexanet, as compared with a minimal reduction with usual care. This effect is consistent with the mechanism of action of the drug, which is to rapidly sequester factor Xa inhibitor molecules to allow normalization of natural hemostatic mechanisms."
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Safety, which included all 530 enrolled patients, was the concern of Andexanet, as 10.3% (27 of 263) of those treated with the agent had thrombolytic events occur vs 5.6% (15 of 267) of those on usual care (difference, 4.6 percentage points; 95% CI, 0.1-9.2; P = .048). In addition, ischemic stroke occurred in 17 patients (6.5%) receiving Andexanet and in 4 patients (1.5%) receiving usual care (difference, 5.0 percentage points; 95% CI, 1.5-8.8). Furthermore, death occurred in 73 patients (27.8%) on Andexanet and in 68 patients (25.5%) receiving usual care (adjusted difference, 2.5 percentage points; 95% CI, –5.0 to 10.0; P = .051).
Coming into the study, the most frequently used factor Xa inhibitor was apixaban (62.5% of patients in the andexanet group and 59.2% in the usual-care group). At baseline, those in the andexanet group (21.4%) and usual-care group (21.1%) had similar rates of history of stroke. After 30 days, 69 of 246 patients (28.0%) in the andexanet group had modified Rankin scale scores of 0 to 3, compared with 31.0% (79 of 225) of those in the usual-care group.
Very large hematoma expansion, defined as an expansion greater than 12.5 ml, or death within 12 hours after randomization, occurred in 11.1% (24 of 216) of patients receiving andexanet vs 16.8% (36 of 214) of those on usual care.
At the conclusion of the trial, investigators noted that determining the potential net benefit of Andexanet treatment in acute ICH will be challenging because the relative clinical effects are difficult to assess. "Possible mechanisms by which andexanet increases the risk of thrombotic events include rapid reversal of anticoagulation in patients at risk for cardioembolic stroke," they wrote. "It is also possible that andexanet has a direct procoagulant effect through the binding of tissue factor pathway inhibitor, an endogenous inhibitor of factors Xa and VIIa that transiently increases D-dimer and prothrombin fragment levels."
