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Connolly SJ 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. PMID: 38749032.

Background

Acute intracerebral hemorrhages (ICH) are a potential consequence of factor Xa inhibitors. They are associated with high mortality and morbidity, with hematoma expansion being a poor prognostic factor. Andexanet alfa, a factor Xa inhibitor reversal agent, has been proposed as a potential solution to improve hemostasis and mitigate hematoma expansion. Thus, the aim of the paper was to compare efficacy and safety of andexanet alfa versus usual care in patients with acute ICH.

Methods

This was a non-blinded, multi-center and multi-country RCT. 530 patients with acute ICH who had taken factor Xa inhibitors within the previous 15 hours were randomly assigned to receive either andexanet alfa or usual care. Primary outcome assessed was hemostatic efficacy, a composite endpoint defined by limited hematoma expansion (≤35% at 12 hours), minimal increase in NIH Stroke Scale score (<7 points at 12 hours), and no need for rescue therapy between 3 to 12 hours. A secondary endpoint looked at the percent change from baseline to nadir in anti-factor Xa activity in the first 2h post randomization. Safety endpoints assessed included thrombotic events and death.

Results

263 patients received andexanet alfa, and 267 received usual care (with 85.5% of them receiving PCC). Hemostatic efficacy was analyzed in an interim analysis that included 452 patients, while the safety analysis included all 530 patients. Hemostatic efficacy was achieved in 67.0% of patients receiving andexanet compared to 53.1% receiving usual care, showing a significant adjusted difference of 13.4 percentage points (P = 0.003). Of note, this result seems to have been driven by the hematoma expansion <35% endpoint (the other two components were not significant). Median reduction in anti-factor Xa activity was significantly greater in the andexanet group (-94.5%) compared to the usual care group (-26.9%) (P<0.001). However, thrombotic events were more frequent in the andexanet group (10.3%) compared to the usual care group (5.6%) (P = 0.048). No significant differences in 30 day modified Rankin Scale (mRS) scores or mortality between groups.

Journal Club Conclusion

Andexanet alfa use significantly decreased hematoma expansion as well as anti-factor Xa activity compared to usual care. However, these are disease-oriented outcomes rather than patient-centered ones. Clinically important outcomes such as neurological disability (mRS) and mortality at 30 days were similar between groups. Furthermore, safety analysis favored the usual care group rather than the treatment arm. Thrombotic events were clearly increased in the andexanet group, raising concerns about the potential harm of the treatment. This study also presents multiple protocols change and with the current evidence, it appears andexanet alfa should not become part of the standard treatment for this population.

EBM Subject - Interim Analysis

Interim analyses can be used by studies to assess for efficacy, safety, futility or even for sample size re-adjustment. Different techniques exist to proceed with such analyses and guide early termination of studies. Although, nontrivial consequences can result from these analyses and therefore impact our interpretation of study results. In this study, early termination was pursued for safety reasons but authors also suggested an efficacy component that we came to question in our analysis considering methodology concerns. Interim analyses are a useful but delicate and risky tools to use and this study is a good example of that.

References

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