Shock Syndromes II
Anticipated limitations when using andexanet in clinical practice:
| (a) | The largest limitation of the ANNEXA-4 trial is the lack of a control group, with little |
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ability to determine how andexanet affects patient-centered outcomes.
| (b) | Given that only 72% of patients were eligible for the efficacy analysis, these results may |
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have an exaggerated effect relative to that of the general population.
| (c) | One of the greatest concerns is the relative short duration of laboratory reversal, given the |
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short half-life of andexanet alfa and its reversible binding with anti-Xa inhibitors.
| (d) | Implications are unclear for patients who continue to have clinical evidence of bleeding |
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beyond the andexanet infusion and the need to repeat doses or extend infusions.
| (e) | Notable exclusion criteria from this trial include requirement of surgery as well as severe |
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brain injury (average GCS score was 14). Implications of short-term reversal may be even
greater for these high-acuity patient populations.
vi.
Safety of andexanet alfa:
| (a) | 10% of the population had a thrombotic event, with most occurring before the initiation |
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of therapeutic anticoagulation.
| (b) | Andexanet alfa does bind to tissue factor pathway inhibitor, an endogenous factor Xa |
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inhibitor.
| (c) | This rate is generally higher than what has been shown for other reversal agents in bleeding |
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patients, including PCCs for warfarin reversal (7%–8%) and idarucizumab for dabigatran
reversal (6.35%–7.4%).
| (d) | It is important to recognize differences in population risks that confound cross-study |
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comparisons, given that the updated ANNEXA-4 analysis included at least double the
population with intracranial hemorrhage compared with other reversal studies. In this
setting, reintroduction of anticoagulation may be delayed.
vii.
The ANNEXA-I trial was a multicenter, multinational, randomized, open-label study designed
to compare the efficacy and safety of andexanet alfa with usual care in patients experiencing
acute intracerebral hemorrhage while receiving factor Xa inhibitors. The primary objective
was to evaluate hemostatic efficacy 12 hours after randomization using end points such as
a 35% or less change in hematoma volume, an increase in the 12-hour NIHSS (NIH Stroke
Scale) score of less than 7 points, and the avoidance of rescue therapies between 3 and 12 hours
after randomization. The trial was designed to achieve 90% power to detect a 10% absolute
difference in hemostatic efficacy, targeting 900 patients. The primary analysis included 452
patients, with 224 in the andexanet alfa group and 228 in the usual care group. Of note, 85.5%
of the usual care group received 4F-PCC. At baseline, intracerebral hemorrhage was present
in 88.4% of patients in the andexanet alfa group and 93.9% in the usual care group. Subdural
hematomas (SDHs) were reported in 5.8% of the andexanet alfa group compared with 1.8%
in the usual care group. The NNT for efficacy was 8, indicating that 8 patients required
treatment with andexanet alfa for 1 patient to benefit over usual care. However, the NNH was
21, highlighting increased risks, including ischemic stroke rates of 6.5% in the andexanet alfa
group versus 1.5% in the usual care group and myocardial infarction reported at 4.2% versus
1.5%, respectively. Critiques of the ANNEXA-I trial pointed to notable limitations affecting its
clinical applicability. One significant concern was the use of composite end points. Around 15%
of the usual care group did not receive active treatment, and there was limited understanding
of 4F-PCC agents and appropriate dosing during the trial. When analyzing the full patient
population, efficacy decreased from 67% to 63.9%, raising questions about the overall benefit.
Despite the trial’s focus on intracerebral hemorrhage, higher rates of SDH were observed in the
andexanet alfa group (5.8% vs 1.8% in the usual care group). In addition, the absence of long-
term follow-up beyond 30 days restricted insights into the sustained benefits and outcomes of
the treatment.